General introduction

Since the pioneering work by Ito, Hayashi, Unimoto and Hashmi in late of last century, homogeneous gold catalysis has witnessed tremendous development by contributions from research groups all over the world. Gold catalysts, possessing unique catalytic reactivity, intrigued a large number of novel approaches to target molecules which cannot be accessed by other methodology. Ynamide, which belongs to a subclass of hetero-substituted alkynes, represents a versatile building block with balanced reactivity and stability and found a series of applications in useful transformations, such as additions, cycloadditions and cycloisomerizations.

As part of our ongoing interest in gold catalysis and ynamide chemistry, in this manuscript, two works involving ynamide in the presence of gold catalyst was presented:

(1). Gold(I)-Catalyzed Rearrangement of Propargyl Ethers of ynamides: A Practical Method for the synthesis of Substituted Allenamides

Allenamides are versatile synthetic building blocks that have seen numerous applications and therefore great efforts have been devoted to the access to such compounds. We have shown that a series of substituted and functionalized allenamides were easily accessible via a gold catalysted 1,5-hydride shift/fragmentation sequence using ynamides as the starting material.

Our method is rapid and practical. It can be performed under very mild conditions (room temperature) with low catalyst loading (4% gold catalyst) and gave excellent yields (up to 99% yield). Besides the good functionality compatibility in the carbon terminal (R1 and R2), our method also tolerate variuous Nitrogen substituents (R' and R''). Moreover, further transformation using in-situ formed allenamides was achieved. Some interesting spiral and diene compounds were also formed in excellent yield.

(2). Dual gold catalysis: a unique approach to derived-tetrahydroquinolines by a formal [4+2] pathway Although vast majority of gold catalysis features π-activation of a multiple bond by a single gold complex, recent innovative advance involving two gold centers in one single molecule was disclosed recently by several research groups and also by our group.

The catalytic cycle was initiated by the formation of gold acetylide and coordination of another gold complex to the triple bond of ynamide. After nucleophilic attack of gold acetylide onto ynamide, gold vinylidene was generated. The formed gold vinylidene was then trapped by double bond, giving rise to aromatic rings.

Introduction générale

Suite aux premiers travaux réalisés par Ito, Hayashi, Unimoto et Hashmi à la fin du siècle dernier, de nombreux groupes de recherche à travers le monde ont contribué à l'important développement de la catalyse homogène à l'or. Ce dernier, possédant une activité catalytique unique, donne accès à un bon nombre de nouvelles synthèses de composés, jusque-là inaccessible en utilisant d'autres méthodes.

Les ynamides, un sous-groupe d'alcynes hétéro-substitués, sont des intermédiaires de synthèse ayant une réactivité et une stabilité modulable. Ils trouvent leur application dans des réactions telles que les additions, les cycloadditions et les cycloisomérisations.

Dans ce manuscrit sont présentés deux travaux impliquant des réactions d'ynamides en présence d'un catalyseur à l'or.

1) Réarrangement d'éthers de propargyliques d'ynamides catalysé par l'or (I) : Un accès pratique aux allénamides substitués. Les allénamides sont des composés qui présentent de nombreuses applications, d'où l'engouement présent pour accéder à ces composés. Nous avons montré que des allénamides substitués et fonctionnalisés sont facilement accessibles par une réaction de transfert d'hydrure [1,5] LG Leaving group

Gold: a fascinating metal

Gold is intimately related to the evolution of humankind's civilizations, symbolizing authority, richness, nobleness, glory and prestige. This can be best illustrated by the fabrication of a wide range of gold artworks from different civilizations, for instance, the golden funerary mask of Tutankhamun from Egypt, various golden handicrafts from ancient China (Figure 1-1), which both created highly-developed civilizations thousands of years ago. Aside from civilized outcomes, the consistent fascination for gold also caused catastrophe to mankind, such as the destruction of the Roman Empire due to Attila's voracity to treasure, the disappearance of the Inca civilization during the 16 th century expeditions for pursuing wealth.

Figure 1-1 Gold arts in ancient civilizations

Gold is soft, dense, malleable and ductile with a bright, slightly reddish yellow color in its purest form, different from other pure metals which are generally gray or slivery white. At high temperature, gold can form alloys with diverse metals such as silver, copper, palladium and nickel to modulate its color, hardness, melting point, ductility and other metallurgical properties. Gold is one of the least "reactive" metals that have been ever discovered, it is resistant to oxidative conditions, strong acidic environment and most other chemical reaction conditions. Due to its chemical inertness, gold often naturally occurs in its elemental (native) form in rocks, veins and alluvial deposits as nuggets or grains. It also presents in alloys with silver, copper, palladium and etc.

Given all its chemical and physical properties, gold is widely used in jewelry, coinage, arts, and modern industries. Gold jewelry industry still found vast majority application of new produced gold nowadays. Many countries hold gold for economic reasons, for instance, inhibiting inflation, preventing currency depreciation, and as a hedge for various possible economic disruptions. In terms of investment and collector purposes, gold is commonly minted into bullion coins, such as Chinese Gold Panda, American Gold Eagle, Canadian Gold Maple Leaf, British Gold Sovereign and so on (Figure 1-2).

Figure 1-2 A few popular bullion coins in world gold market Gold has found widespread application in electrical industry, to be specific, manufacturing thin layer coating on electronic connectors in expensive electrical devices, such as computer, audio-visual equipment, and even spacecraft, due to its excellent performance in conductivity, ductility as well as resistance to oxidation and corrosion. Gold also witnesses a range of other applications in modern industries, including gold solder, photography, embroidery in form of gold thread, as color agent in special glasses, as reflector of electromagnetic radiation in hightech equipment, for heat shielding in automobiles and so forth. Gold has also been employed in medicine, food and drinks in modern times and in chemistry.

According to World Gold Council, there exist 186700 tons of stocks of gold above ground in all, as of 2015.

Gold in organic chemistry: a historical point of view

Although transition metal chemistry has seen tremendous development, gold suffered relative ignorance by the synthetic chemist community until the end of the 20 th century.

There are two reasons behind this neglect. On one hand, native gold has been regarded as chemicals inert for a long time, leading to the prejudice that gold was unsuitable for being used in catalysis. Besides, mechanisms in transition metal chemistry generally involve altering of oxidation states of transition metals, i.e., an oxidative addition/reductive elimination process is involved, however. This is indeed difficult for gold to enter such catalytic cycles. On the other hand, gold was subconsciously considered to be scarce and extremely expensive, leading people to be too reluctant to use it in chemistry. However, other rarest and precious metals such as palladium, platinum, iridium, ruthenium, rhodium and osmium all witnessed broad applications in organic chemistry (Figure 123). The price of gold is comparable to that of platinum although being higher than that of precious metals, implying that organic transformations using gold catalysis would not be much more costly than those employing other metals (Figure 1234). 2 In this context, gold's employment in homogeneous catalysis was unexplored until 1986 when Ito, Hayashi et al. disclosed the asymmetric reaction of aldehydes with isocyanoacetates in the presence of gold(I) complexes containing a chiral ferrocenylphosphine, which provided optically active oxazolines (Scheme 1-1).

3

Scheme 1-1 The first application of gold(I) in homogeneous catalysis

The first investigation of electrophilic gold complexes on the activation of alkynes was implemented in 1991 by Unimoto and Fukuda. It was observed that alkynes reacted with water, alcohols and amines in the presence of Au(III) salts, furnishing ketones, ketals and imines respectively (Scheme 1-2).4

Scheme 1-2 The first report on activation of alkynes by Au(III)

Afterwards, Teles 5 , Hayashi and Tanaka's 6 pioneering work opened up a real "gold rush" for gold(I)-catalyzed transformations. They employed cationic gold(I) complexes to catalyze the nucleophilic addition of alcohols or water to alkynes to yield ketals or ketones (Scheme 1-3). It is worth mentioning that they also observed that ligands (e.g. CO, triphenylphosphite) are of crucial importance in the efficiency of the transformation, what was proposed to be in correlation with the stability of the catalyst.

Scheme 1-3

The first study upon the activation of alkynes by Au(I)

On the basis of this seminar work, a series of research groups all around the world entered this realm, which finally leads to the flourish of homogeneous gold catalysis. A great number of novel transformations have been developed, which will be discussed in details later (Chapter 1, section 5. ).

Theoretical concerns in homogeneous gold catalysis

Gold, with symbol Au from Latin "aurum", is a group 11, d-block transition metal located in period 6 in the periodic table of elements with an [Xe]4f 14 5d 10 6s 1 electronic configuration, atomic number as 79, and atomic weight as 197. Its oxidation states range from -1 to +5, with Au(I) and Au(III) dominating their chemical applications.

Bonding Mode of π-Bonds to Gold

From a mechanistic point of view, gold-catalyzed transformations are generally initiated by the complexation of π-bonds with gold complexes. The bonding situation could be elucidated by use of "Dewar-Chatt-Duncanson model" which qualitatively depicted four couples of orbitals with distinct symmetry to form complexes by orbital overlapping. 7 As an example, herein the coordination of alkynes to transition metals is present (Figure 12345).

The bonding of transition metals and alkynes consists of four components:

(a) Alkyne's p z orbital overlaps with metal's d z 2 orbital to form a σ-symmetric bond with alkyne's electrons delocalized into metallic center, which dominates the bonding of metal and alkyne;

(b) Metal's d xz and alkyne's p* z coalesce to give rise to a π-symmetric bond which can be regarded as back-donation from the metallic center into alkyne; (c) In the case of alkyne, there exists another p orbital, i.e., p y which would donate its electrons into metal's d yz orbital to generate another π-symmetric bond; (d) The fourth component arises from the weak bonding from metal's d xy orbital and alkyne's p y * orbital.

Afterwards, rehybridization occurs resulting from the preferentially depletion of p bonding orbitals rather than the anti-bonding ones due to metal's back-donation. Dewar-Chatt-Duncanson model is well suitable for gold to explain the elongation of π-bonds as well as the loss of linearity or planarity in alkynes or alkenes. Nonetheless, it is not sufficient to interpret gold's peculiar reactivity reported to date. The unique performance of gold complexes in homogeneous catalysis is closely related to the nature of the metallic center when one considers gold's relativistic effects.

Relativistic Effects

According to the theory of relativity, the high-speed electrons orbiting around gold nucleus result in the increasing of mass as well as the decreasing of atomic radius. This directly leads to the strong contraction of 6s and 6p orbitals, namely making them be closer to nucleus and consequently the expansion of 5d and 4f orbitals which are shielded by the former and thereby subject to weaker nuclear attractions. Besides, this helps rationalize gold's greater ionization energy and makes it the most electronegative transition metal (electronegativity of gold is 2.54, similar to that of carbon 2.55 according to Pauling's scale). Moreover, the Au-Au interaction ("aurophicility") is rather prominent with the similar intensity as hydrogen bonding.

The electrons in diffuse 5d orbitals are subject to less electron repulsion and therefore are better held around the gold nucleus, leading to gold's low nucleophicility and the reluctance to undergo oxidative addition which consist the key step in redox catalytic cycle ubiquitously in transition metal chemistry. Moreover, this type of diffuse, thus larger, 5d orbitals makes gold complexes outstanding candidates as soft Lewis acids due to their preference to react through their orbitals instead of charges. On the basis of HSAB theory8 , gold complexes interact favorably with soft bases, for instance, π-systems in alkynes, allenes and alkynes and are less oxophilic. Therefore, gold complexes can be seen as a type of "soft π-acids". On the basis of Pyykko's observations, these relativistic effects are significant for platinum, mercury and reach the summit when it comes to gold (Figure 1-6).9 blocks. This can be attributed to two parameters: the soft Lewis acidity as mentioned above and the back-donation from the gold center to the carbocation generated in intermediates, which must not be neglected as well. The combination of soft Lewis acidity, back-donation and the decreased propensity to undergo β-eliminations collectively contributes to the excellent selectivity, reactivity, compatibility (with oxygen, moisture, functional groups) and mild reaction conditions in homogeneous gold catalysis.

When it comes to the cases wherein both alkenes and alkynes are present in reaction mixture, the initial nucleophilic attack takes place with preferentially onto alkynes over alkenes. It might be surprising when one considers that both alkenes and alkynes could coordinate to gold complexes and that bonding between alkene and gold is even stronger than alkynes. In fact, it relates to a kinetic outcome which derives from the lower energy of LUMO orbitals in alkynes compared with that of alkenes. This phenomenon was designated as "alkynophicility".

Homogeneous Gold Catalysts

Although gold complexes have long been known, its wide application in organic chemistry can be dated back to the end of last century. Since that time, gold complexes have emerged as mild and versatile catalysts or precatalysts for selective activation of multiple bonds such as alkynes, allenes and alkenes toward nucleophilic attack by various nucleophiles. Furthermore, gold catalysts are compatible with air and moisture, allowing some reactions be performed even under "open flask" conditions, thus conferring easier manipulating procedures experimentally.

In general, gold catalysts can be divided into two main types in terms of gold(III) complexes (auric compounds) and gold(I) complexes (aurous compounds), which derived from the two most commonly encountered +1 and +3 oxidation states of gold, albeit ligands and counterions also play vital important role in the efficiency and compatibility of specific transformations. While gold(III) are d 8 complexes, preferentially adopting a square planar, tetracoordinated configuration, the gold(I) catalysts, with filled 5d orbitals (d 10 complexes), are commonly encountered as linear, dicoordinated geometry.

Gold(III) Complexes

Given fact that current blossom of gold catalysis was initiated by the Au(III)-catalyzed transformations, gold(III) have found rather limited applications since then, among which gold(III) salts are mostly involved, e.g. AuCl 3 , AuBr 3 , chloroauric acid (HAuCl 4 ) and its sodium, potassium salts derivatives (NaAuCl 4 , KAuCl 4 ). Reactions catalyzed by these gold(III) salts are largely carried out in polar solvents, such as H 2 O, methanol and acetonitrile; in certain cases, these gold(III) salts are employed with silver salts as co-catalysts, such as AgOTf or AgSbF 6 to increase reactivity.

Hashmi and co-workers were the first to employ gold(III) complexes bearing pyridine derivatives to catalyze organic transformations and the complexes proved to be more reactive and more stable than gold(III) salts. A series of gold(III) complexes based on N-heterocyclic carbenes, salens, porphirins and so forth have already been developed and found application under homogeneous catalytic conditions (Figure 1234567). 10 It is noteworthy that in certain cases gold(III) complexes are proposed to be in situ reduced to their gold(I) counterparts via an oxidative homocoupling mechanism, which serve as the real active species to catalyze the corresponding transformations.

Gold(I) Complexes

Gold(I) complexes have experienced much wider applications in organic transformations compared with their gold (III) counterparts. This can be attributed to their higher stability in reaction medium as well as easier adjustability of electronic and steric properties by switching ligands bound to the metallic center. phosphines, N-heterocyclic carbenes, phosphites have all been prepared and broadly applied in homogeneous gold catalysis.

A few representative examples 11,12,13 are presented below (Figure 1-8).

Silver effects

As aforementioned, commonly employed gold catalysts were in situ generated by treatment of LAuCl with various silver salts to form cationic gold(I) species which are believed to be the catalytically active species although no structural proof for their existence was disclosed so far.

In previously reported mechanistic rationale, [LAu] + has consistently been proposed as the real and exclusive π-philic species with complete ignorance of the function of silver salts.

However, in certain early cases it was observed that the presence of silver was of pivotal importance to obtain the desired experimental results. For instance, in the enantioselective synthesis of vinylcyclohexenes from eneallenes in the presence of gold complexes 17 , different enantioselectivities were observed depending on the use of catalysts generated in situ or preisolated gold catalysts. While the in situ generated catalytic system provided sufficiently good enantiomeric excess, the isolated catalyst afforded sluggish reaction and lower enantioselectivity. Intriguingly, re-addition of AgOTf had no influence on the stereochemical outcome, whereas the AgCl which is insoluble in reaction medium slightly improved the stereoselectivity (Scheme 1-4).

Scheme 1-4 Early observations of silver effects

However, the so-called "silver effects" have long been overlooked until a recent report wherein Shi et al. 18 demonstrated that gold catalysts, with or without the presence of silver salts (in situ formed and filtered through celite, respectively) presented dramatically different activities through systematically reinvestigation of a series of previously reported transformations. Catalyst using NTf 2 -as the counteranion was an exception. 19 . They observed that while the in situ formed gold species gave good to excellent results, the celite-filtered catalysts showed compromised outcomes or even complete loss of reactivity. The addition of silver salts reactivated the catalytic systems, unambiguously indicating the influence of silver salts.

Afterwards, these observations were illustrated by Echavarren et al. through the isolation and X-ray diffraction characterization of a range of chloride-bridged digold(I) complexes (Figure

1-11, I)

. 20 Moreover, this work could also, at least partially, accounted for certain cases wherein excess silver salt was beneficial to the expected outcomes. It was proposed that excess silver salt was used to cleavage the chloride bridge to generate catalytically active cationic gold(I) species. At the same time, Jones and co-workers 21 isolated and determined an Au(I)/Ag(I) complex featuring diphosphine trimetallic chloronium dication incorporating a triangular mixed gold/silver core with silver-arene chelation (Scheme 1-7, II).

Figure 1-11 Bridged digold complexes alkyne, allene and even alkene moieties in complex molecules containing other functional groups, which can be attributed to the relativistic effects as well as the weak, but still remarkable π-back-donation from gold center to carbocation intermediates.

Gold-Catalyzed Homogeneous Reactions

The initial step of gold-catalyzed reactions is always the coordination of the π-systems in alkyne, allene or even alkene to the electrophilic gold(I) or gold(III) complexes, which has been confirmed by the isolation and characterization of a large number of alkyne-, allene-, alkene-and diene-gold complexes. Then the Lewis acidic gold species selectively activate these π-systems toward the addition of various nucleophiles, including heteronucleophiles (e.g. O-, N-and S-nucleophiles) and carbonucleophiles (Figure 1-12). Thereafter, diverse transformations would take place depending on the nature of the generated intermediates.

The final step is the formation of products and regeneration of the active cationic gold species.

This takes place mainly in three types of pathways: protodeauration, direct Au-elimination, or a trapping by an additional electrophile. In contrast to intermolecular nucleophilic attack (Scheme 1-2 and Scheme 1-3), a wider range of Au-catalyzed transformations have been exploited intramolecularly by use of alkynol, allenol and their derivatives to provide oxygen containing heterocycles. For instance, Liu and co-workers 23 reported in 2005 a gold-catalyzed efficient and straightforward synthesis of fully substituted furans and dihydrofurans employing (Z)-2-en-4-yn-1-ols by cycloisomerizations (Scheme 1-5, eq. 1). Almost at the same time, an expedient and interesting access to strained bicyclic ketals was disclosed under homogeneous gold catalysis conditions (Scheme 1-5, eq. 2).

Scheme 1-5 Examples of cycloisomerizations of OH-containing alkynes

Besides free alcohols, other oxygen nucleophiles, such as carboxylic acids, ketones, carbonates, carbamates and boronic acids are all suitable candidates for gold-catalyzed Gagosz and co-workers developed an efficient access to 4-alkylidene-1,3-dioxolan-2-ones by using of propargylic tert-butyl carbonates, which are synthetically useful motifs but still lack efficient approach to access so far (Scheme 1-6, eq. 3). The same group validated the employment of propargylic tert-butyl carbonates in similar transformations. In 2010, Sheppard et al. reported a novel approach to enolate equivalents for efficient aldol condensation via a boronic acid addition onto unactivated alkynes in the presence of gold catalysts. With the aldol products in hand, diverse subsequent transformations were investigated to provide a wide range of useful scaffolds (Scheme 1-6, eq. 4).

Analogously, the potential of allene derivatives in gold-catalyzed transformations have also been widely investigated. Gold complexes possess the ability to coordinate to both of the allenic double bonds and the regioselectivity in subsequent transformations depends on the nature of the precursor, in particular the length of linker between the allenyl and nucleophilc moieties. Generally, four distinct pathways are available with procedures ① and ④ favored in most cases (Scheme 1-7).

Nitrogen Nucleophiles

In analogous to O-nucleophiles, nitrogen-based functionalities have also been employed in a series of cyclizations catalyzed by cationic gold complexes. Free amines, sulfonamides, carbamates, ureas and aziridines can all serve as nucleophiles. These transformations proved to be a very powerful tool for the construction of nitrogen-containing heterocycles.

Generally, the cyclization can proceed by 5-exo-dig or 6-endo-dig pathways, which depends on the relative position of the alkyne and the N-nucleophile. Besides, the electronic properties of the substituents on the alkyne also play an important role in terms of regioselectivity, i.e., alkynes with electron-donating groups are prone to undergo 6-endo-dig cyclizations whereas those with electron-withdrawing substituents proceed via 5-exo-dig pathway. Last but not least, relative steric hindrance in internal alkynes should also be mechanistic rationale, both a sequential and a concerted ring fragmentation/1,2-migration processes following a nitrogen nucleophilic attack onto gold activated alkynes were proposed to interpret the experimental results (Scheme 1-11, eq. 3).

Similar to allenols and allenones, allene derivatives bearing nitrogen nucleophiles have also seen applications in cyclizations. These transformations proceed following the same general mechanism and establish similar regio-and stereoselectivities (Scheme 1-7).

Using allenic precursors containing two vicinal heteroatoms, regio-and stereoselective formations of N-hydroxypyrrolines, dihydroisoxazoles, and dihydro-1, 2-oxazines were explored by Krause and co-workers. 30 In such cases, 5-endo, 5-exo and 6-endo cyclizations can selectively occur with high levels of stereoselectivity, by shifting cationic gold complexes or by protecting the nitrogen atoms (Scheme 1-12). atom toward gold-activated triple bond followed by a 1,3-migration of the group bound to sulfur (Scheme 1-15, eq. 1).

Soon after that, the same group reported a similar transformation in which 3silylbenzo [b]thiophenes were produced in good to excellent yield through an intramolecular capture of the Au-intermediate after the initial nucleophilic addition of the sulfur functionality (Scheme 1-15, eq. 2).

Scheme 1-15 Homogeneous gold catalysis involving sulfur nucleophiles

Carbon nucleophiles

The addition of carbon nucleophiles, such as electron rich aromatic rings, 1,3-dicarbonyl compounds and/or alkenes, alkynes to unactivated multiple bonds have also been accomplished under homogeneous gold catalysis conditions, thus allows for the formation of C-C bonds and/or carbocylcles.

Toste et al. 33 developed an Au-catalyzed Conia-ene reaction under neutral and "open flask" conditions by utilizing β-ketoesters, which reacted with alkynes in an intramolecular manner.

An excellent diastereoselectivity and yield were achieved, providing an efficient and facile access to quaternary carbon centers (Scheme 1-16, eq. 1).

One similar transformation took place with allenes serving as the starting material. In this case, 5-endo cycloisomerizations occur exclusively (Scheme 1-16, eq. 2).

33 (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (b) Jiang, X.; Ma, X.; Zheng, Z.; Ma, S. Chem. Eur. J. 2008, 14, 8572.

Scheme 1-16 Gold(I)-catalyzed nucleophilic addition of 1,3-dicarbonyl compounds

Cycloisomerizations of 1,n-enynes

Cycloisomerizations involving 1,n-enynes have been extensively exploited in the field of homogeneous gold catalysis, in particular the transformations of 1,6-enynes. The mechanistic rationale has been best elucidated on the basis of both experimental and computational contributions. Herein, cycloisomerization of 1,6-enynes has been taken as the example to illustrate general mechanisms (Scheme 1-17). 34 The cycloisomerization of 1,6-enynes begins with the coordination of gold complexes to the alkyne moiety to give rise to complex I. This is followed by nucleophilic attack by the alkene motif via a 5-exo- The cycloisomerzations of 1,7-, 1,8-, and even higher enynes have also intrigued synthetic chemists, albeit they have not been investigated as wildly as 1,6-and 1,5 analogues.

Gold(I)-catalyzed enantioselective polycyclization was also accomplished from polyene, in which the transformation was initiated by the attack of an alkene onto the gold-activated alkyne followed by subsequent tandem trapping by another alkene motif and a terminating nucleophile. The stereochemical outcome of the reaction was in accordance of the "Stork-Eschenmoser hypothesis" (Scheme 1-21). 42

Scheme 1-21 Au(I)-catalyzed polycyclization of polyenes generated nucleophilic allenes by gold-catalyzed rearrangement of propargylic esters (Scheme 1-24, eq. 2). 45 The same strategy was used for the synthesis of highly functionalized oxacycles from propargylic esters (Scheme 1-24, eq. 3). 46

Scheme 1-24 Au(I)-mediated transformations of propargylic carboxylates In 2013, Gagosz and co-workers disclosed a novel gold catalyst/oxidizing agent system for the synthesis of diverse substituted indan-2-ones using propynyl arenes. A new type of a biarylphosphonite gold(I) complex was employed and it proved to be a superior catalyst by comparison with previous reported catalytic systems. Intriguingly, on the basis of their experimental results, it was proposed that the oxidative cyclization proceeded via neither intermediate II or III (Scheme 1-26) but at midway between them, allowing the "anti-Baldwin" generation of adducts (Scheme 1-28). 51

Scheme 1-28 Biarylphosphonite gold(I)-catalyzed synthesis of indan-2-ones

Conclusion and perspective

Homogeneous gold catalysis has emerged as a unique, convenient and efficient tool of significant importance in synthetic organic chemistry. This can be ascribed to gold's relativistic effect and the readily variations of gold complexes. Phosphines, phosphites and Nheterocyclic carbenes are the most common employed ligands in Au(I)-catalyzed transformations. The real catalytically active species are still obscure in most cases, although most mechanistic proposals employed simple [LAu] + as the solely π-acids.

A vast majority of reports to date have been performed intramolecularly, giving rise to 5-or 6membered rings and the regioselectivity was closely related to the substituent patterns of the substrates. Progress in enantioselective version of gold catalysis is still very slow due to the general linear, dicoordinated geometry adopted by gold(I) complexes which imposes sufficiently long distance between the ligand and the active reaction sites. Further investigation onto the mechanism of the chiral induction in reported results and developing more general and efficient catalytic systems are still of great importance and must intrigue further progress in the field of gold catalysis.

Figure 2-1

Given that the electron-donating nitrogen atom is attached directly to double bonds, delocalization of electrons from nitrogen atom to the allenyl moiety renders allenamines much more electron rich than normal allenes, therefore resulting in extremely high reactivity and regioselectivity (via electron bias). By adding electrophiles and nucleophiles sequentially, two consecutive bond formations would occur to allow efficient, expedient and practical construction of sophisticated molecules (Scheme 2-1). However, this enhanced reactivity endowed by nitrogen groups in turns imposed limitations to wide exploitation of allenamine chemistry as they activate allenamines toward hydrolysis (sensitive to moisture) and polymerizations which caused serious problems for their preparations, isolations and manipulations.

Allenamide, which is the topic of this chapter, comes to scene as it represents an ideal allenamine equivalent bearing balanced reactivity and stability and found a range of applications as an important synthon.

Scheme 2-1 General reaction pathways of allenamine and allenamide

The increased stability could be ascribed to the electron-withdrawing group bound to nitrogen atom by conjugation and induced effect, which diminishes electron's flow to the allenyl moiety. The nitrogen-containing functionalities could be sulfonamides, amides, carbamates, phosphinamides, ureas, anilines and some hetero-aromatic rings such as imidazoles, benzimidazoles and so on. On the basis of the stable and reactive nature of

Synthetic methods of allenamides in literature

A series of methodologies have been developed to prepare allenamides, which will be discussed in details in the next paragraphs. As providing a comprehensive review is beyond the scope of this manuscript, herein merely personal selected examples will be presented.

Base-triggered isomerization

Base-triggered isomerization proceeds by prototropic rearrangement of the propargyl amide precursor, thus leading to an atom-economical access to allenamide. For instance, the synthesis of a diverse array of allenamides in the presence of catalytic amount of t-BuOK was developed from the corresponding amides following a two-step protocol (Scheme 2-2, eq 1).

In this case, both chiral and achiral allenamides were accessible. 52a This approach was improved to a one-pot procedure by reacting acridones with propargyl bromides in the presence of a phase transfer catalyst (PTC) to furnish allenamides via in situ generated propargylated intermediates (Scheme 2-2, eq. 2). 52b In the course to prepare N-tosyl-4azahept-1-en-6-yne, Meijere et al. observed concomitant formation of allenamide as a minor product under basic conditions for 16 hours and extended reaction time resulted in even higher yield of allenamide (Scheme 2-2, eq. 3). 52c In the attempt to get access to chiral ynamides from propargyl amides, Hsung and co-workers discovered that in certain cases, the base-induced isomerization process could be arrested at the allenamides stage without formation of desired ynamides (Scheme 2-2, eq. 4). 52d

Transition metal-mediated C-N couplings

Transition metal-catalyzed cross couplings proved to be a facile and convenient synthetic tool for the assembly of C-C and C-X bonds. This strategy could be applied to the preparation of allenamides as well (Scheme 2-3).

Trost et al. reported that allenyl iodides/bromides reacted with a range of amides, ureas and carbamates in the presence of copper catalysts to provide various allenamides in good to excellent yields (Scheme 2-3, eq. 1). 53a Copper catalysts also promoted the coupling between amides/ureas and enantioenriched allenyl halides to give rise to allenamides. In this course the chirality of starting materials was preserved in high levels throughout the process (Scheme 2-3, eq. 2). 53b N-allyl-N-allenylsulfonamide was assembled by a similar coppercatalyzed C-N coupling of N-allylsulfonamides and bromoallenes in moderate to good yield (Scheme 2-3, eq. 3). 53c Palladium-catalyzed Suzuki-Miyaura coupling is also a feasible strategy to get access to multi-substituted allenamides (Scheme 2-3, eq. 4). 53d More recently, a straightforward coupling between readily accessible propargyl bromides and oxazolidinones or hydantoins for the synthesis of allenamides were depicted by Evano and coworkers, by which mono-, di-and tri-substituted allenamides were easily accessible under relatively mild conditions in the presence of copper catalysts (Scheme 2-4). 54

Scheme 2-4 Straightforward synthesis of allenamides from propargyl bromides

Sigmatropic rearrangements

In 2010, Mapp et al. discovered that phosphorimidates, which is readily available from reactions of progargyl alcohols, azides and chlorophosphites, underwent a [3,3]-sigmatropic rearrangement assisted by Pd(II) catalysts to furnish fully protected allenimides. In the case that chiral progargyl alcohols were employed, high levels of chirality transfer were observed.

Thus this work represents a practical and convenient entry to chiral allenimides (Scheme

2-6). 55a

Scheme 2-5 [3,3]-Sigmatropic rearrangement for the synthesis of allenamides [2,3]-sigmatropic rearrangements also proved to be a facile access to allenamides. For instance, Vranken disclosed an Fe(II)-catalyzed tandem sulfimidation and [2,3]-rearrangement procedure to generate N-allenylsulfenimides, presumably via iron-nitrene intermidate (Scheme 2-6, eq. 1). 55b Enantioenriched allenamides were also accessible from chiral progargyl sulfides following consecutive amination/[2,3]-sigmatropic rearrangement pathway (Scheme 2-6, eq. 2). 55c

Reactions involving intramolecular [1, n]-Hydride Shift

Given fact that intramolecular hydride shift represents an attractive strategy for sp 3 C-H bond functionalization, synthetic chemists are becoming increasingly interested in this area and a series of transformations using this strategy was reported recently.

Hydride donors involving ethers and acetals

In 2005, sames and co-workers revealed a C (sp 3 )-H bond functionalization via hydride shift in the presence of Lewis acid, such as Sc(OTf) 3 , BF 3 . Et 2 O and PtCl 4 , with an alkylidenemaloate moiety serving as the hydride acceptor. Notably, they observed that tertiary and secondary C-H bonds α to ethers or carbamates, as well as tertiary C-H bonds at benzylic positions were all directly functionalized under the reaction conditions (Scheme 2-9, eq 1). Later, multisubstituted dihydrobenzopyrans were prepared by the same group from ortho-vinylaryl alkyl ethers by [1,5]-hydride transfer-initiated cyclizations (Scheme 2-9, eq 2). 58

Scheme 2-9 [1,5]-hydride transfer with alkylidenemaloates as hydride acceptors Soon after that, Akiyama et al. found that a sterically hindered substituent ortho to the alkoxy groups could dramatically reduce the reaction time and catalyst loading, furnishing the desired products in excellent yield. 59 Thes observations were reasoned on the basis that the ortho substituent imposed the favorable conformation required for the hydride transfer process (Scheme 2-10).

Hydride donors without heteroatoms

In an attempt to perform [4+3] cycloadditions with dichlorocyclopentanone, Harmata and Schreiner et al. observed an unexpected ene-like reaction between oxyallylic cations and alkenes. 65 On the basis of computational and deuterium labeling experiments, the authors proposed a mechanism involving a [1,5]-hydride transfer as depicted in Scheme 2-16. Upon treatment with triethylamine, the starting material undergoes enolization followed by loss of a chloride anion to generate a zwitterionic intermediate I. After nucleophilic attack by the alkene, a cationic species II forms, which undergoes desilylation-induced [1,5]-hydride shift to give rise to III. Finally, protonation and tautomerization leads to the formation of adduct.

Scheme 2-16 An interrupted [4+3] cycloaddition

Akiyama et al. reported the first example of aliphatic, non-benzylic sp 3 C-H activation involving [1,5]-and [1,6]-hydride shifts. While tertiary C-H bond underwent the transformation smoothly, secondary bonds were unreactive. The use of highly electrophilic benzylidene barbiturate as the hydride acceptor and Sc(OTf) 3 as catalyst proved to be the optimal combination (Scheme 2-17).

Scheme 2-17 Aliphatic sp 3 C-H activation involving [1,5]-and/or [1,6]-hydride shift

Origin and objectives of the project

Reviewing the reports so far for the preparation of the allenamides lead to conclusions that the current approaches suffer some limitations: (a) They require harsh conditions, such as highly elevated temperature and strong basic conditions which led to the limited functional group tolerance and substrate scope; (b) They require highly prefunctionalized substrates, for instance, preformed allenyl motif, such as allenyl halides, are necessary in cross coupling reactions; (c) The conditions of preparation make the isolation of the in situ generated allenamides different and further tandem transformations frequently take place to form other products. In conclusion, the existing methods are specific to a certain type of allenamides and still there is still a lack of general approach to allenamides.

In light of the profound progress in homogeneous gold catalysis and on the basis of our previous work on gold-catalyzed [1,5] hydride shift, we sought to find a solution to these problems and sought for the development of a gold-catalyzed preparation of allenamide.

Results and discussions

Preliminary results and optimization of conditions

To follow our success in the synthesis of multi-substituted allenes from propargylic benzyl ethers by gold-catalyzed [1,5]-hydride shift, we reasoned that an extension of this methodology to the synthesis of allenamides from ynamide precursors could be . It was postulated that the electron distribution biased by the nitrogen-containing substituent would further favor the hydride transfer to the carbon attaching the nitrogen when compared to the initial transformation we reported(Scheme 2-18).

Scheme 2-18 Original idea for synthesis of allenamides by gold-catalyzed [1,5]-hydride shift

In preliminary explorative studies carried out by Dr. Benoit Bolte, it was found that the goldcatalyzed transformation indeed occurred but only traces amount of allenamides was observed. Dienes were obtained as the result of a gold(I) or Brønsted acid-catalyzed isomerization of the formed allenamide along with amide arising from the easy hydrolysis of ynamide substrate. Switching the stabilizing group on the nitrogen atom from carbamates to sulfonamides did not improve to the yield of allenamides and/or dienes, amides being always formed preferentially as the major products. 66 No allenamide was isolated and characterized.

During his preliminary studies, an early conclusion was made that gold-catalyzed [1,5]-H transfer strategy could not be easily applied to the synthesis of allenamides, due to their unstability under "soft Lewis acid" conditions and the vulnerability of ynamide precursor to hydrolysis.

66 Bolte, B., "Synthesis and reactivity study of allenes by gold-catalyzed hydride transfer", thesis submitted to Ecole Polytechnique for a Ph.D. degree, 2012. We considered that the adventitious H 2 O in the solvent was responsible for the hydrolysis of ynamide and that the elevated temperature presumably promoted the polymerization process in slightly acidic solvent (chloroform would decompose into phosgene along with HCl in the presence of oxygen during prolonged storage, this process being accelerated by light).

Consequently, we moved to identify the influence of temperature and moisture on the course of the reaction. Results of this investigation + +are compiled in Table 2.1.

Table 2.1 Optimization of reaction conditions a

Consistent with our proposal, high temperature was deleterious to the desired product (entries 4, 5 and 6), whereas reactions performed at ambient temperature provided the desired allenamide in comparatively higher amount (compare entries 1 and 2, 5 and 8, Table 2.1). While dried solvent did not improve 2.2/2.3 ratio, switching the ligand from XPhos to RuPhos led to a notable increase of the desired allenamide (compare entries 3 and 9). Notably, the reaction carried out at ambient temperature in the presence of RuPhosAu(CH 3 CN)SbF 6 gave rise to allenamide in 30% isolated yield, which was completely converted into 1,3-diene and (E)-but-2-enal in 9:1 ratio after staying in CDCl 3 in NMR tube overnight. In contrast with this observation, no 1,3-diene was formed during the gold-catalyzed transformations (entries 1-9), suggesting that polymerization took place in preference to tautomerization for allenamide under homogeneous conditions, in particular at elevated temperature.

Considering the fact that ligands are generally of crucial importance in transition-metalcatalyzed transformations, we turned our attention to the evaluation of the influence of gold catalysts possessing diverse ligands (Table 2.2). Treatment of the model substrate with gold catalysts possessing phosphines, NHC and phosphites led to low conversion or chemoselectivity. In the course of reactions using NHC derived catalysts, decomposition or polymerization was also observed.

Considering that amide 2.3 was the major product in most cases and that the catalyst screening did not give satisfactory improvement for the desired allenamides, we hypothesized that these experiment results were due to the nature of the nitrogen substituent. The tosylamide still possesses strong electron-donating ability, thus giving the ynamide greater propensity to hydrolysis and the allenamide higher tendency to undergo polymerization in the presence of gold catalyst.

We proposed that altering the nitrogen substituent by introducing more electron withdrawing group would help in stabilizing the ynamide and the in situ formed allenamide by inhibiting the nucleophilic attack of H 2 O onto ynamide and polymerization and/or decomposition of allenamide respectively. The feasibility of this hypothesis was then investigated by using phthalimide derivatives 2.4a as model substrate, which was subjected to gold catalysis at diverse temperature and using various catalysts (Table 2.3).

Table 2.3 Exploration of phthalimide derived allenamide

To our delight, it was observed that although no reaction occurred at ambient temperature (entry 1), the use of BrettPhosAu(CH 3 CN)SbF 6 as the catalyst allows the formation of the desired allenimide 2.5a in 80% NMR yield at 60℃ in CDCl 3 for 1.5 hours. The competitive amide formation was not completely suppressed (less than 20% yield) (entry 2). Considering the higher performance of biphenylphosphine-based catalysts in the transformation of sulfonyl-stabilized ynamide, we firstly focused on this particular ligand. A brief screening of biphenylphosphines indicated that XPhos was superior to RuPhos and BrettPhos for the transformation of phthalimide-derived ynamides. In this case, the allenimide was isolated in 86% yield along with only traces amount of amide (entries 3 and 4). Unexpectedly, IPrAu(CH 3 CN)SbF 6 was not catalytically active in this case, yielding only 4% of the desired compound for 24 hours at 60℃ (entry 5), although NHC based gold complexes have found wild application in homogeneous gold catalysis. It is noteworthy that an elevated temperature was necessary for the success of this transformation. This tends to prove that this protected allenimide was more stable than analogous allenamide and therefore less prone to undergo polymerization or decomposition.

Facile synthesis of variously functionalized and poly-substituted allenimides

With the most favorable nitrogen substituent and optimized reaction conditions in hand, we next turn our attention to examining the substrate scope in order to demonstrate the applicability and efficiency of this methodology.

We first focused on the possibility to vary the substituent at the propargylic position in order to detect any effect of sterics on the course of reaction and on its efficiency. Mono-and di-substituted ynamides possessing various steric demands were found to undergo the gold-catalyzed transformations smoothly in most cases, furnishing the corresponding allenimides 2.5a-c and 2.5e-h in good to excellent yields (Table 2.4). As anticipated, the tertiary propargylic ethers reacted more readily. Disubstituted allenimides 2.5e-h were generated in excellent yields at ambient temperature as the result of the Thorpe-Ingold effect. Interestingly, the synthesis of unsubstituted allenimide 2.5d was also possible with our method albeit in lower yield and after a prolonged reaction time. Moreover, in the case of allenimide bearing a cylohexanyl group 2.5f, 1,3-diene formation was observed which might be due to the strained six-membered ring, however, this could be totally suppressed by changing the solvent from CHCl 3 to a less acidic chlorinated solvent, such as 1,2dichloroethane.

It deserves mentioning that allenimide 2.5f was very sensitive to both slightly acidic and basic conditions, resulting the fact that they could not be isolated using either silica gel or Et 3 Ndeactivated silica for flash column chromatography. After several attempts, it was finally found that deactivated neutral alumina [Al 2 O 3 /H 2 O=20/1 (v/v)] was suitable for its separation while regular neutral Al 2 O 3 also delivered 1,3-dienes.

Deactivation procedure was as followed: a 500 mL beaker was filled with 200 mL of regular neutral Al 2 O 3 followed by the slow addition of 10 mL distilled water while stirring vigorously using a glass rod. After addition, the hot Al 2 O 3 was transferred into a glass bottle, sealed with a cap and the resulting Al 2 O 3 was used for flash column chromatography.

Given fact that the procedures reported to date are scarcely applicable for the synthesis of allenamides containing functional groups, we next turn our attention to examine the functional group tolereance. To my delight, various mono-and di-substituted ynamides 2.4i-v bearing a series of functional groups including carbamate, acetate, ether, silyl ether, phthalmide, acetal, carbonate and substituted aromatic rings were tolerated to provide allenimides 2.5i-v in excellent yields at room temperature within 2 hours.

In the case of 2.4i and 2.4p, the ynamides precursors gave rise to the corresponding allenimides in excellent yields, however, these transformations proceeded much slowly and a prolonged reaction time was required to reach completion. We related this phenomenon to the potential coordination properties of cyano group and carbamate, which could competitively coordinate to the gold center during the course of reaction, thus slowing down the reaction. With regard to mono-substituted allenimides bearing functional groups 2.5t-v, elevated temperature could not be avoided, yet they were consistently compatible with the reaction conditions. To the best of our knowledge, no current methodology to access allenimide and analogues provide such a general functional group tolerance. The present method represents the first general synthesis of functionalized allenimides.

These results demonstrate the practicality and the applicability of our strategy. It is reasonable to expect that this mild and highly efficient preparation of functionalized allenmides will found application in the realm of natural products synthesis and medicinal chemistry.

Table 2.5 Investigation of functionalized allenimides a,b

Having demonstrated the feasibility of the gold-catalyzed strategy for the synthesis of various allenimides, we next sought for a further extension of this approach to the preparation of allenamides, which were found before to have a great propensity to undergo polymerization and/or decomposition in the presence of gold catalysts. After a brief optimization of the reaction conditions, 1,2-dichloroethane proved to be superior solvent in this case when compared to chloroform in which 1,3-dienes were persistently generated along with the desired allenamides. Besides, elevated temperature must not be applied in these cases due to the rapid decomposition of the formed. The reaction could be applied to the synthesis of disubstituted allenamides for which the ynamide precursors were disubstituted at the propargylic position. The substrates benefit from the Thorpe-Ingold effect which allowed the transformation to undergo at room temperature. Gratifyingly, a series of sulfonyl-stabilized allenamides bearing diverse substituents 2.5w-ac were accessible in good to excellent yields by using of XPhosAu(CH 3 CN)SbF 6 as the catalyst. Urea and Phosphoramidate derived allenamides 2.5ad and 2.5ae could also be obtained by the same method albeit prolonged reaction time and a dilute solution were required. We reasoned that a dilute substrate concentration was beneficial to the overall yield because this could efficiently diminish the degree of the polymerization process. Notably, in the case of 2.5ae, reaction proceeded with acetone serving as the solvent. An extended reaction time was needed to reach completion and provide acceptable yield of the desired product. It was indeed observed that the formed allenamide 2.5ae progressively decomposed in chloroform. In the present case the high Lewis base character of acetone should help in disfavoring the polymerization and decomposition process by lowering the π acidity of the electrophilic gold species by complexation.

The required prolonged reaction time, in turns, demonstrated this theory.

Table 2.6 Synthesis of diverse allenamides a,b

Extension of the method to the synthesis of allenamide equivalents

On the basis of our success in synthesizing the allenamides and allenimides, we envisoned that heteroaromatic rings such as pyrroles and indoles, in which the lone electron pair of nitrogen is delocalized into the aromatic ring, could be used as substrate in the hydride transfer process.

Figure 2-4 Electron distribution of pyrrole and indole

We were pleased to observe that the course of this transformation was even more efficient, furnishing the corresponding allenamide equivalents 2.5af-ak (Table 2.7) containing diverse functionalities in excellent yields in generally less than 10 minutes. The slower process in the case of 2.5al could also be attributed to the potential coordination of nitrogen atom in carbamate to metallic center, similar to the situation in 2.5l and 2.5p. Additionally, carbazole and pyrrole derived ynamines were proved to be suitable substrates in our case, undergoing the transformation smoothly to form 2.5am and 2.5an in 82% and 86% yields respectively.

Further transformation of allenamide and allenamide equivalents

To gain some insights into the synthetic utility and efficiency of the generated allenamine derivatives above, we devised a tandem gold-catalyzed [1,5] hydride shift/Freidel-Craft type reaction process. When N-ethynylpyrroles 2.6 and 2.5af were treated with XPhosAu(CH 3 CN)SbF 6 in 1,2-dichloroethane at room temperature, a slow reaction took place that cleanly provided intriguing spirocyclic compounds 2.8 and 2.9. A higher temperature was required in the case of the N-ethynylindole 2.5af, which underwent the same type of transformation at 80℃ to afford product 2.10 in 88% yield after 12 hours (Scheme 2-22).

Scheme 2-22 Synthesis of allenamide and allenamide equivalents Interestingly, 1,3-dienes 2.11-2. 13 were efficiently prepared from starting ynamides 2.5x-z in a one-pot manner at ambient temperature in yields ranging from 83% to 85% via goldcatalyzed allenamides formation followed by an isomerization assisted by neutral alumina (Scheme 2-23).

Scheme 2-23 Synthesis of 1,3-dienes

Mechanistic scenario

From a mechanistic point of view, the gold-catalyzed synthesis of allenamine derivatives was initiated by the coordination of the starting ynamides to the electrophilic cationic gold(I) complex. The hydrogen at the benzylic position then undergoes a gold-assisted [1,5]

Conclusion

In summary, we have disclosed a robust and efficient approach toward the synthesis of various allenamine derivatives from readily accessible ynamides in the presence of gold catalysts. This reaction which proceeds via a [1,5]-hydride transfer was demonstrated to be quite general and mild since a wide range of sensitive functionalized allenimides, allenamides, and N-allenyl indoles, N-allenyl pyrroles were expediently assembled. This report represents the widest substrate scope tolerance reported so far. In particular, we demonstrated the first facile access to various N-allenyl indoles and pyrroles. In view of the broad application of allenamine derivatives as versatile synthons, there is a great chance that the present method will attract more interest of the synthetic community and promote further development of the allenamide chemistry. Further investigation of synthetic application of this process is being carried out in our laboratory.

Chapter 3. Dual gold catalysis: a unique approach to tetrahydroquinoline derivatives by a formal [4+2] annulation process

As earlier mentioned and exemplified in this manuscript, the past decade has witnessed significant progress in homogeneous gold catalysis. To be specific, a series of reactions were initiated by the π-coordination of a C-C multiple bond to "a" cationic gold center. This "a" thermodynamically stable species according to computational results. Coordination of a cationic gold center a [LAu] + to gold acetylide has been calculated to be 22 Kcal mol -1 more favorable than the coordination to an allene while the energy difference between the coordination to alkyne and an allene is very small. Scheme 3-3 Gagosz's mechanistic proposals for the synthesis of medium-sized alkynes Analogously, Liming Zhang revealed an intermolecular version of this reaction for the dimerization of alkynes. In this process, a gold acetylide served as the nucleophile that adds onto another gold(I)-activated alkyne (Scheme 3-4). 69

Scheme 3-4

Corma, Garcia and co-workers reported the formation of σ, π-digold acetylides bearing sterically hindered biphenylphosphine ligands and tested their synthetic potential. 70 naphthalene was also observed in significant amount (Scheme 3-7). this was the starting point of the development in the field of dual gold catalysis.

Scheme 3-7 Unexpected formation of β-naphthalene

On the basis of mechanistic investigations, a gold acetylide was proposed to be formed and involved in the reaction course. So the corresponding gold acetylide of the model substrate was separately prepared and warmed at 80℃ for 24 hours but no conversion was observed.

However, the addition of catalytic amount of the active catalyst (i.e. The formation of gold vinylidene III as a crucial intermediate herein was later proved by the same group (Scheme 3-8, eq 1) 74 and by a parallel work of Liming Zhang (Scheme 3-8, eq 2) 75 .

The generated gold vinylidene was trapped by insertion into C(sp 3 )-H bond. While NHC ligand gave the best results in Hashmi's work, Zhang and co-workers achieved the same success using BrettPhos as the ligand and in the presence of pyridine N-oxide as a weak basic additive. 1,2-hydrogen shift with gold-aryne being the transition state. Subsequent carbene insertion followed by a 1,2-H shift and deauration give rise to species VIII. The latter undergoes catalyst transfer with another molecule of substrate to furnish the final product.

The selective 6-endo-dig pathway raised a significant question now: what determines the reaction pathway of the dual-activated starting material? A number of calculations 80 revealed that these two distinct pathways have a good correlation with the aromaticity of the 6-endodig cyclization mode,i.e. it is preferred when the corresponding cyclization product was sufficiently stable, otherwise, 5-endo-dig mode occurs.

In 2015, this type of dual-activated reaction mode of 1,2-diynes was extended to ynamide substrate. 81 Multisubstituted pyrroles were accessed through the cycloisomerization of Npropargylynamides. Interestingly, the commonly encountered nuleophilic attack at the αposition of ynamide was not observed. Instead the β-position was found to be the active site.

Origin of our project and preliminary results

In the course of our studies to access allenamides, we examined the ligand effects of gold catalyst. This was performed with an intension to improve the yield of the desired product (Table 2.2, Chapter 2). To our great surprise, when RuPhosAuNTf 2 was employed as catalyst, it was found that a completely different compound was obtained (Scheme 3-17). This appears to be rather surprising since all the other catalytic systems gave rise to a mixture of the allenamide and the 1,3-diene in different ratios from model substrate 2.1.

Scheme 3-17 New product in the desired allenamide reaction

This was the first time we observed a product other than allenamide 2.2 or 1,3-diene 2.3.

Surprisingly and somewhat disappointing, this reaction result could not be reproduced although different solvents (d 8 -toluene, CDCl 3 and CD 2 Cl 2 ) and a new batch of starting material were employed (ynamide was unstable even at -30 ℃. 1 H NMR analysis indicated somewhat decomposition of 2.1 before we redo this reaction).

Since the deuterated dichloromethane used for the reaction was dried over K 2 CO 3 and supposing that some might have been introduced into the reaction medium, we carried out the reaction in the presence of K 2 CO 3 as a basic additive. However no expected conversion was observed even with different amounts of potassium carbonate (Scheme 3-18).

Scheme 3-18 Use of potassium carbonate as an additive

Chapeter 3 100 Although this preliminary test of basic additive didn't provide the desired product, the potential influence of basic additives in combination with our knowledge of dual gold catalysis indeed triggered us to further investigate different bases. Thus, a series of pyridines, quinoline, pyridine N-oxide were explored (Table 3.1).

Table 3.1 Examination of different additives

To our delight, bases such as 3,5-dibromopyridine, lutidine and pyridine all reproduced the reaction in Scheme 3-17, giving rise to the same product in modest to good yields using RuPhosAuNTf 2 as the catalyst (entries 2, 3, 4). Simple investigation of other Buchwald's biphenyl ligands indicated that SPhosAuNTf 2 performed slightly better than RuPhosAuNTf 2 , providing the new compound in 70 % NMR yield (entry 4).

Conditions optimization

To confirm the viability of our synthetic design, model substrate 3.2a was synthesized using

Hsung's C-N coupling methodology (Scheme 3-21).

Scheme 3-21 Synthesis of starting material ynamide 3.2a

It is noteworthy that:

(a) To get 3.2a with a high purity, the use of TMS-protected sulfonamide is unavoided. Indeed under the coupling conditions, C-C coupling of the alkynyl bromide with the terminal alkyne leads to the formation of a by-product in non-neglegible amount;

(b) To deprotect TMS group at the terminal position of alkyne, basic conditions (catalytic amount of K 2 CO 3 in methanol) proved to be much better than the use of TBAF (the following aqueous workup caused hydrolysis of ynamide) due to the sensitivity of ynamide.

Ene-diyne 3.2a was subjected to the typical conditions developed in earlier stage of our studies. Gratifyingly, the expected tetrahydroquinoline product was formed although the conversion was low even after a prolonged time (18 hours) (Scheme 3-22).

Scheme 3-22

Considering that pyridine possesses the property to coordinate to gold center, thereby deactivating the gold catalyst, we then examined the influence of the quantity of pyridine (Table 3.2). We were surprised to find that contrary to the previous observation, pyridine was deleterious to this transformation. The less pyridine employed, the better conversion and yield were. Without pyridine, 1-tosyl-1,2,3,4,6,7,8,9-octahydrobenzo [g]quinolone 3.3a was obtained in 51 % NMR yield (entry 4, Table 3.2).

Table 3.2 Influence of the quantity of pyridine on the reactivity Encouraged by this preliminary observation, we next concentrated on optimizing the reaction conditions. At the outset, various gold catalysts were investigated. As shown in Table 3.3, catalysts based on phosphine, phosphite, phosphonite and N-heterocyclic carbene ligands were screened. Among all the examined catalysts, RuPhosAuNTf 2 proved to be optimal in catalyzing the cyclization of 3.2a, furnishing tetrahydroquinoline derivative 3.3a in 82 % isolated yield (entry 1). Temperature was also found to be a crucial parameter. While the reaction with RuPhosAuNTf 2 as the catalyst provided 100 % conversion after 10 hours at 65 ℃, no product was observed at room temperature even after 15 hours (entry 1 vs entry 2). It seems that the efficiency of desired transformation was related to steric bulk of the ligand used. For instance, the more sterically hindered RuPhosAuNTf 2 was more efficient than SPhosAuNTf 2 (entry 1 vs entry 3). Catalysts which are stronger π-acidic species proved to be deleterious to this reaction (entries 7 and 8). N-heterocyclic carbene-based catalyst was also efficient, furnishing 3.3a in 76 % yield.

Table 3.3 Examination of influence of catalysts

After having determined the most efficient gold catalyst for this designed [4+2] annulation reaction, we moved to examine the base effect. It is of significant interest considering that base (pyridine or lutidine) was indispensable for the C(sp 3 )-H activation while pyridine was detrimental for this [4+2] annulation reaction.

Table 3.4 Base screening

Pyridines possessing different electronic and steric properties were investigated. Pyridines with electron withdrawing substituents, such as 2,6-dibromopyridine, 2,6-dichoropyridine and 3,5-dibromopyridine all provided expected product 3.3a in good yield (entries 1, 2 and 4.

Pyridines containing sterically encumbered substituents which inhibit coordination to metal center, such as 2,6-di-tert-butyl-4-methylpyridine also gave rise to 3.3a in good yield and the amount of base used was found to be no influence for this transformation (entries 5 and 6).

Pyridine and lutidine was indeed detrimental to this model reaction, giving rise to 3.3a in 18 % and 32 % yields respectively (entries 3 and 7).

Substrate scope

With the optimal conditions in hand for the model reaction, we next turn our attention to the substrate scope examination. Initially, substrates with different substituent patterns at the α and β positions of the alkene moiety were examined.

It was found that alkyl, aryl groups were all well tolerated under the catalytic conditions, furnishing the corresponding tetrahydroquinolines in modest to good yields (Table 3.5).

Notably, an ether functional group was compatible too, giving rise to tetrahydroquinoline in 80 % yield (entry 4). When a substrate unsubstituted at the α position was used, transformation proved to be sluggish and a 45 % yield of the desired product was obtained for 60 hours (entry 3). We attributed this lower yield and prolonged reaction time to the cabocation-stabilizing effect of the phenyl group and the absence of stabilizing group at the α position, which might change reactive site from β to α position (Scheme 3-23). This prolonged reaction time led to more side reactions and thus lower reaction yield.

Scheme 3-23 Mechanistic explanation for the lower yield of 3.2e

Moreover, the N-stabilizing group could be changed into Ms from Ts and a even more reaction yield (83 %)could be obtained (Table 3.5, entry 9). Beseids six-membered ring, five and seven-membered ring could also be accessible using the typical conditions, furnishing the corresponding dihydroindole and azepine (Table 3.5, entries 7 and 10).

Table 3.5 Substrate scope examination I a Meantime, we also explored the reactivity of the double bonds in aromatic and heteroaromatic rings under the optimized reaction conditions. We were pleased to find that this new type of substrate also underwent the cyclization smoothly, providing the tetrahydrobenzo [g]quinolines in moderate to good yields (Table 3.6). It was found that aromatic rings with both EWG and EDG substituents underwent the transformations smoothly.

In tha case of substrates substituted at the meta position, two regioisomers were observed (Table 3.6, entries 3 and11). When it comes to heteroaromatic rings, such as thiophene and furan, the cyclization process occurred in the presence of basic additives, i.e. 3,5dibromopyridine and a prolonged reaction time (50 hours) was found to be necessary (Table 3.6, entries 14 and 15). Interestingly, in the case of aromatic rings possessing an ortho-halide or para-methoxy group, azulenes, which are dark blue color, were also generated along with the desired tetrahydrobenzo [g]quinolines (Table 3.6, entries 2, 4, 9 and 10).

We attributed the formation of azulene to the cyclization at the ipso-carbon, which is elctron rich when an electron-donating group was present in the ortho-or para-position.

Inspired by this initial discovery, we were deeply intrigued by the wide application of azulene in modern organic electronics. We envisioned that by blocking both ortho positions of the substrate, the cyclization at the ortho position could be inhibited and then azulene could be formed as the major product. To validate this hypothesis, we synthesized two substrates, which were substituted at both ortho-positions (entries 12 and 13) and we were very pleased to find that the corresponding azulenes were indeed formed as the major product. Although azulenes have been known for more than one century, their organic synthesis method was quite limited and generally suffered from long synthetic route, low yield and poor generality.

This result demonstrated a facile and expedient approach to azulenes.

Mechanistic Proposal

To explain the formation the cyclization product and the formation of azulenes, we propsed a mechanism as followed. The transformation was initialted by the formation of gold acetylide, which might be accelerated by the presence of basic additives. This is why base, such as 3,5dibromopyridine is necessary. Afterwards, a 6-exo-dig cyclization gives rise to the sixmemberd ring in conjunction of the formation of gold vinylidene as the key intermediate.

From gold vinylidene, two diverse reaction pathways are possible. A direct cyclization at the ortho-position of the aromatic ring provided the tetrahydrobenzo [g]quinoline product after deprotonation and protodeauration. Alternatively, a spiro cycliztion process worked, furnishing a spiro compound as the key intermediate. Following the ring expansion of the aromatic ring and deauration process, the formation of azulene was observed.

Scheme 3-24 Mechanistic proposal

Conclusion and perspective

We have demonstrated a facile synthesis of tetrahydroquinolines and 1,2,3,4tetrahydrobenzo [g]quinolines from ynamides via 6-exo-dig cyclization process. The formation of gold vinylidene was proposed as the key intermediate, which is trapped by the double in alkenes or aromatic rings. The demonstrated a novel application of gold vinylidene chemistry.

Moreover, a very interesting and facile synthesis of azulene was also discoved. Although azulenes have been known for more than one century, their organic synthesis method was quite limited and generally suffered from long synthetic route, low yield and poor generality.

This result demonstrated a facile and expedient approach to azulenes.

Besides this initial discoveries, a number of further application of this novel chemistry could be envisioned, such as:



General Information

All commercial available reagents were purchased from chemical suppliers (Sigma-Aldrich, Alfa-Aesar, TCI Europe and Fluochem) and were used as delivered without further purification unless otherwise noted. Dried solvents employed in experimental parts were obtained from solvent purification system MB-SPS 800. Reactions carried out under inert atmosphere were performed under an atmosphere of nitrogen and the reaction vessels are vacuumed and then refilled with nitrogen for three times before reagents were added. Flame-dried reaction flask was used if noted. IUPAC names of compounds described in the experimental section were directly generated using ChemBioDraw.

General Procedures

General procedure 1: synthesis of phthalimide-derived ynimides 82,83 In a 500 mL flame dried one-neck round-bottom flask equipped with a magnetic stir bar, CuCl 2 (2.0 mmol, 0.27 g), phthalimide (50 mmol, 7.36 g), Na 2 CO 3 (20.0 mmol, 2.1 g), and 4Å molecular sieves (6.0 g) were combined together. A solution of pyridine (20.0 mmol, 1.6 mL) in 90 mL dry toluene was added to the reaction flask. Afterwards, the reaction flask was stoppered. Then the flask was evacuated and refilled with oxygen gas for three times. Next, one large balloon filled with oxygen gas was connected to the reaction vessel via a short needle. The flask was then placed in a preheated oil-bath at 70 ºC. The reaction mixture was stirred at this temperature for 2 hours and then a solution of (((2-methylbut-3-yn-2-yl)oxy)methyl)benzene (10.0 mmol, 1.74 g) in 10 mL dry toluene was added to the flask over 4 hours by use of a syringe pump. After the addition of this solution, the reaction mixture was allowed to stir at the same temperature for another 30 hours and then the resulting slurry was cooled to room temperature. The crude reaction mixture was filtered warm through celite and the filtrate was concentrated under reduced pressure. To the resulting residual was added 50 mL Et 2 O and the solid which was not dissolved was filtered. The filtrate was concentrated under vacuum again. Then, the resulting reaction mixture was purified by flash chromatography on silica gel to yield the ynimide as dense oil (78 % yield).

General procedure 2: synthesis of sulfonyl-derived ynamides 84

In a flame dried schlenk tube, N-benzyltoluenesulfonamide (1.31 g, 5.0 mmol), K 2 CO 3 (1.38 g, 10.0 mmol), CuSO 4 . 5H 2 O (250 mg, 1.0 mmol), and 1,10-phenanthroline (360.4 mg, 2.0 mmol) was combined together. Afterwards, the schlenk tube was vacuumed and refilled with nitrogen for 3 times and then the alkyne bromide (1.52 g, 6.0 mmol) in 5 mL of toluene was added via a syringe. The resulting reaction mixture was heated in an oil bath at 70 o C for 24 h until the complete consumption of the starting material. Then, the reaction mixture was cooled to room temperature and diluted with 100 mL of EtOAc followed by the addition of 50 mL distilled water. The resulting two-phase mixture was separated and the water phase was washed with 50 mL of EtOAc for three times. The collected organic phase was dried over MgSO4 and then was concentrated under reduced pressure. The resulting crude residue was purified using flash chromatography on Et 3 Ndeactivated silica gel (eluent contains 5 % triethylamine) to give ynamide as clear oil (83 % yield).

General procedure 3: synthesis of N-alkynyl indoles, pyrroles and ureas 3

In a flame dried schlenk tube, 1-(1H-indol-3-yl)ethanone (0.796 g, 5.0 mmol), K 3 PO 4 (2.12 g, 10.0 mmol), CuSO 4 . 5H 2 O (250 mg, 1.0 mmol), and 1,10-phenanthroline (360.4 mg, 2.0 mmol) was combined together. Afterwards, the schlenk tube was vacuumed and refilled with nitrogen for 3 times and then the alkyne bromide (1.52 g, 6.0 mmol) in 5 mL of toluene was added via a syringe.

The resulting reaction mixture was heated in an oil bath at 70 o C for 24 h until the complete consumption of the starting material. Then, the reaction mixture was cooled to room temperature and diluted with 100 mL of EtOAc followed by the addition of 50 mL distilled water. The resulting two-phase mixture was separated and the water phase was washed with 50 mL of EtOAc for three times. The collected organic phase was dried over MgSO4 and then was concentrated under reduced pressure. The resulting crude residue was purified using flash chromatography on silica gel to give ynamide as clear oil (80 % yield).

General procedure 4: synthesis of propargyl benzyl ethers

Step 1: To a solution of 4-phenylbutan-2-one (1.482 g, 10.0 mmol) in 40 mL anhydrous THF was added ethynylmagnesium bromide (0.5 M solution in THF, 24 mL, 12 mmol) at 0°C and the resulting reaction mixture was stirred at 0 °C for 10 min and then warmed to room temperature for 2 h.

Upon complete consumption of the starting material, the resulting solution was quenched with a saturated solution of NH 4 Cl (40 mL). The two-phase mixture was separated and the water phase was extracted with Et 2 O (3×100 mL). The collected organic phase was dried over anhydrous MgSO 4 and then evaporated under reduced pressure. The resulting residual was used in the next step without any further purification.

Step 2: To a solution of 3-methyl-5-phenylpent-1-yn-3-ol obtained in last step in 40 mL anhydrous THF was added NaH (0.48 g, 12 mmol) portionwise at 0°C. After stirring for 1 hour at 0°C, benzyl bromide (2.05 g, 12 mmol) and tetrabutylammonium iodide (369 mg, 1 mmol) was added to the reaction. The reaction was then stirred at room temperature overnight. After the complete consumption of the alcohol indicated by TLC monitoring, the reaction mixture was quenched with a saturated solution of NH 4 Cl (40 mL), extracted with ethyl acetate (3 x 100 mL), dried over MgSO 4 and concentrated under reduced pressure. Purification by flash column chromatography on silica gel afforded the pure propargyl benzyl ether (85% for 2 steps).

General procedure 5: preparation of alkynyl bromide

To a stirred solution of (((2-methylbut-3-yn-2-yl)oxy)methyl)benzene (1.74 g, 10 mmol) in 30 mL of acetone was added N-bromosuccinimide (1.96 g, 11 mmol) and AgNO 3 (170 mg, 1 mmol). The resulting reaction mixture was stirred untill complete consumption of starting material monitored by TLC and was filtered through a celite column. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated K 2 CO 3 and extracted with ether (100 mL × 3). The combined organic phase was dried over anhydrous MgSO 4 , filtered and then concentrated under reduced pressure. Purification by flash column chromatography on silica gel with petroleum ether/ethyl acetate as the eluent provided (((4-bromo-2-methylbut-3-yn-2-yl)oxy)methyl)benzene as colorless oil (98 % yield).

General Procedure 6: Gold catalysis procedure I

To a stirred solution of 0.20 mmol of starting material in chloroform (2 mL) was added XPhosAu(CH 3 CN)SbF 6 and the solution was stirred at indicated temperature until TLC showed complete consumption of starting material. The reaction mixture was purified by flash chromatography directly without any other workup procedure.

General Procedure 7: Gold catalysis procedure II 121

To a stirred solution of 0.50 mmol of starting material in 1,2-dichloroethane (2 mL) was added XPhosAu(CH 3 CN)SbF 6 and the solution was stirred at ambient temperature until TLC showed complete consumption of starting material. The reaction mixture was purified by flash chromatography on deactivated neutral Al 2 O 3 directly without any other workup procedure.

Note 1:

The reaction mixture must not be concentrated after reaction was completed. As soon as starting material was completely consumed, the reaction mixture was submitted to column chromatography.

Note 2: Deactivation procedure was as followed: a 500 mL beaker was filled with 200 mL normal neutral Al 2 O 3 followed by the slow addition of 10 mL distilled water while stirring vigorously using a glass rod. After addition, the hot Al 2 O 3 was transferred into a glass bottle, sealed with a cap and then kept for overnight.

General Procedure 8:

To a stirred solution of 0.50 mmol of starting material in 1,2-dichloroethane (2 mL) was added XPhosAu(CH 3 CN)SbF 6 and the solution was stirred at ambient temperature until TLC showed complete consumption of starting material. Afterwards, newly ordered neutral Al 2 O 3 was added and the resulting slurry was stirred for 2 hours at room temperature followed by flash chromatography.

Preparation of Starting Materials

2-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 65 % (white solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (dd, J = 5.5, 3.1 Hz, 2H), 7.81 (dd, J = 5.5, 3. 13 C NMR (101 MHz, CDCl 3 ) δ 165. 03, 138.96, 135.16, 131.14, 128.28, 127.88, 127.35, 124.23, 81.66, 71.11, 68.37, 66.81, 29.04.

HRMS (EI):

m/z 319.1213 (M + ), calculated for [C 20 H 17 NO 3 ] + : 319.1208.

2-((1-(benzyloxy)cyclohexyl)ethynyl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 56 % (white solid). 11, 139.18, 135.08, 131.23, 128.24, 127.88, 127.25, 124.21, 80.97, 74.63, 69.90, 65.83, 37.36, 25.47, 22.87.

HRMS (EI):

m/z 359.1537 (M + ), calculated for [C 23 H 21 NO 3 ] + : 359.1521.

2-(3-(benzyloxy)-3-methylpent-1-yn-1-yl)isoindoline-1,3-dione 123

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 68 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7. 2H),2H),J = 7.2 Hz,2H),J = 7.3,1.7 Hz,2H),7.25 (ddd,J = 7.3,4.2,1.3 Hz,1H),4.76 (d,J = 11.1 Hz,1H), 4.69 (d,J = 11.1 Hz,1H), 2.02 -1.83 (m, 2H), 1.62 (s, 3H), 1.14 (t, J = 7.4 Hz, 2H).

13 C NMR (101 MHz, CDCl 3 ) δ 165. 07, 139.16, 135.07, 131.22, 128.22, 127.73, 127.23, 124.21, 80.95, 74.75, 69.30, 66.53, 34.65, 25.99, 8.79.

HRMS (EI):

m/z 333.1368 (M + ), calculated for C 21 H 19 NO 3 : 333.1365.

2-(3-(benzyloxy)-3-methyl-5-phenylpent-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 51 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7. 89 -7.82 (m, 2H), 7.76 -7.69 (m, 2H), 7.34 (dd, J = 7.9, 0.9 Hz, 2H), 7. J = 7.3,1.3 Hz 2H),5H),7.10 (m,1H),4.73 (d,J = 11.1 Hz,1H),4.64 (d,J = 11.1 Hz,1H), 3.00 -2.80 (m, 2H), 2.26 -2.01 (m, 2H), 1.61 (s, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 165. 04, 142.23, 139.04, 135.11, 131.23, 128.54, 128.35, 128.26, 127.70, 127.30, 125.72, 124.26, 80.75, 74.12, 69.74, 66.67, 43.98, 30.93, 26.57.

HRMS (EI):

m/z 409.1697 (M + ), calculated for C 27 H 23 NO 3 : 409.1678.

Tert-butyl4-(benzyloxy)-4-((1,3-dioxoisoindolin-2-yl)ethynyl)piperidine-1-carboxylate

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 44 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 7.32 (d, J = 7.1 Hz, 2H), 7.25 (t,J = 7.4 Hz,2H),1H),4.67 (s,2H),2H), (m, 2H), 2.09 -1.97 (m, 2H), 1.84 (m, 2H), 1.39 (s, 9H).

13 C NMR (101 MHz, CDCl 3 ) δ 164. 90, 154.66, 138.53, 135.24, 131.12, 128.32, 127.88, 127.49, 124.32, 79.59, 79.22, 73.01, 70.98, 66.13, 36.66 (br), 28.44.

HRMS (EI):

m/z 460.1995 (M + ), calculated for C 27 H 28 N 2 O 5 : 460.1998.

2-(3-(benzyloxy)-6-((tert-butyldimethylsilyl)oxy)-3-methylhex-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 40 % (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 165. 01, 139.09, 135.08, 131.19, 128.22, 127.73, 127.24, 124.21, 80.98, 74.08, 69.33, 66.49, 63.26, 38.18, 27.88, 26.56, 26.00, 18.37, -5.24.

HRMS (EI):

m/z 477.2340 (M + ), calculated for C 28 H 35 NO 4 Si: 477.2335.

4-(benzyloxy)-6-(1,3-dioxoisoindolin-2-yl)-4-methylhex-5-yn-1-yl acetate

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 38 % (colorless oil). ), 4.17 (t, J = 6.1 Hz, 1H), 2.07 (s, 3H), 2.03 -1.89 (m, 4H), 1.67 (s, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 171. 06, 164.92, 138.82, 135.09, 131.08, 128.19, 127.65, 127.26, 124.18, 80.38, 73.74, 69.62, 66.53, 64.44, 38.45, 26.41, 23.79, 20.91.

HRMS (EI):

m/z 405.1572 (M + ), calculated for C 24 H 23 NO 5 : 405.1576.

2-(3-(benzyloxy)-5-(4-chlorophenyl)-3-methylpent-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 62 % (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 165. 01, 140.72, 138.95, 135.15, 131.43, 131.21, 129.92, 128.41, 128.27, 127.69, 127.34, 124.28, 80.56, 74.04, 69.91, 66.72, 44.01, 30.37, 26.56.

HRMS (EI):

the experiment was carried out twice but no signal for C 27 H 22 ClNO 3 was found.

2,2'-(3-(benzyloxy)-3-methylhex-1-yne-1,6-diyl)bis(isoindoline-1,3-dione)

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 33 % (yellowish solid). (d,J = 11.1 Hz,1H),4.57 (d,J = 11.1 Hz,1H), 3.72 (t, J = 6.9 Hz, 2H), 2.06 -1.79 (m, 4H), 1.54 (s, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 168. 28, 164.89, 138.86, 135.12, 133.79, 132.15, 131.12, 128.23, 127.74, 127.28, 124.20, 123.12, 80.40, 73.82, 69.75, 66.61, 39.23, 38.06, 26.51, 23.86.

HRMS (EI):

m/z 477.1465 [M-CH 3 ] + , calculated for [C 30 H 24 N 2 O 5 -CH 3 ] +: 477.1450.

2-(3-(benzyloxy)-5-(3-bromophenyl)-3-methylpent-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 70 % (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 165. 03, 144.64, 138.93, 135.18, 131.60, 131.18, 129.94, 128.87, 128.31, 127.71, 127.38, 127.28, 124.31, 122.40, 80.49, 73.98, 69.94, 66.73, 43.88, 30.68, 26.58.

HRMS (EI):

the experiment was carried out twice but no signal for C 27 H 22 BrNO 3 was found.

4-(3-(benzyloxy)-5-(1,3-dioxoisoindolin-2-yl)-3-methylpent-4-yn-1-yl)benzonitrile

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 59 % (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 165. 00, 148.09, 138.80, 135.25, 132.16, 131.15, 129.43, 128.29, 127.69, 127.42, 124.32, 119.12, 109.62, 80.30, 73.98, 70.17, 66.79, 43.68, 31.30, 26.55.

HRMS (EI):

m/z 434.1636 (M + ), calculated for C 28 H 22 N 2 O 3 : 434.1630.

2-(3-(benzyloxy)-5-(3,4-dimethoxyphenyl)-3-methylpent-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 45% (colorless oil). 13 C NMR (101 MHz, CDCl 3 ) δ 165. 03, 148.90, 147.15, 139.02, 135.12, 134.93, 131.21, 128.26, 127.73, 127.32, 124.25, 120.26, 111.99, 111.37, 80.74, 74.14, 69.76, 66.70, 55.95, 55.85, 44.26, 30.55, 26.55.

HRMS (EI):

m/z 469.1890 (M + ), calculated for C 29 H 27 NO 5 : 469.1889.

2-(3-(benzyloxy)-3-methyl-4-(3-(trifluoromethyl)phenyl)but-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 28 % (yellowish oil).

10.5 Hz, 2H), 7.43 (d,J = 7.8 Hz,1H),7.35 (t,J = 7.7 Hz,1H),4H),4.71 (d,J = 11.1 Hz,1H),4.61 (d,J = 11.2 Hz,1H),3.21 (d,J = 13.3 Hz, 1H), 3.09 (d, J = 13.3 Hz, 1H), 1.54 (s, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 164. 87, 138.72, 137.34, 135.14, 134.54, 131.15, 130.05 (q, J = 31.9 Hz), 128.62 (q, J = 270.6 Hz), 128. 23,127.86 (q,J = 3.7 Hz),127.55,127.31,124.27,123.52 (q,J = 3.6 Hz),79.82,74.30,71.15,66.74,47.79,26.30.

HRMS (EI):

m/z 463.1399 (M + ), calculated for C 27 H 20 F 3 NO 3 : 463.1395.

2-(3-(benzyloxy)but-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 66 % (white solid). 1H), 4.43 (q, J = 6.6 Hz, 1H), 1.50 (d, J = 6.6 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 165. 09, 137.82, 135.21, 131.11, 128.40, 128.19, 127.71, 124.32, 79.41, 70.60, 68.95, 64.60, 22.05.

HRMS (EI

2-(3-(benzyloxy)oct-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 42 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7. 2H),2H),1H),4.87 (d,J = 11.8 Hz,1H),4.60 (d,J = 11.8 Hz,1H),4.38 (t,J = 6.6 Hz,1H),2H),2H),4H), 0.90 (t, J = 7.0 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 165.11, 137.98, 135.12, 131.19, 128.34, 128.13, 127.62, 124.27, 78.87, 70.58, 69.45, 68.88, 35.56, 31.47, 24.98, 22.53, 14.00.

HRMS (EI):

m/z 361.1686 (M + ), calculated for C 23 H 13 NO 3 : 361.1678.

2-(3-(benzyloxy)-3-cyclopropylprop-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 22 % (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 165.27, 138.06, 135.45, 131.32, 128.61, 128.45, 127.92, 124.53, 76.95, 72.24, 70.51, 69.88, 15.21, 3.54, 2.43.

HRMS (EI):

m/z 331.1205 (M + ), calculated for C 21 H 17 NO 3 : 331.1208.

2-(3-(benzyloxy)prop-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 54 % (white solid).

13 C NMR (101 MHz, CDCl 3 ) δ 165. 07, 137.24, 135.23, 131.01, 128.40, 128.20, 127.84, 124.34, 75.94, 71.47, 69.90, 57.31.

HRMS (EI):

m/z 291.0890 (M + ), calculated for C 18 H 13 NO 3 : 291.0895.

2-((4-(benzyloxy)tetrahydro-2H-pyran-4-yl)ethynyl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 29 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3. 13 C NMR (101 MHz, CDCl 3 ) δ 164. 94, 138.58, 135.19, 131.18, 128.32, 127.90, 127.47, 124.32, 79.51, 72.17, 70.87, 65.87, 64.68, 37.73.

HRMS (EI):

m/z 361.1322 (M + ), calculated for C 22 H 19 NO 4 : 361.1314.

2-(3-(benzyloxy)-3-methyl-5-(2-methyl-1,3-dioxolan-2-yl)pent-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 22 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 7. 2H),2H),1H),4.68 (d,J = 11.1 Hz,1H),4.60 (d,J = 11.1 Hz,1H),4H),4H), 1.55 (s, 3H), 1.30 (s, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 164. 97, 139.07, 135.06, 131.22, 128.19, 127.67, 127.21, 124.20, 109.90, 80.79, 73.95, 69.51, 66.54, 64.60, 36.30, 33.57, 26.55, 23.94.

HRMS (EI):

The experiment was carried out twice but no signal for C 18 H 19 NO 4 was found.

2,2'-(3-(benzyloxy)hex-1-yne-1,6-diyl)bis(isoindoline-1,3-dione)

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 36 % (yellowish solid). 13 C NMR (101 MHz, CDCl 3 ) δ 168. 30, 164.97, 137.72, 135.13, 133.80, 132.17, 131.16, 128.36, 128.16, 127.67, 124.29, 123.17, 78.14, 70.68, 69.90, 68.22, 37.63, 32.88, 24.60.

HRMS (EI):

m/z 478.1525 (M + ), calculated for C 29 H 22 N 2 O 5 : 478.1529.

Benzyl (4-(benzyloxy)-6-(1,3-dioxoisoindolin-2-yl)hex-5-yn-1-yl) carbonate

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 26 % (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 165. 00, 155.14, 137.71, 135.34, 135.17, 131.15, 128.55, 128.43, 128.38, 128.29, 128.12, 127.72, 124.32, 78.12, 70.68, 69.90, 69.49, 68.17, 67.81, 31.89, 24.65.

HRMS (EI):

m/z 483.1678 (M + ), calculated for C 29 H 25 NO 6 : 483.1682.

2-(3-(benzyloxy)-5-phenylpent-1-yn-1-yl)isoindoline-1,3-dione

This compound was prepared using general procedure 1 and was purified by flash chromatography on silica gel. Yield: 48 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3. 13 C NMR (101 MHz, CDCl 3 ) δ 165. 07, 141.38, 137.87, 135.16, 131.18, 128.58, 128.38, 128.18, 127.69, 125.88, 124.31, 78.56, 70.73, 69.83, 68.11, 37.25, 31.47.

HRMS (EI):

m/z 395.1525 (M + ), calculated for C 26 H 21 NO 3 : 395.1521.

Methyl 1-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-1H-indole-3-carboxylate

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 68 % (white solid). 13 C NMR (101 MHz, CDCl 3 ) δ 164. 28, 138.79, 138.43, 134.93, 128.37, 127.62, 127.47, 125.39, 124.55, 123.70, 121.98, 111.29, 110.88, 74.75, 73.97, 71.01, 66.76, 51.36, 29.20.

HRMS (EI):

m/z 347.1514 (M + ), calculated for C 22 H 21 NO 3 : 347.1521.

1-(1-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-1H-indol-3-yl)ethanone

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 62 % (yellowish solid). 77, 138.82, 138.59, 135.23, 128.37, 127.57, 127.47, 125.08, 124.98, 124.21, 122.96, 119.76, 111.05, 74.72, 74.10, 71.01, 66.76, 29.21, 27.68.

HRMS (EI):

m/z 331.1573 (M + ), calculated for C 22 H 21 NO 2 : 331.1572.

1-(1-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-2-methyl-1H-indol-3-yl)ethanone

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 44 % (colorless oil). 25, 145.31, 138.73, 137.22, 128.39, 127.63, 127.51, 125.88, 123.83, 123.68, 121.24, 116.37, 111.06, 78.58, 73.01, 71.23, 66.83, 31.53, 29.31, 13.57.

HRMS (EI):

m/z 345.1719 (M + ), calculated for C 23 H 23 NO 2 : 345.1729.

1-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-5-nitro-1H-indole

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 50 % (yellow s olid). 62, 138.80, 137.06, 134.23, 132.46, 128.36, 127.54, 127.44, 121.34, 117.36, 107.80, 105.60, 74.42, 74.37, 71.04, 66.75, 29.23.

HRMS (EI):

m/z 334.1321 (M + ), calculated for C 20 H 18 N 2 O 3 : 334.1317.

Methyl 1-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-5-methoxy-1H-indole-2-carboxylate

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 48 % (white solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (d,J = 8.9 Hz,1H),2H),2H),2H), 7.00 (dd, J = 9.0, 2.4 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 4.71 (s, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 1.65 (s, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 160. 51, 156.37, 139.24, 135.68, 129.47, 128.28, 127.80, 127.31, 126.38, 117.56, 112.83, 112.62, 103.37, 74.97, 74.75, 71.33, 66.77, 55.76, 51.88, 29.30.

HRMS (EI):

m/z 377.1627 (M + ), calculated for C 23 H 23 NO 4 : 377.1627.

9-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-9H-carbazole

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 29 % (white solid). 13 C NMR (101 MHz, CDCl 3 ) δ 140. 55, 139.15, 128.33, 127.73, 127.36, 126.71, 123.50, 121.99, 120.36, 111.06, 74.48, 71.49, 66.72, 29.66.

HRMS (EI):

m/z 339.1619 (M + ), calculated for C 24 H 21 NO: 339.1623.

(

1-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-2,5-dimethyl-1H-pyrrol-3-yl)(phenyl)methanone

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 32 % (colorless oil). 72, 140.12, 139.09, 138.79, 131.41, 130.32, 128.98, 128.35, 128.06, 127.58, 127.47, 120.43, 109.77, 77.49, 74.11, 71.12, 66.77, 29.21, 12.65, 12.12.

HRMS (EI):

m/z 371.1881 (M + ), calculated for C 25 H 25 NO 2 : 371.1885.

Methyl 1-((1-(benzyloxy)cyclohexyl)ethynyl)-1H-indole-3-carboxylate

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 52 % (yellowish oil). 31, 139.03, 138.50, 135.03, 128.36, 127.64, 127.42, 125.41, 124.57, 123.70, 122.00, 111.34, 110.80, 76.32, 74.46, 73.20, 65.75, 51.38, 37.53, 25.45, 22.96.

HRMS (EI):

m/z 387.1830 (M + ), calculated for C 25 H 25 NO 3 : 387.1834.

Tert-butyl 4-((1H-indol-1-yl)ethynyl)-4-(benzyloxy)piperidine-1-carboxylate

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 38 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.1, 0.8 Hz, 1H), 7.32 (dd, J = 7.9, 1.0 Hz, 2H), 7.29 -7.12 (m, 5H), 7.10 (d, J = 3.4 Hz, 1H), 6.50 (dd, J = 3.4, 0.8 Hz, 1H), 4.69 (m, 2H), 3.72 (s, 2H), 3.42 -3.30 (m, 2H), 2.12 -1.98 (m, 2H), 1.98 -1.86 (m, 2H), 1.40 (s, 9H).

13 C NMR (101 MHz, CDCl 3 ) δ 154. 71, 138.66, 138.15, 128.77, 128.37, 127.81, 127.67, 127.51, 123.70, 122.11, 121.29, 110.98, 105.62, 79.67, 78.82, 72.93, 70.19, 65.88, 40.64 (br), 36.97 (br), 28.44.

HRMS (EI

Tert-butyl 4-((1H-pyrrol-1-yl)ethynyl)-4-(benzyloxy)piperidine-1-carboxylate

This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 47 % (colorless oil). 71, 138.68, 128.37, 127.64, 127.51, 124.70, 110.60, 80.91, 79.64, 72.56, 65.93, 65.84, 40.58 (br), 36.76 (br), 28.48. This compound was prepared using general procedure 3 and was purified by flash chromatography on silica gel. Yield: 44 % (yellowish solid). 13 C NMR (101 MHz, CDCl 3 ) δ 193.56, 154.63, 147.01, 138.31, 128.41, 127.64, 127.52, 124.79, 121.62, 107.32, 79.81, 77.43, 72.53, 70.56, 65.98, 40.34, 37.59, 36.63, 28.42, 23.18, 21.82.

HRMS (EI

HRMS (EI):

m/z 348.1834 [M-Boc] + , calculated for [C 27 H 32 N 2 O 4 -Boc] + : 348.1838.

N-(3-acetylphenyl)-N-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-4-methylbenzenesulfonamide

This compound was prepared using general procedure 2 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 60 % (yellowish oil). 66, 145.37, 139.52, 138.98, 138.08, 132.62, 130.25, 129.60, 129.43, 128.30, 128.23, 127.73, 127.51, 127.34, 125.71, 78.04, 73.57, 71.12, 66.52, 28.93, 26.59, 21.66.

HRMS (EI):

m/z 461.1659 (M + ), calculated for C 27 H 27 NO 4 S: 461.1661.

N-benzyl-N-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-4-methylbenzenesulfonamide

This compound was prepared using general procedure 2 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 68 % (colorless oil). 13 C NMR (101 MHz, CDCl 3 ) δ 144. 61, 139.12, 134.56, 134.41, 129.63, 129.01, 128.46, 128.33, 128.18, 127.77, 127.59, 127.20, 78.18, 73.70, 70.98, 66.23, 55.43, 28.85, 21.59. HRMS (EI): m/z 433.1710 (M + ), calculated for C 26 H 27 NO 3 S: 433.1712.

N-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-4-methyl-N-phenylbenzenesulfonamide

This compound was prepared using general procedure 2 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 59 % (white solid). 86, 139.16, 138.98, 133.07, 129.37, 129.01, 128.26, 128.21, 128.04, 127.50, 127.22, 126.01, 78.64, 72.84, 71.14, 66.47, 28.96, 21.57.

HRMS (EI

N-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-N-butyl-4-methylbenzenesulfonamide

This compound was prepared using general procedure 2 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 60 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (d, J = 8.3 Hz, 2H), 7.28 -7.13 (m, 7H), 4.44 (s, 2H), 3.23 (t, J = 7.1

Hz, 2H), 2.30 (s, 3H), 1.57 -1.48 (qn, J = 7.2 Hz, 2H), 1.45 (s, 6H), 1.26 (sex, J = 7.5 Hz, 2H), 0.82 (t, J = 7.4 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 144. 48, 139.20, 134.60, 129.62, 128.21, 127.66, 127.56, 127.22, 78.13, 72.80, 71.12, 66.35, 51.02, 29.91, 29.06, 21.55, 19.42, 13.53.

HRMS (EI

N-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-N-phenylmethanesulfonamide

This compound was prepared using general procedure 2 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 52 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.41 -7.37 (m, 2H), 7.36 -7.22 (m, 7H), 7.17 (tt, J = 7.5, 1.5 Hz, 1H), 4.59 (s, 2H), 2.93 (s, 3H), 1.52 (s, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 139. 26, 138.68, 129.42, 128.28, 128.17, 127.46, 127.28, 125.28, 77.78, 73.49, 71.19, 66.62, 36.52, 29.03.

HRMS (EI

N-benzyl-N-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-4-methoxybenzenesulfonamide

This compound was prepared using general procedure 2 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 44 % (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 163. 69, 139.16, 134.48, 129.97, 129.02, 128.49, 128.34, 128.21, 127.59, 127.23, 114.21, 78.39, 73.69, 71.02, 66.23, 55.67, 55.40, 28.89.

HRMS (EI):

m/z 449.1656 (M + ), calculated for C 26 H 27 NO 4 S: 449.1661.

Tert-butyl 4-((N-benzyl-4-methylphenylsulfonamido)ethynyl)-4-(benzyloxy)piperidine-1carboxylate

This compound was prepared using general procedure 2 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 44 % (colorless oil). 61, 144.88, 138.75, 134.46, 134.24, 129.81, 128.98, 128.58, 128.52, 128.25, 127.70, 127.60, 127.37, 80.80, 79.50, 77.39, 73.02, 71.27, 65.50, 55.30, 40.64, 36.68, 28.46, 21.62.

HRMS (EI):

m/z 574.2511 (M + ), calculated for C 33 H 38 N 2 O 5 : 574.2501.

1-(3-(benzyloxy)-3-methylbut-1-yn-1-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

This compound was prepared using general procedure 3 and was purified by flash chromatography on Et 3 N-deactivated silica gel (eluent contains 5 % triethylamine). Yield: 41 % (white solid).

1 H NMR (400 MHz, Acetone) δ 7.25 (d, J = 7.3 Hz, 2H), 7.16 (t, J = 7.4 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 7.05 -6.95 (m, 4H), 4.60 (s, 2H), 3.23 (s, 3H), 1.52 (s, 6H).

13 C NMR (101 MHz, Acetone) δ 153. 53, 140.36, 130.97, 128.95, 128.92, 128.41, 127.96, 124.36, 122.80, 109.97, 109.21, 77.74, 72.31, 71.77, 67.11, 29.56, 27.75.

HRMS (EI):

m/z 320.1531 (M + ), calculated for C 20 H 20 N 2 O 2 : 320.1525.

Catalysis and Products

2-(3-methylbuta-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using flash column chromatography on silica gel. Reaction time: 2 h. Yield : 93% of white solid.

1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (dd, J = 5.4, 3.0 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 6.54 -6.49 (sept, J = 2.6 Hz, 1H), 1.86 (d, J = 2.6 Hz, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 196.22, 166.11, 134.04, 132.12, 123.21, 106.12, 85.57, 21.22.

HRMS (EI):

m/z 213.0784 (M + ), calculated for C 13 H 11 NO 2 : 213.0790.

2-(2-cyclohexylidenevinyl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 2 h.

Yield : 94% (white solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 7.62 (dd, J = 5.5, 3.0 Hz, 2H), 6.52 -6.39 (m, 1H), 2.29 -2.20 (m, 2H), 2.19 -2.09 (m, 2H), 1.71 -1.48 (m, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 192. 91, 166.12, 134.00, 132.17, 123.18, 112.87, 85.39, 32.19, 26.91, 25.96.

HRMS (EI):

m/z 253.1113 (M + ), calculated for C 16 H 15 NO 2 : 253.1103.

2-(3-methylpenta-1,2-dienyl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 94% (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (dd, J = 5.5, 3.0 Hz, 2H), 7.68 (dd, J = 5.5, 3.0 Hz, 2H), 6.61 (q, J = 2.7 Hz, 1H), 2.10 (m, 2H), 1.84 (d, J = 2.7 Hz, 2H), 1.07 (t, J = 7.4 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 195. 24 , 166.09 , 134.02 , 132.14 , 123.18 , 112.15 , 87.43 , 27.76 , 19.80 , 11.84 .

HRMS (EI):

m/z 227.0941 (M + ), calculated for C 14 H 13 NO 2 : 227.0946.

2-(3-methyl-5-phenylpenta-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 97% (white solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.73 (dd, J = 5.4, 3.1 Hz, 2H), 7.60 (dd, J = 5.4, 3.0 Hz, 2H), 7.21 -7.07 (m, 4H), 7.05 -6.93 (m, 1H), 6.53 -6.50 (sex, J = 2.6 Hz, 1H), 2.83 -2.68 (m, 2H), 2.42 -2.23 (m, 2H), 1.81 (d, J = 2.6 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 195. 90, 166.04, 141.84, 134.08, 132.16, 128.40, 128.23, 125.72, 123.24, 110.07, 87.59, 36.21, 33.60, 20.14.

HRMS (EI):

m/z 303.1266 (M + ), calculated for C 20 H 17 NO 2 : 303.1259.

Tert-butyl 4-(2-(1,3-dioxoisoindolin-2-yl)vinylidene)piperidine-1-carboxylate

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 8 h. Yield : 95% (yellowish solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.1 Hz, 2H), 6.63 (s, 1H), 3.66 (dd, J = 11.8, 6.0 Hz, 2H), 3.44 (m, 2H), 2.37 -2.22 (m, 4H), 1.46 (s, 9H).

13 C NMR (101 MHz, CDCl 3 ) δ 193. 72, 165.88, 154.67, 134.13, 132.08, 123.26, 109.07, 86.67, 79.64, 44.28 (br), 31.50, 28.42.

HRMS (EI):

m/z 354.1567 (M + ), calculated for C 20 H 22 N 2 O 4 : 354.1580.

2-(6-((tert-butyldimethylsilyl)oxy)-3-methylhexa-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 92% (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 6.61 (sex, J = 2.6 Hz, 1H), 3.65 (t, J = 6.4 Hz, 2H), 2.16 (m, 2H), 1.87 (d, J = 2.6 Hz, 3H), 1.78 -1.71 (m, 2H), 0.87 (s, 9H), 0.03 (d, J = 1.6 Hz, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 195.46, 166.08, 134.04, 132.22, 123.23, 110.41, 87.21, 62.67, 31.02, 30.50, 25.96, 20.09, 18.34, -5.31, -5.33.

HRMS (EI):

m/z 371.1915 (M + ), calculated for C 21 H 29 NO 3 Si: 371.1917.

6-(1,3-dioxoisoindolin-2-yl)-4-methylhexa-4,5-dien-1-yl acetate

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 98% (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.74 (dd, J = 5.4, 2.9 Hz, 2H), 7.63 (dd, J = 5.3, 3.0 Hz, 2H), 6.57 (sex, J = 2.6 Hz, 1H), 4.03 (t, J = 6.6 Hz, 2H), 2.15 -2.04 (m, 2H), 1.95 (s, 3H), 1.86 -1.74 (m, 5H).

13 C NMR (101 MHz, CDCl 3 ) δ 195.35, 171.04, 165.99, 134.10, 132.08, 123.24, 109.63, 87.62, 63.94, 30.90, 26.36, 20.91, 20.05.

HRMS (EI):

m/z 299.1161 (M + ), calculated for C 17 H 17 NO 4 : 299.1158.

2-(5-(4-chlorophenyl)-3-methylpenta-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 97% (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (dd, J = 5.4, 3.0 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.18 -7.08 (m, 4H), 6.62 -6.57 (sex, J = 2.6 Hz, 1H), 2.89 -2.72 (m, 2H), 2.50 -2.29 (m, 2H), 1.88 (d, J = 2.6 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 195. 99, 165.99, 140.19, 134.12, 132.08, 131.41, 129.75, 128.26, 123.26, 109.73, 87.75, 35.82, 32.83, 20.11.

HRMS (EI):

m/z 337.0864 (M + ), calculated for C 20 H 16 ClNO 2 : 337.0870.

2,2'-(3-methylhexa-1,2-diene-1,6-diyl)bis(isoindoline-1,3-dione)

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 93% (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.83 -7.80 (m, 4H), 7.72 -7.64 (m, 4H), 6.66 (sex, J = 2.7 Hz, 1H), 3.85 -3.62 (m, 2H), 2.32 -2.03 (m, 2H), 1.92 (qn, J = 7.4 Hz, 2H), 1.88 (d, J = 2.6 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 195.22, 168.29, 165.98, 134.00, 133.76, 132.17, 123.22, 123.11, 109.56, 87.79, 37.60, 31.84, 26.25, 20.06.

HRMS (EI):

m/z 386.1276 (M + ), calculated for C 23 H 18 N 2 O 4 : 386.1267.

2-(5-(3-bromophenyl)-3-methylpenta-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 95% (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.34 (s, 1H), 7.21 (dt, J = 7.7, 1.7 Hz, 1H), 7.17 -7.04 (m, 2H), 6.64 -6.59 (sex, J = 2.7 Hz, 1H), 2.88 -2.75 (m, 2H), 2.48 -2.31 (m, 2H), 1.89 (d, J = 2.6 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 195. 92, 165.98, 144.17, 134.09, 132.13, 131.47, 129.76, 128.82, 127.07, 123.27, 122.29, 109.69, 87.81, 35.75, 33.16, 20.13.

HRMS (EI):

m/z 381.0361 (M + ), calculated for C 20 H 16 BrNO 2 : 381.0364.

4-(5-(1,3-dioxoisoindolin-2-yl)-3-methylpenta-3,4-dien-1-yl)benzonitrile

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 12 h. Yield : 97%

(yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 196. 02, 165.87, 147.42, 134.25, 131.97, 129.21, 123.26, 118.89, 109.59, 109.36, 88.02, 35.17, 33.51, 20.07.

HRMS (EI):

m/z 328.1214 (M + ), calculated for C 21 H 16 N 2 O 2 : 328.1212.

2-(5-(3,4-dimethoxyphenyl)-3-methylpenta-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 97% (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 6.75 -6.69 (m, 3H), 6.61 (sex, J = 2.6 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 2.83 -2.72 (m, 2H), 2.46 -2.34 (m, 2H), 1.89 (d, J = 2.6 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 195.91, 166.01, 148.72, 147.10, 134.46, 134.06, 132.12, 123.21, 120.12, 111.83, 111.12, 110.07, 87.56, 55.81, 55.78, 36.27, 33.18, 20.13.

HRMS (EI):

m/z 363.1466 (M + ), calculated for C 22 H 21 NO 4 : 363.1471.

2-(3-methyl-4-(3-(trifluoromethyl)phenyl)buta-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 98% (yellowish oil). 13 C NMR (101 MHz, CDCl 3 ) δ 196. 73, 165.85, 139.55, 134.13, 132.52, 132.08, 130.55 (q, J = 31.9 Hz), 128.67, 126.02 (q, J = 3.7 Hz), 124.16 (q, J = 270.6 Hz), 123.30, 123.25 (q, J = 3.7 Hz), 108.94, 87.31, 41.47, 19.31.

HRMS (EI):

m/z 357.0975 (M + ), calculated for C 20 H 14 F 3 NO 2 : 357.0977.

2-(buta-1,2-dien-1-yl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at 60 ℃ and was purified using column chromatography on silica gel. Reaction time: 1 h. Yield : 86% (white solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (dd, J = 5.4, 3.1 Hz, 2H), 7.64 (dd, J = 5.5, 3.0 Hz, 2H), 6.60 (dq, J = 5.9, 2.9 Hz, 1H), 5.78 -5.69 (m, 1H), 1.78 (dd, J = 7.2, 2.9 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 199. 65, 165.88, 134.15, 132.05, 123.33, 96.36, 87.41, 15.18.

HRMS (EI):

m/z 199.0638 (M + ), calculated for [C 12 H 9 NO 2 ] + : 199.0633.

2-(octa-1,2-dienyl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at 60 ℃ and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 1 h. Yield : 78%

(yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 6.74 -6.70 (dt, J = 6.2, 2.8 Hz, 1H), 5.84 (q, J = 6.6 Hz, 1H), 2.18 (ddd, J = 14.8, 6.9, 2.9 Hz, 2H), 1.52 (dd, J = 14.9, 7.4 Hz, 2H), 1.40 -1.28 (m, 4H), 0.93 -0.86 (t, J = 7.2 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 198. 70, 165.89, 134.12, 132.10, 123.33, 101.64, 88.02, 31.35, 29.52, 28.16, 22.44, 14.01.

HRMS (EI):

m/z 255.1262 (M + ), calculated for C 16 H 17 NO 2 : 255.1259.

2-(3-cyclopropylpropa-1,2-dienyl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at 60 ℃ and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 1 h. Yield : 60%

(yellowish oil). 197.82, 165.83, 134.17, 132.08, 123.36, 105.63, 89.14, 10.10, 7.14, 6.90.

HRMS (EI):

m/z 255.0792 (M + ), calculated for C 14 H 11 NO 2 : 255.0790.

2-(propa-1,2-dienyl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at 60 ℃ and was purified using column chromatography on silica gel. Reaction time: 4 h. Yield : 35% (white solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (dd, J = 5.4, 3.1 Hz, 2H), 7.66 (dd, J = 5.5, 3.1 Hz, 2H), 6.75 (t, J = 6.7 Hz, 1H), 5.41 (d, J = 6.7 Hz, 2H).

13 C NMR (101 MHz, CDCl 3 ) δ 204. 45, 165.72, 134.37, 132.06, 123.56, 88.33, 85.51.

HRMS (EI):

m/z 185.0475 (M + ), calculated for C 11 H 7 NO 2 : 185.0477.

2-(2-(2H-pyran-4(3H,5H,6H)-ylidene)vinyl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 5 h. Yield : 94% (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (dd, J = 5.4, 3.1 Hz, 2H), 7.64 (dd, J = 5.4, 3.0 Hz, 2H), 6.61 -6.56 (m, 1H), 3.81 -3.70 (m, 4H), 2.37 -2.25 (m, 4H).

13 C NMR (101 MHz,CDCl 3 ) δ 193.39,165.94,134.15,132.07,123.28,108.31,86.66,68.09,32.31. This compound was obtained following general procedure 6 at room temperature and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 93% (yellowish oil).

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (dd, J = 5.3, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 6.63 (m, 1H), 4.00 -3.89 (m, 4H), 2. 30 -2.10 (m, 2H), 1.97 -1.79 (m, 5H), 1.34 (s, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 195.17, 165.98, 134.03, 132.12, 123.20, 110.36, 109.69, 87.50, 64.63, 36.65, 29.06, 23.84, 20.18. This compound was obtained following general procedure 6 at 60 ℃ and was purified using column chromatography on silica gel. Reaction time: 2 h. Yield : 81% (yellowish solid).

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 7.80 -7.73 (m, 4H), 7.69 -7.61 (m, 4H), 6.71 (dt, J = 6.1, 3.0 Hz, 1H), 5.82 (q, J = 6.4 Hz, 1H), 3.74 -3.69 (m, 2H), 2.20 (m, 2H), 1.91 -1.82 (qn, J = 7.4 Hz, 2H).

13 C NMR (101 MHz, CDCl 3 ) δ 198. 78, 168.33, 165.77, 134.14, 133.82, 132.17, 132.08, 123.36, 123.16, 100.39, 88.87, 37.47, 27.20, 26.77. This compound was obtained following general procedure 6 at 60 ℃ and was purified using column chromatography on silica gel. Reaction time: 1.5 h. Yield : 82% (yellowish oil).

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.42 -7.30 (m, 5H), 6.77 (dt, J = 6.1, 3.0 Hz, 1H), 5.86 (q, J = 6.4 Hz, 1H), 5.14 (s, 2H), 4.25 (t, J = 6.5

Hz, 2H), 2.38 -2.19 (m, 2H), 1.93 (qn, J = 6.8 Hz, 2H).

13 C NMR (101 MHz,CDCl 3 ) δ 198.86,165.76,155.15,135.31,134.21,132.01,128.55,128.45,128.28,123.39,100.33,88.82,69.48,67.42,27.34,25.61.

HRMS (EI):

m/z 377.1265 (M + ), calculated for C 22 H 19 NO 5 : 377.1263.

2-(5-phenylpenta-1,2-dienyl)isoindoline-1,3-dione

This compound was obtained following general procedure 6 at 60 ℃ and was purified using column chromatography on silica gel. Reaction time: 1 h. Yield : 75 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (dd, J = 5.4, 3.1 Hz, 2H), 7.66 (dd, J = 5.4, 3.1 Hz, 2H), 7. 23 -7.14 (m, 4H), 7.08 (t, J = 6.9 Hz, 1H), 6.66 (dt, J = 5.9, 2.8 Hz, 1H), 5.82 (q, J = 6.4 Hz, 1H), 2.82 -2.76 (m, 2H), 2.44 (ddd, J = 15.8, 6.8, 2.9 Hz, 2H).

13 C NMR (101 MHz, CDCl 3 ) δ 199. 02, 165.81, 141.47, 134.20, 132.06, 128.52, 128.31, 125.89, 123.37, 100.78, 88.59, 34.60, 31.10.

HRMS (EI):

m/z 289.1105 (M + ), calculated for C 19 H 15 NO 2 : 289.1103.

Methyl 1-(3-methylbuta-1,2-dienyl)-1H-indole-3-carboxylate

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 10 min. Yield : 99 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 8. 11 -8.05 (m, 1H), 7.77 (s, 1H), 7.44 -7.38 (m, 1H), 7.21 -7.15 (m, 2H), 6.81 (qn, J = 2.5 Hz, 1H), 3.81 (s, 3H), 1.82 (d, J = 2.5 Hz, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 193. 95, 165.27, 135.87, 132.07, 127.12, 123.23, 122.33, 121.78, 110.51, 109.49, 108.64, 94.03, 51.06, 21.70.

HRMS (EI):

m/z 241.1096 (M + ), calculated for C 15 H 15 NO 2 : 241.1103.

1-(1-(3-methylbuta-1,2-dienyl)-1H-indol-3-yl)ethanone

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 10 min. Yield : 96 % (white solid).

1 H NMR (400 MHz, CDCl 3 ) δ 8. 41 -8.33 (m, 1H), 7.78 (s, 1H), 7.56 -7.49 (m, 1H), 7.35 -7.28 (m, 2H), 6.94 (qn, J = 2.5 Hz, 1H), 2.55 (s, 3H), 1.96 (d, J = 2.5 Hz, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 194. 08, 193.06, 136.15, 132.49, 126.81, 123.68, 122.94, 122.65, 118.20, 110.43, 109.60, 94.05, 27.75, 21.73.

HRMS (EI

1-(2-methyl-1-(3-methylbuta-1,2-dienyl)-1H-indol-3-yl)ethanone

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 10 min. Yield : 92 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7. 89 -7.86 (m, 1H), 7.46 -7.40 (m, 1H), 7.20 -7.10 (m, 2H), 6.60 (qn, J = 2.5 Hz, 1H), 2.68 (s, 3H), 2.56 (s, 3H), 1.82 (d, J = 2.5 Hz, 6H).

13 C NMR (101 MHz,CDCl 3 ) δ 198.19,194.66,144.11,135.89,126.68,122.31,120.68,115.23,110.85,106.33,90.93,31.71,21.29,13.27.

HRMS (EI):

m/z 239.1308 (M + ), calculated for C 16 H 17 NO: 239.1310.

1-(3-methylbuta-1,2-dienyl)-5-nitro-1H-indole

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 10 min. Yield : 92 % (white solid). 13 C NMR (101 MHz,CDCl 3 ) δ 193.77,143.25,133.99,133.73,131.68,120.75,115.46,109.72,107.34,103.86,94.26,21.79. 13 C NMR (101 MHz, CDCl 3 ) δ 195. 09, 162.23, 155.03, 133.75, 127.29, 127.15, 116.60, 113.51, 111.59, 106.06, 102.81, 94.37, 55.66, 51.70, 21.92.

HRMS (EI

HRMS (EI):

m/z 271.1202 (M + ), calculated for C 16 H 17 NO 3 : 271.1208.

9-(3-methylbuta-1,2-dienyl)-9H-carbazole

This compound was obtained following general procedure 7 (substate concentration 0.1 M) at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 10 min. Yield : 82 % (colorless oil).

1 H NMR (400 MHz, Acetone) δ 8.14 (ddd, J = 7.8, 1.1, 0.8 Hz, 2H), 7.76 (d,J = 8.3 Hz,2H),7.48 (ddd, J = 8.4, 7.2, 1.2 Hz, 2H), 7.41 (qn, J = 2.6 Hz, 1H), 7.27 (ddd, J = 7.9, 7.3, 0.9 Hz, 2H), 1.99 (d, J = 2.6 Hz, 6H).

13 C NMR (101 MHz,Acetone) δ 195.68,140.35,127.01,124.56,120.99,120.92,111.13,107.79,93.27,22.42. This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 12 h. Yield : 86 % (yellowish oil). 198.14, 192.15, 140.95, 136.36, 130.88, 129.01, 127.88, 127.80, 119.65, 110.48, 105.44, 91.84, 21.12, 13.04, 12.71. 64, 165.30, 135.89, 132.08, 127.13, 123.12, 122.30, 121.77, 116.25, 110.65, 108.53, 93.78, 51.05, 32.52, 27.15, 25.82.

HRMS (EI

HRMS (EI

HRMS (EI):

Experiment was carried out twice but no signal was found for C 18 H 19 NO 2 .

Tert-butyl 4-(2-(1H-indol-1-yl)vinylidene)piperidine-1-carboxylate

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 30 min. Yield : 94 % (colorless oil).

1 H NMR (400 MHz, Acetone) δ 7.68 (dd, J = 8.3, 0.7 Hz, 1H), 7.58 (d,J = 7.9 Hz,1H),2H),7.21 (ddd,J = 8.3,7.2,1.1 Hz,1H), 7.09 (ddd, J = 8.0, 7.2, 0.9 Hz, 1H), 6.58 (dd, J = 3.3, 0.6 Hz, 1H), 3.67 -3.57 (m, 4H), 2. 50 -2.30 (m, 4H), 1.47 (s, 9H).

13 C NMR (101 MHz,Acetone) δ 191.68,154.95,136.31,130.52,126.94,123.01,121.70,121.03,112.24,111.22,104.37,96.57,79.76,45.00 (br),32.86,28.56.

HRMS (EI):

m/z 324.1839 (M + ), calculated for C 20 H 24 N 2 O 2 : 324.1838.

Tert-butyl spiro[piperidine-4,1'-pyrrolizine]-1-carboxylate

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on silica gel. Reaction time: 12 h. Yield : 97 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 6.89 (d, J = 4.0 Hz, 1H), 6.73 (d, J = 2.1 Hz, 1H), 6.24 (t, J = 2.6 Hz, 1H), 6.10 (d, J = 3.2 Hz, 1H), 5.73 (d,J = 3.7 Hz,1H),3.82 (m,2H),3.45 (ddd,J = 13.4,10.3,3.0 Hz, 2H), 1.75 (ddd,J = 15.4,10.4,4.0 Hz,2H),1.50 (m,11H).

13 C NMR (101 MHz, CDCl 3 ) δ 154. 95, 142.04, 126.53, 125.95, 111.18, 111.03, 102.39, 79.56, 46.57, 40.65, 33.76, 28.49. 13 C NMR (101 MHz, CDCl 3 ) δ 165. 49, 157.75, 130.27, 129.92, 129.53, 122.40, 122.10, 121.99, 121.80, 109.50, 101.48, 50.71, 46.55, 22.53. 27, 154.83, 142.16, 135.22, 129.10, 123.79, 123.47, 99.54, 46.40, 40.43, 37.79, 33.65, 28.44, 23.71, 21.44.

HRMS (EI

HRMS (EI

HRMS (EI

N-(3-acetylphenyl)-4-methyl-N-(3-methylbuta-1,2-dienyl)benze-nesulfonamide

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 3 h.

Yield : 88 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.81 (dt, J = 7.8, 1.5 Hz, 1H), 7.47 (d,J = 8.4 Hz,2H), (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.16 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 6.73 (qn, J = 2.5 Hz, 1H), 2.41 (s, 3H), 2.36 (s, 3H), 1.40 (d, J = 2.5 Hz, 6H).

13 C NMR (101 MHz,CDCl 3 ) δ 196.81 ,192.69 ,143.98 ,138.63 ,137.62 ,135.26 ,134.02 ,129.50 ,129.24 ,128.93 ,127.85 ,127.64 ,109.15 ,99.58 ,26.49 ,21.57 ,21.11 .

HRMS (EI):

m/z 355.1260 (M + ), calculated for C 20 H 21 NO 3 S: 355.1242.

N-benzyl-4-methyl-N-(3-methylbuta-1,2-dienyl)benzenesulfonamide

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 3 h.

Yield : 85 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (d,J = 8.3 Hz,2H),7.50 (d,J = 8.4 Hz,2H),5H), 6.75 (qn, J = 2.5 Hz, 1H), 4.40 (s, 2H), 2.61 (s, 3H), 1.55 (d, J = 2.5 Hz, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 193. 53 , 143.55 , 136.57 , 135.38 , 129.60 , 128.18 , 127.51 , 127.26 , 127.07 , 108.91 , 97.01 , 50.21 , 21.56 .

HRMS (EI):

m/z 327.1300 (M + ), calculated for C 19 H 21 NO 2 S: 327.1293.

4-methyl-N-(3-methylbuta-1,2-dienyl)-N-phenylbenzenesulfonamide

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 5 h.

Yield : 95 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d,J = 8.3 Hz,2H),7.18 (m,5H),2H), 6.73 (qn, J = 2.4 Hz, 1H), 2.35 (s, 3H), 1.39 (d, J = 2.3 Hz, 6H).

13 C NMR (101 MHz, CDCl 3 ) δ 192. 85 , 143.56 , 138.12 , 135.74 , 129.35 , 129.29 , 128.57 , 128.17 , 127.67 , 108.56 , 99.86 , 21.57 , 21.11 .

HRMS (EI):

m/z 313.1131 (M + ), calculated for C 18 H 19 NO 2 S: 313.1136.

N-butyl-4-methyl-N-(3-methylbuta-1,2-dienyl)benzenesulfonamide

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 3 h.

Yield : 91 % (yellowish oil). 193.03 , 143.87 , 136.07 , 129.83 , 127.45 , 108.60 , 97.54 , 46.73 , 30.08 , 21.76 , 21.57 , 20.26 , 13.74 .

HRMS (EI):

m/z 293.1452 (M + ), calculated for C 16 H 23 NO 2 S: 293.1449.

N-(3-methylbuta-1,2-dienyl)-N-phenylmethanesulfonamide

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 3 h.

Yield : 87 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7. 36 -7.22 (m, 5H), 6.60 (qn, J = 2.4 Hz, 1H), 2.92 (s, 3H), 1.52 (d, J = 2.4 Hz, 6H).

13 C NMR (101 MHz,CDCl 3 ) δ 192.60 ,138.17 ,129.04 ,128.90 ,128.34 ,108.95 ,99.39 ,38.03 ,21.12 .

HRMS (EI):

m/z 237.0828 (M + ), calculated for C 12 H 15 NO 2 S: 237.0823.

N-benzyl-4-methoxy-N-(3-methylbuta-1,2-dienyl)benzenesulfonamide

This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 3 h.

Yield : 85 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d,J = 9.0 Hz,2H),5H), 7.01 (d, J = 9.0 Hz, 2H), 6.59 (p, J = 2.5 Hz, 1H), 4.24 (s, 2H), 3.88 (s, 3H), 1.40 (d, J = 2.5 Hz, 6H).

13 C NMR (101 MHz,CDCl 3 ) δ 193.57 ,163.01 ,136.62 ,129.99 ,129.34 ,128.19 ,127.51 ,127.07 ,114.18 ,108.89 ,97.05 ,55.65 ,50.20 ,21.57 . 86 , 154.47 , 143.70 , 136.17 , 135.47 , 129.68 , 128.30 , 127.22 , 127.19 , 127.05 , 111.54 , 98.08 , 79.69 , 50.27 , 43.88 , 31.68 , 28.39 , 21.54 193.75 , 153.15 , 131.38 , 128.54 , 122.69 , 122.23 , 110.06 , 108.84 , 108.40 , 91.46 , 27.24 , 22.31 . This compound was obtained following general procedure 8 and was obtained as colorless oil (83 % yield). 92 , 140.05 , 136.05 , 135.47 , 129.86 , 128.59 , 127.43 , 126.89 , 126.85 , 126.70 , 115.27 , 113.98 , 49.40 , 21.52 , 18.78 . This compound was obtained following general procedure 8 and was obtained as colorless oil (88 % yield).

HRMS (EI

HRMS (EI

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d,J = 8.3 Hz,2H),3H),7.19 (d,J = 8.2 Hz,2H),7.14 (d,J = 14.2 Hz,1H),2H), 5.03 (d,J = 14.3 Hz,1H),2H), 2.35 (s, 3H), 1.81 (d, J = 1.2 Hz, 3H).

13 C NMR (101 MHz, CDCl 3 ) δ 143. 99 , 140.00 , 136.26 , 135.81 , 130.30 , 129.61 , 129.47 , 129.45 , 129.08 , 127.48 , 115.06 , 113.83 , 21.55 , 18.92 .

HRMS (EI):

m/z 313.1146 (M + ), calculated for C 18 H 19 NO 2 S: 313.1136.

General Information

All commercial available reagents were purchased from chemical suppliers (Sigma-Aldrich, Alfa-Aesar, TCI Europe and Fluochem) and were used as delivered without further purification unless otherwise noted. Dried solvents employed in the experimental parts were obtained from solvent purification system MB-SPS 800. Reactions carried out under inert atmosphere were performed under an atmosphere of nitrogen and the reaction vessels are vacuumed and then refilled with nitrogen for three times before reagents were added. were next added and the resulted suspension was heated at 70 ℃ for 24 h. When the reaction mixture was cooled to rt, the crude reaction mixture was diluted with water, extracted with diethyl ether and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel using petroleum ether/EtOAc (containing 5 % triethylamine) as the eluent to provide the desired (E)-4-methyl-N-(pent-4-yn-1-yl)-N-(3-phenylpent-3-en-1-yn-1-yl)benzenesulfonamide (yellowish oil, 62 % yield).

General Procedures

General

Note:

In this procedure, TMS was removed in the course of the reaction and no further deprotection step was needed.

General procedure 6: Gold catalysis

To a stirred solution of 0.20 mmol of ynamide starting material in chloroform (2 mL) was added RuPhosAuNTf 2 (5 mmol%) at room temperature and the solution was stirred at preheated 70 ℃ oil bath until TLC showed complete consumption of starting material. Then the reaction mixture was concentrated under reduced pressure and then purified by flash column chromatography on silica gel using petroleum ether/EtOAc as the eluent.

Preparation of Starting Materials

N-(cyclohex-1-en-1-ylethynyl)-4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamide

This compound was prepared from 4-methyl-N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1-(bromoethynyl)cyclohex-1-ene using general procedure 3.

Yield: 65 % (yellowish oil). 60, 134.46, 134.08, 129.78, 127.75, 119.93, 82.92, 79.58, 72.45, 69.34, 50.48, 29.53, 26.96, 25.72, 22.41, 21.75, 21.59, 15.66. 84, 134.46, 131.43, 129.92, 128.37, 127.94, 127.78, 122.80, 82.81, 82.19, 70.88, 69.50, 50.53, 27.05, 21.77, 15.68. 3308,3065,2929,2595,2239,1599,1494,1443,1367,1171, 1095

HRMS (EI

HRMS (EI

N-((2-bromophenyl)ethynyl)-4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamide

This compound was prepared from 4-methyl-N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1-bromo-2-(bromoethynyl)benzene using general procedure 3.

Yield: 70 % (yellowish oil). 91, 134.30, 132.46, 132.22, 129.88, 128.69, 127.65, 127.00, 125.00, 124.50, 86.52, 82.69, 70.12, 69.51, 50.41, 26.80, 21.64, 15.54. Yield: 75 % (yellowish solid). 41, 144.87, 134.52, 129.95, 129.44, 127.82, 123.96, 123.87, 116.38, 114.37, 82.84, 82.08, 70.91, 69.51, 55.41, 50.55, 27.11, 21.80, 15.71. 3308,3007,2941,2838,2240,1576,1465,1368,1187,1096

HRMS (EI

HRMS (EI

N-((4-methoxyphenyl)ethynyl)-4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamide

This compound was prepared from 4-methyl-N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1-(bromoethynyl)-4-methoxybenzene using general procedure 3.

Yield: 68 % (yellowish oil). 59, 144.70, 134.45, 133.45, 129.83, 127.74, 114.64, 113.98, 82.86, 80.66, 70.47, 69.42, 55.36, 50.56, 26.99, 21.72, 15.65. 3308,3043,2958,2938,2840,2242,1606,1512,1366,1248,1171, 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d,J = 8.4 Hz,2H),7.34 (d,J = 8.4 Hz, 2H), 5.16 -5.12 (m, 1H), 5.12 -5.09 (m, 1H), 3.44 (t, J = 6.9 Hz, 2H), 2.43 (s, 3H), 2.24 (td, J = 7.0, 2.7 Hz, 2H), 1.97 (t, J = 2.6 Hz, 1H), 1.91 -1.79 (m, 5H).

HRMS (EI

13 C NMR (100 MHz, CDCl 3 ) δ 144. 78, 134.36, 129.83, 127.70, 126.07, 119.71, 82.76, 81.54, 72.44, 69.41, 50.36, 26.98, 23.55, 21.71, 15.59. 13 C NMR (100 MHz, CDCl 3 ) δ 166. 64, 145.09, 134.45, 130.66, 130.03, 129.57, 128.88, 127.83, 127.76, 85.52, 82.67, 70.97, 69.62, 52.30, 50.50, 27.14, 21.79, 15.67. 3308,2954,2251,2234,1718,1606,1438,1369,1288,1172,1109 86, 139.77, 136.46, 134.56, 129.97, 128.82, 128.50, 127.75, 126.17, 107.56, 84.21, 82.83, 70.65, 69.50, 50.58, 27.05, 21.81, 15.70. 3308,3033,2939,2263,2221,1599,1449,1367,1171 Yield: 72 % (white solid). 1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.5 Hz, 2H), 7.21 -7.13 (m, 3H), 6.63 (s, 1H), 3.42 (t, J = 6.9 Hz, 2H), 2.38 (s, 3H), 2.21 (td, J = 7.0, 2.7 Hz, 2H), 1.97 (d, J = 1.6 Hz, 3H), 1.91 (t, J = 2.7 Hz, 1H), 1.84 (qn, J = 6.9 Hz, 2H).

HRMS (EI

HRMS (EI

HRMS (EI

13 C NMR (100 MHz, CDCl 3 ) δ 144. 81, 136.94, 134.54, 134.36, 129.91, 128.98, 128.37, 127.81, 127.12, 119.29, 82.87, 81.53, 74.84, 69.47, 50.53, 27.11, 21.80, 19.47, 15.72. 3308, 3065, 3026, 2955, 2877, 2252, 2223, 1598, 1494, 1442, 1367, This compound was prepared from 4-methyl-N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1-bromo-4-(bromoethynyl)benzene using general procedure 3.

HRMS (EI

Yield: 77 % (yellowish solid).

1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (d,J = 8.4 Hz,2H),7.41 (d,J = 8.5 Hz,2H),7.36 (d,J = 8.4 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 3.53 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.28 (td, J = 7.0, 2.7 Hz, 2H), 2.00 (t, J = 2.7 Hz, 1H), 1.92 (qn, J = 6.9 Hz, 2H).

13 C NMR (100 MHz, CDCl 3 ) δ 144. 98, 134.47, 132.79, 131.62, 129.98, 127.76, 122.00, 121.85, 83.37, 82.73, 70.07, 69.57, 50.51, 27.11, 21.79, 15.68. 3308,2939,2877,2239,1598,1489,1368,1171,1117 (s, 9H), 3.50 (t, J = 6.9 Hz, 2H), 2.43 (s, 3H), 2.28 (td, J = 7.0, 2.7 Hz, 2H), 1.98 (t, J = 2.7 Hz, 1H),

HRMS (EI

1.91 (qn, J = 7.0 Hz, 2H).

13 C NMR (100 MHz, CDCl 3 ) δ 153. 05, 144.80, 138.64, 134.46, 129.87, 127.72, 117.75, 108.90, 82.77, 81.17, 70.79, 69.44, 60.97, 56.20, 50.47, 27.04, 21.70, 15.63. 3308,2941,2844,2258,1599,1578,1465,1411,1372,1236,1132, Yield: 65 % (yellowish oil).

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d,J = 8.4 Hz,2H),4H),2H), 3.57 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.30 (td, J = 7.0, 2.7 Hz, 2H), 2.05 -1.94 (m, 3H).

13 C NMR (100 MHz, CDCl 3 ) δ 144. 98, 135.21, 134.56, 132.60, 129.99, 129.27, 128.67, 127.88, 126.54, 123.03, 87.23, 82.81, 69.53, 68.51, 50.57, 26.97, 21.81, 15.71.

HRMS (EI):

This experiment was carried out twice but no corresponding signal was observed.

IR (CDCl 3 ): ν (cm -1 ) 3691, 3308, 3068, 2939, 2877, 2239, 2121, 1599, 1438, 1369, 1171 Yield: 66 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (d,J = 8.4 Hz,2H),3H),7.25 (tdd,J = 7.5,5.3,2.6 Hz,1H),2H), 3.55 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.29 (td, J = 7.0, 2.7 Hz, 2H), 1.99 (t, J = 2.7 Hz, 1H), 1.94 (qn, J = 7.0 Hz, 2H). 77, 69.51, 64.71, 50.51, 26.95, 21.78, 15.67.

HRMS (EI):

This experiment was carried out twice but no corresponding signal was observed.

IR (CDCl 3 ): ν (cm -1 ) 3691, 3308, 3067, 2940, 2248, 1600, 1496, 1454, 1369, 1171 Yield: 60 % (yellowish oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (d,J = 8.3 Hz,2H),7.49 (t,J = 1.8 Hz,1H),1H), 7.37 (d,J = 8.3 Hz,2H), 7.28 (dt, J = 7.8, 1.3 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 3.53 (t, J = 6.9 Hz, 2H), 2.46 (s, 3H), 2.29 (td, J = 6.9, 2.5 Hz, 2H), 2.00 (t, J = 2.6 Hz, 1H), 1.92 (qn, J = 6.9 Hz, 2H).

13 C NMR (100 MHz, CDCl 3 ) δ 145. 06, 134.48, 133.94, 130.97, 130.04, 129.85, 129.81, 127.79, 124.95, 122.20, 83.64, 82.72, 69.79, 69.62, 50.52, 27.13, 21.83, 15.70. 3308,3068,2940,2877,2595,2238,1597,1556,1368,1187 (t, J = 6.9 Hz, 2H), 2.44 (s, 3H), 2.32 -2.27 (m, 5H), 2.04 (qn, J = 6.9 Hz, 2H), 1.98 (t, J = 2.6 Hz, 1H).

HRMS (EI

13 C NMR (100 MHz, CDCl 3 ) δ 145. 01, 139.72, 134.64, 132.00, 130.01, 127.92, 124.77, 124.14, 90.09, 82.90, 70.33, 69.53, 50.76, 26.92, 21.83, 20.90, 15.76. 3308,2926,2876,2261,2239,2121,1599,1369,1188,1171 2.47 (s, 3H), 2.28 (td, J = 7.0, 2.7 Hz, 2H), 1.99 (t, J = 2.6 Hz, 1H), 1.92 (p, J = 7.0 Hz, 2H).

HRMS (EI

13 C NMR (100 MHz, CDCl 3 ) δ 144. 95, 134.47, 133.19, 129.98, 127.95, 127.82, 127.12, 122.83, 85.70, 82.77, 69.53, 64.27, 50.70, 27.02, 21.83, 15.71. 3308,3112,2940,2876,2264,2248,2229,1599,1433,1371,1171 62, 137.09, 134.59, 133.42, 132.82, 129.76, 129.09, 128.62, 127.88, 121.65, 119.87, 82.63, 80.93, 80.20, 72.67, 53.65, 29.23, 25.62, 22.35, 21.76, 21.56 3305,3031,2933,2862,2261,2230,1600,1450,1367,1187,1170,

HRMS (EI

N-(but-3-yn-1-yl)-N-(cyclohex-1-en-1-ylethynyl)-4-methylbenzenesulfonamide

This compound was prepared from 4-methyl-N-(4-(trimethylsilyl)but-3-yn-1yl)benzenesulfonamide and 1-(bromoethynyl)cyclohex-1-ene using general procedure 3.

Yield: 70 % (yellowish oil). 78, 134.59, 134.56, 129.86, 127.79, 119.86, 79.95, 79.08, 72.86, 70.58, 50.25, 29.54, 25.77, 22.43, 21.80, 21.60, 18.45. IR (CDCl 3 ): ν (cm -1 ) 3692, 3309,3031,2932,2862,2338,2254,1728,1683,1599,1368,1169, 13 C NMR (100 MHz, CDCl 3 ) δ 145. 07, 134.46, 130.04, 127.68, 84.35, 82.59, 69.55, 66.99, 64.35, 58.80, 50.41, 31.92, 29.25, 29.16, 28.98, 28.38, 26.84, 22.75, 21.78, 19.68, 15.60, 14.22. 3308,2930,2858,2263,2249,2164,1600,1460,1372,1187,1172, Yield: 66 % (yellowish solid).

HRMS (EI

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.9 Hz, 2H), 7.21 (tt, J = 8.4, 6.3 Hz, 1H), 6.88 (dd, J = 8.5, 7.0 Hz, 2H), 3.56 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.29 (td, J = 6.9, 2.6 Hz, 2H), 1.99 (t, J = 2.7 Hz, 1H), 1.94 (qn, J = 6.9 Hz, 2H).

13 C NMR (100 MHz, CDCl 3 ) δ 162.89 (d,J = 252.7),162.83 (d,J = 252.7),145.06,134.34,129.99,129.11 (t,J = 9.9 Hz),127.93,111.22 (d,J = 24.1 Hz),111.22 (d,J = 12.9 Hz), 102.08 (t, J = 19.8 Hz), 91.34 (t, J = 2.9 Hz), 82.72, 69.54, 58.85, 50.49, 26.90, 21.82, 15.68. IR (CDCl 3 ): ν (cm -1 ) 3691, 3050,2939,2878,2246,1623,1582,1469,1371,1241,1172 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (d, J = 7.2 Hz, 2H), 7.39 -7.34 (m, 3H), 6.61 (d, J = 2.7 Hz, 1H), 6.44 -6.35 (m, 1H), 3.52 (t, J = 6.9 Hz, 2H), 2.45 (s, 3H), 2.25 (t, J = 6.9 Hz, 2H), 1.97 (s, 1H), 1.90 (qn, J = 6.9 Hz, 2H).

HRMS (EI

13 C NMR (100 MHz, CDCl 3 ) δ 145. 04, 144.14, 136.70, 134.51, 130.01, 127.75, 117.39, 111.22, 86.17, 82.67, 69.54, 61.76, 50.61, 26.90, 21.79, 15.65.

HRMS (EI):

m/z 327.0933 [M] + , calculated for [C 18 H 17 NO 3 S] + : 327.0929.

IR (CDCl 3 ): ν (cm -1 ) 3691, 3308, 3068, 2940, 2878, 2230, 1599, 1492, 1367, 1172, 1094

4-methyl-N-(3-methyleneoct-1-yn-1-yl)-N-(pent-4-yn-1-yl)benzenesulfonamide

This compound was prepared from 4-methyl-N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1-bromo-3-methyleneoct-1-yne using general procedure 3. Yield:

58 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.17 -5.15 (m, 1H), 5.12 (q, J = 1.4 Hz, 1H), 3.46 (t, J = 6.9 Hz, 2H), 2.44 (s, 3H), 2.25 (td, J = 7.0, 2.6 Hz, 2H), 2.12 (dd, J = 8.2, 6.9 Hz, 2H), 1.97 (t, J = 2.6 Hz, 1H), 1.87 (qn, J = 6.9 Hz, 1H), 1.47 (tdd,J = 8.7,7.3,6.2 Hz,2H),4H), 0.89 (t, J = 7.0 Hz, 3H).

13 C NMR (100 MHz, CDCl 3 ) δ 144. 77, 134.48, 131.19, 129.87, 127.79, 119.06, 82.82, 82.02, 71.76, 69.43, 50.44, 37.44, 31.21, 27.90, 27.05, 22.62, 21.79, 15.67, 14.19. 3308,2958,2931,2859,2263,2228,1599,1447,1366,1170 Yield: 64 % (colorless oil).

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.25 (q, J = 6.6 Hz, 1H), 3.56 (dt, J = 9.0, 6.8 Hz, 1H), 3. 50 -3.35 (m, 2H), 3.28 (dt, J = 9.0, 6.7 Hz, 1H), 2.44 (s, 3H), 2.24 (td, J = 7.0, 2.7 Hz, 2H), 1.96 (t, J = 2.7 Hz, 1H), 1.86 (qn, J = 6.9 Hz, 2H), 1.53 (qn, J = 6.9

Hz, 2H), 1.41 (d, J = 6.6 Hz, 3H), 1.34 -1.22 (m, 8H), 0.96 -0.80 (m, 3H).

13 C NMR (100 MHz, CDCl 3 ) δ 144. 77, 134.53, 129.84, 127.81, 82.79, 77.82, 71.35, 69.43, 68.83, 65.50, 50.30, 31.96, 29.82, 29.30, 27.03, 26.35, 22.75, 22.33, 21.77, 15.66, 14.23.

HRMS (EI):

This experiment was carried out twice but no corresponding signal was observed.

IR (CDCl 3 ): ν (cm -1 ) 3691, 3308, 2956, 2931, 2858, 2246, 1599, 1366, 1171, 1096

N-(cyclohex-1-en-1-ylethynyl)-N-(pent-4-yn-1-yl)methanesulfonamide

This compound was prepared from N-(5-(trimethylsilyl)pent-4-yn-1-yl)methanesulfonamide and 1-(bromoethynyl)cyclohex-1-ene using general procedure 3. Yield: 66 % (colorless oil).

1 H NMR (400 MHz, CDCl 3 ) δ 6.07 (tt, J = 3.6, 1.6 Hz, 1H), 3.57 (t, J = 6.9 Hz, 2H), 3.08 (s, 3H), 2.32 (td, J = 7.0, 2.7 Hz, 2H), 2.14 -2.07 (m, 4H), 2.00 (t, J = 2.7 Hz, 1H), 1.95 (qn, J = 7.0 Hz, 2H), 1.66 -1.54 (m, 4H).

13 C NMR (100 MHz, CDCl 3 ) δ 134. 84, 119.82, 82.76, 78.84, 72.89, 69.61, 50.40, 37.97, 29.64, 27.24, 25.79, 22.44, 21.60, 15.66. IR (CDCl 3 ): ν (cm -1 ) 3691, 3308,3027,2940,2862,2260,2254,1724,1682,1436,1358,1164 N

HRMS (EI

Catalysis and Products

All the gold-catalyzed reactions were carried out following the general procedure 6:

To a stirred solution of 0.20 mmol of ynamide starting material in chloroform (2 mL) was added RuPhosAuNTf 2 (5 mmol%) at room temperature and the solution was stirred at preheated 70 ℃ oil bath until TLC indicated complete consumption of starting material. Then the reaction mixture was concentrated under reduced pressure and then purified by flash column chromatography on silica gel using petroleum ether/EtOAc as the eluent. 13 C NMR (100 MHz, CDCl 3 ) δ 143. 39, 137.06, 135.47, 134.28, 134.08, 129.60, 129.33, 127.86, 127.23, 125.31, 46.56, 29.37, 28.90, 26.17, 23.33, 23.30, 21.77, 21.63. 13 C NMR (100 MHz, CDCl 3 ) δ 143. 61, 136.62, 134.86, 132.52, 131.04, 131.01, 129.62, 128.02, 127.10, 126.85, 126.80, 125.69, 122.74, 46.83, 27.32, 22.67, 21.57 3544,3308,3064,3029,2932,2887,2260,1703,1599,1486,1404,1351,1164,1092 7-bromo-1-tosyl-1,2,3,4-tetrahydrobenzo [g]quinoline

HRMS (EI

Yield: 72 % (yellowish oil); Reaction time: 18 h. 82, 136.50, 135.33, 132.18, 132.00, 130.96, 129.73, 129.13, 128.85, 127.11, 126.00, 122.57, 119.56, 46.84, 27.44, 22.54, 21.65 13 C NMR (100 MHz, CDCl 3 ) δ 153. 02, 147.18, 143.56, 140.66, 136.68, 134.90, 129.90, 129.63, 128.61, 127.11, 121.97, 121.73, 120.88, 61.48, 61.25, 55.98, 46.89, 27.29, 22.62, 21.61. IR (CDCl 3 ): ν (cm -1 ) 3691, 2958,2931,2859,2254,1599,1500,1422,1342,1164,1092 6-(heptyloxy)-6-methyl-1-tosyl-2,3,4,6-tetrahydro-1H-cyclopenta [b]pyridine Yield: 95 % (colorless oil); Reaction time: 24 h. 2H), 1.34 (s, 3H), 1.30 -1.17 (m, 8H), 0.88 (t, J = 6.9 Hz, 3H).

HRMS (EI

13 C NMR (100 MHz, CDCl 3 ) δ 144. 08, 135.92, 135.71, 135.17, 134.90, 129.57, 127.61, 116.98, 85.97, 64.34, 46.63, 32.02, 30.89, 29.39, 26.20, 23.83, 23.21, 23.01, 22.79, 21.70, 14.27. 13 C NMR (100 MHz, CDCl 3 ) δ 135. 93, 134.35, 133.82, 130.02, 126.44, 123.22, 46.67, 38.53, 29.40, 28.82, 26.71, 23.29, 23.25, 22.42. 3013,2937,2861,2842,2264,2254,1602,1501,1420,1339,1155

HRMS (EI

HRMS (EI

  suivi d'une fragmentation, le tout catalysé par de l'or et en utilisant des ynamides comme substrats. Notre méthode est rapide et pratique. En effet, la réaction se fait dans des conditions douces (température ambiante) avec une charge catalytique faible (4 mol% de catalyseur à l'or) et donne d'excellents rendements (jusqu'à 99%). En plus d'une bonne compatibilité fonctionnelle sur le carbone terminal (R1 et R2), notre méthode tolère aussi des substituants azotés variés (R' et R''). De plus, d'autres transformations in-situ sur les allénamides formés in-situ ont été effectuées. Quelques composés spiros et diènes interessants ont été obtenus avec des rendements excellents. 2) Catalyse duale à l'or : Une synthèse originale de dérivés tertahydroquinolines par un mécanisme formel d'addition [4+2] Bien qu'une vaste majorité de la catalyse à l'or contient une activation du système π d'une liaison multiple par un seul complexe d'or, des innovations récentes mettant en jeu deux atomes d'or sur une seule molécule ont été développées par plusieurs groupes, dont le nôtre. Le cycle catalytique est initié par la formation de l'acétylénure d'or et par la coordination d'un autre complexe d'or de la liaison triple de l'ynamide. Après une attaque nucléophile de l'acétylenure d'or sur l'ynamine, un vinylidène d'or est formé. Ce dernier est piégé par la double liaison, donnant naissance au cycle aromatique.

Figure 1 - 3

 13 Figure 1-3 Relative atomic abundance of chemical elements in earth's upper crust

Figure 1 - 4

 14 Figure 1-4 Prices of precious metals on May, 10 th 2016

Figure 1 - 5

 15 Figure 1-5 Dewar-Chatt-Duncanson model for alkyne-metal bond

Figure 1 - 6

 16 Figure 1-6 Calculated relativistic contraction of the 6s orbital

Figure 1 - 7

 17 Figure 1-7 Selected examples of gold(III) complexes

Figure 1 -

 1 Figure 1-10 Representative examples of preformed catalysts

Figure 1 -

 1 Figure 1-12 General pathways of nucleophilic addition

Scheme 1 -

 1 Scheme 1-20 Au(I)-catalyzed tandem transformations of 1,2-enynes

  stabilized derivative of allenamine (Figure2-1) belongs to a subclass of allenes, representing a type of versatile and powerful synthetically important building block.

  allenamide, the past 15 years has witnessed broad investigations of allenamide chemistry, including addition reactions, aldol reactions, cyclizations, ring closing metathesis, cycloadditions and deprotonations (Figure2-2).

Figure 2 - 2

 22 Figure 2-2 Outline of allenamide chemistry

Scheme 2- 3

 3 Scheme 2-3 Synthesis of allenamides by copper-catalyzed C-N coupling

Scheme 2- 12

 12 Scheme 2-12 Functionalization of C-H bond α to amines In 2012, Maulide group disclosed a one-pot C-H functionalization procedure, in which Grignard reagents or lithium alkynyl trifluoroborates were directly added to position α of the amine moiety with the concomitant reduction of the aldehyde. The overall transformation took place via the formation of an intermediate aminal. The utility of this methodology was nicely demonstrated by the expedient synthesis of (±)-indolizidine 167B. 62

  Scheme 3-1 Toste's synthesis of trienesOn the basis of deuterium labeling and crossover experiments, evaluation of primary kinetic effect in combination with computational chemistry, the authors presented a unique mechanism involving a nucleophilic attack of the allene moiety onto a phosphinegoldcoordinated phosphinegold acetylide. This was the first proposal of a simultaneous participation of two gold complexes in a gold-catalyzed process (Scheme 3-2). It is worth noting that the two gold centers are located in the same alkynyl moiety, which is the more

  Scheme 3-5Widenhoefer and co-workers 73 revealed that (IPr)AuCl/AgSbF 6 formed unstable π-complexes with terminal arylacetylene at low temperature, which were transformed into σ, π-digold acetylide complexes by warming the temperature to 0 ℃ (Scheme 3-6).

  IPrAuNTf 2 ) led to almost exclusive formation of the β-product. Based on these experiments and additional kinetic studies (Figure 3-1), the authors proposed that during the course of the reaction, two different reaction pathways compete. At the beginning of the reaction, a single gold activation of one alkyne moiety leads to the generation of the α-isomer, slowly the πcoordinated alkyne was converted into a gold acetylide, which cooperates with another cationic gold(I) species to give rise to the β-isomer selectively. This proposal was confirmed by studying the additive effects of additives among which triethylamine and aluminum oxide were shown to favor the formation of β-isomer (98:2) with high selectivity. It was also found that an equilibrium between the gold acetylide and the active gold(I) catalyst were required for efficient transformation and a high β-selectivity.

Figure 3 - 1

 31 Figure 3-1 Conversion and yields of α-isomer and β-isomer against reaction time

  Scheme 3-8 C(sp 3 )-H bond activation involving gold vinylidene

Scheme 3- 9

 9 Scheme 3-9 Hashmi's proposal involving C-H activation to benzofulvenes This modification was based on a new discovery of stereospecific addition to alkenes by potential gold vinylidene intermediates. 77 Intermediate V underwent deauration to furnish the vinyl gold (I) species VI, which gave rise to a gem-diaurated species after coordination with [Au] + . Species VI and VII are in a side equilibrium. Catalytic cycle was completed by a catalyst transfer, which was validated by deuterium labeling experiments: 93 % of deuterium atom at terminal position of alkyne was transferred into the gold position of intermediate VI (Scheme 3-10).

Fully 1 H 1

 11 Scheme 3-19 Tentative mechanism for the formation of compound 3.1The mechanistic proposal is very similar to the previous proposal by Hashmi an Zhang, however, this mode of reaction has not been reported so far. On the basis of the above mechanistic proposal for the formation of 3.1, we envisioned that the replacement of the C-H single bond at the γ-position of ynamide with a C=C double bond would lead to the formation of intermediate IX, which could evolve into aromatic product 3.3 after cyclization. This formal unprecedented [4+2] strategy would represent a facile approach to tetrahydroquinolines (Scheme 3-20).

Figure 3 -

 3 Figure 3-2 X-ray structure of azulene



  Trapping benzyne-gold intermediate with other reagent (ROH, F-, reduction with cyclooctane…) Attemps to generate vinylidene and trap them with other sources of electrophiles: activated epoxide, enamides....  Selective synthesis of azulenes (colored), use of dibromoazulenes as bricks for econductors by linking them with acetylene (LED applications)

  NMR spectra were recorded at room temperature in the given solvent on a Bruker Avance DPX 400 instrument operating at the indicated frequency for the specified nucleus given in mega Hertz (MHz). Chemical shifts δ are given in parts per million (ppm) using tetramethylsilane (TMS) as the standard reference sample for 1 H-NMR and13 C-NMR spectra and are calibrated in relation to the deuterated solvent (CDCl 3 : 7.26 / 77.16 ppm; CD 2 Cl 2 : 5.32 / 53.80 ppm; d 6 -acetone: 2.05 / 29.84 ppm). Coupling constants J are given in Hertz (Hz). Signal multiplicities are depicted using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sex = sextuplet, sept = septuplet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, tt = triplet of triplet, dq = doublet of quartet, ddd = doublet of doublet of doublet, ddt = doublet of doublet of triplet, bs = broad singlet. High-resolution mass spectrometry by eletron impact (EI) was performed on a JMC GCmate II mass spectrometer and fragment signals were given in mass per charge number (m/z).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.87 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 7.33 (d, J = 7.1 Hz, 2H), 7.29 -7.23 (t, J = 7.4 Hz, 2H), 7.22 -7.13 (m, 1H), 4.69 (d, J = 11.1 Hz, 1H), 4.62 (d, J = 11.1 Hz, 1H), 3.72 -3.55 (m, 2H), 1.95 -1.71 (m, 4H), 1.57 (s, 2H), 0.85 (s, 9H), 0.01 (s, 6H).

125 1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.94 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.5, 3.1 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.34(t, J = 7.5 Hz, 2H), 1H), 4.78 (d, J = 11.1 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 7.32 (d, J = 7.0 Hz, 2H), 7.29 -7.22 (m, 2H), 7.21 -7.08 (m, 5H), 4.72 (d, J = 11.1 Hz, 1H), 4.61 (d, J = 11.1 Hz, 1H), 2.95 -2.78 (m, 2H), 2.17 -1.90 (m, 2H), 1.59 (s, 3H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.76 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 7.62 (dd, J = 5.4, 3.0 Hz, 2H), 7.30 (d, J = 7.1 Hz, 2H), 7.24 (t, J = 7.4 Hz, 2H), 7.16(t, J 126 = 7.2 Hz, 1H), 4.67

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.1 Hz, 2H), 7.31 (d, J = 7.0 Hz, 2H), 7.25 (t, J = 7.5 Hz, 2H), 7.22 -7.14 (m, 2H), 7.10 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.61 (d, J = 11.1 Hz, 1H), 2.93 -2.81 (m, 2H), 2.16 -1.96 (m, 2H), 1.59 (s, 3H).

8. 1

 1 Hz, 2H), 6H), 7.16 (t, J = 7.0 Hz, 1H), 4.70(d, J = 11.1 Hz, 1H), 4.58(d, J = 11.1 Hz, 1H), 2H), 2H), 1.59 (s, 3H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.86 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 7.34 (d, J = 7.1 Hz, 2H), 7.27 (t, J = 7.4 Hz, 2H), 7.18 (m, 1H), 6.79 -6.65 (m, 3H), 4.74 (d, J = 11.1 Hz, 1H), 4.63 (d, J = 11.1 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 2.94 -2.77 (m, 2H), 2.10 (m, 2H), 1.61 (s, 3H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.1 Hz, 2H), 7.32 (d, J = 7.1 Hz, 2H), 7.26(t, J = 7.3 Hz, 2H), 1H), 4.77 (d, J = 11.6 Hz, 1H), 4.50(d, J = 11.7 Hz,

  ): m/z 319.1065 [M-CH 3 ] + , calculated for [C 20 H 18 NO 3 -CH 3 ] + : 305.1052.

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.95 (dd, J = 5.5, 3.1 Hz, 2H), 7.82 (dd, J = 5.4, 3.1 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.30 -7.26 (m, 1H), 4.87 (d, J = 11.8 Hz, 1H), 4.64 (d, J = 11.8 Hz, 1H), 4.22 (d, J = 6.5 Hz, 1H), 1.42 -1.32 (m, 1H), 0.68 -0.57 (m, 3H), 0.54 -0.45 (m, 1H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.87 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 7.35 -7.19 (m, 9H), 5.08 (s, 2H), 4.80 (t, J = 9.9 Hz, 1H), 4.50(d, J = 11.7 Hz, 1H), 4.35 (t, J = 5.8 Hz, 1H), 2H), 4H).

  ): m/z 330.1740 [M-Boc] + , calculated for [C 27 H 30 N 2 O 3 -Boc] + : 330.1732.

  ): m/z 280.1580 [M-Boc] + , calculated for [C 23 H 28 N 2 O 3 -Boc] + : 280.1576.

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7. 5H), 6.75 (d, J = 3.3 Hz, 1H), 6.56 (d, J = 3.3 Hz, 1H), 4.69 (s, 2H), 3.74 (br, 2H), 3.52 -3.31 (m, 2H), 2.80 (t, J = 6.2 Hz, 2H), 2.57 -2.45 (m, 2H), 2.18 (m, 2H), 2.03 (m, 2H), 1.95 (m, 2H),1.47 (s, 9H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J = 8.3 Hz, 2H), 7.25 -7.13 (m, 10H), 7.09 (d, J = 7.2 Hz, 2H), 4.41 (s, 2H), 4.21 (s, 2H), 2.31 (s, 3H), 1.33 (s, 6H).

  ): m/z 404.1311 [M-CH 3 ] + , calculated for [C 25 H 25 NO 3 S-CH 3 ] + : 404.1320.

  ): m/z 384.1641 [M-CH3] + , calculated for [C 23 H 29 NO 3 S] + : 384.1633.

  ): m/z 328.0996 [M-CH 3 ] + , calculated for [C 19 H 21 NO 3 S-CH 3 ] + : 328.1007.

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.82 (d, J = 9.0 Hz, 2H), 7.38 -7.21 (m, 10H), 6.93 (d, J = 9.0 Hz, 2H), 4.53 (s, 2H), 4.35 (s, 2H), 3.83 (s, 3H), 1.46 (s, 6H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.74 (dd, J = 5.4, 3.1 Hz, 2H), 7.64 (dd, J = 5.5, 3.0 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.50 (sex, J = 2.7 Hz, 1H), 2.90 -2.76 (m, 2H), 2.42 -2.29 (m, 2H), 1.80 (d, J = 2.5 Hz, 3H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.4, 3.0 Hz, 2H), 7.57 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 6.67 -6.62 (sex, J = 2.6 Hz, 1H), 3.52 (d, J = 2.2 Hz, 2H), 1.83 (d, J = 2.6 Hz, 3H).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 6.78 (d, J = 6.2 Hz, 1H), 5.71 (dd, J = 7.5, 6.4 Hz, 1H),1.46 -1.36 (m, 1H), 0.80 (dd, J = 8.1, 2.4 Hz, 2H), 0.60 -0.56 (m, 2H).

13 C

 13 NMR (101 MHz, CDCl 3 ) δ

  ): m/z 255.0904 (M + ), calculated for C 15 H 13 NO 3 : 255.0895.

  ): m/z 313.1295 (M + ), calculated for C 18 H 19 NO 4 : 313.1314.

  ): m/z 372.1108 (M + ), calculated for C 22 H 16 N 2 O 4 : 372.1110.

  ): m/z 225.1152 (M + ), calculated for C 15 H 15 NO: 225.1154.

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 8.53 (d, J = 1.7 Hz, 1H), 8.02 (dd, J = 8.7, 2.0 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 3.2 Hz, 1H), 6.97 (qn, J = 2.5 Hz, 1H), 6.66 (d, J = 3.2 Hz, 1H), 1.98 (d, J = 2.5 Hz, 6H).

  ): m/z 228.0898 (M + ), calculated for C 13 H 12 N 2 O 2 : 228.0899. This compound was obtained following general procedure 7 at room temperature and was purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 10 min. Yield : 94 % (colorless oil).

  ): m/z 233.1205 (M + ), calculated for C 17 H 15 N: 233.1204.

  ): m/z 342.1947 (M + ), calculated for C 20 H 26 N 2 O 3 : 342.1943.

  ): m/z 214.1104 (M + ), calculated for C 13 H 14 N 2 O: 214.1106.

  ): m/z 327.1292 (M + ), calculated for C 19 H 21 NO 2 S: 327.1293.

  Signal multiplicities are depicted using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sex = sextuplet, sept = septuplet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, tt = triplet of triplet, dq = doublet of quartet, ddd = doublet of doublet of doublet, ddt = doublet of doublet of triplet, bs = broad singlet. High-resolution mass spectrometry by electron impact (EI) was performed on a JEOL JMCGCmate II mass spectrometer and fragment signals were given in mass per charge number (m/z). IUPAC names of compounds described in the experimental section were directly generated using ChemBioDraw.

1 :step 1 :step 1 :

 111 To a stirred solution of 4-pentyn-1-ol (0.84 g, 10 mmol) in DCM (40 mL) at 0 0 C were added triethylamine(1.52 g, 15 mmol) and then methanesulfonyl chloride(1.72 g, 15 mmol) was added dropwise at this temperature. After complete consumption of the starting material monitored by TLC(1 hour), the crude mixture was poured into water and DCM was added and the organic layer was washed with 2 N aq. HCl solution, brine, dried over Na 2 SO 4 and then concentrated under reduced pressure to afford the desired product as yellowish oil, which was used in the next step without further purification.step 2: To a stirred solution of the obtained pent-4-yn-1-yl methanesulfonate in CH 3 CN (40 mL) at room temperature was added TsNH 2 (2.05g, 12 mmol) and K 2 CO 3 (2.76 g, 20 mmol).The resulted mixture was heated at 70 ℃ until TLC showed complete consumption of the starting material (24 hours). Then, H 2 O and EtOAc were added and the reaction mixture was separated. The water phase was extracted with EtOAc for three times and the combined organic phase was dried over anhydrous MgSO 4 , filtered and then concentrated under reduced pressure. Flash column purification on silica gel afforded the desired 4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamide(1.7 g, 72 % yield).step 3: This reaction was carried out under inert atmosphere and flame-dried glassware was used. To a stirred solution of 4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamide (1.7 g, 7.2 mmol) in dry THF (28 mL) was added 2.5 M n-BuLi (6.4 mL) at -78 ℃. The mixture was stirred at -78 ℃ for 1 hour. Afterwards, TMSCl (2.0 g, 18 mmol) were added at -78 ℃, and then the mixture was warmed to room temperature for 1h (TLC indicated the complete consumption of the starting material). To the solution was added 3 M aq. HCl solution and then stirred for 6 hours, then the organic phase was separated, dried over anhydrous MgSO 4 and evaporated under reduced pressure. The residue was purified through flash chromatography to provide the desired 4-methyl-N-(5-(trimethylsilyl)pent-4-yn-1-yl)benzenesulfonamide (1.0 g, 45 % yield).General procedure 2: Synthesis of alkynyl bromideTo a stirred solution of 1-ethynylcyclohex-1-ene (1.06 g, 10 mmol) in 30 mL of acetone was added N-bromosuccinimide(1.96 g, 11 mmol) and AgNO 3 (170 mg, 1 mmol). The resulting reaction mixture was stirred untill complete consumption of starting material monitored by TLC and was filtered through a celite column. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with saturated K 2 CO 3 and extracted with ether (100 mL × 3). The combined organic phase was dried over anhydrous MgSO 4 , filtered and then concentrated under reduced pressure. Purification by flash column chromatography on silica gel with petroleum ether/ethyl acetate as the eluent provided 1-(bromoethynyl)cyclohex-1ene as colorless oil(1.76 g, 95 % yield).Generalprocedure 3: Synthesis of N-(cyclohex-1-en-1-ylethynyl)-4-methyl-N-(pent-4-yn-1yl)benzenesulfonamide 85 In a flame-dried schlenk tube, N-benzyltoluenesulfonamide (1.55 g, 5.0 mmol), K 2 CO 3 (1.38 g, 10.0 mmol), CuSO 4 . 5H 2 O (250 mg, 1.0 mmol), and 1,10-phenanthroline (360.4 mg, 2.0 mmol) was combined. Afterwards, the schlenk tube was vacuumed and refilled with nitrogen for 3 times and then the 1-(bromoethynyl)cyclohex-1-ene (1.11 g, 6.0 mmol) in 5 mL of toluene was added via a syringe. The resulting reaction mixture was heated in a pre-heated oil bath at 70 o C for 24 h until the complete consumption of the starting material. Then, the reaction mixture was cooled to room temperature and diluted with 20 mL of EtOAc and the resulting mixture was filtered through celite. The filtrate was concentrated and the residual was used in the next step without further purification. step 2: A schlenk tube containing K 2 CO 3 (345 mg, 2.5 mmol) was vacuumed and refilled pent-4-yn-1-yl)benzenesulfonamide obtained in last step in 25 mL of dry methanol was added. The resulting reaction mixture was stirred at room temperature for 4 hours until the complete consumption of the starting material indicated by TLC monitoring and then was concentrated under reduced pressure. The resulted residual was purified by flash column chromatography on silica gel using petroleum ether/EtOAc (containing 5 % triethylamine) as the eluent to provide the desired N-(cyclohex-1-en-1-ylethynyl)-4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamide. General procedure 4: Synthesis of 4-methyl-N-(3-methylbut-3-en-1-yn-1-yl)-N-(pent-4-yn-1yl)benzenesulfonamide 86 To a 500 mL round-bottom flask equipped with a stir-bar, CuCl 2 (135 mg, 1.0 mmol), 4-methyl-N-(5-(trimethylsilyl)pent-4-yn-1-yl)benzenesulfonamide (3.1 g, 10.0 mmol) and sodium carbonate (1.06 g, 10.0 mmol) were added. The reaction flask was purged with oxygen gas for 0.5 hour. A solution of pyridine (0.79 g, 10.0 mmol) in 25 mL dry toluene was added to the reaction flask via a syringe. Two large balloons filled with oxygen gas were connected to the reaction flask via needles. The flask was placed in a pre-heated oil-bath at 70 °C. A solution of 2-methylbut-1-en-3-yne (0.33 g, 5 mmol) in 25.0 ml dry toluene was added to the flask over 5 hours via a syringe pump. The resulted reaction mixture was allowed to stir at 70 °C for another 36 hours and then cooled to room temperature. Afterwards, EtOAc (50 mL) was added and the mixture was filtered using a celite column. The resulted solution was concentrated under reduced pressure and was used in the next step without further purification. step 2: A schlenk tube containing K 2 CO 3 (345 mg, 2.5 mmol) was vacuumed and refilled with nitrogen for 3 times and then 4-methyl-N-(3-methylbut-3-en-1-yn-1-yl)-N-(5-(trimethylsilyl)pent-4-yn-1-yl)benzenesulfonamide obtained in last step in 25 mL of dry methanol was added. The resulting reaction mixture was stirred at room temperature for 4 hours until the complete consumption of the starting material indicated by TLC monitoring and then was concentrated under reduced pressure. The resulted residual was purified by flash column chromatography on silica gel using petroleum ether/EtOAc (containing 5 % triethylamine) as the eluent to provide the desired N-4-methyl-N-(3-methylbut-3-en-1-yn-1yl)-N-(pent-4-yn-1-yl)benzenesulfonamide (44 % yield).General procedure 5: Synthesis of (E)-4-methyl-N-(pent-4-yn-1-yl)-N-(3-phenylpent-3-en-), Cs 2 CO 3 (2.60 g, 8.0 mmol), and copper(I) iodide (76 mg, 0.4 mmol). The tube was fitted with a rubber septum, evacuated under high vacuum and backfilled with nitrogen for 3 times. Dry and degassed DMF (4 mL) and N,N'-dimethylethylenediamine (60 µL, 0.6 mmol)

N

  ): m/z 260.0063[M-Ts] + , calculated for [C 20 H 18 BrNO 2 S-Ts] + : 260.0075.IR (CDCl 3 ): ν (cm -1 )3691, 3308, 3068, 2940, 2877, 2260, 2238, 1599, 1434, 1369, 1171 -N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1-(bromoethynyl)-3-methoxybenzene using general procedure 3.

  -N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 2-methylbut-1-en-3-yne using general procedure 4. Yield: 46 % (yellowish oil).

  and (E)-(4-bromobut-1-en-3-yn-1-yl)benzene using general procedure 3. Yield: 48 % (yellowish oil).

  and 1-(bromoethynyl)-4-fluorobenzene using general procedure 3.

  -N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and (Z)-(1,1-dibromopenta-1,3-dien-3-yl)benzene using general procedure 5. Yield: 62 % (yellowish oil).

  (bromoethynyl)-1,2,3-trimethoxybenzene using general procedure 3. Yield: 80 % (white solid).1 H NMR (400 MHz, CDCl 3 ) δ 7.82(d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.58 (s, 2H), 3.82

  ): m/z 427.1469 [M] + , calculated for [C 23 H 25 NO 5 S] + : 427.1453. IR (CDCl 3 ): ν (cm -1 ) 3691,

  and 1-(bromoethynyl)-2-chlorobenzene using general procedure 3.

  and 1-(bromoethynyl)-2-fluorobenzene using general procedure 3.

13 C

 13 NMR (100 MHz, CDCl 3 ) δ 162.55 (d, J = 250.5 Hz), 144.95, 134.42, 133.10 (d, J = 1.3 Hz), 129.96, 129.53 (d, J = 7.8 Hz), 127.84, 124.00 (d, J = 3.7 Hz), 115.48 (d, J = 20.8 Hz), 111.50 (d, J = 15.7 Hz), 86.95 (d, J = 3.0 Hz), 82.

  and 1-bromo-3-(bromoethynyl)benzene using general procedure 3.

  -N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1,3-dibromo-2-(bromoethynyl)-5-methylbenzene using general procedure 3. Yield: 78 % (white solid).1 H NMR (400 MHz, CDCl 3 ) δ 7.95(d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.33 (s, 2H), 3.59

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.84(d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.27 (dd, J = 5.2, 1.1 Hz, 1H), 7.18 (dd, J = 3.6, 1.2 Hz, 1H), 6.98 (dd, J = 5.2, 3.6 Hz, 1H), 3.53 (t, J = 7.0 Hz, 2H),

  )ethynyl)benzyl)benzenesulfonamide and 1-(bromoethynyl)cyclohex-1-ene using general procedure 3. Yield: 65 % (white solid).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.82(d, J = 8.3 Hz, 2H), 7.47 (dd, J = 7.6, 1.5 Hz, 1H), 7.42 (dd, J = 7.9, 1.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.30 (dd, J = 7.7, 1.5 Hz, 1H), 7.25 (dt, J = 7.6, 1.5 Hz, 1H), 5.87 (tt, J = 3.8, 1.8 Hz, 1H), 4.73 (s, 2H), 3.26 (s, 1H), 2.45 (s, 3H), 2.11 -1.99 (m, 2H),1.98 -1.95 (m, 2H), 1.62 -1.45 (m, 4H).

13 C

 13 NMR (100 MHz, CDCl 3 ) δ 144.

  ): m/z 327.1300 [M] + , calculated for [C 19 H 21 NO 2 S] + : 327.1293.

  (400 MHz, CDCl 3 ) δ 7.79(d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 3.42 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H), 2.29 (t, J = 7.1 Hz, 2H), 2.21 (td, J = 6.9, 2.7 Hz, 2H), 1.97 (t, J = 2.8 Hz, 1H), 1.85 (qn, J = 7.0 Hz, 2H),1.55 -1.47 (m, 2H), 1.41 -1.34 (m, 2H), 1.30 -1.20 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H).

  and 2-(bromoethynyl)-1,3-difluorobenzene using general procedure 3.

  ): m/z 373.0954 [M] + , calculated for [C 20 H 17 F 2 NO 2 S] + : 373.0948.

  -N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 2-(bromoethynyl)furan using general procedure 3. Yield: 45 % (yellowish oil).

  -N-(5-(trimethylsilyl)pent-4-yn-1yl)benzenesulfonamide and 1-((4-bromobut-3-yn-2-yl)oxy)heptane using general procedure 3.

  ): m/z 265.1149 [M] + , calculated for [C 14 H 19 NO 2 S] + : 265.1136.

  )benzenesulfonamide and 1-(bromoethynyl)cyclohex-1-ene using general procedure 3. Yield: 40 % (yellowish oil).

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.78(d, J = 8.3 Hz, 2H), 7.49 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.30 (td, J = 7.3, 1.9 Hz, 1H), 7.25 -7.15 (m, 2H), 5.81 (dq, J = 4.1, 2.0 Hz, 1H), 4.49 (s, 2H), 3.66 (d, J = 2.7 Hz, 2H), 2.45 (s, 3H), 2.19 (t, J = 2.7 Hz, 1H), 2.01 -1.97 (m, 2H),1.95 -1.87 (m, 2H), 1.57 -1.45 (m, 4H).

  ): m/z 341.1440[M] + , calculated for [C 20 H 23 NO 2 S] + : 341.1449. IR (CDCl 3 ): ν (cm-1 ) 3011, 2937, 2861, 2841, 2262, 2251, 1599, 1496, 1353, 1163, 10931-tosyl-1,2,3,4-tetrahydrobenzo[g]quinolineYield: 80 % (white solid); Reaction time: 18 h.1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 7. 1H), 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.46 (s, 1H), 7.42 (m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 2H), 2.49 (t, J = 6.5 Hz, 2H), 2.34 (s, 3H), 1.77 (qn, J = 6.4 Hz, 2H).

  ): m/z 427.1459 [M] + , calculated for [C 23 H 25 NO 5 S] + : 427.1453.

1 H

 1 NMR (400 MHz, CDCl 3 ) δ 7.73(d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 5.73 (d, J = 2.4 Hz, 1H), 5.64 (q, J = 2.1 Hz, 1H), 3.70 (ddd, J = 12.2, 7.2, 3.5 Hz, 1H), 3.63 (ddd, J = 12.2, 7.2, 3.5 Hz, 1H), 3.02 (m, 2H), 2.40 (s, 2H), 2.34 (t, J = 5.8 Hz, 2H), 1.84 -1.71 (m, 2H), 1.39 (qn, J = 7.0 Hz,

  ): m/z 265.1125 [M] + , calculated for [C 14 H 19 NO 2 S] + : 265.1136. IR (CDCl 3 ): ν (cm -1 ) 3691,

  -2,3,4,6,7,12-hexahydro-1H-benzo[e]naphtho[2,3-b]azepine

  It has been demonstrated that ligand is of vital importance in adapting catalytic reactivity of gold catalysts, therefore significantly affecting the route a specific transformation could undergo. Gold catalysts based on ligands such as

10 (a) Hashmi, A. S. K.; Weyrauch, J. P.; Rudolph, M.; Kurpejović, E. Angew. Chem. Int. Ed. 2004, 43, 6545.(b) Reeds, J. P.; Whitwood, A. C.; Healy, M. P.; Fairlamb, I. J. S. Chem. Commun. 2010, 46, 2046. (c) Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529. (d) Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org.

Lett. 2006, 8, 325.

3 COOH, H 3 PW 12 O 40

  While gold catalysis has led to the development of a range of novel transformations on the basis of unique reactivity of gold(I) complexes, gold-mediated enantioselective catalysis was constrained to certain cases. Furthermore, extensive and very careful optimization of reaction conditions is generally required, what can be attributed to the linear dicoordinated geometry of gold complexes. This structural arrangement imposed sufficiently long distance between ligand and reactive site, thus curbing the transfer of stereochemical information of chiral ligand to substrate. In general, the success reported to date in enantioselective gold catalysis involves two strategies, that is, the use of chiral ligands, especially axially chiral binaphthyl phosphines and/or the employment of chiral silver salts based on axially binaphthyl phosphonates. Several representative examples commonly involved are listed in Figure1-9. , H 2 SO 4 ) as co-catalysts. This allows the in situ generation of real catalytically active species.

	More recently, alternative catalytically active complexes were reported through the
	application	of	specific	ligands,	such	as	bistrifluoromethanesulfonimidate,
	hexafluoroantimonate, and benzotriazole to allow for the direct formation of air and moisture
	stable, storable and particularly easy-manipulating gold catalysts, excluding the use of silver
	salts or strong acids as co-catalysts. The relatively weakly coordinated ligands (e.g. nitriles,
	alcohol, arenes, etc.) need to be replaced by substrates via π-coordination in reaction media,

14

Figure

1

-9 Representative complexes employed in enantioselective gold catalysis

14

(a) Murai, M.; Uenishi, J. i.; Uemura, M. Org.

Lett. 2010, 12, 4788. (b)

Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J.

Am. Chem. Soc. 2005, 127, 18002. (c)

Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. J. Am.

Chem. Soc. 2007, 129, 14148. (d)

Alonso, I.; Trillo, B.; López, F.; Montserrat, S.; Ujaque, G.; Castedo, L.; Lledós, A.; Mascareñas, J. L. J. Am. Chem. Soc. 2009, 131, 13020. (e) Teller, H.; Flügge, S.; Goddard, R.; Fürstner, A. Angew. Chem. Int. Ed. 2010, 49, 1949. (f) Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496.

From an experimental point of view, these gold(I) complexes need to be activated by a prior abstraction of the halides, hydroxides, or methyl groups by using silver salts (AgOTf, AgSbF 6 , AgBF 4 , AgNTf 2 , AgPF 6 , AgClO 4 , AgOTs, AgO 2 CF 3 ), other inorganic salts(NaBAr 4 , KBAr 4 ) or strong Brønsted acids (HBF 4 , HOTf, HNTf 2 , CF thereafter provoking cationic gold(I) species participate in the catalytic cycle. Several representative gold(I) catalysts

15,16

which fall into this type are listed in Figure 1-10.

15 (a) Mézailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133. (b) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (c) Henrion, G.; Chavas, T. E. J.; Le Goff, X.; Gagosz, F. Angew. Chem. Int. Ed. 2013, 52, 6277. (d) Ochida, A.; Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006, 128, 16486. (e) Ricard, L.; Gagosz, F. Organometallics 2007, 26, 4704. 16 (a) Amijs, C. H. M.; López-Carrillo, V.; Raducan, M.; Pérez-Galán, P.; Ferrer, C.; Echavarren, A. M. J. Org. Chem. 2008, 73, 7721. (b) de Frémont, P.; Marion, N.; Nolan, S. P. J. Organomet. Chem. 2009, 694, 551. (c) de Fremont, P.; Stevens, E. D.; Fructos, M. R.; Mar Diaz-Requejo, M.; Perez, P. J.; Nolan, S. P. Chem. Commun. 2006, 2045.

provide intermediate IV (Scheme 1-7) whereas route

	Scheme 1-8 Cycloisomerization to furans from allenic ketones
	Afterwards, Gevorgyan and co-workers disclosed an efficient access to a variety of bromo-,
	iodo-, chloro-, silyl-, seleno-, aryl-, alkyl-, and thio-mutisubstituted furans through an
	interesting 1,2-group migration mechanism 27 (Scheme 1-9). Au(III) salts, which are more
	oxophilic, were shown to play a crucial important role in the regioselectivity to provide 3-
	substituted furans whereas the more carbophilic Au(I) alternatively furnished 2-substituted
	furans via a 1,2-hydride shift.
	Scheme 1-9 Au(III)-catalyzed 1,2-group migration to substituted furans
	Allenol derivatives are also suitable substrates and have found application in the realm of Scheme 1-10 Representative examples of Au-catalyzed cycloisomerizations of allenols
	homogeneous catalysis employing gold complexes. In contrast to allenones, allenols could
	take advantage of the axis chirality of the allenic moiety, in which high levels of axis-to-center A few enantioselective reactions have also been accomplished by several research groups.
	chirality transfer was very often observed. Moreover, the regioselectivity can be modulated
	by adjusting the length and the nature of substituents on the linker between the allenic and
	nucleophile moieties. For example, α-and β-hydroxyallenes underwent 5-and 6-endo
	cycloisomerization respectively to ①
	which gave rise to intermediate I (Scheme 1-7) via a 5-or 6-exo pathway was favored for γ-
	and δ-hydroxyallenes (Scheme 1-10) 28 .
	27 (a) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500. (b) Dudnik, A. S.; Sromek, A.
	W.; Rubina, M.; Kim, J. T.; Kel'i, A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440. (c) Xia, Y.; Dudnik, A. S.;
	Gevorgyan, V.; Li, Y. J. Am. Chem. Soc. 2008, 130, 6940. (d) Dudnik, A. S.; Xia, Y.; Li, Y.; Gevorgyan, V. J. Am. Chem.
	Soc. 2010, 132, 7645. 28 (a) Hoffmann-Röder, A.; Krause, N. Org. Lett. 2001, 3, 2537. (b) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
	(c) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128, 9066.

Scheme 1-11.

  considered when interpreting the chemical outcomes of the cyclizations. Several examples 29 which fall into this classification are present in

	Hammond and Xu et al. reported a convenient synthesis of α-CN and/or α-CF 3 nitrogen
	containing heterocycles using tandem nucleophilic additions in which the in situ formed
	imines or enamines are trapped by a second nucleophile, e.g. TMSCN and/or TMSCF 3 (Scheme
	1-11, eq. 1). The starting materials underwent either exo-or endo-cyclizations to give, in
	accordance with Baldwin's rule, 5-and/or 6-membered rings, depending on the nature of the
	substrates. Hashmi and co-workers discovered the preparation of polycyclic indole scaffolds
	through a gold catalyzed nucleophilic addition/cyclization sequence (Scheme 1-11, eq. 2).
	Scheme 1-11 Gold catalyzed transformations of N-nuleophiles
	Gagosz and co-workers disclosed an intriguing and unprecedented transformation of 2H-
	azirines, which can be regarded as the synthetic equivalent of alkenyl nitrenes under gold
	catalysis conditions, thus allowing the formation of polysubstituted pyridines. In the
	29 (a) Han, J.; Xu, B.; Hammond, G. B. Org. Lett. 2011, 13, 3450. (b) Wang, T.; Shi, S.; Pflästerer, D.; Rettenmeier,
	E.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Chem. Eur. J. 2014, 20, 292. (c) Prechter, A.; Henrion, G.; Faudot
	dit Bel, P.; Gagosz, F. Angew. Chem. Int. Ed. 2014, 53, 4959.

5.6.3. Sufur nucleophiles

	Scheme 1-13 Enantioselective hydroaminations of allenes
	Gold-catalyzed enantioselective hydroazidation and hydroamination were developed by the
	same group 31 in an intermolecular manner employing acyclic diaminocarbene (ADC) gold(I)
	complexes, giving rise to stereodivergent allylic amines precursors (Scheme 1-14, eq. 1 and eq.
	2).
	Scheme 1-14 Gold(I)-mediated intermolecular hydroaminations
	Starting materials with mercapto groups cannot be used in palladium-catalyzed reactions,
	which can be attributed to catalyst poisoning due to the strong coordinating properties of
	sulfur. Conversely, gold complexes saw some applications in this area. For example,
	Nakamura and co-workers 32 provided a convenient and facile access to 2,3-disubstituted
	Scheme 1-12 Au(I)-catalyzed transformations of allenes containing vicinal nucleophiles benzothiophenes via a carbothiolation process, which occurs through the attack of sulfur
	Toste et al. reported the enantioselective hydroamination of allenes for the synthesis of
	pyrazolidines, isoxazolidines and tetrahydrooxazines using gold catalysts possessing a chiral 31 (a) LaLonde, R. L.; Wang, Z. J.; Mba, M.; Lackner, A. D.; Toste, F. D. Angew. Chem. Int. Ed. 2010, 49, 598. (b) biarylphosphine ligand. 5-or 6-exo Products were exclusively formed (Scheme 1-13). Khrakovsky, D. A.; Tao, C.; Johnson, M. W.; Thornbury, R. T.; Shevick, S. L.; Toste, F. D. Angew. Chem. Int. Ed.
	2016, ASAP. 32 (a) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem. Int. Ed. 2006, 45, 4473. (b) Nakamura, I.; Sato, T.;
	Yamamoto, Y. Angew. Chem. Int. Ed. 2006, 45, 4473.

dig or 6-endo-dig pathway to generate intermediates II and/or III respectively. Then, intermediate II could undergo two distinct skeletal rearrangements, namely, single cleavage and double cleavage. The single cleavage skeletal rearrangement takes place via a ring opening of the three-membered ring in II with concomitant

	Scheme 1-17 General mechanism for cycloisomerization of 1,6-Enynes 34
	The transformation of 1,6-enynes can alternatively takes place via a 6-endo-dig pathway,
	leading to the three-
	1,3-
	migration of the terminal carbon (CR 3 R 4 ) of the alkene to the carbon attached to R 1 of the
	alkyne. This results in the formation of intermediate IV. Compound V arises from a 1,3-
	migration of the internal carbon (CR 2 ) of the double bond to the carbon (CR 1 ) attached to R 1
	of the alkyne via an endo-single cleavage of intermediate II. Under double cleavage
	condition, the terminal carbon(CR 3 R 4 ) of the alkene would insert into the alkyne carbons
	with simutaneous cleavage of the double bond and triple bond, allowing the formation of
	intermediate VI, which finally gives rise to VII after protodeauration.

membered ring gold carbene III which would gave VIII after direct protodeauration. Alternatively, III could isomerize into intermediate IX via a ring expansion en

	Bicylco[4.1.0]heptane derivatives were enantiomerically produced 36 by a cycloisomerization cationic gold(I) intermediate and the hydrogen atom formed a σ-complex preceding the final
	of 1,6-enynes containing an O-linker via 6-endo-dig pathway in the presence of a chiral productive hydride transfer (Scheme 1-19, eq 3).
	dinuclear gold(I) catalyst (Scheme 1-18, eq. 2).
	Scheme 1-18 Examples of cycloisomerizations of 1,6-enynes
	Formally, 1,5-enynes prefer to undergo endo-type cycloisomerization which can be attributed Scheme 1-19 Examples of cycloisomerizations of 1,5-enynes
	to the favorable formation of bicyclo[3.1.0]hexane scaffolds. The exo-type cyclization indeed leads to a more strained intermediate, therefore less stable and favorable. The In the presence of an external nucleophile and/or in the case of substrates containing another
	cycloisomerization of 1,5-enynes catalyzed by gold catalysts proceed through an exclusive 5-potential nucleophile, the formed gold(I) intermediate in the cycloisomerization step could be
	endo-dig pathway to give rise to bicycle[3.1.0]hexenes bearing a cyclopropane motif with a intercepted in a cascade process, therefore leading to a further increase in molecular
	high stereoselectivity (Scheme 1-19, eq. 1). 37 Highly functionalized cyclopentenes were complexity. Propargyl vinyl ethers react with gold(I) complexes to provide 2-hydroxy-3,6-
	stereoselectively constructed from 3-silyloxy-1,5-enynes following a mechanism involving dihydropyran derivatives stereoselectively in the presence of H 2 O, while precursors with an
	route to X following a formal deauration. Intermediate XI can also be formed through a ring-opening isomerization, which would give rise to product IV after direct deauration. appropriate pendant alcohol allowed for the stereocontrolled construction of bicyclic tandem 6-endo cycloisomerization/pinacol rearrangement of the in situ formed gold(I) carbocationic species. In this case, counterions played a crucial role with SbF 6 spiroketal frameworks (Scheme 1-20, eq. 1 and eq. 2). 40 Analogously, a tandem -displaying -counterion lead to complete loss of cycloisomerization/hydroamination transformation of 1,6-enynes was described for the excellent catalytic activity whereas catalysts with a BF 4 synthesis of carbo-and heterocyclic derivatives bearing amino functional groups under mild reactivity 38 (Scheme 1-19, eq. 2). 1,5-Enynes bearing large and flexible rings at the propargylic position underwent consecutive cycloisomerization/C sp3 -H bond insertion instead of 1,2-alkyl conditions in good to excellent yields (Scheme 1-20, eq 3). 41
	A few representative examples involving gold-catalyzed cycloisomerization of 1, n-enynes are shift 38 , leading to the formation of tetracyclic products. 39 When the mechanism of C-H bond
	shown in the following paragraphs. insertion process was studied, inverse primary kinetic isotope effects were observed. This is
	Echavarren and co-workers reported that 1,6-enynes containing a terminal alkynes different from that of C-H bond insertion of common metal-carbenoid or hydride transfer
	underwent exclusively 5-exo-dig cyclizations followed by single cleavage to give rise to 1,3-process toward carbocation species, thus leading to the envision that it is more likely that
	dienes in the presence of an in situ generated gold(I) catalyst 35 (Scheme 1-18, eq. 1).
	36 Chao, C.-M.; Beltrami, D.; Toullec, P. Y.; Michelet, V. Chem. Commun. 2009, 6988. 37 Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858. 38 Kirsch, S. F.; Binder, J. T.; Crone, B.; Duschek, A.; Haug, T. T.; Liébert, C.; Menz, H. Angew. Chem. Int. Ed. 2007, 34 Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028. 35 Nieto-Oberhuber, C.; Muñoz, M. P.; Buñuel, E.; Nevado, C.; Cárdenas, D. J.; Echavarren, A. M. Angew. Chem. Int. Ed. 2004, 43, 2402. 46, 2310. 39 Horino, Y.; Yamamoto, T.; Ueda, K.; Kuroda, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2809. 40 Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132. 41 Leseurre, L.; Toullec, P. Y.; Genêt, J.-P.; Michelet, V. Org. Lett. 2007, 9, 4049.

Scheme 1-22 Tandem cycloisomerization and hydroarylation 5.8. Gold-catalyzed rearrangement of propargylic carboxylates

	1,6-Enynes react with electron rich aromatic and/or heteoaromatic rings to afford
	stereocontrolled carbo-and heterocycles under homogeneous gold catalysis conditions
	following a Friedel-Crafts-type addition and cycloisomerization sequence. 43
	Under homogeneous gold catalysis conditions, propargylic carboxylates could undergo 1,2-or
	1,3-acyloxy migrations via 5-exo-dig (path a) and 6-endo-dig (path b) pathwayS, providing
	access to α-acyloxy-α,β-unsaturated carbenes I and allene-gold intermediate II respectively
	(Scheme 1

-23). Scheme 1-23

	For instance, functionalized 2,5-dihydrofurans were accessed from propargylic benzoates in
	the presence of Ph 3 PAuNTf 2 via a tandem benzoate migration and nucleophilic addition of
	hydroxyl group onto an in situ formed allene-gold(I) complexe. Notably, the stereochemical
	information was completely retained after the two-step isomerization process (Scheme 1-24,
	eq. 1). 44 An intermolecular formation of C(sp 2 )-C(sp 3 ) bonds was achieved from in situ
	43 Toullec, P. Y.; Genin, E.; Leseurre, L.; Genêt, J.-P.; Michelet, V. Angew. Chem. Int. Ed. 2006, 45, 7427. 44 Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8, 1957.

-25). Scheme 1-25 5.9. Oxidation

	moiety. The transformation proceed via a 1,2-migration of carboxylate/cyclopropanation
	cascade (Scheme 1Mechanistically, gold-mediated oxidations are initiated by the coordination of alkynes to
	cationic gold complexes (i.g.,I). This was followed by the attack of the O-nuleophiles
	containing a potential leaving group en route to formation of intermediate II. With the
	assistance of back-bond-donation of the gold center, II formally evolved into gold(I) carbenoid
	III with the concomitant exclusion of the leaving group (i.g.,
	1,4-Enynes bearing a propargyl acetate undergo a gold-mediated rearrangement to give rise
	to allene derivatives. A subsequent electrophilic addition of the pendant alkene moiety allows
	the synthesis of 5-en-2-yn-1-yl acetates which can be further converted into 2-cycloalken-1-
	ones. 47 Enantioselective construction of medium rings 48 was accomplished in the presence of
	chiral binuclear gold(I) complexes from propargylic carboxylates tethered with an alkene
	45 Yu, Y.; Yang, W.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2013, 52, 7586. 46 Teng, T.-M.; Liu, R.-S. J. Am. Chem. Soc. 2010, 132, 9298. 47 Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. 48 Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056.

LG). Subsequently, various transformations can operate to generate diverse products depending on the nature of the internal and/or external reacting partners and the alkyne precursors. This leads to the generation of a key intermediate IV, which gives rise to a variety of products with the regeneration of active gold catalyst (Scheme 1-26).

	Scheme 1-27 Au(I)-catalyzed oxidations via in situ α-oxo gold(I) carbenoids
	Gold-catalyzed oxidations have been implemented by use of various potential oxidants,
	including sulfoxides, pyridine N-oxides, nitrones, nitroso-and nitrobenzenes and even
	epoxides. Oxidations involving the use of pyridine N-oxides have been largely studied and
	illustrated by several research groups, e.g., Zhang, Gagosz, Toste, Hashimi, Liu, Davis and Li.
	Herein several examples which fall into this class of gold-catalyzed oxidations are listed.

2. Hydride donors involving amines In

58 (a) Pastine, S. J.; McQuaid, K. M.; Sames, D. J. Am.

Chem. Soc. 2005, 127, 12180. (b)

McQuaid, K. M.; Long, J. Z.; Sames, D. Org.

Lett. 2009, 11, 2972. 59

Mori, K.; Kawasaki, T.; Sueoka, S.; Akiyama, T. Org.

Lett. 2010Lett. , 12, 1732

. Scheme 2-10 Influence of ortho substituent on reaction rate, catalyst loading and yield In 2009, sames et al. reported a highly reactive catalytic system consisting of boron trifluoride etherate and ethylene glycol, which allowed rapid [1,5]-hydride transfer/cyclization with α, βunsaturated ketones serving as the hydride acceptor. The authors related this success to the in situ generated strongly activating alkenyl-oxocarbenium intermediates. In the absence of ethylene glycol, prolonged reaction time was required (Scheme 2-11). 60 Scheme 2-11 Boron trifluoride etherate/ethylene glycol co-catalytic system 3.2009, Seidel et al. documented the synthesis of tetrahydroquinolines by a tandem [1,5]hydride shift/cyclization cascade promoted by Lewis acid, i.e. gadolinium(III) triflate. In their studies, C-H bond α to pyrrolidine serves as the hydride donor with alkylidenemalonate being the hydride acceptor (Scheme 2-12, eq. 1). Yuan and co-workers reported the stereoselective synthesis of spirooxindole tetrahydroquinolines following a tandem hydride shift/ring closure sequence with FeCl 3 serving as the catalyst (Scheme 2-12, eq. 2). 61 60 McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131, 402. 61 (a) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 11, 129. (b) Han, Y.-Y.; Han, W.-Y.; Hou, X.; Zhang, X.-M.; Yuan, W.-C. Org.

Lett. 2012, 14, 4054.

  polymerization in the presence of gold catalyst as shown by the presence of broad multiple peaks as shown NMR spetra. It is noteworthy that in this case 1,3-diene, derived from allenamide isomerization was not observed.

	Scheme 2-21 Initial investigation of the synthesis of allenamide
	Scheme 2-20 Original idea in this project
	Ynamide bearing a terminal alkyne 2.1 was chosen as the model substrate to initiate our
	investigation (Scheme 2-21). Treatment of ynamide 2.1 with XPhosAu(NCCH 3 )SbF 6 in
	deuterated chloroform (CDCl 3 ) at 60 ℃ for 15 min provided α, β-unsaturated amide 2.3 as the
	major product along with only traces of allenamide 2.2. No [4+2] cycloaddition product was
	detected. CDCl 3 was used in order to monitor the reaction course and for being able to

Scheme 2-19 Dr. Benoit Bolte's preliminary attempts for access to allenamides On the basis of these observations, we envisioned a gold-mediated cascade hydride shift/tautomerization/[4+2] cycloaddition processes with an intension to take advantage of the in situ generated allenamides to provide quinoline derivatives (Scheme 2-20).

observe NMR spectroscopy of the formation of reaction intermediate. Surprisingly, benzaldehyde, the side product of

[1,5]

-H transfer procedure (Scheme 2-19, path a) was observed in notable NMR yield. We surmised that the in situ generated allenamide underwent a rapid

Table 2

 2

.2 Screening of gold catalysts Figure 2-3 Tested ligands in Table 2.2

Table 2 .4

 2 Examination of substituents at proparylic position a,b

Table 2 .

 2

7 Synthesis of allenamide equivalents a,b

  means that only one metal center is involved in the mechanistic scenario, as shown in a number of reported catalytic cycles. This mono activation of alkynes by a gold center is quite common in gold catalysis and other mechanistic possibilities involving several metal centers have been long-standing ignored. However, recent contributions by several research groups revealed a novel reactivity mode in which two gold centers work with the same substrate molecule, one gold complex being σ-coordinated to a terminal alkynyl group and the other gold center being π-coordinated to a different triple bond in the substrate. This rencent advance in homogeneous gold catalysis is the topic of this chapter. By analogy with vast majority of discoveries, dual gold catalysis has standed as a curiosity of laboratory before being supported by calculations and developed in several new methodologies.

Fundamental principles as well as research results from our group in this field will be presented in the following sections.

  It wasfound that these diaurated species smoothly catalyzed the intermolecular alkene-alkyne [2+2] cycloadditions to give cyclobutene in higher yield. The transformation was found to be more selective compared to earlier results reported by Echavarren 71 . Although the digold acetylide

69 Sun, S.; Kroll, J.;

Luo, Y.; Zhang, L. Synlett 2012, 2012, 54. 70

(a) Grirrane, A.; Garcia, H.; Corma, A.; Álvarez, E. ACS Catalysis 2011, 1, 1647. (b) Grirrane, A.; Garcia, H.; Corma, A.; Álvarez, E. Chem.

Eur. J. 2013, 19, 12239. 71

López-Carrillo, V.; Echavarren, A. M. J. Am.

Chem. Soc. 2010, 132, 9292.

Table 3 .6

 3 Substrate scope examination II a

  ): m/z 265.1471 (M + ), calculated for C 18 H 19 NO: 265.1467.

	Methyl 1-(2-cyclohexylidenevinyl)-1H-indole-3-carboxylate
	This compound was obtained following general procedure 7 at room temperature and was
	purified using column chromatography on water-deactivated neutral Al 2 O 3 . Reaction time: 10
	min. Yield : 96 % (colorless oil).
	1 H NMR (400 MHz, CDCl 3 ) δ 8.20 (ddd, J = 6.1, 3.2, 0.6 Hz, 1H), 7.89 (s, 1H), 7.58 (dd, J = 6.2,
	3.1, 1H), 7.33 -7.27 (m, 2H), 6.96 -6.93 (qn, J = 1.8 Hz,1H), 3.93 (s, 3H), 2.42 -2.26 (m, 4H),
	1.80 -1.68 (m, 4H), 1.67 -1.59 (m, 2H).

13

C NMR (101 MHz, CDCl 3 ) δ 190.

  ): m/z 274.1683 (M + ), calculated for C 16 H 22 N 2 O 2 : 274.1681.

	Methyl 1,1-dimethyl-1H-pyrrolo[1,2-a]indole-9-carboxylate
	This compound was obtained following general procedure 7 at 80 ℃ and was purified using
	column chromatography on silica gel. Reaction time: 12 h. Yield : 88 % (colorless oil).
	1 H NMR (400 MHz, CDCl 3 ) δ 8.12 -8.09 (m, 1H), 7.31 (ddd, J = 4.8, 2.8, 0.6 Hz, 1H), 7.18 -
	7.15 (m, 2H), 7.01 (d, J = 4.1 Hz, 1H), 5.77 (d, J = 4.1 Hz, 1H), 3.87 (s, 3H), 1.53 (s, 6H).

methyl-3-(3-methylbuta-1,2-dienyl)-1H-benzo[d]imidazol-2(3H)-one

	. HRMS
	(EI): m/z 468.2076 (M + ), calculated for C 26 H 32 N 2 O 4 S: 468.2083.
	1-This compound was obtained following general procedure 7 (substrate concentration 0.1
	M)at room temperature and was purified using column chromatography on water-
	deactivated neutral Al 2 O 3 . Reaction time: 20 h. Yield : 82 % (yellowish oil).
	1 H NMR (400 MHz, Acetone-d 6 ) δ 7.18 (dt, J = 7.8, 1.1 Hz, 1H), 6.99 -6.89 (m, 3H), 6.85 (p, J =
	2.7 Hz, 1H), 3.23 (s, 3H), 1.78 (d, J = 2.7 Hz, 6H).

  ): m/z 367.1254 [M] + , calculated for [C 21 H 21 NO 3 S] + : 367.1242.

IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 367.1251 [M] + , calculated for [C 21 H 21 NO 3 S] + : 367.1242.

IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 395.1182 [M] + , calculated for [C 22 H 21 NO 4 S] + : 395.1191.

IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 363.1300 [M] + , calculated for [C 22 H 21 NO 2 S] + : 363.1293.

	IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 377.1436 [M] + , calculated for [C 23 H 23 NO 2 S] + : 377.1449.

	IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 415.0244 [M] + , calculated for [C 20 H 18 BrNO 2 S] + : 415.0242.

IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 415.0259 [M] + , calculated for [C 20 H 18 BrNO 2 S] + : 415.0242.

IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 506.9508 [M] + , calculated for [C 21 H 19 Br 2 NO 2 S] + : 506.9503.

	IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 343.0713 [M] + , calculated for [C 18 H 17 NO 2 S 2 ] + : 343.0701.

IR (CDCl 3 ): ν (cm -1 ) 3691,

sp 2 carbon missed probably because of peaks overlap at ppm 127.88) HRMS

  . (1

(EI): m/z 389.1436 [M] + , calculated for [C 24 H 23 NO 2 S] + : 389.1449. IR (CDCl 3 ): ν (cm -1 ) 3691,

  NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.01 (dq, J = 4.0, 1.8 Hz, 1H), 3.53 -3.46 (m, 2H), 2.55 -2.48 (m, 2H), 2.45 (s, 3H), 2.10 -2.05 (m, 4H), 1.97 (t, J = 2.7 Hz, 1H), 1.65 -1.52 (m, 4H).

1 H

13 C NMR (100 MHz, CDCl 3 ) δ 144.

  ): m/z 397.2089[M] + , calculated for [C 24 H 31 NO 2 S] + : 397.2075.

IR (CDCl 3 ): ν (cm -1 ) 3691,

  ): m/z 357.1771 [M] + , calculated for [C 21 H 27 NO 2 S] + : 357.1762.

IR (CDCl 3 ): ν (cm -1 ) 3691,

  CDCl 3 ) δ 7.50(d, J = 8.3 Hz, 2H), 7.49 (s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.70 (s, 1H), 3.82 -3.69 (m, 2H), 2.77 (br, 2H), 2.68 (br, 2H), 2.38 (s, 3H), 2.35 (t, J = 6.8 Hz, 2H), 1.78 (qn, J = 3.2 Hz, 4H),1.64 -1.52 (m, 2H).

	1-tosyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]quinoline
	Yield: 82 % (yellowish oil); Reaction time: 10 h.

1 H NMR (400 MHz,

2 carbon missed probably because peaks overlap.) HRMS (EI

  ): m/z 377.1445 [M] + , calculated for [C 23 H 23 NO 2 S] + : 377.1449. IR (CDCl 3 ): ν (cm -1 ) 3691,

.

(1 sp

  NMR (400 MHz, CDCl 3 ) δ 8.22 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.69(d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.8, 2.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 7.14(d, J = 8.4 Hz, 2H), (m, 2H), 2.57 -2.46 (t, J = 6.4 Hz, 2H), 2.35 (s, 3H), 1.77 (qn, J = 6.4 Hz, 2H).

1 H 13 C NMR (100 MHz, CDCl 3 ) δ 143.

  , calculated for [C 20 H 18 BrNO 2 S] + : 415.0242. NMR (400 MHz, CDCl 3 ) δ 8.13 (s, 1H), 7.63 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.1

	IR (CDCl 3 ): ν (cm -1 ) 3691, 3308, 2959, 2873, 2255, 1590, 1494, 1353, 1165, 1092, 1063
	6,7,8-trimethoxy-1-tosyl-1,2,3,4-tetrahydrobenzo[g]quinoline
	Yield: 78 % (white solid); Reaction time: 4 h.
	Hz, 2H), 6.96 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 3.95 (s, 3H), 3.88 -3.82 (m, 2H), 2.50 -2.43 (m,
	2H), 2.35 (s, 3H), 1.72 (qn, J = 6.4 Hz, 2H).

. (1 sp 2 carbon missed probably because peaks overlap) HRMS (EI): m/z 415.0231 [M] + 1 H

  ): m/z 403.2176[M] + , calculated for [C 23 H 33 NO 3 S] + : 403.2181. NMR (400 MHz, CDCl 3 ) δ 7.40 (s, 1H), 6.83 (s, 1H), 3.84 -3.71 (m, 2H), 2.88 (s, 3H), 2.78 (t, J = 6.8 Hz, 2H), 2.74 (br, 2H), 2.69 (br, 2H), 2.02 -1.92 (m, 2H), 1.77 (qn, J = 3.4 Hz, 3H).

IR (CDCl 3 ): ν (cm

-1 ) 3691, 3392, 2931, 2859, 2258, 1706, 1600, 1409, 1334, 1162

, 1079 1-(methylsulfonyl)-1,2,3,4,6,7,8,9-octahydrobenzo[g]quinoline Yield: 83 % (white solid); Reaction time: 12 h.

1 H

Ito, Y.; Sawamura, M.; Hayashi, T. J. Am.Chem. Soc. 1986, 108, 6405.

(a) Fukuda, Y.; Utimoto, K. J.Org. Chem. 1991,

56, 3729. (b) Fukuda, Y.; Utimoto, K. Synthesis, 1991, 1991, 975. (c) Fukuda, Y.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 2013. 5 Teles, J. H.; Brode, S.; Chabanas, M. Angew.Chem. Int. Ed. 1998, 37, 1415. 6 Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew.Chem. Int. Ed. 2002, 41, 4563.

Simonneau, A. "Gold-Catalyzed Cycloisomerization Reactions Through Activation of Alkynes", Springer Thesis, 2014. DOI: 10.1007/978-3-319-06707-0. And references cited therein.

(a) Pearson, R. G. J. Am.Chem. Soc. 1963, 85, 3533. (b) Pearson, R. G. J.Chem. Educ. 1968, 45, 581. (c) Pearson, R. G. J.Chem. Educ. 1968, 45, 643.

(a) Pyykko, P.; Desclaux, J. P. Acc. Chem.Res. 1979, 12, 276. (b) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (c) Pyykkö, P. Angew.Chem. Int. Ed. 2002, 41, 3573. (d) Pyykkö, P. Angew. Chem. Int. Ed. 2004, 43, 4412.

H NMR (400 MHz, CDCl 3 ) δ 7.84 (dd, J = 5.4, 3.1 Hz,

2H), 7.72 (dd, J = 5.5, 3.1 Hz, 2H), 7.46(d, J =

H NMR (400 MHz, CDCl 3 ) δ 7.83 (dd, J = 5.5, 3.1 Hz,

2H), 7.70 (dd, J = 5.5, 3.1 Hz, 2H), 7.60(d, J =

H NMR (400 MHz, CDCl 3 ) δ 7.93 (dd, J = 5.5, 3.1 Hz,

2H), 7.81 (dd, J = 5.5, 3.1 Hz, 2H), 2H), 2H), 1H), 4.67 (s, 2H), 4.47 (s, 2H).

N-((4-bromophenyl)ethynyl)-4-methyl-N-(pent-4-yn-1-yl)benzenesulfonamide

Abbreviations

Units

Yield: 88 % (colorless oil); Reaction time: 10 h.

1 H NMR (400 MHz, CDCl 3 ) δ 7.62 (s, 1H), 7.47 (d,J = 8.3 Hz,2H),7.18 (d,J = 8.2 Hz,2H),6.88 (s,2H),2H), 2.38 (t, J = 6.6 Hz, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 1.59 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 143.51, 136.92, 136.75, 136.22, 129.61, 128.91, 127.71, 127.19, 126.00, 125.59, 46.63, 26.24, 21.66, 21.64, 21.41. 3691,3030,2954,2927,2870,2259,1599,1505,1343,1165,1093 Methyl 1-tosyl-1,2,3,4-tetrahydrobenzo[g]quinoline-7-carboxylate Yield: 78 % (white solid); Reaction time: 18 h.

HRMS (EI

1 H NMR (400 MHz, CDCl 3 ) δ 8.44 (s, 1H), 8.27 (s, 1H), 7.99 (dd, J = 8.6, 1.7 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.49 (d,J = 8.3 Hz,2H),7.16 (d,J = 8.3 Hz,2H),3.96 (s,3H),2H), 2.62 -2.52 (m, 2H), 2.35 (s, 3H), 1.80 (qn, J = 6.3 Hz, 2H).

13 C NMR (100 MHz, CDCl 3 ) δ 167. 36, 143.91, 137.21, 136.53, 134.73, 131.54, 130.09, 129.83, 129.77, 128.46, 128.19, 127.14, 127.11, 125.13, 121.75, 52.32, 46.97, 27.55, 22.56, 21.64. 3691,3308,3032,2954,2256,1716,1635,1599,1464,1354,1231,1163,1092 6-phenyl-1-tosyl-1,2,3,4-tetrahydroquinoline Yield: 45 % (white solid); Reaction time: 60 h.

HRMS (EI

Abstract :

Gold catalysts, possessing unique catalytic reactivity, intrigued a large number of novel approaches to target molecules which cannot be accessed by other methodology. Ynamide, which belongs to a subclass of heterosubstituted alkynes, represents a versatile building block with balanced reactivity and stability and found a series of applications in useful transformations, such as additions, cycloadditions and cycloisomerizations. As part of our ongoing interest in gold catalysis and ynamide chemistry, in this manuscript, two works involving ynamide in the presence of gold catalyst was presented:

(1). Gold(I)-Catalyzed Rearrangement of Propargyl Ethers of ynamides: A Practical Method for the synthesis of Substituted Allenamides (2). Dual gold catalysis: a unique approach to derived-tetrahydroquinolines by a formal [4+2] pathway