Coralie Gelis

Guillaume Levitre

Dr Jérémy Merad

Pascal Retailleau

Dr Luc Neuville

Géraldine Masson
email: geraldine.masson@cnrs.fr

+ G Levitre

Dr + P Retailleau

Highly Diastereo-and Enantioselective Synthesis of Cyclohepta[ b ]indoles by Chiral-Phosphoric-Acid-Catalyzed (4+3) Cycloaddition

come

Highly Diastereo-and Enantioselective Synthesis of Cyclohepta[b]indoles via Chiral Phosphoric Acid-Catalyzed (4+3)-Cycloaddition

Coralie Gelis, + Guillaume Levitre, + Jérémy Merad, + Pascal Retailleau, Luc Neuville and Géraldine Masson* Abstract: A highly enantio-and diastereoselective formal (4+3)cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols using a chiral phosphoric acid catalyst is reported. The approach described herein provides efficient access to 6-aminotetrahydrocyclohepta [b]indoles in good yields with excellent levels of enantioselectivity (>98:2 dr and up to 98% ee) and mostly complete diastereoselectivity. Mild reaction conditions, easy scale-up, and versatile derivatization highlight the practicality of this methodology. The mechanism study suggests that cycloaddition occurs in a stepwise fashion, after formation of an ion pair between the chiral catalytic phosphate and the intermediate carbocation.

Cyclohepta [b]indole unit is present in a large number of natural products, and pharmaceutical drugs. [1,2] Examples include exotines A and B isolated from Murraya exotica, [2a] actinophyllic acid from the leaves of Alstonia actinophylla, [2b] ervitsine from Pandacea boiteau, [2c] and a synthetic sirtuin 1 inhibitor (Figure 1). [2d,e] Although their prominence in natural and non-natural bioactive molecules has stimulated considerable synthetic efforts in this area, [1,2] the construction of cyclohepta [b]indoles in a stereodefined way remains challenging [3] and very few methods account for the asymmetric formation of such molecules. [START_REF] Gritsch | Enantioselective synthesis of cyclohepta[END_REF] . Multi-step syntheses have been reported by the groups of Gaich [4a] and Zheng and You [4b] in which the cyclohepta [b]indole moiety was delivered by a diastereoselective cyclization of enantioenriched preformed precursor. In 2011, Enders et al. reported the first enantioselective synthesis of the corresponding seven-membered ring based on two consecutive Friedel-Crafts reactions catalyzed by a chiral thioamide and Au I sequentially. [4c] Even though the enantioselectivity was excellent (up to 99% ee), this elegant approach is mainly limited to the formation of mono-substituted benzocyclohepta [b]indoles. Two years later, Hong et al. described an enantioselective organocatalytic one pot, two-step sequential process to synthesize trisubstituted cyclohepta [b]indoles with excellent enantioselectivity, albeit moderate diastereoselectivity. [4d] In this context, the development of a straightforward procedure for the synthesis of enantiopure cyclohepta [b]indoles is highly desirable. Among the practicable strategies, [1,[3][START_REF] Gritsch | Enantioselective synthesis of cyclohepta[END_REF][5][6][7] (4+3)-cycloadditions [START_REF] Mascarenas | Comprehensive Organic Synthesis[END_REF] appear as the most efficient, direct, and economical approach. Surprisingly, only one asymmetric version has been disclosed by Sun et al. in which Rh-catalyzed dearomative (4+3)-cycloaddition of vinylindoles led to cyclohepta [b]indolines with high ee. [9] However, the formation of more complex and easily post-functionalizable scaffolds would be particularly useful considering the structural diversity of biologically active cyclohepta [b]indoles. In this way, we wish to report the first highly diastereo-and enantioselective preparation of polysubstituted cyclohepta [b]indoles based on an organocatalyzed (4+3)-cycloaddition process. As part of a program directed toward the stereoselective synthesis of heterocycles, [10] we recently described an efficient enantioselective synthesis of trisubstituted cyclopenta [b]indoles [10c] via a chiral phosphoric acid-catalyzed (3+2)-cycloaddition between alkylideneindoleninium ions generated in situ from indolylarylmethanols [11] and enecarbamates as dienophiles. [START_REF] Merad | Recent reviews on chiral phosphoric acid catalysis: a)[END_REF][START_REF] Fan | Selected examples of enantioselective (3+2)-cycloadditions: a)[END_REF] We also reported that chiral phosphoric catalysts were able to efficiently catalyze asymmetric nitroso-Diels-Alder reactions with 1,3-diene-1-carbamates. [10b,14] Since (4+3)-cycloadditions have already been established starting from indolylarylmethanols, [1,6h-m] we reasoned that dienecarbamates could suit well as partners to develop the first catalytic enantioselective (4+3) cycloadditions in the presence of a chiral phosphoric acid. To validate this assumption, we initially attempted to conduct the reaction of indolyl(phenyl)methanol derivative 1a with benzyl (penta-1,3-dien-1-yl)carbamate 2a with and 5 mol% of (R)-3,3'-bis(2,4,6-triisopropylphenyl)-BINOL (TRIP) phosphoric acid 4 in CH2Cl2 in the presence of 4 Å molecular sieves. Gratefully, the reaction proceeded smoothly to afford the corresponding 6-aminotetrahydrocyclohepta [b]indole 3a in 78% yield with 91% ee as a single all-cis diastereomer (entry 1). Toluene was found to be a better solvent furnishing 3a in slightly better yield with 97% ee (entry 2). Lowering the reaction temperature markedly decreased the yield of 3a and did not have a significant effect on the enantioselectivity (entry 3). Performing the same reaction in the absence of 4 Å MS led to a lower yield, indicating the deleterious effect of water on the overall process (entry 4). Other drying agents were evaluated, but 4 Å MS provided the best results in terms of both yield and enantioselectivity (entries 3 vs 5-8). Diversely substituted carbamates can react with 1a but the best results were obtained with Cbz-protected dienamines (entries 3 vs 9 -12).

Table 1. Survey of Reaction Conditions for Enantioselective (4+3)-Cycloaddition [a] Entry Solvent Additive Product Yield [%] [b] ee [%] [c,d] [a] Reaction conditions: 1a (0.10 mmol), 2 (0.11 mmol) and 4 (0.005 mmol) in 2.0 mL of solvent for 18 h at RT. [b] Yields refer to chromatographically pure all cis-isomer 3 determined to be higher than 98/2 by 1 H NMR. [c] ee values were determined by HPLC with a chiral stationary phase. [d] All cisconfiguration was determined by X-ray single crystal structure analysis of racemate (+/-)-3w and the absolute configuration (6R,9S,10R) was assigned by X-ray single crystal structure analysis of enantioenriched 9 (see Supporting Information). [e] Performed at 0°C. [f] With 1.0 mmol scale of 1a. [e] Performed with ent-4 as a catalyst.

Having optimized the reaction conditions for the synthesis of the tetrahydrocyclohepta [b]indol-6-yl)carbamate 3a, we investigated the scope of 4-catalyzed diastereo-and enantioselective (4+3)cycloaddition reactions of 1a with a variety of dienes 2. In general, the reaction proceeded smoothly with excellent diastereo-and enantioselectivity. For instance, the diene carbamates bearing branched or linear alkyl chains at the C4 position led to corresponding cycloadducts (3e-3f) in good yields. Chiral dienecarbamate derived from (R)-citronellol gave 3g with an excellent enantiomeric excess. Additionally, silyl ethers (3h) are compatible functional groups in this process. The diastereoselectivity was substantially affected when non terminal substituted dienes were used. Nevertheless, appreciable level of selectivity remained as observed for compounds 3i and 3j (3:1 dr) with excellent enantioselectivity for the major isomer (96% and 97% ee respectively). On the other hand, substituents at the C3 position of dienes does not affect the selectivity (3k). Next, the scope of the reaction was successfully extended to other 3indolylmethanols 1 under similar conditions. Dipole precursors 1 bearing either electron-rich or electron-deficient aryl groups at 1' position worked well providing the corresponding cyclohepta [b]indoles 3l-3o in generally high enantioselectivities (87-98%). Chalenging ortho-substituted aryl groups were also tolerated in the cycloaddition, forming 3p in respectable yield and high enantioselectivity. The displacement of the methoxy group onto the indole C5-position also provides good results in term of yields and selectivity (3q). Finally, we observed that the electronic property of the substituents on the indole did not Scheme 1. Scope of the enantioselective (4+3)-cycloaddition. [a,b,c,d] [a] General reaction conditions: 1 (0.10 mmol), 2 (0.10 mmol), and 4 (0.005 mmol) in 2.0 mL of toluene at 0°C to RT for 18 h with 4 Å MS. [b] Yield of isolated pure product after column chromatography. [c] Determined by HPLC analysis on a chiral stationary phase. [d] If unspecified, dr >98/2, determined by 1 H NMR. [e] Synthesized using ent-4 catalyst (10 mol%).

influence much on the enantioselectivity, but strongly affected the reaction yield. For instance, unsubstituted indoles (3r-3u) led to the desired products in good yields whereas the presence of electron poor substituents decreased the yield considerably (3v). To our delight, indole bearing both an electron-poor and an electron-rich aromatic moiety was successfully used to form 3w in a respectable yield. More remarkably, the pinacol boronic ester was tolerated allowing further functionalizations of 3x using cross-coupling reactions. To finish, new opportunities in terms of scaffold diversity and potential post-transformations were offered by the synthesis of 3y in lower yields but high enantioselectivity.

The mechanism of the cycloaddition is assumed to initially involve of H2O from 1 to generate an ion pair between the newformed indolium and chiral phosphate. In the meantime, hydrogen bonding between the dienecarbamate NH and the Lewis basic phosphoryl oxygen ensures a highly organized transition state in the enantio-determining step (Scheme 3). Based on the model proposed by Goodman, [15] the facial selectivity (Re face of the indole and Si face of the diene) can be rationalized by the chiral environment provided by the tethering phosphoric acid as proposed on scheme 3. Taking into account the reported conformations of cylohepta-1,4-dienes [16] and the one of natural products exotines (solution and solid state conformation), [2a] we can hypothesize that a bent boat-like conformation would be operative in the ring-closing step to afford the all-cis product as the major isomer. In the absence of R 1 group (3f and 3g), an easy rotation around the C1-C2 bond would bring the aromatic substituent in a more favorable equatorial position leading to a lower diastereoselectivity (see supporting information). The stepwise representation of this reaction is consistent with our previous work on the (3+2)cycloaddition, [10a] as well as other reports, [12, 13a-f] Moreover, the trapped iminium intermediate 5 was isolated in 6% yield when Scheme 3. Activation model via a putative transition state. the reaction between 1g and 2a was performed in the presence of EtOH (15 eq).

To demonstrate the practicality and scalability of this procedure, we conducted the reaction on a larger scale (1.0 mmol) under standard conditions, which furnished the pure cyclohepta [b]indole product 3a (83% yield and 97% ee) without any loss of efficiency and selectivity (Table 1,entry 9). Pleasingly, 3a can be readily transformed into other interesting derivatives owing to the presence of functional groups. For instance, indole addition to 3a using 5 mol% of Bi(OTf)3 as Lewis acid [START_REF] Jaratjaroonphong | Selected examples concerning carbamates[END_REF] to trigger the formation of benzyl cation intermediate resulted in 72% yield of 6 as a single diastereomer providing efficient acces to natural related biologically active products. [18] Moreover, using PtO2, the endocyclic olefin was chemoselectively hydrogenated in good yield without affecting the N-benzyl group. The carbamate functional group is ideally placed and can also serve as an anchorage point for selective transformations. As illustration, the treatment of 3a with TsOH.H2O afforded diene 8 in respectable yield with no change of enantioselectivity. Finally, subjection of 1a to aqueous basic conditions did not lead to the anticipated Cbz deprotection. Instead, unexpected ketone 9 was isolated as the sole product in 78% yield without racemization. Its structure was unambiguously identified through an X-ray crystal structure determination (see supporting information). Transition metal-free allylic isomerization of alcohols leading to ketone have already been reported. Depending on the base used, they involve a deprotonation/reprotonation or a radical pathway. Accordingly, a plausible mechanism could follow a base-mediated allylic isomerization leading to an enamide that would next be hydrolized under the conditions. [19] Then, addition of allylmagnesium chloride to 9 resulted in the formation of 10 in 78% yield with high diastereoselectivity (95:5).

Scheme 3. Scale-Up and synthetic transformation of 3a. Reaction conditions [a] Indole (1 eq), Bi(OTf)3 (5.0 mol%), toluene/EtOAc (2/1), RT; [b] PtO2 (5 mol%), H2 (1 atm), EtOAc, RT. [c] TsOH.H2O (5.0 eq), THF, RT. [d] LiOH (20 eq), dioxane/H2O (1.25:1), reflux, 12 h. [e] AllylMgCl (3.0 eq), THF, 0 °C to RT, 3 h.

We reported the first catalytic enantioselective formal (4+3)cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols to furnish 6-amino-tetrahydrocyclohepta [b]indoles containing 2 to 3 stereogenic centers in good yields with excellent diastereoand enantioselectivities (up to 99% ee). The trapping experiments provided sound evidence that the present reaction proceeded via a stepwise mechanism. The excellent yields, enantioselectivities, and operational simplicity make this methodology attractive for the synthesis of natural cyclohepta [b]indole products.

Figure 1 .

 1 Figure 1.Representative cyclohepta[b]indole compounds.

Acknowledgements

We thank ICSN and CNRS for financial support; C.G. and G.L. thank Saclay University for the doctoral fellowships; J.M. gratefully acknowledges CNRS for a postdoctoral fellowship.

Keywords: (4+3)-cycloaddition• chiral phosphoric acid • cyclohepta [b]indoles • heterocycle • hydrogen bonding


Regio-, Diastereo-and Enantioselective Nitroso Diels-Alder Reaction of 1,3-Diene-1-carbamates Catalyzed by Chiral Phosphoric acids

Jonathan Pous, † Thibaut Courant, † Guillaume Bernadat, ‡ Bogdan I. Iorga, † Florent Blanchard, † and Géraldine Masson* † † Institut de Chimie des Substances Naturelles CNRS, Univ. Paris-Sud, 1, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France ‡ Équipe Molécules Fluorées et Chimie Médicinale, Laboratoire BioCIS (UMR-8076) -LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, 92296 Châtenay-Malabry Cedex, France Supporting Information Placeholder ABSTRACT: Chiral phosphoric acid-catalyzed asymmetric nitroso-Diels-Alder reaction of nitrosoarenes with carbamate-dienes afforded cis-3,6-disubstituted dihydro-1,2-oxazines in high yields with excellent regio-, diastereo-and enantioselectivities. Interestingly, we observed that the catalyst is not only able to control enantioselectivity but also is able to reverse regioselectivity of the non-catalyzed nitroso-Diels-Alder reaction. Regiochemistry reversal as well as asynchronous concerted mechanism were confirmed by DFT calculations.

The nitroso Diels-Alder (NDA) 1 reaction has attracted considerable attention among synthetic chemists because of the utility of the resulting 3,6-dihydro-1,2oxazines for the synthesis of natural products and biologically active molecules. [START_REF]For review of NDA reactions[END_REF][START_REF] Bodnar | For review on the synthetic applications of NDA products see[END_REF] Therefore, development of asymmetric, catalytic versions of the NDA reaction have been the subject of numerous researches. [START_REF]For review of NDA reactions[END_REF] However, control of the regioselectivity, [START_REF] Sauer | For discussions on regioselectivity in NDA reaction[END_REF] fast background reaction(s) and the high propensity for dimerization of nitroso compounds 4 under acidic conditions made development of a catalytic enantioselective intermolecular process challenging. [START_REF]For review of NDA reactions[END_REF][START_REF] Chow | For the first asymmetric intramolecular NDA reaction[END_REF] The first intermolecular enantioselective NDA reaction was reported by Ukaji and Inomata using a stoichiometric amount of a Zn(II) tartaric acid ester complex. 6 A major breakthrough came from Yamamoto's group, 7 which reported that a copper complex could catalyze the intermolecular asymmetric NDA reaction of 2-nitrosopyridines with cyclic and acyclic dienes. Although cycloadducts were generally isolated with a high enantiomeric excess, this method is only effective for 2-nitrosopyridine dienophiles. Afterwards, the same group 8 described two efficient organocatalytic asymmetric NDA reactions of cyclic dienes employing a pyrrolidine-derived tetrazole 8a,9 or BINOL-derived Brønsted acid, 8b respectively, as chiral catalyst. In spite of these notable achievements, most of efficient enanti-oselective NDA reactions were mainly restricted to specific nitroso dienophiles or cyclic dienes.

In light of the recent development of chiral phosphoric acid-catalyzed asymmetric transformations 10 of secondary enamides 11 that have been disclosed by us 12 and others, 13 we reasoned that 1,3-diene-1-carbamates bearing an NH directing group would be ideal partners for implementing an enantioselective catalytic NDA reaction. Indeed, the dienecarbamate as well as nitrosoarene could be activated through double hydrogen bonding to control both regio-and enantioselection (Scheme 1).

Scheme 1. Bifunctional catalyst for the enantioselective NDA reaction

To validate our hypothesis, we examined the reaction of benzyl (penta-1,3-dien-1-yl)carbamate 1a with commercially available nitrosobenzene 2a in the presence of 5 mol % of chiral phosphoric acid 4 in DCM at -30 °C (Table 1). As shown in Table 1, all catalysts tested were capable of catalyzing the reaction with complete Oregioselectivity 3,8b,13f and excellent diastereoselectivity in favor of the cis-diastereomer. However, enantioselectivity varied widely with the size of the substituents on the 3,3'-positions of 4 (entries 1-4). [START_REF] Akiyama | For recent reviews on chiral phosphoric acid catalysis[END_REF] We found that the bulkier (S)-3,3'-bis (2,4,6-triisopropylphenyl)-BINOL (TRIP) phosphoric acid 4d provided cycloadduct 3a in a much higher yield and enantiomeric excess (entry 4). When the catalyst loading was reduced to 1 mol%, the enantioselectivity was maintained at almost the same level, although the yield decreased to 33% (entry 5). However, by simply increasing reaction time from 3 to 16 h, the yield of 3,6-dihydro-1,2-oxazine 3a (entry 6) was enhanced to reach 98%. A survey of reaction solvents with 5 mol% of 4d revealed that toluene was effective to slightly improve enantioselectivity (entry 7). Finally, performing the reaction in toluene at a lower temperature (-50°C) resulted in an improvement of both yield and enantioselectivity (entry 8). It is interesting to note that regioisomer 6a was not detected under phosphoric acid-catalyzed NDA reaction. The scope of this Brønsted acid-catalyzed NDA reaction was next investigated using our optimized conditions. As shown in table 2, various nitrosoarenes bearing electron-donating and withdrawing groups at the para position 14 could be successfully employed to afford 3,6dihydro-1,2-oxazines 3b-3i in good yields, with complete regioselectivity and excellent diastereo-and enantioselectivities. In addition, both ortho-and meta-substituted nitrosoarenes efficiently provided the corresponding cycloadducts 3j and 3k with excellent enantioselectivities (Table 2). Pleasingly, this asymmetric NDA reaction was found to be successful with various 1,3-diene partners (Table 2). Notably, several carbamate-dienes 1b-d bearing alkyl (such as benzyl and hexyl) or aryl (such as phenyl) groups at the C-4 position readily participated in the reaction, leading to the obtention of 1,6-dihydro-1,2oxazines 3l-3n with yields and enantioselectivities of the same order (Table 2). At the same time, the 3,4dialkylsubstituted diene 1e was also a successful substrate of this NDA reaction, providing cycloadduct 3o with an excellent enantioselectivity (91% ee). The presence of functional groups such as silyl ether (3p), alcohol (3q) and double bond (3r) is well tolerated in the NDA reaction as well. To our delight, the enantiomerically pure dienecarbamate 1h having one endocyclic double bond afforded 3r as a single diastereomer. Finally, the catalytic system also proved to be efficient for various carbamates (Alloc, Fmoc, p-Br-Cbz, p-NO2-Cbz and perfluoro-Cbz) and amides affording highly substituted 3,6-dihydro-1,2-oxazines 3s-3x with excellent ee's (Table 2). Absolute configuration of chiral centeres in compound 3w was determined to be 3S and 6S by single crystal X-ray diffraction analysis (see Supporting information).

Table 2. Substrate scope of 1,3-diene-1carbamates 1 and nitrosoarenes 2 with 1a. a-c

a General conditions: 1a (0.05 mmol), 2 (0.10 mmol) and 4 (0.0025 mmol) in toluene at -50°C. b Yields refer to chromatographically pure product. c Determined by HPLC analysis on chiral stationary phases. d Using catalyst 4e R = 2,4,6-(Me)3-C6H2.

The following control experiments were carried out in order to gain some mechanistic insight. When the reaction of 1,3-diene 1a and nitrosobenzene 2a was conducted in the absence of catalyst, the other regioisomer 6a was exclusively obtained in 80% yield (entry 9, Table 1). Moreover, as described in Table 1, only 1 mol% catalyst was required to completely reverse the regioselectivity of the NDA reaction (entry 6, Table 1). 8,[START_REF] Momiyama | Example of reverse regioselectivity[END_REF] These findings indicate that the chiral phosphoric acid catalyst is highly active. To confirm this, we performed kinetic studies by measuring the rate of conversion of 1a with or without catalyst (see Supporting Information). As expected, we found that the phosphoric acid-catalyzed reaction was much faster than the uncatalyzed one. To probe the origin of the regioselectivity reversal, 2b,3,5a,15 two different transition state models, 7 and 8, were proposed (Scheme 2). The high azaphilicity of phosphoric acid catalysts 9 could result in the preferential formation of H-bond with nitrogen N of nitroso 2, thus favoring the regioisomer 3. In this assembly 8, the phosphoric acid would form hydrogen bonds with 1,3-diene 1 and the nitrogen atom of 2 to favour the isomer 3.

Scheme 2. Activation models and possible reaction mechanism

To improve our understanding of the mechanism and the regio-and stereochemistry observed experimentally, DFT calculations were performed at the B3LYP/6-31G* level. 16 First, electronic structures of dienophile 2a and N-acylenamide (R 1 =Me, R 2 =Ph and R 3 =H) 1m calculated, and opposed to each other in order to locate states leading to regioisomers 3x and 6x on the potential energy surface (Figure 1). The free energy difference between these two scenarios was consistent with formation of 6 as the major product in the of catalyst. Then, the equivalent transition states were studied again, this time in the presence of each enantiomer of phosphoric acid catalyst 4e (Figure 2), in order to explain both the regioselectivity inversion and the stereochemical outcome of the reaction. Among the 4 possible combinations of regio-and stereochemisty, the transition state leading to regio-and stereoisomer 3x in the presence of (S)-4e catalyst had the lowest activation energy (Figure 2). This result was in accordance with 3x being indeed the major product obtained experimentally. Calculation of the IRC of this theoretically most favored pathway revealed an asynchronous concerted mechanism (Path a in Scheme 2) 2b,5a,17 with a concomitant boatto-half-chair conformational change of the dihydrooxazine ring, to the detriment of an alternative stepwise 7 vinylogous O-nitroso aldol reaction followed by intramolecular aminalization (Path b in Scheme 2; see also Supporting information).

The structure found for this transition state confirmed dual activation of substrates by the catalyst, with the formation of a hydrogen bond network. Moreover, on this preferred pathway, we observed a total proton transfer from phosphoric acid to the (basic) nitrogen belonging to the nitroso derivative. This finding led us to wonder whether the sole protonation of the nitroso partner sufficed to control the regioselectivity of the reaction. 5a,15b To investigate and isolate the influence of this factor, we performed a series of experiments involving non phosphoric, non-chiral acid catalysts with decreasing pKa (see Supporting Information). 10i The strongest acids (CSA, pTSA) were found responsible of a total regiochemistry inversion in favor of derivative 3, 8b,13f to the credit of our speculation, whereas reactions conducted in the presence of weaker acids (such as benzoic acid) yielded almost exclusively isomer 6. This hypothesis was further studied in the course of a last series of computational transition state searches, where the nitrogen atom of the nitroso derivative was protonated in the absence of any counteranion. The energy barriers found were in agreement with the role supposedly played by the proton in regioselectivity (see Supporting information).

Synthetic transformation of 3,6dihydro-1,2-oxazines 3

With optically pure 3,6-dihydro-1,2-oxazines 3 obtained, we next demonstrated the synthetic utility of the NDA products (Scheme 3). Hydrogenation of the 1,2-oxazine product 3a using an H-Cube apparatus (17) gave valuable 1,4-amino-alcohol 10 in good yield after hydrogenolysis of the double bond, reduction of aminal and N-O bond cleavage. Reduction of 3a with triethylsilane in the presence of BF3.OEt2 gave direct access to the corresponding 6-methyl-3,6-dihydro-1,2-oxazine in 77% yield without any loss of enantioselectivity (ee =96%). 18 In summary, we have developed an efficient enantioselective NDA reaction of nitrosoaryl derivatives with carbamate dienes catalyzed by chiral phosphoric acids. This cycloaddition is applicable to a wide range of nitrosoaryl derivatives and carbamate dienes, providing a highly diastereo-and enantioselective route to (3S,6S)-dihydro-1,2-oxazines 3. Early mechanistic studies seem to indicate that the present NDA reaction proceeds via a highly asynchronous concerted mechanism.

ASSOCIATED CONTENT Supporting Information

Experimental procedures, characterization data, copies of spectra, crystallographic data, and details of the DFT calculations. This material is available free of charge on the ACS Publication Website http://pubs.acs.org.

Figure 1 .

 1 Figure 1. a) Free energy profiles for the spontaneous (uncatalyzed) reactions yielding regioisomers 3x (blue) and 6x (red). b) Structure of the transition state for the red pathway, with the lowest energy barrier.

Figure 2 .

 2 Figure 2. a) Free energy profiles for the (S) and (R)-4e-catalyzed reactions yielding enantiomers 3x (respectively red and blue). b) Structure of the transition state for the red pathway, with the lowest energy barrier.

Table 1 . Survey of reaction conditions for NDA of 2a. a

 1

	entry	cat	solvent	temp	time (h)	yield (%) b (3a or 6a)	ee (%) c,d (3a or 6a)
	1	4a	CH2Cl2	-30°C	3	60 (3a)	20 (3a)
	2	4b	CH2Cl2	-30°C	3	80 (3a)	65 (3a)
	3	4c	CH2Cl2	-30°C	3	47 (3a)	17 (3a)
	4	4d	CH2Cl2	-30°C	3	98 (3a)	90 (3a)
	5	4d	CH2Cl2	-30°C	3	33 (3a)	87 (3a) e
	6	4d	CH2Cl2	-30°C	16	98 (3a)	88 (3a)
	7	4d	toluene	-30°C	16	73 (3a)	93 (3a)
	8	4d	toluene	-50°C	16	80 (3a)	98 (3a)
	9		toluene	rt	3	80 (6a) d

a General conditions: 1a (0.05 mmol), 2a (0.10 mmol) and 4 (0.0025 mmol). b Yields refer to chromatographically pure product.

c

Determined by HPLC analysis on chiral stationary phases. d >95:5 dr. e With 1 mol% of 4.

ACKNOWLEDGMENT

We thank ICSN for financial support and doctoral fellowships to J.P.; T.C. thanks MESR for a doctoral fellowship, University of Paris XI. The IT department of Université Paris-Sud as well as ICSN are acknowledged for providing computing resources.

AUTHOR INFORMATION

Corresponding Author

Dr. G. Masson : Institut de Chimie des Substances Naturelles CNRS, Univ. Paris-Sud, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France Fax: (+) 33 1 69077247 E-mail: geraldine.masson@cnrs.fr


Clément Lebée

Morgan Languet

Clémence Allain

Géraldine Masson

α-Carbamoylsulfides as N-Carbamoylimine Precursors in the Visible Light Photoredox-Catalyzed Synthesis of α,α-Disubstituted Amines

A general and practical photoredox-promoted addition of nucleophiles to N-acylimines generated in situ from α-amidosulfides using Ru(bpy)3(PF6)2 as the photocatalyst is reported. The broad scope of the reaction toward various nucleophiles and amidosulfide derivatives was explored. This novel protocol provides a rapid, mild, and efficient access to valuable α,α-disubstituted amines in respectable yields.

The use of masked N-acyl and N-carbamoylimines has been proven to be a powerful strategy in the preparation of synthetically useful -substituted amines. 1 Consequently, many precursors containing a good leaving group such as such as O-alkyl, OH, sulfone, halide, benzotriazole or amide have been investigated for the generation of imines (or iminium ions). 2 However, in some cases, strong acids or bases are required, which precludes the presence of acid-or base-sensitive functional groups. In this regard, we recently reported a NIS (N-Iodosuccinimide) mediated aza-Friedel-Crafts (aza-FC) reaction using α-carbamoylsulfide as easily available imine precursors. 3 However, while the reaction proceeds under neutral and mild conditions, the formation of molecular iodine during the reaction can limit the substrate scope of the reaction. Scheme 1. Proposed work hypothesis

As a continuation of this research program, we sought to develop a new method for the preparation of N-carbamoylimines from carbamoylsulfides that would be mild, practical, and highly func-tional-group-tolerant. Our approach was inspired by the work of Bowers, 4,[START_REF] Del Giacco | Examples of laser flash photolysis of alkylsulfides[END_REF] who showed that photo-oxidation of thioglycosides in the presence of Iridium photocatalyst, BrCCl3 and visible light generates oxocarbenium ions, which can be then trapped with alcohols to form O-glycosides (Scheme 1, eq 1). We thought that visible light photocatalysis [START_REF]For recent reviews on photoredox catalysis[END_REF]7 could be used to generate in situ the N-carbamoyliminium 2 from α-aminosulfides 1 under mild conditions (Scheme 1, eq 2). Indeed, the photoinduced single-electron oxidation of the neutral species 1 might produce a sulfur radical cation 2. The latter could then undergo C-S bond cleavage to give an N-acyliminium ion 4, which can proceed with nucleophiles to provide the addition product 6.

To test this hypothesis, we selected an appropriate reaction for optimization. The initial studies focused on aza-FC reaction of Nacylimines generated in situ from α-amidosulfides. 1,3,5-Trimethoxybenzene (5a) was chosen as arene nucleophile with tert-butyl (1-(ethylthio)-3-phenylpropyl)carbamate (1a) as the substrate. To our delight, by using a Ruthenium photoredox catalyst 3a in CH3CN, we were able to isolate the desired aza-FC 6a in 60 % yield (Table 1, entry 1). The yield was further improved by adding 10 equivalents of hexafluoroisopropanol (HFIP) or t-BuOH as a protic additive (enties 2 and 3). In particular, t-BuOH was chosen for the further optimization as it is cheaper. The amount of alcohol was also important, and less or more than 10 equivalents t-BuOH decreased the yield (entry 3 vs. entries 4 and 5). Although the role of alcohol is not fully understood, it may increase the solubility of radical cation 2 as described in previous reports. 4,8 However, in the course of our electrochemical study, we found that the oxidation potential of 1a was reduced in presence of t-BuOH (see Supporting Information) hence favoring the formation of 4. In contrast, no beneficial effect was observed when the reaction was performed in the presence of the hazardous BrCCl3 as oxidative quencher (Table 1, entry 6). 4,[START_REF]For recent reviews on photoredox catalysis[END_REF] Different photocatalysts 3b-e (entries 5-7) were also screened. While the organic photocatalyst Eosin Y 3e (entry 9) was found to be a suitable catalyst for this reaction, 9 better result was obtained with [Ru(bpy)3(PF6)2] 3a (entry 3). Next, we studied the reactivity in different solvents, and the yield significantly dropped when MeCN was replaced by tetrahydrofuran (THF), CH2Cl2 or t-BuOH (see Supporting Information). The reaction was improved further by increasing the substrate concentration (Table 1, entry 11). Further studies revealed that the nature of the substituent on the S atom of the α-amidosufides influenced the efficiency of the reaction (entries 12-14). The use of S-aryl (1b, entry 12) and Sbenzyl (1c, entry 13) derivatives resulted in lower yields than with the S-t-butyl (1d, entry 14) and S-Et (1d, entry 11) derivatives. It is noteworthy that no reaction occurred in the absence of a photocatalyst or light (Table 1, entries 15 and16). These experiments indicate that the photoredox catalysis is essential for this process. Table 1. Survey of reaction conditions for the photocatalyzed alkylation of 1. We next examined the scope of α-amido or α-carbamoylsulfides 1 that participate in this photocatalyzed aza-FC reaction. As summarized in Scheme 2, the reaction of aliphatic carbamoylsulfides whether linear or α-branched, afforded the corresponding aza-FC adducts 6b-6e in moderate to excellent yields. The photocatalytic system also proved to be efficient for various imines bearing functional groups such as benzyl ether (1e), acetal (1j) and amine (1k). Most remarkably, these imine precursors bearing an alkyne functional group such as (1i), which were totally unstable in our previous NIS-assisted protocol, worked well. 3a This was demonstrated as the -carbamoylsulfides 1f being converted into the N-Boc propargylic amine 6f which is an important building blocks for the synthesis of nitrogencontaining compounds. 2m,10 Several protecting groups bonded to the nitrogen of 1, including carbamates (6a and 6i) and amides (6g and 6h) were tolerated. We also found that, contrary to our previous studies, 3 enantioenriched -carbamoylsulfides 1j and 1k whose corresponding -substituted imines are known to be sensitive towards racemization, were successfully engaged in this reaction. 11 For instance, the imine precursors derived from Dglyceraldehyde acetonide 1j led to aza-FC adduct 6j as a single disastereomer with no racemization. Similarly, L-proline derivative 1k yielded to an enantiomerically pure mixture (3:1) of two inseparable diastereomers in 62 % yield. On the other hand, various aromatic and heteroaromatic α-amidosulfides effectively participated in this reaction, leading to the aza-FC adducts 6l-6m in good yields. No noticeable difference in reactivity was observed when electron-rich and electron-poor functional groups were present in the aromatic ring (6n and 6o). Scheme 2. Substrate scope of the aza-FC reaction of -amidosulfide derivatives 1. a,b a Reaction conditions: 1 (0.10 mmol), 1,3,5-trimethoxybenzene 5a (0.15 mmol), 3a (0.025 equiv), t-BuOH (10.0 equiv) in MeCN (0.5 mL) irradiated at rt for 24 h. b Yields referred to chromatographically pure product. c dr determined by 1 H-NMR analysis of crude mixtures

1 photocat. 3 additive (x equiv) 6a yield (%) a,b
Extension of this novel photoredox protocol to other nucleophiles than 5a was delightfully successful (Scheme 3). Under the same conditions, various heterocycles such as 2-methoxythiophene 5b and indoles 5c-5d afforded the C-alkylated aza-FC products 6p, 6q, 6r and 6s in moderate to good yields. It is worth noting that this is complementary to our early developed NIS-catalyzed approach in which the 3-alkylindoles furnished only N-alkylated products. 3 In the case of indole 5c, bis(indolyl) product derived 7, which display important biological activities, 12 was isolated as a single product. Interestingly, no acid was required to promote the double addition of 5c to the in situ-generated N-Boc imine 1a. 2d- f,13 On the other hand, reaction of amide-protected 1g with indole 5c under similar reaction conditions only delivered the desired aza-FC product 6r, indicating the influence of protecting groups on the reactivity of 4. The process also worked with nitrogen nucleophiles such as indazole 5e and pyrazole 5f yielding to 6t and 6u in 91 % and 70 % yield, respectively. We further explored the potential for a Strecker-type reaction. Surprisingly, when attempting to trap the N-carbamoyl iminium 1a with TMSCN, we did not isolate any desired product. Fortunately, the use of KCN 5g was successful leading to 6v in excellent yield. Next, we found that 1,3-dicarbonyls such as acetylacetone 5h underwent addition to 1a and 1l yielding to Mannich product 6w and 6x. Although the yields were moderate, no acid or base was added to trigger the nucleophilic addition of 5h. Scheme 3. Substrate scope with respect to the nucleophile. a,b a General conditions: 1 (0.10 mmol), nucleophile 5 (0.15 mmol), 3a (0.025 equiv), t-BuOH (10.0 equiv) in MeCN (0.5 mL) irradiated at rt for 24 h. b Yields referred to chromatographically pure product. c From 1a. d With KCN (0.3 mmol) and a mixture MeCN:H2O (0.5 mL:0.5 mL).

To gain more insight into the pathway of this photocatalytic reaction, several control experiments were conducted. We have first measured the oxidation potential of the -carbamoylsulfides 1 used in our studies. The oxidation potential of the sulfur atom of 1a was found to be 1.17 V vs. SCE in CH3CN. This indicates that the electron-transfer pathway after its excitation of Ru 2+ is not possible, as the oxidation potential of *Ru 2+ (0.77 V vs. SCE in CH3CN) is too low. [START_REF]For recent reviews on photoredox catalysis[END_REF]14 To proceed, the reaction requires the formation of stronger oxidizing Ru 3+ (1.33 V vs. SCE in CH3CN) via oxidative quenching of *Ru 2+ . Since BrCCl3 was an inefficient quencher (Table 1, entry 6), we hypothesized that molecular oxygen might act as an oxidative quencher of *Ru 2+ . Indeed, when the reaction was carried under anaerobic condition, only starting material 1a was recovered (see Supporting Information), thus confirming the oxidative quenching role of molecular oxygen. A parallel experiment showed that the addition of oxygen results in slight decrease of reaction time (see Supporting Information). On the basis of the above results as well as other reports, [START_REF]For recent reviews on photoredox catalysis[END_REF]15 a plausible mechanism for this process is outlined in Scheme 4. The oxidative quenching of *Ru 2+ by the O2 generates the Ru 3+ and superoxide radical anion (O2 •-). Sulfur radical cation 2, formed by the Ru 3+ -promoted oxidation of 1, undergoes a fragmentation to generate the iminium 4, S-centered radical (sulfanyl radical) 7 and Ru 2+ . Subsequent addition of nucleophiles to 4, followed by hydrogen atom abstraction mediated by superoxide radical ion, provides the desired products 6 and hydroperoxyl radical (HO2 • ). It is also possible that O2 could be regenerated in course of disproportionation reactions of hydroperoxyl radical (HO2 • ). This might explain why that addition of O2 into the reaction medium was not necessary (see Supporting Information).

Meanwhile the sulfanyl radical 7, formed upon cleavage of the C-S bond, may evolve according to two different routes: a) either 7 dimerizes to form disulfide 8 or, b) 7 propagates the radical chain reaction by oxidation of 1 leading to 2 and thiolate anion 9. The latter, based on the work Matsuda et al, 16 can be photooxidized to produce the disulfide 8 via 7. To distinguish between these two plausible reaction pathways, we performed additional experiments. We irradiated 1a in presence of 1,3,5trimethoxybenzene (5a) and 3a with blue LEDs for 1 h (see Supporting Information). In this condition, 6a was isolated in 8 % yield (instead of 90 % after 24 h of irradiation, Table 1, 11). However, an increase in yield (30 %) was obtained when 1a was stirred under dark conditions for 24 h after 1 h irradiation. These latter experiments indicate that although chain-propagating oneelectron oxidation by 7 seems effective, it is not the dominant pathway. Consequently, it is reasonable to assume that 2 was mainly generated by electron transfer from the oxidized Ru 3+ photocatalyst. Scheme 4. Plausible reaction mechanism.

In summary, we have developed a practical photoredox-catalyzed synthesis of N-carbamoyl α,α-disubstituted amines from readily available α-amidosulfides under mild conditions. This methodology has wide scope, including several examples of nucleophiles, and moderate to excellent yields. A promising asymmetric amine synthesis with excellent diasteroselectivity was also achieved by using a chiral α-amidosulfides. Moreover, the photoredox protocol relies on the use of nonhazardous chemicals, features a simple experimental procedure, and is performed under mild conditions.

We believe that such a protocol could find useful applications in view of the synthesis of functionalized building blocks, potentially biologically active substances, and natural products.

ASSOCIATED CONTENT Supporting Information

Detailed experimental procedures and spectral data for all new compounds are provided. This material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGMENT

We thank ICSN and CNRS for doctoral fellowships to C.L. and M.L. thanks Labex Charmmmat for a financial support of Master.

AUTHOR INFORMATION

Corresponding Author * E-mail: geraldine.masson@cnrs.fr Author Contributions ‡ These authors contributed equally. All authors have given approval to the final version of the manuscript.


Dr Thibaut Courant

Géraldine Masson
email: masson@icsn.cnrs-gif.fr

Photoredox Initiated α-Alkylation of Imines via a Three-Component Radical/Cationic Reaction

Keywords: alkylation, multicomponent, domino, photoredox catalysis, enamides

The α-alkylation of imines is a valuable carbon-carbon bondforming strategy which is still an underdeveloped area, [1][START_REF] Ooi | For phase-transfer catalytic asymmetric α-alkylation of glycine derivatives[END_REF][START_REF]For Reviews on α-alkylation of carbonyl compounds, see: a) D. Caine in Comprehensive Organic Synthesis[END_REF] despite the synthetic potential of its α-branched imine products. 4 The direct C-H bond functionalization of imines with alkyl halides has proven challenging due to competing side reactions, such as Mannich condensation, N-alkylation and hydrolysis. [1,5] The indirect approach based on the intermolecular nucleophilic alkylation reaction of enamine [START_REF]For representative reviews on enamine catalysis, see: a) Enantioselective Organocatalysis[END_REF] or enamide [7] derivatives was not found more efficient. Moreover, the only corresponding products reported were α-alkylated carbonyl compounds. [START_REF] Hatakeyama | alkylation of carbonyl compouds via the enamines form[END_REF] To the best of our knowledge, there is no efficient method for the preparation of α-alkylated imines. In this communication, we disclose a novel αalkylation reaction of imines which can be achieved by photoredox-mediated direct intermolecular C-H functionalization of enamide derivatives, involving a radical-cationic domino process.

Recently, Friestad et al. [9] reported an interesting tin-mediated non-reductive radical alkylation of tertiary enamides, forming two carbon-elongated homologs via oxidation and proton-transfer through N-amidoradical intermediates. [START_REF] Aurrecoechea | Radical addition to enamines[END_REF][11][12] Based on this, we envisaged that the same radical/cationic process in the presence of a nucleophile might provide an expedient synthesis of α-alkylated imines. The principle of this multicomponent domino process is depicted in Scheme 1. [START_REF] Godineau | radical and radical-ionic multicomponent reactions[END_REF]14] After radical reduction of alkyl halide 2, the resulting alkyl radical 5 would react with enamide 1 to produce α-amidoalkyl radical 6. The oxidative radical-polar crossover [15] could then furnish an N-acyliminium cation 7, which should be trapped by a suitable nucleophile. Alcohol 3 was chosen as a nucleophile of choice to generate β-alkylated αamidoether 4, which is a stable precursor of α-alkylated imine [16, 14f] and can be found in a number of biologically important natural products. [START_REF] Boal | For representatives examples of hemiaminal ethers found in natural products[END_REF][START_REF] Li | For references about asymmetric synthesis of hemiaminal ethers[END_REF] To initiate this radical/cationic domino process, a free radical redox initiator, which was compatible with the nucleophile was selected. As visible light photoredox catalysis [START_REF] Teplý | For reviews on photoredox catalysis, see: a)[END_REF] has emerged as an efficient tool to promote single-electron transfer (SET) redox transformations since the success of MacMillan et al., [20] Yoon et al., [21] Stephenson et al. [22] and others, [23] suitable environmentally friendly photoredox catalysts were chosen. [24] Scheme 1. Rational design for a three-component radical/cationic reaction of enamide, alkyl halide and alcohol.

Initial studies centred on examining the reaction of (E)-benzyl prop-1-enylcarbamate (1a), diethyl bromomalonate (2a) and ethanol (3a), in the presence of Et 3 N (2 eq), [Ru(bpy) 2 Cl 2 ] (8, 1.5 mol%), and light from a 25 W compact fluorescent lamp. As described in Table 1, we were able to obtain the desired threecomponent adduct 4a as a 3:2 mixture of diasteromers, although the reaction was not clean. In order to optimize the reaction, photoredox catalysts, alcohols and solvents were screened. To our delight, a change from Ru-containing photocatalyst to Ir(ppy) 2 (dtbbpy)PF 6 (9) furnished the product in higher yield (79%, Table 1, entries 1 vs. 2 ). The change in the nature of the base (DIPEA in the place of Et 3 N) lowered the yields (entry 3). The reaction proceeds in various solvents, except DMF. Dichloromethane was found to be the solvent of choice in both yield and reaction rate to give product 4a in almost quantitative yield, within 3 hours (entry 7). Reduced reaction time to less than one hour was observed under same conditions but in sunlight (entries 7 vs. 8). Additional alcohols, namely MeOH and iPrOH, were also found to be suitable nucleophiles, albeit slightly lower in yield, to give corresponding β-alkylated α-carbamidoethers 4b and 4c respectively (entries 11 and 12). After having identified the optimal conditions of the threecomponent radical/cationic process, the scope of the enamide substrates 1 was investigated (Table 2). We were pleased to find that the reaction conditions developed were applicable to a range of enamides to provide good to excellent yields of α-alkylated imines adducts 4, in short reaction time (1 to 3h). It is noteworthy that no side products, such as homocoupling products or those deriving from reduction of the malonyl radical or the αamidoalkyl radical, were detected. [22j] Several protecting groups at the nitrogen of 1 such as Boc (entry 3), alloc (entry 6), methylcarbonate (entry 9) and acetate (entry 8) were tolerated. However, a slightly lower yield was noted with a triple bond bearing carbamate protecting group, even when an excess of enecarbamate was used (entry 7). This method was also compatible with silylated alcohols (entries 2 and 3). In addition, a β-branched cyclopropyl enecarbamate participated successfully in the reaction to afford 4g in 92% yield (entry 4). Most remarkably, the radical-polar crossover process worked well with aliphatic ketone-derived enamides. This was demonstrated as the N-acyl enamide from cyclohexanone being converted into the quaternary carbon-containing β-alkylated α-amidoether 4k which is a corresponding α-alkylated ketamine (entry 8). Interestingly, the endocyclic enecarbamate worked well to afford a suitable framework 4m for the construction of a number of nitrogen containing heterocycles (entry 10). The photoredox-initiated α-alkylation of enamides provided a convenient synthesis to highly functionalized precursor of αalkylated imines 4, which are important synthetic intermediates for several transformations. [15] To illustrate this, 4a was easily prepared on a 5-mmol scale using 0.5 mol% of iridium(III) catalyst (4 mg). Its reduction using triethylsilane (TESH) and AgOTf proceeded smoothly to afford amine 10 in quantitative yield (Scheme 2). The cyanation of 4a was also carried out, using AgOTf and TMSCN to give easy access to a highly functionalized precursor of amino acid 11. [25] Finally, a Friedel-Crafts alkylation [START_REF]For reviews on Friedel-Crafts reaction, see: a) Organic Synthesis[END_REF] of indole 12 was performed with 10 mol% of phosphoric acid catalyst 14 in toluene at 60 °C. The desired product 13 was isolated as a mixture of diastereomers in a ratio of 2 : 1, with 86% yield over two steps. Additionally, no undesirable bisindolyl by-product was isolated. [27] Scheme 2. Synthetic application of β-alkylated α-carbamidoethers 4.

Control experiments were carried out to investigate whether an ionic pathway was involved in this three-component reaction. It was found that no reaction proceeded in the absence of any of the reaction partners, including [Ir(ppy) 2 (dtbbpy)]PF 6 (9) and light. One equivalent of TEMPO totally suppressed the reaction. These control experiments confirm that the alkylation of enamides occurs through a radical/cationic pathway and two possible mechanisms are proposed in Scheme 3. In the first mechanism (Path A), a strong reductant *Ir 3+ is formed from the photoredox initiator after its excitation with weak fluorescent light. [20b,22e] Then, the reduced iridium species carry out a single electron transfer (SET) to activate the carbon-bromine bond, forming the electron-deficient alkyl radical 5 and a bromide anion, and regenerating the Ir 4+ catalyst. Enamide 1 then reacts with the electrophilic radical generated to give nucleophilic α-amido radical intermediate 6, [28] which could be rapidly oxidized into Nacyliminium cation 7, either by SET from Ir 4+ , or by bromine atom transfer and subsequently trapped by the ethanol component. [START_REF]Oxygen as the oxidant of 6 was excluded because when the reaction was performed in strict exclusion of O 2 , similar yield was obtained and reaction time observed[END_REF] On the basis of previous proposed mechanism, the radical propagation probably occurs through an atom transfer mechanism [START_REF] Curran | [END_REF] However, this mechanism does not explain the role of Et 3 N which does not seem to be limited solely to trapping HBr [START_REF] Curran | [END_REF] Indeed, only a complex mixture could be observed when the reaction was conducted with one equivalent or without a tertiary amine (Table 1, entry 9-10). Similar results were also obtained with bases other than Et 3 N such as NaHCO 3 , K 2 CO 3 , lutidine. To investigate these issues, we hypothesized that, since the oxidation potential of iridium(III) is high (1.60 V vs. NHE in CH 3 CN), [START_REF] Mcdaniel | Potentials measured relative to Normal hydrogen electrode (NHE)[END_REF] it might oxidize enamide derivatives 1 in the absence of Et 3 N. [32][START_REF] Koike | For an example of photooxidation of enamines[END_REF][START_REF]Oxidation potential data for secondary enecarbamates or secondary enamides were not available, only the potential of tertiary enamide[END_REF] On this basis, a second mechanism, which involves the reductive quenching of the excited state of *Ir 3+ by Et 3 N to produce the reducing Ir 2+ species (-1.51 V vs. SCE in CH 3 CN) [24b,35] and the ammonium radical cation, [20c,22i] is postulated (Path B). Then, alkyl radical 5, formed by the Ir 2+mediated reduction of 2, reacts with 1 to provide α-amidoradical 6. Reduction of *Ir 3+ or radical propagation, and subsequent addition of alcohol, afford the desired product 4. In this case, only a catalytic amount of tertiary amine is, therefore, required; and the excess of the base neutralizes HBr, formed in the reaction media. Scheme 3. Proposed mechanism.

In summary, we have described a photoredox-initiated threecomponent domino synthesis of N-carbamoyl α-alkylated imines from easily accessible starting materials. Key features of this approach are its operational simplicity, high atom-economy, wide substrate scope and good to excellent chemical yields. The ready accessibility to α-alkylated imines, which are stables precursors in many useful synthetic transformations, makes the methodology particularly attractive in organic synthesis. Synthetic potentials have also been illustrated in various transformations into functionalized amines.

Experimental Section

General protocol: A flame-dried tube under argon atmosphere (1 atm) is charged with Ir(ppy) 2 (dtbbpy)PF 6 catalyst 9 (1.3 mg, 1.5 µmol) in 1 mL of dry dichloromethane or dry acetonitrile. Enecarbamate 1 (0.1 mmol), diethyl bromomalonate 2a (37 µL, 0.2 mmol), Et 3 N (28 µL, 0.2 mmol) and alcohol 3 (1 mmol) were added in this order. The tube heterogenous solution was degassed by three freeze-pump-throw cycles and the tube was irradiated with 25W fluorescent lamp. After reaction completed (judged by TLC monitoring), the solvent is removed in vacuo and the residue was purified by flash chromatography on silica gel [Heptane/EtOAc : 7/3] to afford the corresponding product 4.

Entry for the Table of Contents

  Photocatalysis

Table 1 .

 1 Survey of reaction conditions for the photoredox-initiated three-component radical/cationic reaction.

	Entry	3	Cat.	Solvent	Et 3 N	4	t [h]	Yield %] [a,b]
	1	3a	8	MeCN	2 eq	4a	24	60
	2	3a	9	MeCN	2 eq	4a	12	79
	3	3a	9	MeCN	2 eq	4a	12	65 [c]
	4	3a	9	toluene	2 eq	4a	12	79
	5	3a	9	EtOH	2 eq	4a	12	78
	6	3a	9	DMF	2 eq	4a	12	0 [d]
	7	3a	9	CH 2 Cl 2	2 eq	4a	3	>99
	8	3a	9	CH 2 Cl 2	2 eq	4a	1	>99 [e]
	9	3b	9	CH 2 Cl 2	-	4b	1	-
	10	3b	9	CH 2 Cl 2	1 eq	4b	1	-
	11	3b	9	CH 2 Cl 2	2 eq	4b	1	88
	12	3c	9	CH 2 Cl 2	2 eq	4c	1	62

[a] Reaction conditions: enecarbamate (1a) (0.1 mmol), diethyl-2-bromomalonate (2a) (0.2 mmol), 3 (1.0 mmol), 8 or 9 (0.001 mmol), c = 0.10 M at RT.

[b]

Isolated yield after column chromatography.

[c]

Et 3 N was replaced by DIPEA.

[d]

Nonreductive radical alkylated enecarbamate was isolated.

[e]

Sunlight was used.

Table 2 .

 2 Photoredox-Initiated Alkylation of enamide derivatives.

	Entry	Product	4	Yield [%]/(dr) [a,b,c]
	1		4d	>99 (1:1)
	2		4e	95 (3:2)
	3
			4f	84 (1:1)
	4		4g	92 (1:1)
	5		4h	62
	6		4i	60 (1:1)
	7		4j	45 (1:1)
	8		4k	74 (1:1)
	9		4l	62
	10		4m	48 (1:1)
	[a] Reaction conditions: enecarbamate (1a) (0.1 mmol), diethyl-2-bromomalonate
	(2a) (0.2 mmol), Et 3 N (0.2 mmol), 3 (1.3 mmol), 9 (0.001 mmol), c = 0.10 M at RT.
	[b] Isolated yield after column chromatography. [c] dr determined by 1H-NMR
	analysis of crude mixtures.

Acknowledgements

Financial supports from CNRS are gratefully acknowledged. T. C. thanks MESR for a doctoral fellowship, University of Paris XI.


Aurélien Alix

Claudia Lalli

Pascal Retailleau

Géraldine Masson

Highly Enantioselective Electrophilic α-Bromination of Enecarbamates -Chiral Phosphoric Acid and Calcium Phosphate Salt Catalysts

published or not. The documents may come   L'archive ouverte pluridisciplinaire

Highly Enantioselective Electrophilic α-Bromination of Enecarbamates -Chiral Phosphoric Acid and Calcium Phosphate Salt Catalysts

Aurélien Alix, ‡ Claudia Lalli, ‡ Pascal Retailleau, and Géraldine Masson* Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France. KEYWORDS. Organocatalysis, Bromination, Chiral phosphoric acid, Enecarbamate, Enantioselective reversal.

Supporting Information Placeholder

ABSTRACT: Metal-free chiral phosphoric acid or chiral calcium phosphate, both catalyzes highly enantio-and diastereoselective electrophilic α-bromination of enecarbamates to provide an atom economic synthesis of enantioenriched vicinal haloamines. Both enantiomers can be formed by simply switching catalyst from phosphoric acid to its calcium salt in good yields and excellent diastereo-and enantioselectivities.

Vicinal haloamine is a versatile structural motif for synthesis of various biologically active compounds and can serve as key intermediates for further transformations. 1,[START_REF] Barton | [END_REF][START_REF] Li | For representatives methods of vicinal haloamines preparation[END_REF] However, to date only a few examples of their asymmetric synthesis have been described. 4 Among the reported different syntheses, electrophilic halo-functionalization of enamides represents one of the most convenient and straightforward approaches for attaining chiral vicinal haloamine compounds in regio-and stereoselective manner. 5 Despite the recent advance in the catalytic asymmetric halogenation of carbonyl, 4c-d,6 acyl chloride, 7 1,3dicarbonyl, 8 oxindole 9 and enyne compounds, 10 no example of an enantioselective α-halogenation of enamides is extant. 11

Scheme 1. Working hypothesis

Chiral phosphoric acids [START_REF] Akiyama | For seminal studies on the use of binol-derived phosphoric acids[END_REF][START_REF] Akiyama | For recent reviews on chiral phosphoric acid catalysis[END_REF] and chiral phosphate metal salts 9d,14 were found effective in catalyzing enantioselective addition of enamide compounds [START_REF] Evano | Selected reviews dealing with enamides as nucleophiles[END_REF] to various electrophiles, such as carbonyl, 16c imine, 16a,b,d-g,j azodicarboxylate 16i and nitroso compounds. 16h Recently, it was reported on activation of N-halogenosuccinimide toward highly enantioselective reactions catalyzed by chiral phosphoric acid or chiral sodium phosphate. 9d,17 Inspired by the successful employment of these catalysts, and combined with our interest in enantioselective transformations, 16e-g,i,j we envisioned that chiral phosphoric acids or their metal salts 3 could catalyze enantioselective electrophilic α-halo-functionalization of enamide compounds (Scheme 1). Moreover, the N-halogenosuccinimide electrophile (2), including a masked nucleophilic component, could be incorporated into the electrophilic iminium intermediate 5 (Scheme 1), leading to a valuable aminal 4 18 for retro-inverso synthesis of peptide mimics. 19 Herein, we report the first enantioselective α-bromo-functionalization of enecarbamates through a domino bromination/nucleophilic addition. This approach also led to the discovery that chiral phosphoric acid (3, M = H) and its calcium salt (3, M = Ca) give access to both enantiomeric vicinal haloamine products. a Reaction conditions: enecarbamate 1a (0.1 mmol), NBS (2) (0.05 mmol), 3 in 1 mL of toluene for 14 h. b Under similar condition, 0.5 mL of toluene. c Reaction using (Z)-enecarbamate 1a. d Reaction performed for 48 h. e Yields referred to chromatographically pure major diastereoisomer. f Determined by chiral HPLC analysis. g Determined by 1H NMR of the crude material. h (1R,2S)-enriched-4a. i Reaction was performed with 1.2 equiv. of enecarbamate 1a (0.6 mmol). j (1S,2R)-enriched-4a.

To validate our hypothesis, we began our studies by examinating the reaction of (E)-N-(benzyl prop-1-en-1-yl)carbamate (1a) with N-bromosuccinimide (NBS, 2) in the presence of 10 mol% of a chiral phosphoric acid 3 at room temperature. As shown in Table 1, both reactivity and enantioselectivity were dramatically affected by the structure of the chiral phosphoric acid. The highest diastereo-and enantioselectivity was ob-tained when (R)-3,3'-bis (2,4,6-triisopropylphenyl)-BINOL (TRIP) phosphoric acid (3e) was used (88% ee and 9:1 dr, entry 5). 20 Additionally, it was found that significant reduction of catalyst loading to only 1 mol% in a more concentrated condition (c 0.1 M) improved the reaction diastereo-and enantioselectivity (>95:5, 98% ee, 99% yield, entries 9 vs. 5). Comparable enantioselectivity was obtained when the catalyst loading was reduced to 0.1mol%, despite reduced yield (entry 11). Reducing the amount of enecarbamate 1a to 1.2 equivalents with respect to 2 provided the 4a in lower yield (entry 13).The absolute configuration of the major cis-isomer 4a was unambiguously determined to be 1R and 2S by X-ray analysis [see the Supporting Information (SI)]. As the stereochemical outcome of electrophilic bromination can be dependent of the enecarbamate geometry, the reaction with (Z)-enecarbamate (1a) was investigated. It was found that the (Z)-isomer 1a still gave the same enantiomer of 4a as the major product albeit with lower yield (entry 12). However, to our surprise, reverse enantioselectivity of product 4a to supply (1S,2R)-cis-4a was observed by changing the catalyst from 3e to its corresponding metal salts (Li, 3f; Ca, 3g), still with excellent ee and dr values (entries 14 and 15). 21 Both enantiomers of 4a can, thus, be prepared efficiently. 14a,b,21 We next examined the scope of the enecarbamate component in this enantioselective domino process, catalyzed by chiral phosphoric acid 3e or its calcium salt 3g. Representative results are summarized in Table 2. In general, the 3e-catalyzed reaction proceeded smoothly with high diastereo-and enantioselectivity, and excellent yield greater than 90%. This reaction works well for a broad range of substituted enecarbamates bearing a linear or a branched alkyl group as well as heteroalkyl substituents. Introduction of steric hindrance at the αposition of the ene moiety resulted in a slight decrease in the yield without affecting the enantioselectivity of the process (entry 8). Even the β,β-disubstituted enecarbamate 1n afforded the corresponding bromoaminal product 4n containing a quaternary center with 96% ee (entry 13). In contrast, the vinylcarbamates substituted by aryl groups on β-position failed to participate in this electrophilic α-bromination probably, because of their lower nucleophilicity. [START_REF]Only unreacted enecarbamate was recovered when chiral phosphoric acid as well as its calcium salt were used as catalyst. (23) MALDI-TOF data of 3g exhibits a peak at m/z 1543 corresponding to dimeric species[END_REF] Modification of the carbamate moiety from benzyl to ethyl, propargyl, allyl or tert-butyl carbamate afforded the bromoaminal products (4b to 4f, entries 1-5) with similar diastereo-and enantioselectivities. It is worthy to note that no bromination of unsaturated bonds present on enecarbamates was observed whether on the carbamate moiety (entries 2 and 3) or the lateral chain (entry 7), thus demonstrating the high chemo-and regioselectivity of this reaction. 17 We also investigated enantioselective electrophilic α-bromination using the optimized reaction conditions with calcium salt 3g. A variety of selected enecarbamates 1 reacted with good enantioselectivity to afford, in all cases, the opposite enantiomer of the products formed using corresponding phosphoric acid 3e. We also found that, contrary to our previous studies, N-protecting group of 1 has an influence on the enantiomeric excess, where diminished enantioselectivity was observed when Boc or Alloc was used (entries 14 and 15).

Then, we became interested in pursuing experiments designed to test the mechanistic hypothesis outlined in scheme 1. Different modes of activation of NBS by 3 could be proposed, such as hydrogen bonding, metallic bonding or proton transfer with formation of a chiral bromonium ion intermediate. 9d,17 Inspired by the elegant work of Denmark et al.,17c we investi -gated the addition of achiral Lewis base Ph 3 P=S known to favor the ion-pairing mechanism. Under this condition, whichever using catalyst either 3e or 3g, similar results in terms of reaction rate, yield and ee were observed (cf. SI). The reversal phenomenon of enantioselectivity by phosphate salt 3g was preserved whereas the same enantiomer should have been observed with a mechanism involving a chiral bromonium ion intermediate. We also carried out a control experiment with a two-component catalyst composed of TRIP phosphoric acid 3e and Ca(iPrO) 2 , furnishing the desired product in 95% ee with the same selectivity than 3e. It can, therefore be suggested that 3e would activate NBS through either hydrogen bonding or ion-pairing. At this stage, it is not possible to distinguish these two activation modes. On the other hand, earth metal bonding interaction between 3g and NBS would be evoked. Then, we carried out a nonlinear effect experiment to gain further insight into the active Ca phosphate salt catalyst structure. We observed a positive nonlinear effect in the 3g-catalyzed αbromation of enecarbamates (cf. SI), which indicates that the active catalyst was a dimeric species rather than Ca II -free phosphoric acid or mono(phosphate) salt. 14,23 In addition, it is worth noting that secondary enecarbamates gave no reaction, in the presence of 3e or 3g, suggesting that activation of NBS alone is not sufficient to achieve effective α-bromination.

Scheme 2. Proposed transition state model Scheme 3. Ring opening of succinimide

Based on these observations, we assumed that 3e and 3g acted as a bifunctional catalyst activating both NBS and the enecarbamate via hydrogen bonding and metal chelation, respectively. While a precise understanding of the origin of enantioselectivity reversal awaits further study, two different transition state models, 6 and 7, were postulated (Scheme 2). Phosphoric acid 3e with the sterically bulky 2,4,6-triisopropylphenyl group efficiently hindered the Re face of NBS, and the enecarbamate could only attack the Si face of NBS leading to the (S)imine intermediate. In contrast, the other face (Re-face) was fully accessible with calcium bis(phosphate) complex 3g to furnish the (R)-isomer. 14 In both cases, a highly diastereoselective nucleophilic addition reaction of imide to (S)-or (R)imine would then furnish the observed cis-bromoaminal (1R,2S)-4a or (1S,2R)-4a, respectively.

To illustrate the synthetic potential of this novel catalytic enantioselective domino bromination / succinimide addition, we developed conditions to open the succinimide ring. We were delighted to observe that such ring opening can be carried out by fast filtration on basic resin to generate valuable aminal 8 18 with retention of enantiopurity (Scheme 3). Furthermore, the multifunctionality of the 1,2-bromoaminal products allowed for a short-step, stereoselective synthesis of other various useful chiral building blocks such as aziridines, 5e,f,i 1,2-ether/thioether-aminals, 5e,g,l imidazolidin-2-ones 5e and pyrrolizidines. 24 In conclusion, we have reported the first enantioselective chiral phosphoric acid-catalyzed electrophilic α-bromination of enecarbamates. [START_REF] Phipps | During submission of our manuscript, Toste reported fluorina[END_REF] The efficiency of the system allows reactions to be run under mild conditions at room temperature with a modest amount of catalyst (1 mol%). We have also shown an unprecedented reversal of enantioselectivity for a catalytic bromination reaction by a chiral calcium phosphate salt. The high efficiency and operational simplicity of this procedure makes it a practical protocol for synthesis of chiral vicinal haloamines.

ASSOCIATED CONTENT

Experimental details, characterization data, HPLC enantiomer analysis, and 1 H and [START_REF] Akiyama | For recent reviews on chiral phosphoric acid catalysis[END_REF] C NMR spectra for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

Table 1 . Optimization of enantioselective α-bromination of enecarbamates a

 1

	entry	R	3 (mol %)	yield (%) e	ee (%) f /dr g
	1	C6H5/H (3a)	10 a	33	51/(75:25) h
	2	4-ClC6H4 [H8]/H (3b)	10 a	39	52/(75:25) h
	3	2-naphthyl/H (3c)	10 a	44	62/(85:25) h
	4	1-naphthyl/H (3d)	10 a	39	64/(85:25) h
	5	2,4,6-tri-iPr3C6H2/H (3e)	10 a	87	88/(90:10) h
	6	3e	5 a	87	88/(90:10) h
	7	3e	2 a	87	90/(>95:5) h
	8	3e	1 b	89	94/(>95:5) h
	9	3e	1 b	99	98/(>95:5) h
	10	3e	0.5 b	75	94/(>95:5) h
	11	3e	0.1 b	56	92/(>95:5) h
	12	3e	1 b,c	67	86/(>95:5) h
	13	3e	1 b	64	98/(>95:5) h,i
	14	2,4,6-tri i PrC6H2/Li (3f)	1 b,d	74	-96/(>95:5) j
	15	2,4,6-tri i PrC6H2/Ca (3g)	1 b,d	78	-98/(>95:5)

Table 2 . Enantioselective direct α-bromation of enecarba- mates: scope of substrates a

 2

	entry	R 1	4	Yield (%) b	ee (%) d
	1		(1R,2S)-4b	90	91 e
	2		(1R,2S)-4c	75	91 e
	3		(1R,2S)-4d	81	86 e
	4		(1R,2S)-4e	92	90 e
	5		(1R,2S)-4f	99	94 e
	6		(1R,2S)-4g	93	96 e
	7		(1R,2S)-4h	90	97 e
	8		(1R,2S)-4i	77	92 e
	9		(1R,2S)-4j	46	92 e
	10		(1R,2S)-4k	72	91 e
	11		(1R,2S)-4l	94	84 e
	12		(1R,2S)-4m	94	98 e
	13		4n	66	96 f
	14		(1S,2R)-4d c	62	-88 g
	15		(1S,2R)-4f c	67	-81 g
	16		(1S,2R)-4i c	74	-86 g
	a Reaction conditions: enecarbamate 1a (0.2 mmol), NBS (2) (0.1 mmol), 3e or 3g (1
	mol%) in toluene (1.0 mL) at RT for 14 h.

b

Yields of chromatographically pure product. c Reaction performed for 48h. d Enantiomeric excess was determined by chiral HPLC analysis. e (1R,2S)-enriched-4. f Absolute configuration was not determined. g (1S,2R)-enriched-4.

ACKNOWLEDGMENT

We wish to thank the ICSN and CNRS for financial supports and ANR for post-doctoral fellowships (to A.A. and C.L.). We also acknowledge Prof. Jieping Zhu for his generous support

AUTHOR INFORMATION

Corresponding Author masson@icsn.cnrs-gif.fr.

Author Contributions ‡These authors contributed equally.

Notes

The authors declare no competing financial interest.

TOC Template (9 cm x 3-1/2 cm)