Thanh Binh Nguyen

A S Castanet

Dr G Dujardin

Pr R Dhal

Dr A Martel

Recent Advances in the Synthesis of Heterocycles via Reactions Involving Elemental Sulfur

Keywords: Elemental sulfur, Heterocycle, Sulfur heterocycle, Nitrogen heterocycle, Thiophene

Introduction

It is well known that heterocycles are among the most significant molecules for everyday life, ranging from natural products and bioactive substances to functional materials. The role played by modern organic chemistry is to develop cheaper, greener, more direct and more sustainable synthetic methods of these molecules while avoiding environmental problems and natural resource depletion.

As a waste produced by modern oil and gas refineries at 70 million tons per year, sulfur is an extremely cheap raw material. Its low toxicity along with its unique physical properties (stable, odorless, non-hygroscopic, free-flowing solid at rt) makes this substance a user-friendly synthetic tool [1] of both sulfur-containing and sulfur-free heterocycles.

At the beginning of 2017, we have reviewed significant organic reactions involving elemental sulfur for the period 2000-2016. [2] From 2017, reports on such reactions prospered thanks to its amazingly rich chemistry along with all the above-mentioned qualities of this element as a reagent. Since elemental sulfur is one of the central molecules of our research, we feel the need to prepare this short review to provide the readers with a detailed and comprehensive overview of development on the organic synthesis with this element from 2017 until now. However, reminders of reactions reported before this period will be given when necessary.

Due to the complexity of the reactivities of elemental sulfur, we arbitrarily divide its organic reactions into two main categories based on the presence or not of the starting sulfur in the final products. For the first category, sulfur is undeniably the best source of sulfur atoms in the formation of organosulfur. If sulfur is not incorporated in the final product, it can act as an oxidant, reductant or catalyst as a single component or in combination with other catalysts.

Sulfur is in general not very reactive under ambient conditions but can become highly reactive upon heating and/or in the presence of a base or a transition metal ion or complex. With appropriate choices of activating conditions, its reactivity could be strongly modified.

Scheme 1

Similar transformation was observed with cyclopentanone 4, leading to fused thiophene 5, whereas complex mixtures were obtained with higher cycloalkanones (cyclohexanone, cycloheptanone)

Scheme 2

The generation of the key scaffold but-2-en-1-one could be achieved in different manners. For example, Deng et al performed the condensation of phenylacetaldehyde 6 with 1,3-diketone (7, R = Alkyl) or b-ketoester (7, R = OAlkyl) with K2CO3/KHCO3 (3.5 equiv) as base catalysts in the presence of sulfur (Scheme 3). [4] In this case, the initially formed but-2en-1-one 8 underwent an isomerization to its thermodynamically more stable regioisomers but-3en-1-one 9, which reacted with sulfur to produce thiophenes 10 in good yields.

Scheme 3

Alternatively, dihydrofuran 15, a synthetic equivalent of but-3-en-1-one 9, could react with elemental sulfur in the presence of morpholine catalyst in a similar manner (Scheme 4). This intermediate 15 could be generated by triethylamine catalyzed threecomponent reaction between penta-2,4-dione 11, benzaldehyde 12 and a-pyridiniumacetophenone bromide 14 (generated from reaction between phenacyl bromide 13 and pyridine). [5] Scheme 4

Likewise, 1,3-diketo compounds such as 4hydroxycoumarine, ethyl acetoacetate, dimedone and cyclohexa-1,3-dione could be used in place of penta-2,4-dione, whereas p-nitrobenzyl chloride displayed the same reactivity in this kind of multicomponent reactions. Selected examples were shown in Scheme 5.

Scheme 5

The combination of aromatic aldehydes and phenacyl bromides could be replaced by chalcones 17 as a unique component (Scheme 6). [6] In this case, the first step was a Michael addition of 1,3-diketone or bketoester 18 to chalcones 17 catalyzed by triethylamines whereas the second step followed exactly the same pathway.

Scheme 6

Conjugated butenyne or enyne system bearing a trifluoromethyl group such as 19 reacts in the same manner (Scheme 7). [7] Thiophene 21 was expected to be generated from the reaction of 19 with sulfur upon heating with K2CO3 in DMF was found to be further trapped by gaseous chlorodifluoromethane 20 via difluorocarbene to give 22. Similar reactivity was observed with elemental selenium. Gewald reaction is unarguably one of the best methods to synthesize 2-aminothiophenes. [START_REF] Bozorov | For some reviews on Gewald reactions[END_REF] One of its important version consists in a three-component assembly of ketones with acetonitriles substituted by a strong electron withdrawing group (such as ester, amide, nitrile) and elemental sulfur. Recently, the Gewald reaction condition was proven to be compatible to boronate substrates 23, leading to the corresponding 2-aminothiophenes 24 readily functionalized by known boron chemistry (Scheme 8). [9] Scheme 8.

The Michael-Gewald four component reaction was developed to increase rapidly the molecular diversity. [10] For this purpose, the carbonyl components for the Gewald reaction 27 were formed by the conjugate addition of different indole derivatives 25 to α,β-unsaturated aldehydes 26 (Scheme 9). This is followed by an in situ Gewald three-component reaction which results in the formation of compound 28 bearing an indole and a 2-aminothiophene moiety separated by one-carbon spacer.

Scheme 9.

The carbonyl component in Gewald reaction could be replaced by a benzylidenemalononitrile 29, which could be easily generated by condensation of an aldehyde with malononitrile (Scheme 10). [11] Alternatively, direct four-component reaction could be accomplished with proline catalyst.

Scheme 10.

One of the limitations of Gewald reaction is the acetonitrile components should be substituted by a strong electron donating group. Moreover, chalcones were not previous known as the ketone component for this reaction. In view of this missing literature, we have developed a new version of Gewald reaction between chalcones 30, arylacetonitriles 31 and sulfur (Scheme 11). [12] Scheme 11.

The first step of formation of Michael adduct 32 between chalcones and arylacetonitriles was efficiently performed with DBU as a strong organic base catalyst. These conditions led to the expected adduct 32 even at rt form less than 30 min. On the other hand, DABCO was found to be particularly useful base catalyst for subsequent thienylation of 4-cyano-1-propanones 32, leading to a wide range of fully substituted 2aminothiophenes 33. Compared to classical Gewald reaction, our transformation consists in an additional oxidizing aromatization with S8/DMSO. The strategy was successfully applied to a wide range of arylacetonitriles and chalcones and could also be extended to cyclohex-2-enone and benzalacetone, despite in lower yields.

When cyanoacetate 34 was submitted to the same conditions, the reaction stopped at the stage of formation of trans-dihydrothiophene adduct 35 without further aromatization (Scheme 12).

Scheme 12.

It was found that the low valent transition metalphosphine complexes systems genenated in situ from [M]-Ph3P-Et3Al (1:2:4) could catalyze thienylation of N,N-dimethylhept-2-yn-1-amine 36 to 37 along with the formation of thioamide 38 in various proportions (Scheme 13). [13] Thiophene 37 was selectively formed in 58% yield when γ-Al2O3-supported Co(OAc)2 was used as Co catalyst precursor.

Scheme 13.

Interestingly, bis-thiophene 40 was formed exclusively from decadiynediamine 39 with elemental sulfur catalyzed by Co(acac)2-PPh3-AlEt3 (1:2:4) (Scheme 14). The diaryldiacetylene 41 system could be thienylated to 42 with elemental sulfur and a suitable base such as NaSH or t-BuONa even at rt (Scheme 15). [14] Scheme 15.

Heating was required for polyaromatic or heteroaromatic substrates.

Theoretically, the transformation consists in a double addition of dihydrogen sulfide to two triple bonds.

Treatment of 43 with NaSH generated from the reduction of S8 with NaBH4 in DMF led to the corresponding sulfur heterocycles 44-45 in moderate yields (Scheme 16). [15] The reaction followed as sequence of nucleophilic sulfuration and cyclization. When substituted by a phenyl group, the product exists as benzylidene form 45, whereas aromatic form 44 is exclusive for t-butyl derivative. Scheme 16.

Thiophenes fused with aromatic carbocycles

Benzothiophenes

2-Nitrochalcones 46, readily obtained from classical Claisen-Schmidt condensation between onitrobenzaldehydes and acetophenones, could serve as excellent precursors for the synthesis of 2benzoylbenzothiophenes 47 (Scheme 17). [16] When treated with sulfur in the presence of DIPEA or similar tertiary amines, chalcones 46 underwent a cascade of reactions of alkene sulfuration, aromatic sulfurative denitration and cyclization in the absence of transition metal catalyst. Later, this reaction was found to be operational even at rt when DMSO was used as additive. [17] The reaction conditions tolerated in general many functional group, including halogen, which serve at starting point for further functionalization of benzothiophenes products. Notably, the sulfurative denitration was specific for ortho-nitro groups, while other meta and para-nitro groups remained untouched.

Scheme 17.

The strategy of sulfurative denitrative cyclization was further applied to o'-nitrochalcones 48, leading consistently to thioaurones 49 (Scheme 18). This family of products, well known for their photochromic properties with application as photoswitch, was previously synthesized via multistep sequences involving malodorous thiol/sulfide precursors as well as strong bases. Interestingly, the reactions were found to proceed even at rt for substrates bearing electron withdrawing groups. With substrates which are substituted by strong and multiple electron donating groups or/and sterically demanding, the expected products could be formed at higher temperatures in satisfactory yields.

Scheme 18.

Very recently, Miura et al. proposed a synthesis of benzothiophene 52 by rhodium-catalyzed threecomponent coupling reaction of arylboronic acids 50, alkynes 52, and elemental sulfur with silver acetate as oxidant (Scheme 19). [18] An interesting feature of this method is the formation of benzothiophenes 52a with high regioselectivity when non symmetrical alkynes were used. The reaction proceeded via a sequence of alkyne insertion, C-H activation, and then sulfur atom transfer to the metallacycle intermediate. Likewise, dibenzothiophenes 54 can be assembled from the parent biarylboronic acids 53 (Scheme 20). The reaction was found to proceed at rt with stoichiometric amount of silver acetate oxidant.

Scheme 20.

Yoshida et al found that the degree of annulative cyclization of 1,1-diphenylethylene 55 could be controlled by simply changing the quantity of iodine oxidant and reaction time (Scheme 21). [19] Scheme 21.

Disulfurative thienylation to 57 occurred upon prolonged heating excess molecular iodine, whereas shorter reaction time with stoichiometric amount of I2 led to 3-phenyl product 56.

Similar conditions applied to diphenylacetylene 58 produced both benzothiophenes 59 and 60 in low yields (Scheme 22). It should be noted that the reaction required sulfur and iodine in large excess.

Scheme 22.

Non symmetrical o,o-lithiated diphenylacetylene 61 could be sulfurated with elemental sulfur to provide tetracyclic fused benzothiophenes 62a-b after oxidation with K3Fe(CN)6 in low yield as a mixture of both regioisomers (Scheme 23). [20] Subsequent desulfuration with metallic copper led convergently to benzothienobenzothiophene 63 in excellent yield, despite high temperature of the process.

Scheme 23.

Nitro groups in a polycyclic aromatic system were known to be displaced by a sulfur group when heated with elemental sulfur. [21] Recent exploitation of this unique chemistry was used to synthesize various molecules with interesting properties. [22] For example, 1-nitroperylene 64 reacted with sulfur in Nmethylpiperidone at 180 ºC to provide fused thiophene 65 (Scheme 24). [23] Scheme 24.

The reactions were found to be considerably facilitated in extensive fused aromatic system with electron withdrawing groups. Indeed, the reaction of mononitroperylene 66a with sulfur to produce thiophene 67 in good yield at 153 ºC (Scheme 25). [24] Scheme 25.

Notably, dinitroperylene 66b reacted with sulfur at lower temperature to provide thiophene product 68. [25] The degree of sulfuration seemed strongly dependent on the reaction temperature. This reaction was in agreement with the previous result observed with parent tetracarboxylic acid derivative. [26] 1-Ethynylanthaquinones 69 reacted readily when heated with a basic solution of sulfur in ethanol (Scheme 26). Both 2-H and 2-Cl substrates were competent substrates, leading to benzothiophenenaphthoquinone fused products 70 in good to excellent yields. [27] It is obvious that the naphthoquinone facilitates this sulfurative annulation.

Scheme 26.

Naphthylphenylacetylene 71 reacted with sulfur at rt with NaOH as a base in DMF to provide fused thiophene 72 in low yield along with its dimer disulfide 73 (Scheme 27). [28] When the reaction was performed at higher temperature with NEt3 as a base, the reaction resulted in thiophene 72 in excellent yield.

Scheme 27.

A fourfold thienylation of tetraethynylperylene 73 could be achieved via heating with large excess of sulfur upon prolonged heating in DMF (Scheme 28). [29]

(8 equiv) N N R O O R O O X O 2 N N N R O O R O O S S S DMF 120 ºC, 3 h X = NO 2 , 66b R = pent-3-yl N N R O O R O O S X = H, 66a R = 2,5
O N O N R O O R Ph O N O N R O O R Ph S O N O N R O O R Ph S S) 2 S 8 ( 6

1.5.2. Thiophene fused with azulene

Thienylation of azulyl aryl acetylenes 75 could be achieved by heating with elemental sulfur in DMF (Scheme 29). [30] Scheme 29.

In view of the regiochemistry of this transformation, it is concluded that the azulene ring is more reactive than the benzene rings (substituted or not) as well as naphthalene, thiophene and ferrocene rings.

Thiophene fused with heteroaromatic cycles

Thiophene fused with indole

N-Ethynylindole 77 could be cyclized into fused heterocycles 81 via a one-pot transformation including: (i) lithiation with strong base n-BuLi at low temperature to 78, (ii) sulfurative cyclization of 78 with elemental sulfur to 78 via 79, and (iii) S-alkylation of 80 with alkyl halides (Scheme 30). [31] Contrary to the previous cases of sulfurative cyclization of aromatic ethynyl system, all the reactions of this approach occur at or below rt.

Scheme 30.

In 2019, Zhang et at reported as synthesis of 8Hthieno[2, 3-b]indoles 83 via oxidative sulfuration of Friedel-Craft adducts 82 between indoles and chalcones (Scheme 31). The reaction occurred in DMSO at 120 °C in the presence of excess NaOt-Bu and provided a wide range of fused heterocycles in good yields. [32] Scheme 31.

When the position 2 of the indole core is substituted as in 84, the thienylation proceeded on the phenyl ring, leading to bis-hetarene 85 in a moderate yield.

Scheme 32.

In 2017, Deng et al reported a regiodivergent threecomponent access to fused indole-thiophene heterocycles 87 or 89 by heating indoles with acetophenones and elemental sulfur (Scheme 33). [33] In the presence of HI as a strong acidic promoter, the reaction proceeded via 86 as a result of a first step of Friedel-Craft reaction between indole and acetophenone followed by oxidative thienylation with elemental sulfur. On the other hand, when DMF was used as the solvent in the absence of the strong acid, the first step was as Willgerodt reaction of acetophenone with DMF, which acted as a high temperature dimethylamine source to provide 88. This step allowed migration of the electrophilic center to the end of acetophenone and reversed the regiochemistry of the reaction. [34] Scheme 33.

In a similar manner, cinnamic acid 91, which could involve in a decarboxylative Willgerodt pathway in DMF, displayed the same reactivity (Scheme 34). [35] Scheme 34.

A similar set of conditions involving a stoichiometric amount of molecular iodine was applied to cyclohexanones 93 (Scheme 35). [36] In this case, based on the regiochemistry of the final fused heterocycles when 4-substituted cyclohexanones were used, the formation of Friedel-Craft adducts 96 by the attack of C-3 of indoles 93 to the ketone function of cyclochexanones 94 was the first step. Iodine played an important role in this reaction, acting as both precursor for in situ generation of strongly acidic HI to catalyze the Friedel-Craft and as oxidant for sulfuration and aromatization.

Scheme 35.

Yu et al reported a synthesis of 4H-thieno [3,2b]indole 98 via thermal sulfuration of 97 with elemental sulfur in HMPA (Scheme 36). [37] Although the mechanism was not fully understood, the reaction involved scission of the triple bond with subsequent recombination of the benzylidyne group. When Ar 1 is replaced by a methyl group, the reaction proceeded via a different pathway, leading to thieno [3,4-c]quinoline-4(5H)-thione products 100 as a result of a cascade involving demethylation and disulfuration (see section 2.3.2). Scheme 36.

Thiophenes fused with fused pyridines

Construction of thieno [3,4-c]quinoline-4(5H)thione 100 was accomplished by heating of 1phenylpropynes 99 with sulfur in HMPA (Scheme 37). [37] The methyl group of the triple bond as well as methylthio were removed during this cascade of disulfuration.

Scheme 37.

Khan et al developed a synthesis of 2benzoylthieno[2, 3-b]quinolines 102 from 2-haloquinolinyl ketones 101 (Scheme 38). [38] According to the proposed mechanism, the first step was a dehydrogenation of the propanone moiety to chalcone.

The presence of the pyridine would facilitate the subsequent displacement of the chloro by sulfur. While the reaction conditions were relatively complex with the involvement of copper-TEMPO-2,2'-bipyridine catalysts and tetrabutylammonium acetate as an ionic reaction medium, the reaction followed the same pathway as for the reaction of o-nitrochalcones with sulfur in the presence of a tertiary amine previously described by our group (Section 2.2.1). [16], [17] Scheme 38.

Huang et al reported a copper-catalyzed threecomponent access to a variety of benzo [4,5]thieno [3,2c]isoquinoline and thieno [3,2-c]isoquinoline 105 from methylketoxime acetates 103, o-halobenzaldehydes 104, and elemental sulfur (Scheme 39). [39] It was postulated that 3-aminobenzothiophene would be formed from sulfuration of acetophenone oxime acetate.

Scheme 39.

Acetylenes 106 bearing an aza anthraquinone moiety was found to react easily with elemental sulfur in a basic alcoholic solution (Scheme 40). [27] The very short reaction time (5 min) could be explained by the presence of both ketone groups in the pyridine ring, which would facilitate the first step of aromatic sulfuration to fused thiophenes 107. Scheme 40. [4',5']thieno [3',2':4,5]imidazo [1,2a]pyridine Benzothieno-imidazo[1,2-a]pyridines 109 could be prepared in excellent yields (89-99%) via sulfenylative cyclization of intramolecular sulfenocyclization of 2-(2-halophenyl)imidazo[1,2-a]pyridine 108 using sulfur powder in the presence of copper catalyst (Scheme 41). [40] Since AcOH was one of the reaction solvents and could react instantaneously with t-BuOK to provide KOAc, the real base in this reaction should be KOAc.

Benzo

Scheme 41.

Thieno[2,3-d]pyrimidine

Thieno[2, 3-d]pyrimidin-4-amines 111 could be conveniently synthesized via four-component reactions of ketones 110 and malononitrile with elemental sulfur in formamide (Scheme 42). [41] Scheme 42.

The reaction was based on a first step of threecomponent Gewald reaction, which occurred at lower temperature, followed by cyclocondensation of the Gewald adduct 112 with formamide. The second step required high temperature up to 200 °C and Na2HPO4 as a catalyst. The presence of a catalytic amount of triphenylphosphine was found to be beneficial to the reaction by preventing the dimerization of 112. A wide range of acetophenones as well as 2phenylacetophenone, propiophenone and cyclohexanone could be used as the ketone component in good to excellent yields.

9H-Thieno[3,2-b]chromen-9-one

The skeleton of 114 could be formed by a cascade reaction of conjugated o-hydroxy dienone 113 with sulfur and chlorodifluoroacetate as difluorocarbene source (Scheme 43). [42] The reaction was initiated by a base-induce cyclization into chromenone, followed by double sulfuration and carbene insertion.

Thiophene fused with thiazole

In 2018, Deng et al reported a multicomponent access to thiophene-thiazole fused systems 116. [43] On heating methyl ketone oxime acetates 115 with benzaldehydes and elemental sulfur in the presence of copper catalyst and Li2CO3 as a base in DMSO, a cascade of bis-heteroannulation was efficiently accomplished (Scheme 44). The method could also be applied to benzylideneacetone and (E)-3-methylpent-3-en-2-one oxime acetates to yield 116d and 116e, respectively.

Scheme 44.

Inspired from this seminal finding, other extensions were developed by the same group and other (Scheme 45). All approaches were based on three-component reaction of sulfur with a C4N1-synthon 117 and a C1synthon 120, which provide C4N1 and C1 fragments, respectively for the assembly of thieno [3,2-d]thiazole core 121. First, acetophenones oxime acetates could be replaced by a-azidostyrene although much less efficiently with only one example in 33% yield (entry 1). [44] Secondly, phenylacetylenes could be used as C1synthon with loss of one carbon atom (entry 2). [44] In both of these cases, the reactions required highly basic guanidine base triazabicyclodecene (TBD) in near stoichiometric amount.

Third, the presence of copper catalyst was found to be unessential as mentioned in the following cases (entries 3-10). Activated methyl groups could act as the C1-synthon as in the cases of methylhetarenes wherein the methyl group is in 2-or 4-position to the nitrogen atom of the azaheterocycles (entry 3), [45] or acetophenones (entry 4), [46] the reactions were accomplished with alkaline carbonates as the base catalyst.

Since acetophenone oxime acetates were prepared via two-step sequence from the parent acetophenones, an access involving directly acetophenones and a suitable nitrogen source would be highly desirable. Urea was suggested for this purpose (entries 5-6). [47] By choosing appropriate additive, the reactions could proceed with loss (entry 5) or conservation (entry 6) of the methyl carbon of the acetophenone substrates. Moreover, it should be noted that acetophenone oximes themselves could be used directly as C4N1synthon with other acetophenones as C1-synthon (entry 7). [48] Phenylacetic acids as well as their methyl esters could be employed as C1-synthon (entry 8). [49] 2-Acetonapthone as well as other acetylated poly(hetero)aromatic analogs could be used as C4synthon with benzylamines as C1N1-synthon (entry 9). [50] In this case the amino group of benzylamines acted as nitrogen building block for the construction thieno [3,2-d]thiazole core. It is evident that the polyaromatic system in 2-acetonapthone contributes to the success of the sulfuration of its (C-1)-H bond, thus facilitate the formation of fused thieno [3,2-d]thiazole. Indeed, similar reaction conditions applied to acetophenone resulted in 2,4-diphenylthiazole. Finally, Isothiocyanates could be used as C1-synthon, providing a convenient access to N-substituted thieno [3,2-d]thiazole derivatives. [51 In this case, reactions of alkyl isothiocyanates resulted in lower yields.

(12 equiv) N N S R 1 R 2 NH 2 N N S Ph NH 2 selected examples: N N S Ph Ph NH 2 N N S Ph Me NH 2 N N S NH 2 96% 97% 91% 87% NC H 2 N S R 1 R 2 via 113 114 S 8 O S O SCF 2 H ClCF 2 COONa MeOK (3 equiv) OH O R R R = H, 65% R = 4-MeO, 66% (6 equiv
Concerning the reaction pathway, although the detailed mechanism was not fully elucidated, 3aminobenzothiophene was suggested to be the key intermediate, which is generated by successive sulfuration of the methyl group and the o-C-H bond. Thanks to the presence of the sulfur atom of the benzothiophene ring, 3-aminobenzothiophene could be considered as an electron-enriched aniline, readily underwent an o-sulfuration upon heating as previously known. [85]- [90] Subsequent oxidative condensation with C1-synthon promoted by elemental sulfur leading to benzothiophenes is a well-known process for the chemistry of this element.

Scheme 45

According to the proposed reaction pathway, it is possible that 2-aminobenzothiophene 125 displays similar behavior (Scheme 46). [52] Generated in situ from o-bromophenylacetonitriles 122 by copper-catalyzed sulfuration with elemental sulfur, this heteroaromatic amine could be further sulfuration and trapped with a benzadehyde to provide 2phenylbenzo [4,5]

1,2-and 1,3-Dithioles and other sulfa heterocycles with sulfur as the only heteroelement

1,2-Dithiole-3-thione motif is found in numerous pharmaceuticals with interesting biological and medicinal utility. Reported recent syntheses were based on the use of elemental sulfur as both threesulfur atom donor and redox reagent on different derivatives of 1-arylpropynes 127 such as trifluoromethyl 127a [53] (Scheme 47, entry 1) or propargylamines 127b (Scheme 47, entry 2). [54] In both cases, the reactions were performed in the presence of copper(I) salts as catalyst at 120 °C. Sulfides issued from disproportionation reaction of elemental sulfur in the presence of inorganic bases such as Cs2CO3 and K3PO4, were suggested to initiate the reaction in these two cases. Alternatively, the reaction of arylpropenes 128a under thermal conditions required higher temperatures (Scheme 47, entry 3). [55], [56] When a simple 1-arylpropene such as anethole 128b was used as a substrate (Scheme 47, entry 4), [56] Ar 1 various reaction conditions were applied to reduce the reaction time from several hours under conventional heating to 10 min under microwave irradiation, resulting in an improvement in yield and overcoming the undesired by-product formation associated with conventional methods. [57] Curphey found that the combination of P4S10, hexamethyldisiloxane (HMDO) and elemental sulfur was capable of converting 3-oxoesters 131 to dithiolethiones 132 with comparable or superior yields to those obtained with Lawesson's reagent. [58] Interestingly, the byproducts of this method may be removed by a classical hydrolytic workup or by simple filtration through silica gel without chromatography, as required for Lawesson's reagent.

H 2 N O H 2 N O Me O Me Ar 1 S S N Ar 1 Ar 1 Ar 1 H 2 N O H 2 N O Me O Me Ar 1 S S N Ar 1 O Ar 1 Ar 1 NOH Me O Me Ar 2 S S N Ar 1 O Ar 2 Ar 1 NOAc Me RO 2 C Ar 2 R = H, Me S S N Ar 2 Ar 1 Ar 1 O Me H 2 N Ar 2 S S N Ar 2 Ar 1 Ar 1 NOAc Me N C Ar 2 S S S N N H Ar1 Ar2
Recently, this method has been adapted to the synthesis of dithiolethiones presented in Scheme 48. [59] Tetramethoxypropane 131 could be transformed into unsubstituted dithiolethiones with P4S10/S8 without HMDO reducing agent since the two acetal group could play this role.

Open chain 3-oxoesters 131a as well as their cyclic 131b and benzo fused 131c analogues reacted smoothly to give substituted dithiolethiones 132a-c. Aldehyde derivative of malonate 131d under enol form reacted in the same manner, leading to ester 132d in moderate yield. o-Bromothiobenzamides 133 were found to react with elemental sulfur to provide benzodithioles 134 under copper-catalyzed conditions (Scheme 49). [60] Although the details on mechanism, especially the position of newly introduced sulfur atom, were not fully determined, it was proposed that the first step of the transformation is a migration of the sulfur atom of the thioamide function to the o-position via coppercatalyzed Ullmann coupling reaction and subsequent introduction of the sulfur from S8. When elemental selenium Se8 was used instead of S8, o-sulfur substituted products 135 were formed. In general, Naryl products 134a were obtained in higher yields than N-alkyl 134b, which was tested for only one example.

Similar reactivity was previously observed with ochlorobenzamidines [107] and o-bromobenzamides [108] (See section 2.8).

Scheme 49.

An unusual decarboxylative tetrasulfurative hexamerization of phenylacetic acid 136 was observed upon heating this acid with sulfur, N-methylpiperidine and DMSO (Scheme 50). [61] Thiobenzaldehyde 138 generated in situ from decarboxylative sulfuration of phenylacetic acid with sulfur-N-methylpiperidine complex Sn-NMP was suggested to be the key intermediate involving in this oligomerization reaction. The next step was a dimerization of thiobenzaldehyde to dithiobenzoin 139 via a similar mechanism of benzoin condensation catalyzed by Sn-NMP complex. Further sequence of condensation of dithiobenzoin 139 as its ene-dithiol tautomer 140 with another molecule of thiobenzaldehyde 138 to trimer 141 and oxidative dimerization of trimer 141 resulted in hexamer 137.

Scheme 50.

Perfluoroolefins 142 were known to react with sulfur in the presence of an alkaline fluoride as a catalyst (CsF or KF) the corresponding perfluorothioketones, which could involve in a wide range of cycloaddition reactions (Scheme 51). [62] Scheme 51. Generation of thioketones for cycloadditions According to the proposed mechanism of formation, the first step was a reversible addition of fluoride to the perfluoroolefin to form carbanion 143 stabilized by the presence of multiple fluorine atoms. Subsequent nucleophilic attack of 143 on sulfur resulted in thiolate 144, existing in equilibrium with thioketone 145, which acted as dienophile in the next step of

S 8 R F R' F F F MF R F R' F F F F M R F R' F F F M S F R F S R' F F F -MF +MF thioketone olefin S-heterocycle
cycloaddition. In the case of nonsymmetrical olefins, it is clear that this process could lead to mixture of two isomeric carbanions 143.

It was found that the reaction of perfluoroolefin, sulfur and conjugated diene proceeded at 25-65 °C in DMF solvent in the presence of CsF (or KF) as a catalyst led to diverse adducts. [62], [63] Scheme 52.

The reaction is general and can be applied to both linear and cyclic perfluorinated olefins. Some examples were given for thioketone 147 generated from perfluorocyclopentene 146 with cyclohexa-1,3diene 148, 2,3-dimethyl-1,3-butadiene 149, antharence 150 and cyclohepta-1,3,5-triene 151 (Scheme 52). It should be noted that the adduct with cyclohepta-1,3,5triene 153 is indeed the result of the reaction of the thioketone 147 and bicyclo[4.1.0]hepta-2,4-diene 152, existing in equilibrium with cycloheptatriene 151.

Similar reactions of perfluoropent-2-ene 153 were reported to be complex due to the generation of mixture of two regioisomeric thioketones, one of which is non-symmetrical (Scheme 53).

Scheme 53.

The reaction with quadricyclane was slightly exothermic, leading to the formation of three isomers 155a, 155b and 155c, with significant prevalence of symmetrical isomer 155a. [62] Cyclopentadiene 156 also was found to be active in this reaction, leading to the formation of three cycloadducts 157a-c. [62] The reaction with 9-methylanthracene 158 as diene was found to proceed at higher temperature due to the low solubility of this hydrocarbon at rt. [62] An unusual result was obtained in the reaction with cycloheptatriene 159, the reaction resulted in the formation of a mixture of two isomeric tetracyclic compounds 160a and 160b. [62] The reaction required a stochiometric amount of CsF to increase the conversion.

It was demonstrated that the reaction of hexafluoropropene 161, sulfur and vinyl ether catalyzed by CsF, proceeded under mild conditions, leading to the corresponding 2,2bis(trifluoromethyl)thietanes 163 (Scheme 54). [64] Scheme 54.

The addition of second mole of sulfur to the solution of 2,2-bis(trifluoromethyl)-4-alkoxy-thietanes 163a,b inserted another sulfur atom into thietane ring with the formation of the corresponding cyclic disulfides 3,3bis(trifluoromethyl)-alkoxy-1,2-dithietanes 164. On the other hand, if the addition of second equivalent of sulfur preceded that of vinyl ether 162, 2,2bis(trifluoromethyl)-4-alkoxy-1,3-dithiolanes 165 was formed exothermically. This procedure failed to produce the corresponding 1,3-dithiolanes from electron deficient olefins, such as dimethyl maleate or 1,1-bis(trifluoromethyl)ethylene but rapidly yield 1,3dithiolene 167 with dimethyl acetylenedicarboxylate 166. [64] A mixture of two adducts 169a,b of similar structure was obtained in 44% combined yield when perfluoropent-2-ene 168 was allowed to react with sulfur under similar conditions (Scheme 55). [62] Scheme 55.

Some unusual but interesting results were observed when propargylamines 170 or 171 were heated with sulfur in the presence of Co(acac)2-PPh3-AlEt3 (1:2:4) catalyst (Scheme 56) with dithiolactone 172 or 173 was formed, respectively. [13] Scheme 56. 4-Arylbutyrolactones 174 were found to react with sulfur to provide thiolactones 175 with InCl3 catalyst and phenylsilane as a deoxygenating agent in moderate yields (Scheme 57). [65] The reaction was found to depend strongly on the structure of the lactone skeleton.

F 3 C F F F S S CF 3 CF 3 F 3 C F 3 C S CF 3 CF 3 R 25 ºC, 2 d CsF cat. DMF 45-65 ºC R 163a, R = OEt, 81% 163b, R = O-n-Pr, 69% 163c, R = SEt, 68% S 8 (1 equiv) rt, 24-36 h S CF 3 F 3 C R S R = OEt, 63% R = O-n-Pr, 53% R 1. 2. rt S 8 S S R CF 3 CF 3 R = OEt, 66% R = O-n-Pr, 83% CO 2 Me MeO 2 C 2.

Scheme 57.

Copper was known to promote (i) [3+2] cycloaddition reactions of alkynes with azides to 1,2,3triazoles, and (ii) C-H alkylsulfuration of monosubstituted 1,2,3-triazoles with alkyl sulfonate and elemental sulfur. Consequently, a combination of these two reactions in one pot involving bearing two reactive functions would be an excellent strategy for synthesis of triazoles fused with a sulfa heterocycle 180-181 (Scheme 58). [66] For this purpose, two types of reactions were proposed: (i) alkyne 176 with tosylate-azide 178 and (i) alkyne-tosylate 177 with azide 179. In both cases, the whole sequence was found to be initiated by an azide-alkyne [3+2] cycloaddition.

Scheme 58.

ortho-Nitrophenylethylnyl thiother 184 generated in situ from trimethylsilyl alkyne 182 was found to undergo a cascade of reactions to tetracycle 185 at rt (Scheme 59). [67] Since the isolation proved to be complex, this reaction was not further developed. Scheme 59.

Thiazole

Trisubstituted thiazoles 187 bearing an electron withdrawing group in the position 5 such as benzoyl or ester could be synthesized via sulfuration of the corresponding enamine 186 with elemental sulfur in the presence of FeCl3 as a catalyst under aerobic conditions (Scheme 60). [68] Scheme 60.

In order to construct thiazole 189 with a free 2amino group, Fu et al employed unsubstituted cyanamide with enaminone 188 and sulfur (Scheme 61). [69] In this case, a cascade of 2-sulfuration of enaminone, nucleophilic addition of cyanamide and cyclization was proposed as the reaction pathway leading to the product with a wide range of aromatic, heteroaromatic and unsaturated substituents R.

Scheme 61.

Wu et al found that thiazol-2(3H)-one heterocycles 192 could be obtained via reaction of adducts of A 3 coupling reaction 190 with thiocarbonyl generated in situ from sulfur and carbon monoxide (Scheme 62). [70] Phloroglucinol triformate 191 could be used as a solid source of carbon monoxide. The reaction proceeded with gentle heating with a strong base such as t-BuOK in DMSO.

Scheme 62.

A major inherent drawback of these approaches to thiazoles 187, 189 and 192 is the diversity of the products depends only in the only one organic starting material, which is not readily available and should be synthesized. To overcome this constraint, several multicomponent strategies starting from simple and readily available substrates have been investigated.

Jiao et al focused on the combination of phenylacetaldehydes 193 with primary amines 194 and sulfur, including benzylamines and long chain aliphatic amines under Cu-catalyzed aerobic oxidative conditions (Scheme 63). [71] According to the proposed mechanism, enamine 197 generated from phenylacetaldehyde and primary amine was sulfurated by S8 in the a position to the phenyl ring to generate polysulfurated amine 198. After aerobic oxidation took N-methylmorpholine Similarly, when phenylacetaldehyde was replace by acetophenone, regioisomers 2,5-diarylthiazoles 200 were obtained upon heating the reaction mixture in DMSO with isonicotinic acid additive (Scheme 64). [50] The reaction required a higher temperature but copper catalyst was not necessary. The reaction scope is however limited to benzylamines.

+ S 8 (3 equiv) N H O R 1 R R 2 N R 1 R R 2 O S DMSO,
(20 mol %) N-methylpiperidone 100 ºC, 16 h R = Ph, 70% R = 2-furyl, 50% R = 2-pyrrolyl, 50% R = 2-thienyl, 77% R = 2-thiazolyl, 71% R = 4-Py, 50% R = β-stryryl, 41% R O 190 191 192 S 8 + + selected examples: R HN R 1 R 2 S N R O R 1 R 2 t-BuOK (2 equiv) DMSO S N-n-Bu Ph O Me Me S N-n-Bu Ph O S N-n-Bu O S NBn Ph O Bn Bn 92% 94% 73% 53% R 3 R 3 O O O CHO CHO OHC (1 equiv) ( 3

Scheme 64.

Terminal alkynes 201 and isothiocyanates 202 were found to combine with sulfur in the presence of copper catalyst to provide 3,4-disubstituted lthiazol-2(3H)ones 203 (Scheme 65). [72] Copper was hypothesized to catalyze the first step of sulfuration of alkyne, followed by a nucleophilic addition to isothiocyanate and cyclization to the product. The reaction conditions were applicable to both substrates bearing either aryl or alkyl group.

Scheme 65.

Deng and Huang focused on the assembly of acetophenone, benzaldehyde, ammonia and sulfur to thiazole (Scheme 66). This five-component provided a wide range of trisubstituted thiazoles 204 from in expensive starting materials although the reaction conditions were harsh. [73] Scheme 66.

When ketones 205 bear an alkyl chain longer than methyl were used, the construction of thiazole products 206 required only one equiv of benzaldehyde (Scheme 67).

Scheme 67.

With methyl alkyl ketones 207, the reaction was demonstrated to follow the same sequence to provide 4-methyl thiazoles as a reactive intermediate, which underwent benzylidenation with another equiv of benzaldehyde to give 208 (Scheme 68). In this case, using of benzoic acid additive helped lower reaction temperature.

Scheme 68.

Isothiazoles

Isothiazoles 211 could be formed easily via threecomponent reaction of isocyanides 209 with acetylenes 210 bearing two electron withdrawing group and elemental sulfur in CS2 and CH2Cl2 without any added catalyst. High yields were obtained even at rt. The first step of the reaction was hypothesized as an addition of isocyanide to the triple bond, followed by a cyclizing sulfuration via different pathways. [74] Scheme 69.

Benzothiazoles

From o-haloanilines

Sulfur could be used as a sulfide source in the reaction with an o-iodoaniline 212 to provide the coresponding 2-aminothiophenol, which could further involve in an oxidative condensation reaction with a suitable C-2 precursor 213 and result in 2-substituted benzothiazoles 214 (Scheme 70). [75]- [82] Scheme 70.

Benzaldehydes (entries 1-2), benzylamines (entries 3-4), dibenzyl disulfides (entry 5), phenylacetic acids (entry 6), benzyl chlorides (entry 7) could be used as C-2 precursor. Phase transfer agents such as tetrasubstituted ammonium salts could also be used for this purpose. In this case, both benzyl and long chain alkyl could act as C-2 precursors with higher reactivity for the benzyl group (entry 8 vs entry 8). Notably, these phase transfer agents should be used in equimolar amounts, i.e. only one substituent involved in the reaction. When phenylacetylenes (entries 10-11) or acetophenone tosyl hydrazines (entries 12-13) were used as C-2 precursors, the benzothiazole products were formed with loss or conservation of the carbon skeleton according to the reaction conditions. In most cases, the reactions required a copper catalyst, except for tetrasubstituted ammonium salts (entries 8-9).

From o-hydroanilines

The thermal reaction of anilines with sulfur has been known for over one century to give rise to 2aminothiophenols and the corresponding polysulfides. [83] In the presence of a wide range of substrates that provide the C-2 building block for benzothiazole core, the formation of this heterocycle upon heating of simple anilines or naphthylamines was observed. [84] Some selected significant examples were presented in Scheme 71. Heating primary aromatic amines with elemental sulfur and 2-or 4-picoline (entries 1-4, 9-10), benzylic ester (entry 5), thioacetanilide (entry 6), benzyl alcohol (entry 7), acetophenone (entry 8), 2-methylquinoline (entry 11-12), 2-methylbenzothiazole (entry 13), 4methylpyrimidine (entry 14), benzaldehyde (entry 15)… produced 2-substituted benzothiazoles. [85]- [90] entry Reaction ref Interestingly, since H2S generated during the course of the reaction could reduce a nitro group, the starting aniline could be replace by the corresponding nitrobenzene as described in entry 12.

1 [85] 2 [85] 3
Under these classical conditions, refluxing the reaction mixtures was very common, possibly as a mean to control the temperature. The reactions with substrates bearing non activated methyl groups such as toluene, p-cresol or p-xylene (entries 16-18) required higher temperature and were performed under high pressure. [91] Based on these observations, some modifications have been developed recently. In 2017, a synthesis of 2-substituted naphtho[2, 1-d]thiazoles 217 via heating of the corresponding N-substituted 2-naphthylamines 215 with elemental sulfur at 140 °C was reported (Scheme 72). [92] The reaction could proceed via the oxidation of the N-methylene group into the corresponding imine 216. Substrates bearing a substituent R that is aromatic, heteroaromatic, styryl, ester or benzoyl are competent substrates. When R is an aliphatic group such as t-Bu, the expected product was obtained in moderate yield.

Scheme 72.

In the aniline series 218, four examples were reported in which the aniline ring was substituted by electron donating groups, possibly for facilitating the key step of sulfuration (Scheme 73).

Scheme 73.

The main drawback of the method is the starting substrates N-substituted anilines were not readily available and should be prepared from NH2 anilines via reduction of their imines with aldehydes. To avoid this unnecessary operation, Deng et al. suggested a direct access to benzothiazoles 223 from anilines and benzaldehydes. [93] The reaction was found to be improved by adding iodide salts such as KI, NH4I and molecular sieves. While the reactivity was found to be only slight influenced by the nature of the substituents on aromatic aldehydes, the success of the reaction depended strongly on the nature of aromatic amine substrates 220 and 221. As in the previous case, [92] 2naphthylamine 220 was proven to be more reactive than anilines 221 and its reactions could proceed at 140 ºC. In cases of anilines 221, despite the presence of multiple electron donating groups such as alkyl, alkoxy, their reactivity remained lower than that of 2napthylamine 220. The role of oxygen is not essential in this reaction since both sulfur and DMSO could act as oxidants for this transformation.

Similar conditions were also applied to the couple aniline 221/2-methylquinoline 222 (Scheme 74). [94] Scheme 74.

When styrenes or phenylacetylenes 22were used as C-2 precursors for the formation of benzothiazoles, the reaction was found to proceed via Willgerodt mechanism with the oxidation of the terminal carbon atom along with reduction of the internal carbon (Scheme 75). [95] Scheme 75.

The reaction with acetophenones as C-2 building block in the presence of I2/TBAI/DMSO occurred with loss of one carbon, benzothiazoles products were obtained with an aromatic 2-substituent (Scheme 76). [96] Scheme 76.

When tert-butyl hydroperoxide/KI was added to the reaction mixtures as oxidant, the method could be extended to ether substrates 228 as C-2 precursors (Scheme 77). [97] Scheme 77.

This system of oxidant was known to oxidize ether into oxonium 230, which was next attack by amino species to provide the corresponding imines 231. Thanks to stronger oxidizing potential of TBHP,

S

Ph N

S

S 8 R + N S R' R (2 equiv) + N S Ph R R = MeO, 81% R = CN, 68% R = F, 72% R = CF 3 , 70% R =
TBHP/KI R'-C=O-R" R N R'
further reactions on 230 provided 229 benzothiazoles with wider scope for both C-2 substituents and anilines bearing an electron withdrawing group. The main drawback of this method is however the use of ether substrates in large excess (4 equiv), especially for volatile ones (as solvent).Recently, the reaction with aromatic aldehydes was applied to the synthesis of βcarboline tethered thiazolo [4,5-c]carbazole 234 with luminescent properties from 1-formyl-9H-b-carbolines 233, arylamines (including 3-aminocarbazoles 232) and elemental sulfur with molecular iodine as a catalyst (Scheme 78). [98] Alternatively, the corresponding acetal of aldehydes 233 could be used instead of aldehyde with KI was employed in place of I2, opening up avenues for the synthesis of benzothiazoles from acetals when aldehydes are unstable.

Scheme 78.

When iron salt in catalytic amount was added to the reaction medium, the by-product H2S generated during the oxidative sulfuration process could be trapped and used to reduce in situ nitrobenzenes to anilines.

Scheme 79.

Consequently, the formation of benzothiazoles from benzyl alcohols followed a similar pathway (Scheme 79). The reaction temperature for this cascade transformation remained high (160 °C).

From o-aminothiophenols

When 2-aminothiophenols are readily available, the corresponding benzothiazoles could be synthesized by the reaction with styrenes or phenylacetylenes and sulfur as report by Deng et al (Scheme 80). [99] Since the aromatic sulfuration step, which is most energetically demanding, is not required, the reaction temperature is significantly lower than similar reactions of the corresponding o-unsubstituted anilines. [95] Scheme 80.

From o-halonitrobenzene

All the above-mentioned methods suffer from at least one of the following drawbacks: high reaction temperatures, availability of the starting material, regioselectivity, requirement of copper catalyst, ligand, strong base, limited scope of substrates. In this context, we suggested a new strategy to broaden the scope of benzothiazole synthesis while using inexpensive and readily available starting materials even in a wide range of structures. In 2013, we disclosed a threecomponent reaction involving o-halonitrobenzenes, elemental sulfur and 4-picoline bearing an activated methyl group to produce 2-pyridylbenzothiazole under solvent-free conditions (Scheme 81). [100] The products were formed as a result of a cascade of metal-free nitro group displacement by sulfur, reduction of the nitro group, oxidation of the methyl group, and condensation to form benzothiazoles core. Interestingly, the reaction conditions could be applied to all four halogens in o-halonitrobenzenes substrates. Later, it was found that the method could be extended to benzylamines, [101] phenylacetic acids, [102] acetophenones [103] as reducing partners. In all cases, sulfur was found to be an external complementary reducing agent.

Scheme 81.

The generality of this transformation was recently demonstrated with benzaldehydes, benzyl alcohols, dibenzyl disulfide, phenylglycine, mandelic acid, phenylglyoxalic acid [104] as well as benzyl chlorides (Scheme 82). [105] In the last case with benzyl chlorides, N-methylpiperidine was used as solvent, in which one equivalent was involved in the generation quaternary N-benzylated piperidinium, which underwent next the redox condensation with o-chloronitrobenzene substrates.

Scheme 82.

Although the reaction mechanism is not fully determined, we have suggested the following mechanism adapted for benzaldehyde substrate (Scheme 83). The reaction started with the formation of polysulfide chain 238 by the attack of the base to S8 molecule. This polysulfide could act as both oxidant for oxidation of aldehyde and sulfur nucleophile for displacement of the halogen atom of ohalonitrobenzene. At this moment, an intramolecular

From cyclohex-2-enone O-acetyl oximes

An original way to construct napthothiazoles and benzothiazoles 244 was developed by Deng et al via three-component reaction of a-tetralone/conjugated cyclohexenone oxime acetates 243, with aldehydes and elemental sulfur (Scheme 84). Different aldehydes could be used with a-tetralone oxime acetates 243 although lower yields were observed with some aliphatic aldehydes. [106] While examples of conjugated cyclohexenone oxime acetates substituted in 2-or 3position or fused with furan/thiophene were given with reasonable yields, the reaction of the simplest cyclohexenone oxime acetate was not reported. While all the used aldehydes are commercially available, the method required oxime acetates in excess (1.5 equiv). Mechanistically, a key step of this transformation consists in a thiolation with elemental sulfur of the neighboring methylene to the oxime acetate moiety, followed by condensation with aldehyde and subsequent aromatization.

Scheme 84.

Benzoisothiazole

Upon prolonged heating of o-chlorobenzamidines 245 with sulfur and K3PO4, benzoisothiazoles 246 were produced (Scheme 85). [107] The key step of this transformation was suggested to be an attack of the amidine moiety of 245 to elemental sulfur to form the N-S bond, and subsequent cyclization via intramolecular aromatic nucleophilic substitution of the chlorine by the newly introduced sulfur. Consequently, high reactivity was noticed with substrates bearing electron withdrawing groups. Although the method could be applied to N-alkyl or NH2 amidines, the substrate scope is limited to substituents which are not sensitive to strong base K3PO4 such as alkyl, alkoxy, halo and CF3.

Scheme 85.

When benzamides [108] were used in place of benzamidines, Liu et al found that o-iodo derivatives 247 were particularly reactive for a similar transformation, especially in the presence of CuBr2 as a catalyst (Scheme 86). The expected benzoisothiazole products 248 could be formed for less than 10 min upon microwave irradiation with sulfur and triethylamine.

Scheme 86.

Previously, a similar reaction with bromo derivative 249 was studied in the presence of up to 50 mol % of copper catalyst and ligand 1,10-phenanthroline (Scheme 87). [109] It should be noted that the ester function could favor sulfur incorporation.

Scheme 87.

Another strategy for the synthesis of benzoisothiazolone 252 based on o-C-H functionalization was studied (Scheme 88). [110] Although benzamides with unsubstitued o-positions could be used, the method requires 2-(Nmethylbenzimidazolyl)isopropyl as an N,N-bidentate directing group. Furthermore, the use expensive nickel triflate catalyst, strong oxidant KMnO4 and high molecular weight additive TBAI as well as high temperature under high pressure conditions makes the reactions less attractive as a synthetic method. Previously, (2-pyridyl)isopropyl directing group was developed for similar transformations. [111] Scheme 88. All four reported methods were based on redox catalysis of I2/I -couple. Suitable oxidant or oxidation conditions could be applied for recycling of I2 from I -, including K2S2O8, [112] TBHP [115] as well as more sophisticated electrolytic [113] or flavin-catalyzed aerobic [114] conditions. Mechanistically, the first step was an iodination of the methyl group of 253 into 255 to facilitate the introduction of sulfur chain to the carbon skeleton. Subsequent shortening of sulfur chain and elimination of tolylsulfinic acid of 256 produced the expected heterocycle.

Hydrazone substrates under enamine form 258 could be generated in situ directly from conjugated enaminones and tosyl hydrazine as illustrated by the example given in Scheme 90. Subsequent steps followed the same pathway as described in Scheme 89. While aromatic and heteroaromatic as well as cinnamyl ketone were competent substrates, reaction of alkyl ketones did not result in the expected heterocycles, probably due undesirable reactions on these side chains. Scheme 90.

1,2,4-Thiadiazole

This kind of heterocycles 263 could be prepared via oxidative coupling of benzamidines 261 and sulfur with a C-5 precursor 262 of various natures, ranging from CS2, 2-methylquinolines, benzaldehydes to benzyl halides and acetophenones (Scheme 91). In all cases, the reaction required a base to activate sulfur. Scheme 91.

1,2,3,4-Thiatriazole

A one-pot two-step synthesis of 5-aryl-1,2,3,4thiatriazoles 266 was developed (Scheme 92). [122] Starting from aromatic nitriles 264, the first step consists in a formation of the corresponding thiohydrazides 265 from hydrazine hydrate and elemental sulfur. DMSO was found to be a particularly useful solvent in accelerating this first step. Subsequent diazotization of thiohydrazides with nitrous acid induced the cyclization into 1,2,3,4thiatriazoles 266. While excellent yields were observed with aromatic cyanides, benzyl cyanide or tert-butyl cyanide was not successful substrates, probably due to low stability of the corresponding thiohydrazides.

Benzothiazines

In 2017, we disclosed a synthesis of sultams 268 by heating o-nitrochalcones 267 with elemental sulfur (Scheme 93). [123] Two set of conditions have been developed based on the use of a weak base such as 3picoline or N-methylmorpholine to promote the incorporation of elemental sulfur into the onitrostyrenes without loss of any atom. Mechanistically, the reaction was thought to be initiated by an addition of the nitrogen base to the double bond of o-nitrochalcone substrate 267 followed by a sulfuration of the resulting zwitterion 269. Subsequent migration of two oxygen atoms of the nitro group to newly installed sulfur atom occurred with cyclization to the sultam product 268.

Scheme 93.

The strategy was subsequently applied to onitrostilbazole substrates 274 to provide a wide range of sultams 275 bearing different heterocyclic substituents (Scheme 94). [124] Scheme 94.

Benzothiazine derivative 278 could be synthesized in 52% yield via a one one-pot synthetic strategy from the reaction of o-alkynylaniline 276 (Scheme 95). [75] The first step was a formation of isothiocyanate 277 with difluorocarbene generated from sodium bromodifluoroacetate in the presence of a copper salt catalyst and a base. Addition of dibutylamine to isothiocyanate 277 will induce cyclization to 278. It should be emphasized that the introduction of only one carbon of the isothiourea function into 278 required high molecular weight sodium bromodifluoroacetate as well as 3 equiv of base to trap hydrogen halides (1 HBr and 2 HF).

Scheme 95.

A three-component reaction of o-iodobenzamides 279, elemental sulfur and dichloromethane providing 2,3-dihydrobenzothiazinones 280 was described (Scheme 96). Using copper/1,10-phenanthroline catalyst, the reaction consisted in a first step of thiolation of aromatic C-I bond and subsequent reaction with CH2Cl2. [108] Scheme 96.

A four-component reaction of acetophenone with two molecules of anilines and sulfur leading to 2Hbenzo [b] [1,4]thiazin-2-imine 281 was reported (Scheme 97). [126] This transformation was based on the o-sulfuration of anilines at high temperature with elemental sulfur to provide o,o'-diamino diphenyl oligo sulfides, which was previously described. [83], [84] While the scope of acetophenones is relatively large, competent anilines should not bear electron withdrawing group.

Scheme 97.

Although sulfur could interfere any step of this cascade transformation, its role was shown to be essential only in the sulfuration step. Indeed, compound 281 could be obtained via three component reaction of o-aminothiophenol, aniline and acetophenone under similar conditions at lower temperature without sulfur (Scheme 98). [127] Scheme 98.

1,2,3,4-Tetrahydroquinolines and N-substituted anilines 282 were found to react with cyclohexanones 283 and sulfur under similar aerobic conditions (KI or I2 catalyst, DMSO additive, PhCl solvent) to provide phenothiazines 284 (Scheme 99). [128] While the I2-catalyzed reaction of N,Ndiarylanilines with sulfur leading to phenothiazines was known for more than one century, [129] there is an obvious possibility for the involvement of phenothiazines in the transformation, which could be generated from oxidative condensation of 1,2,3,4tetrahydroquinolines or N-substituted anilines 282 with cyclohexanones.

Fused 1,3,6-thiadiazepine

A three-component reaction of 1-(2aminoaryl)pyrroles 285, simple ethers, and elemental sulfur for constructing aza-heterocycle-fused 1,3,6benzothiadiazepines 286 under iodine-catalyzed conditions has been developed (Scheme 100). [130] Simple ethers such as THF, MeTHF, tetrahydropyran, diethyl ether… act as reactive solvent in this reaction. Scheme 100.

1,3-Oxathiolan-2-one

Wu et al developed a carbonylation procedure involving the cyclization of propargylic alcohols 287 with elemental sulfur and gaseous carbon monoxide. With DBU (10 mol %) as the catalyst, elemental sulfur and carbon monoxide can form carbonyl sulfide O=C=S and react with propargylic alcohols (Scheme 101). [131] Good to excellent yields of the desired 1,3oxathiolan-2-ones 288 are obtained even at room temperature for secondary and tertiary alcohol substrates. However, primary propargylic alcohols failed to give the product, probably due to instability under the present conditions. When phloroglucinol triformate was used as a solid CO surrogate, the same reactions requires higher temperature (60 ºC) and longer reaction time (48 h). [132] A three-component reaction of nitromethane and elemental sulfur with a wide range of oxiranes 289 was developed with silver salt catalyst (Scheme 102). [133] This reaction procedure provides a practical strategy to construct 1,3-oxathiolane heterocycles 290 with high functional group tolerance and good to excellent yields. Although the stereochemistry aspect of this work was not well documented for both starting oxiranes and 1,3-oxathiolane, only one product was described for each reaction. According to the proposed mechanism, the ring opening of oxiranes 289 was effected with sulfurnitromethane adduct 291 generated from two starting components by a silver-catalyzed process (Scheme 103). Subsequent cyclization of the resulfying nitrosulfide 292 to 1,3-oxathiolane product with nitrite ion as a leaving group proceeded via an SN2 pathway, which explained low yields (nitroethane, nitropropane) or even absence of reactivity (nitroisopropane) with higher homologs of nitromethane (Scheme 103).

2,3-Dihydrobenzo[b][1,4]oxathiine

This heterocycle scaffold 294 could be synthesized by copper-catalyzed sulfuration with elemental sulfur of o-iodophenyl propargyl ether 293 (Scheme 104). [134] 282 283 284

+ + S 8 NH R O R' (1.2 equiv) ( 4
CH 3 NO 2 H 2 O, 55 ºC, 16 h O R 2 R 4 R 1 R 3 (1.5 equiv) (2.4 equiv) AgOAc (15 mol %) S CH 2 O R 3 R 1 R 2 R 4 S CH 2 O S CH 2 O Me Me Me Me S CH 2 O S CH 2 O Et Ph Ph Ph 92% 48% 81% 79% proposed mechanism CH 3 NO 2 AgOAc S O R S O 2 N R -O O H 2 C S R S 6 S CH 2 NO 2 -S 7 S 8 S 8 + + H 2 O, 55 ºC, 16 h O (1.5 equiv) (2.4 equiv) AgOAc (15 mol %) S O R NO 2 R = Me, R' = H, 61% R = Et, R' = H, 52% R = R' = Me, trace R' R' R Scheme 104.

Sulfur-free heterocycles

Reaction

of o-hydroxylphenyl-functionalized enaminones 295 with sulfur and molecular iodine resulted in the formation of chromone sulfides 296 (Scheme 105). [135] Substrates bearing electronwithdrawing group such as chloro atom in the phenyl ring of 295 were not able to yield the corresponding chromone sulfide products.

Scheme 105.

In a similar manner, o'-hydroxychalcones 297 reacted with sulfur in the presence of sodium chlorodifluoroacetate to yield 3-(difluoromethylthio)chromen-4-ones 298. [42] Mechanstically, the reaction was started by a baseinduce cyclization of o'-hydroxychalcones 297 to chroman-4-ones 299, which were next sulfurated by S8 to 300 and next oxidized by TEMPO to chroman-4-one sulfides 301 (Scheme 106). The final products 298 were obtained by a combination of sulfides 301 with difluorocarbene generated from chlorodifluoroacetate followed by a protonation. Better results were obtained with chalcones unsubstituted on the phenol ring. However, the reaction failed o-substituted chalcones (R = 1-naphthyl, 2-methoxyphenyl) as well as when R = 2-Py, NMe2 or alkyl.

Scheme 106.

A synthesis of indolizine thioketones 304 was developed from 2-picolines a-substituted by an EWG 302, aryl propynals 303 and elemental sulfur (Scheme 107). [136] While 2-picoline substrates bearing an oxygenated EWG (ester, acetyl) reacted rapidly (within 1 h), those having nitrogenated EWG (CN, amides) required molecular iodine (10 mol %) as a catalyst with longer reaction time (4 h). The transformation is initiated by a condensation between the methylene moiety of picolines 302 and the aldehyde function of 303, followed by a cyclization and sulfuration. Scheme 107.

3 Elemental sulfur not acting as a sulfur source

Elemental sulfur acting as oxidizing agent

One of the most interesting aspects of elemental sulfur is it can act as an oxidant to oxidize selectively a nucleophilic compound Nu 1 into an electrophilic intermediate El 1 . This highly reactive species could be attacked by excess starting nucleophilic compound Nu 1 or by another nucleophilic component Nu 2 that is stable to the oxidation sulfur, leading to final adduct Nu 1 -El 1 or Nu 2 -El 1 (Scheme 108). Although the basic idea is simple, the scope of this strategy is extremely large with appropriate choice of substrates as well as reaction conditions.

Scheme 108.

We found that all the reactions reviewed in this section could be conveniently classified as formal cycloadditions promoted by sulfur. Accordingly, this will be applied throughout this section.

Five-membered ring syntheses 3.1.1.1 [4+1]

Sulfur-promoted Willgerodt-Kindler type reactions were developed as an innovative strategy to achieve oxidative cyclocondensation. The main different with the original Willgerodt-Kindler reaction is a bisnucleophile is used in place of amine. Such a modification would result in cyclized product with hydrogen sulfide as a by-product. Consequently, even though sulfur is not present in the final heterocyclic products, the reaction follows a similar Willgerodt rearrangement mechanism.

In 2017, we developed this strategy for the synthesis of 2-substituted benzoxazoles 307 starting from oaminophenols 306 and ketones 305 (Scheme 109). [137] The reactions required both sulfur and Nmethylpiperidine in stoichiometric amounts and could be applied to a wide range of methyl ketones, including acetophenones, acetylhetarenes and methyl alkyl ketones with satisfactory yields.

O O SCF 2 H Ph O O SCF 2 H O O SCF 2 H Ph O O SCF 2 H R 70% O R = 1-Np, 2-MeOC 6 H 4 , 2-Py, NMe 2 , t-Bu 0% Br X X 73% 46% O R O X O R O S - O R O S - TEMPO :CF 2 from ClF 2 CCO 2 Na

Scheme 109.

One of the most striking experimental proofs of a Willgerodt-type pathway is the migration of the benzoxazolyl moiety to the end of the chain when ethyl ketone and higher analogues 308 were used (Scheme 110). It should be noted that the yields of 310 dropped with the distance of migration, which is in full agreement with Willgerodt reaction mechanism.

Scheme 110.

This strategy was next adapted to the synthesis of benzoxazoles or benzimidazoles from 2-aminophenols or o-phenylenediamines with phenylacetylenes as a more expensive synthetic equivalent of acetophenones. [138] Very recently, we could apply this method to the synthesis of 2-substituted benzoxazoles 312 via oxidative coupling of benzaldehydes or cyclohexane carboxaldehyde 311 with o-aminophenols 309 by sulfur in DMSO (Scheme 111). [139] The reaction was found to be efficiently catalyzed by sodium sulfide. Although similar approaches were previously known with other oxidants, including molecular oxygen, the reaction based on elemental sulfur was particularly attractive in term of low reaction volume as solid sulfur was used stoichiometric amount.

Scheme 111.

Monoamide of maleic acids 314 could involve in a decarboxylative coupling reaction with bisnucleophiles 315 such as 2-aminophenol, ophenylenediamine or 1,3-propanediamine promoted by sulfur/N-methylpiperidine/DMSO to provide ahetarylacetamides 316 (Scheme 112). [140] Such a decarboxylation was found to occur under mild condition of heating, which could be explained by the presence of the amide function of electron attracting nature. Interestingly, the starting substrates monoamide of maleic acids could be easily prepared in the same pot by spontaneous equimolar combination of amines 313 with cheap maleic anhydride.

Scheme 112.

In a similar manner, fumaric acid monoester displayed the same reactivity, leading to ahetarylacetates (Scheme 113).

Scheme 113.

A synthesis of 2-(trifluoromethylmethyl)benzazoles 319 involving sulfur was described from the parents osubstituted anilines 317 and 2-bromo-3,3,3trifluoropropene 318 (Scheme 114). [141] Scheme 114.

The obvious drawback of this method the use of radical initiators ADVN and B2Pin2 in near stoichiometric amounts as well as sulfur and expensive 2-bromo-3,3,3-trifluoropropene in large excess (7 equiv).

Sulfur was found to promote oxidative cyclocondensation of acylhydrazides 320 and isonitriles 321 to produce 2-amino-1,3,4-oxadiazoles 322 upon heating in DMSO (Scheme 115). [142] Scheme 115. The method was compatible with aliphatic, aromatic and heteroaromatic substrates. In situ formation of isothiocyanates by thermal reaction of isonitriles 321 and sulfur was hypothesized as the key step.

[3+2]

One of the strategies for the formation of heterocycles based on formal cycloaddition was previously relied on non-redox condensation (substitution and addition/elimination) between a bisnucleophile with a bis-electrophile. The latter precursor is in general highly reactive, not readily available in a wide range of structure, and therefore should be prepared prior to the reaction. On the other hand, in the oxidative condensation approach, by using an oxidant compatible with the bis-nucleophile, the bis-electrophile could be generated in situ from monoelectrophile, which is more stable and more readily available. Accordingly, the expected heterocycles could be obtained in a more direct manner with cheaper precursor. Sulfur was suggested to be the oxidant of choice in our reaction between 2-aminopyridines 323 with cyclohexanones as well as higher homologs 324 (Scheme 116). [143] Scheme 116.

The reactions were performed under solvent-free conditions, using 5 equiv of sulfur and at a temperature near the melting point of pure sulfur to keep the reaction mixture liquid. The reaction could be extended to 2-aminobenzothiazole, aminopyrazine and 2-aminopyrimidine. Highly oxidizable under aerobic conditions bis-nucleophiles such as ophenylenediamines could be used in the same manner for synthesis of fused quinoxalines (See section 3.1.2).

Several versions of this strategy have been developed. First, Deng et al disclosed in the same time their study focused on the use of 2aminobenzothiazoles 326 as 1,3-bis-nucleophile in place of 2-aminopyridines under aerobic conditions in DMSO at temperature up to 130 °C (Scheme 117). [144] The reaction involved in only one equivalent of sulfur, suggesting that bot oxygen and DMSO could act as complementary oxidants. The reaction was found to be less efficient when performed under argon. It should be noted that, this set of aerobic oxidative coupling conditions was not compatible with 2-aminopyridine.

Scheme 117.

Second, cycloalkanone components could be replaced by phenylacetaldehydes and other aliphatic aldehydes 328 (Scheme 118). [145] The reactions performed in mixture of DMSO/cyclohexane required a higher temperature (120 ºC) but with a shorter reaction time (1 h).

Scheme 118.

Mechanistically, it was suggested that the reaction was initiated by a condensation of the two substrates to imine 330 in an equilibrium with enamine 331 (Scheme 119). [143] Subsequent sulfuration of 331 by elemental sulfur would lead to polysulfide imine 332, existing in an equilibrium with enamine 333. Cyclization of 333 to 334 followed by elimination of hydropolysulfide chain from 334 resulted in tricyclic 325.

Scheme 119.

2-Picolines a-substituted 335 by an electron withdrawing group could react with a primary amine to yield imidazo [1,5-a]pyridine 336 under oxidative conditions promoted by elemental sulfur in DMSO (Scheme 120). [146] While both benzylamines and aliphatic amines could be used as the primary component, only 2-picolines with an a-ester or acarboxamide were found to be reactive. Reactions failed with EWG = CN or Bz, presumably due to their incompatibility with amine at high temperature. The proposed mechanism was depicted with the oxidation of the methylene moiety of picolines and subsequent condensation with amine as the first step. By simply heating phenylacetonitrile with elemental sulfur and DMSO in the presence of a catalytic amount of DABCO, we accomplished an unusual oxidative trimerization leading to polysubstituted pyrrole heterocycle 337 in excellent yields with E configuration (Scheme 121). [147] The reaction conditions in general were not applicable to osubstituted phenylacetonitrile substrates. Mechanistically, the reaction was initiated by an oxidation of phenylacetonitrile with sulfur to thiobenzoyl cyanide 338. As a bis-electrophile, this thioketone could condense with two other phenylacetonitrile molecules to provide trimer 339-340, which would undergo isomerization and cyclization to the trimer product.

[2+2+1]

In 2018, Huang and Deng et al reported a convenient multicomponent access to tetrasubstituted imidazoles 342 from oxidative condensation of enolizable ketones 341 with two molecules of aliphatic amines (Scheme 122). [148] Scheme 122.

This reaction involved both sulfur (1 equiv) and oxygen (1 atm) as oxidants. Cyclohexanones and higher homologs as well as acyclic ketones were competent carbonyl substrates. With regard to amines, benzylic type ones shown better reactivity although npentylamine and n-hexylamine could also be used with moderate yields (51% for both cases).

In order to introduce two different amines (a benzyl amine and an aliphatic amine), a one-pot two-step protocol was suggested: (1) non oxidative condensation of benzylamine with ketone 341 to Nbenzylimine; (2) reaction of the resulting imine Nbenzylimine with the aliphatic amine under oxidative conditions of S8 and O2 (Scheme 123). Scheme 123.

Six-membered ring syntheses 3.1.2.1 [4+2]

Although o-phenylenediamine 344 is well known for its rapid oxidation under ambient conditions, easily darkening in air, this bis-nucleophile is relatively stable with sulfur even at high temperature (Scheme 124). Based on this compatibility, we studied the oxidative coupling between o-phenylenediamine 344 and cycloalkanones 324. [143] The corresponding quinoxalines 345 could be easily obtained when heated with sulfur at near melting point of this elemental.

Scheme 124.

In case of quinoxaline 346 derived from cyclohexanones, a further direct introduction of a substituted amino group to the a-methylene group with simultaneous aromatization leading to 1aminophenazines 347 could be achieved when heating with elemental sulfur and DMSO (Scheme 125). [149] Scheme 125.

We noticed also that when a monosubstituted cyclohexanone 324 was heated with two equivalent of o-phenylenediamine, fused pentacycle 348 was formed in DMSO (Scheme 126). Reasonable yields could be achieved when a strong acid such as TFA, HCl, PTSA… was used as a catalyst. [150] Scheme 126.

According to the proposed mechanism, the reaction introduction of a second o-phenylenediamine to 2,3-(tetramethylene)quinoxaline occurred via a sequence of imine-enamine tautomerization/Michael addition/aromatization/Michael cyclizing addition /aromatization (Scheme 127). The global process consists in removal of seven hydrogen molecules.

R 2 R 1 O H 2 N R 2 + N N R R 1 R 2 R CyH, O 2 , 120 ºC, 36 h 3.5 equiv KHCO 3 (1 equiv) S 8 (1 equiv) N N Ph Bn ( ) n n = 1, 82% n = 2, 90% n = 3, 82% n = 7, 57% N N Ph Bn R 1 R 2 R 1 = Ph, R 2 = Me, 40% R 1 = R 2 = Ph, 70% R 1 = R 2 = Me, 70% N N R R R = 3-Py, 73% R = 2-thienyl, 70% R = 1-Np, 60 R = n-Pent, 51% N = n-Bu, 51%
selected examples: With cycloheptanone, introduction of two molecules o-phenylenediamine took place under the same conditions with lower yields (Scheme 128). Notably, in this case, the aromatization of the cycloheptane core is not possible, suggesting that the aromatization in the previous case with monosubstituted cyclohexanone is not a driving force for this kind of reaction.

341 343 R 2 R 1 O H 2 N Ph + N N Ph Alk R 1

Scheme 128.

When 1,4-cyclohexadione monoprotected as dioxolane derivative 349 was submitted to the same reaction with o-phenylenediamine, phenazine 350 was formed as a result of an introduction of only one molecule o-phenylenediamine with ring opening of dioxolane and aromatization of the cyclohexanone ring (Scheme 129). The ring opening step was shown be independent of the presence of the acid catalyst.

Scheme 129.

In the presence of K2CO3 as a basic activator, sulfur was found to promote an oxidative condensation of indole 351 with o-salicylaldehydes 352 to yield chromeno[2, 3-b]indole 353 (Scheme 130). [151] Scheme 130.

[5+1]

The methyl group of an acetophenone or pinacolone 354 could be oxidized with elemental sulfur in DMSO (Scheme 131). [152] In the presence of an anthranilamide 355 as s bis-nucleophile, the corresponding product could be formed. The reaction required Nmethylpiperidine in stoichiometric amount as a sulfur activator. Notably, a wide range of secondary anthranilamides 355 could be easily obtained in onepot via catalyst-free and solvent-free decarboxylative condensation reaction of a primary amine with isatoic anhydride.

Scheme 131.

The method could be applied to the synthesis of natural product tryptanthrin 359 starting from oaminoacetophenone 357 and isatoic anhydride (Scheme 132). Scheme 132.

[1+2+3]

1,3,5-Triaryltriazines 362 could be synthesized by sulfur-promoted oxidative condensation of one molecule of benzyl chloride 361 with two molecules of benzamidine 360 under basic conditions (Scheme 134). [119] Scheme 133.

The first step of this transformation is an oxidation of the methyl moiety of benzyl chloride 361 as well as its derivatives issued from nucleophilic displacement of chloro group by other nucleophiles present in the

S 8 O NH 2 NH 2 + N N H + N HN NH HN N H NH 2 H 2 N H 2 N N N N H NH 2 H + HN NH N HN N N N N -2H 2 S H + S 8 -3H 2 S S 8 -2H 2 S N N N N H 2 N H 2 N + DMSO 100 ºC, 16 h R R O R R R R R = H, 30% R = Me, 35% S
N N O O R 1 R 1 Me O S 8 (4 equiv) N-methylpiperidine (1 equiv) DMSO 80-100 °C, 16 h H 2 N N H O R 2 N N O O R' Ph R' = 3-Py, 55% R' = 2-thienyl, 90% R' = t-Bu, 26% R = H, 70% R = 4-OMe, 78% R = 4-Cl, 54% R = 4-Br, 54% R = 3-OMe, 55% R = 3-Cl, 62% R = 3-CO 2 Me R = 2-OMe, 73% N N O O Ph + R 2 N N O O Ph Me N N O O Ph Ph N N O O Ph Ph 82% 74% 73%
(1.2 equiv reaction medium. Subsequent condensation with two benzamidines 360 followed by cyclization and aromatization would result in the expected product 362. The reaction failed however with 4-methoxybenzyl chloride. When both benzamidines and sulfur were used in excess (2 and 5 equiv based on benzyl chlorides, respectively), the reaction led to 1,2,4-thiadiazoles (See section 2.9.2).

[2+1+2+1]

A metal-free synthetic approach to monosubstituted 1,2,4,5-tetrazines 364 was developed based on multicomponent reaction between dichloromethane, hydrazine hydrate and nitriles 363 in two step (Scheme 134). [153] Sulfur was used as oxidative promoter in the first step followed by a second step of aromatization under diazotization conditions. According to the proposed mechanism, the first steps were a reaction of the sulfur-hydrazine adduct and hydrazine itself with DCM, followed by an addition step of nitrile to provide mixture of two adducts, which undergo a cyclization to hexahydrotetrazine (Scheme 135). Finally, a double elimination followed by an oxidative aromatization step would lead to monosubstituted tetrazine.

Seven-membered ring syntheses

a-Chloroacetamides 366 could be conveniently used as one-carbon building-block in the synthesis of dibenzo [1,3]diazepines 367 starting from 2,2′biphenyldiamines 365 in the presence of sulfur activated by triethylamine (Scheme 136). [154] The reaction was suggested to proceed via a Willgerodt type reaction to form 2-thioxoacetamide, which was trapped by the two amino group of 2,2′biphenyldiamines 365. While the scope of achloroacetamides 366 is large, with N-aromatic, Naliphatic and NH2 amides are all competent substrates, the reaction is strongly affected by substituent pattern on the 2,2′-biphenyldiamines 365 of both steric (omethyl or o,o'-dimethyl substrate) and electronic (electron withdrawing group such as nitro in the para position to the amino group) reasons. a-Fluoro, bromo or iodo acetamide reacted in the same manner as achloroacetamide with the lowest efficiency with abromoacetamide.

Scheme 136.

When a-chloroacetic acid 368a was used in place of a-chloroacetamide, thiourea product was yielded as a result of a further decarboxylation (Scheme 137). Ethyl a-chloroacetate 368b reacted in the same manner with a slightly lower yield.

Elemental sulfur acting as catalyst for redox condensations

Iron-sulfur catalyst

The nitro group is well known as one of the most versatile and readily available nitrogen containing functional groups. The nitro group has been widely used as a precursor of nitrogen compounds including azaheterocycles but traditionally with prior reduction in a separate step. In 2013, we have reported iron/sulfur catalyst generated from the elemental forms of both components to promote the redox condensation between o-nitroanilines and o-nitrophenols 370 with a wide range of 2-or 4-methyl hetarenes 371 such as 2and 4-picolines, quinadine, lepidine and 2methylbenzimidazole (Scheme 138). [155] Scheme 138.

As mentioned above, the reaction is limited to hetarenes bearing a 2-or 4-methyl. To expand the scope of the reaction, others reducing partners could be considered. When aliphatic alkylamine 375 and 376 were used as reducing partners or when onitrobenzamides 374 were used as oxidizing partners with primary benzylamines 377, FeCl3•6H2O and S8 catalyst showed its superior catalytic activity, leading to benzimidazoles 378 and quinazolinones 379 (Scheme 139). [156] When the 2-phenethylamine 380 was use instead of benzylamine, another mode of redox condensation occurs with an initial oxidation of the a-methylene to imine (Scheme 140). Subsequently, the b-methylene group became more reactive and underwent a further oxidation. [157] Consequently, quinoxalines 381 were formed as a result of the oxidation of two carbon atoms. Longer aliphatic amines such as octylamine were shown to be less reactive with competitive formation of the 6-heptylbenzimidazole.

Scheme 140.

Some limitations of the reaction became obvious. First, the methyl group of methylhetarene should locate in the 2 or 4 position of the heterocycle for an efficient stabilization of the corresponding reactive intermediate. Second, using four-electron donor benzylamines with six-electron acceptor nitro group required additional benzylamine to act as reducing agent with the formation of by-products. We proposed phenylacetic acids 380 as an alternative reducing partners, which underwent decarboxylation and 6-electron oxidation (Scheme 141). [158] Scheme 141.

This catalyst system could also be applied to 2,2'dinitrodiphenyldisulfide (Scheme 142).

Scheme 142.

Interestingly, sodium sulfide was also found to be a suitable for acting as both sulfur source for Fe/S catalyst and external complementary reducing agent when benzyl alcohols or glycols were used as reducing agent. [159] Recently, we found that benzyl cyanides 384 could act efficiently as benzylidyne source (Scheme 143). [160] In this case, the cyano group acts as a leaving group and can be trapped as non-toxic thiocyanide ion when sulfur was used in excess amounts. Recent applications include synthesis of 2arylbenzazoles via redox coupling of onitrophenols/thiophenols/anilines with dibenzyl disulfide. [161]

Sulfur catalyst

Recently, we reported a benzazolation reaction of anilines o-substituted by a cyclizable group such as OH or NH2 387 by dibenzyl disulfide 386 using DMSO as an oxidant in near stoichiometric amount in the presence of sulfur as a catalyst and N-methylpiperidine as a sulfur activator. [162] Since the expected benzazole products 388 did not contain sulfur issued from the starting dibenzyl disulfide 386, these sulfur atoms were extruded to the reaction medium and could in turn act as a catalyst (Scheme 144). Consequently, the catalyst loading of sulfur could be lower significant. Indeed, excellent yields could be obtained even with 1 and 5 mol % of sulfur catalyst (based on atomic sulfur) for benzoxazole and benzimidazole, respectively.

Scheme 144.

A plausible mechanism was proposed for aliphatic amine (Scheme 145). Adduct of this amine with sulfur could induce a fragmentation of dibenzyl disulfide to generate in situ thiobenzaldehyde, which is a key intermediate of this reaction. Highly electrophilic, the thioaldehyde function could react easily with oaminophenol with elimination of H2S and the corresponding adduct could be oxidized by either sulfur or DMSO to provide thioamide. The methylene moieties of 5,6,7,8-tetrahydroquinoline 390 and isoquinoline 391 could be oxidized and coupled with an o-phenylenediamine in the presence of sulfur and TFA in catalytic amounts and DMSO as an oxidant (Scheme 146). This strategy offered an inexpensive and rapid way to construct fused phenazine-pyridine heterocycles 391-392. [150] Sulfur was found to be an efficient catalyst for oxidative coupling of two molecules o-aminophenols with a cyclohexanone with DMSO as an oxidant. The heteropropellane products 393 could be formed in excellent yields and good functional group tolerance (Scheme 147). It should be noted that the reaction proceeded with complete regio-and stereo-selectivity. In all cases, the coupled products were the most thermodynamically stable stereoisomers of all possibility with two axial C-N bonds and two equatorial C-O bonds.

Starting monosubstituted substrate, while 3-and 4substituted cyclohexanones led convergently to the same results in term of regio-and stereo-chemistry, 2substituted cyclohexanones had only the position 6 as reactive site, resulting in only one possible regioisomer. We emphasized that only one stereoisomer was observed in all these cases with the substituent R in equatorial position. In all the cases, although sulfur was used up to 3 equiv, the reaction should proceed via 6e -reduction of the nitro group of o-nitrophenols and concomitant oxidation of phenylacetic acids (6e -), benzyl chlorides (4e -) and benzaldehydes (2e -). While the oxidation step could be achieved with elemental sulfur with hydrogen sulfide as the byproduct, the reduction of nitro could be done by either hydrogen sulfide to regenerate sulfur or by sulfur itself to yield sulfur compounds with sulfur in its positive oxidation states.

Elemental sulfur acting as catalyst for nonredox condensations

Elemental sulfur (in 20 mol % as S8 or 160 mol % as atomic sulfur) was found to promote the condensation of anilines o-substituted by a cyclizable group (such as NH2, OH, SH) 394 with a-bromo-a,adifluoro acetamides/acetates 395 to provide the corresponding benzazole-2-yl carboxamides or carboxylates 396 (Scheme 149). [166] The reactions proceeded at high temperature for ophenylenediamines (130 °C for 16 h), whereas oaminothiophenols reacted under milder conditions (90 °C, 12 h). High nucleophilicity of polysulfide, generated in situ from the reaction of sulfur with Na2CO3 at elevated temperature, was inarguably responsible for this condensation with triple dehydrohalogenation via cascade of nucleophilic substitution and addition/elimination steps.

Scheme 149.

Sulfur was found to catalyze efficiently the condensation of 2-aminopyridines 397 as bis-1,3nucleophiles and b-ketoester 398 as bis-1,3electrophiles, leading to 2H-pyrido[1,2-a]pyrimidin-2ones 399 under solvent-free conditions (Scheme 150). [167] The reactions conditions tolerate a wide range of functional groups and can be extended to 2-aminothiazole. In term of redox balance, the global transformation is only a simple condensation with removal of a water and an ethanol molecules without change in oxidation states of any atom. It could be possible that, as in the previous case, [166] highly nucleophilic polysulfide generated in situ from the reaction of sulfur with 2-aminopyridine, acted as nucleophilic catalyst.

Conclusion

In this update review, the recent advances in organic synthesis of heterocycles involving elemental sulfur from 2017 are discussed. When sulfur is employed as a sulfur precursor, the strategy opens new avenues to sulfa heterocycles with a broad range of applications while avoiding many inconveniences related to the handle of other sulfur precursors, especially disagreeable odor of volatile thiols and sulfides compounds. On the other hand, sulfur was found to be a versatile reagent for oxidation reactions and oxidative coupling, not only as an excellent alternative oxidant to its smaller congener oxygen as well as other commonly used oxidizing agents but also as an oxidant with unique, rich and tunable chemistry. In this field, the study for catalytic reactions involving this element as the sole catalyst or in combination with iron was recently initiated and explored. As mentioned above, these approaches are particularly attractive and promising, since both sulfur and iron are abundant, easily available, nontoxic with a wide range of reactivities known in biological world. Diverse heterocyclic compounds including sulfur containing and sulfur-free heterocycles can be synthesized easily and conveniently. In most cases, the transformations proceed via cascade and/or multicomponent processes with the formation of many new bonds and allow access to original heterocyclic structures that are much more complex or "impossible" to obtain otherwise. However, some challenges are still to be explored. In some cases, the reported reaction conditions remained harsh with prolonged heating at high temperature under pressure with large excess solvents and additives. We are focusing our effort on development of milder reaction conditions.

Consequently, more efficient methods using this element in heterocyclic chemistry are continuously disclosed, and their application for the synthesis of drugs and materials, especially in large scale and low cost, is anticipated.

REVIEW

  Scheme 7.

  Scheme 28.

  Scheme 43.

  Scheme 47.

  Scheme 48.

  R = n-Bu, 65% R = n-Pentyl, 56%

  , 3-Py, 2-furyl, n-Bu, t-Bu, TMS R' = Ar, Cy, i

  Scheme 83.

  Scheme 92.

  Scheme 99.

  Scheme 101.

  Scheme 102.

  Scheme 103.

  Scheme 120.

  Scheme 121.

  Scheme 127.

  Ph, Ar 2 = Ph, 82% Ar 1 = Ph, Ar 2 = 4-ClC 6 H 4 , 73% Ar 1 = 4-BrC 6 H 4 , Ar 2 = Ph, 62% Ar 1 = 4-F 3 CC 6 H 4 , Ar 2 = Ph, 72%

  Scheme 134.

  Scheme 135.

  Scheme 137.

  Scheme 139.

  Scheme 143.

  Scheme 145.

  Scheme 146.

  Scheme 147.o-Nitrophenols were found to condense with phenylacetic acids, benzyl chlorides and benzaldehydes to provide 2-phenylbenzoxazoles (Scheme 148).

  Scheme 148.

  Scheme 150.

Recent

  Advances in the Synthesis of Heterocycles via Reactions Involving Elemental Sulfur Adv. Synth. Catal. Year, Volume, Page -Page Thanh Binh Nguyen*

  -(t-Bu 2 )C 6 H 3

				S 8
				(6 equiv)
				DMF
			153 ºC, 17 h
	68, 71%							67, 80%
				EtOH, NaOH			Y = n-Bu, Ph, 4-Me 2 NC 6 H 4 4-MeOC 6 H 4
	O	O	+	S 8	50-78 ºC 5-100 min	O	O	Me OH	OH	OMe
	R		Y	(3 equiv)	R = H, NO 2 X = H, Cl	R		Me
	X					S	Y		70-92% yields
	69					70
	70								72

Ar Ar Ar 77 78 79 80 S 8

	Ph	O	N R	O	Ph	S 8 (32 equiv) 140 ºC, 48 h DMF	Ph Ph	S S	O	N R	O	S S	Ph Ph	Ph	N R	82 O		Ph	+		S 8 (5.3 equiv)	NaOt-Bu (3.3 equiv) DMSO, 120 ºC, 24 h	R Ph N	83 Ph S	O	R = H, 89% R = Me, 70% R = Ph, 85% R = Bn, 84%
							85%
	Ph	O	N	O	Ph						O	N	O
			R		R = 1-hexylheptyl			R
			73									74
																Ph
																	O	84 H N	Ph		+		S 8 (5.3 equiv)	120 ºC, 24 h 45% NaOt-Bu (3.3 equiv) DMSO,	N R	85 Ph	S	O
		MeO 2 C					S 8		MeO 2 C
												S
							DMF
						110-140 ºC
				75								76
				Ph, 67% p-Me 2 NC 6 H 4 , 39% p-NCC 6 H 4 , 61% p-O 2 NNC 6 H 4 ,23%		1-naphthyl, 66% 2-naphthyl, ,48% 2-thienyl, 21% 3-thieny, 24% Ferrocenyl, 24%
																									Ph
																					N				Ph
																					Me		HI (50 mol %)	S 8
																	S 8 (2 equiv)		Ph	O	Me	L-Phe (1 equiv) 130 °C, 4 h	86	N Me	87 Me N	S
																						HOAc
																						DMF
																					150 °C, 16 h
																									N Me	Ph
		N	THF (1.3 equiv) n-BuLi			N	Li	(2.5 equiv) -78 ºC to rt			N		SLi			Ph		88 S NMe 2		S 8	89 Me N	S
			-78 ºC, 1 h					rt, 1 h
		Ph					Ph					Ph
													S 8
				N S 81, 60%	S	Ph Me	n-PrBr rt, 1h (1.1 equiv)			N LiS		S	Ph			N Alk	+	Ph		O	OH	+	S 8 (6 equiv)	150 °C, 16 h DMF	Alk N	S	Ph
																	90						91, (2 equiv)	92

  thieno[2,3-d]thiazole 124.

	Scheme 46.

  equiv) 35-60 ºC,24 h place on the alkyl group of amine 198 to imine 199, cyclization and aromatization would lead to thiazole product 195. In general yields obtained with benzylamines were better than with aliphatic amines.

	Scheme 63.

Table 1

 1

	entry	conditions	product	ref
		S8 (1.5 equiv), CS2 (2.5 equiv)		[116]
	1
		MeONa, MeOH, reflux, 6 h.		[117]
	2			[118]
		S8 (5 equiv), K3PO4 (5 equiv),
		DMSO, 120 ºC, 24 h.
	3			[118]
		S8 (5 equiv), Na2CO3 (4 equiv)
	4			[119]
		DMSO, 120ºC, 24 h.
		S8 (10 equiv), LiOt-Bu (4
		equiv)
	5			[120]
		PhMe or DMSO, 140 ºC, 12
		h.
		S8 (5 equiv), PdCl2 (10 mol %)
	6	K2HPO4 (5 equiv)		[121]
		DMSO, 130 ºC, 24 h.