Recent Advances in the Synthesis of Thiophene Derivatives by Cyclization of Functionalized Alkynes

This review is intended to highlight some recent and particularly interesting examples of the synthesis of thiophene derivatives by heterocyclization of readily available S-containing alkyne substrates.


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In this review, we will highlight some recently developed efficient and selective syntheses of thiophene derivatives by cyclization of readily available S-containing alkyne substrates, which have allowed a significant step forward toward a direct and atom-economical entry to this very important class of aromatic heterocycles. As a matter of fact, these processes may allow the construction of the thiophene ring with the desired substitution pattern in a regiospecific manner and in only one step, usually with high atom economy (particularly in the case of cycloisomerization reactions), and starting from readily available starting materials (as the acetylenic S-contaning precursors can be easily prepared in a few step from commercially available compounds through simple synthetic steps).
As will be seen, many of these cyclization reactions leading to thiophenes have been performed under mild conditions (even at rt, in particular with iodocyclizations) in classical organic solvents, either dipolar aprotic (such as N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), or MeCN), apolar or slightly polar (such as toluene, THF, or CH2Cl2), or protic ones (such as MeOH). However, particularly during the last years, the possibility to carry out these processes in unconventional solvents, such as ionic liquids (ILs) has been successfully verified. This has allowed the easy and convenient recycling of the reaction medium and/or of the catalyst (in the case of metal-catalyzed heterocyclizations).
We have structured the review into different Sections. Section 2 will deal with metal-catalyzed or base-promoted heterocyclizations, while in Section 3 iodocyclization reactions will be discussed. Carbocyclization of S-containing alkyne substrates is the topic of Section 4. In Section 5, some miscellaneous methods that cannot be classified into the previous categories are treated. We would like to point out here that most of the mechanisms shown in this review are based on mechanistic pathways proposed by the authors, on the basis of the existing knowledge and, in some cases, of some additional experimental evidences (product stereochemistry, reactivity pattern of the substrates, and so on). Only in a few cases these hypotheses have been corroborated by computation calculations (one example is the iodocyclization of 1-mercapto-3-yn-2-ols 23 in ionic liquids, Section 3, while, to the best of our knowledge, no kinetic studies have been reported so far. Another aspect worth mentioning concerns the reaction conditions reported in the review: they refer to the optimized conditions, usually established after a careful study on the influence of the reaction parameters (such as the catalyst loading, reagents molar ratios, solvent, temperature and so on) on substrate reactivity and product yield.

Synthesis of Thiophene Derivatives by Metal-Catalyzed or Base-Promoted Heterocyclization of S-Containing Alkyne Substrates
Metal-catalyzed heterocyclization of functionalized alkynes bearing a suitably placed heteronucleophilic group is a powerful methodology for the regioselective and atom-economical synthesis of substituted heterocycles starting from readily available acyclic substrates (Scheme 1, Y = heteroatom) [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49]. The generally accepted mechanism for this important transformation involves the electrophilic activation of the triple bond by coordination to the metal center, followed by either exo or endo cyclization (ensuing from intramolecular nucleophilic attack by the -YH group to the coordinated triple bond) and protonolysis (Scheme 1 This is clearly related to the fact that an anti-coordination of the triple bond to Pd(II) may be less efficient, for steric reasons, in the presence of a substituent at C-3 [56].
A 5-endo-dig S-cyclization was also involved in the synthesis of substituted thiophenes 24 by Pd-catalyzed heterocyclodehydration of readily available 1-mercapto-3-yn-2-ols 23, recently reported by our research group [64]. The cyclization reaction is catalyzed by PdI2 in conjunction with an excess (10:1 molar ratio) of KI, and takes place either in MeOH at 50-100 °C (Table 2) or in an ionic liquid, such as BmimBF4, at 80 °C. These are optimized conditions, after a careful study on the influence of the reaction parameters (such as the KI:PdI2 molar ratio, the catalyst loading, and so on) on substrate reactivity and product yield. In the case of the reactions carried out in BmimBF4, the catalyst-solvent system could be recycled several times without appreciable loss of activity (Table 3) [64]. This protocol generalized the previous finding by Aponick and coworkers, who reported the Au/Ag-catalyzed transformation of 1-mercapto-4-phenylbut-3-yn-2-ol into 2-phenylthiophene, carried out using 5 mol % of Au[P(t-Bu)2(o-biphenyl)]Cl and 5 mol % of AgOTf in THF at 40 °C in the presence of molecular sieves 4A [65]. The heterocyclodehydration process takes place by 5-endo-dig intramolecular nucleophilic attack of the thiol group to the triple bond coordinated to the metal center, with elimination of HI, followed by dehydration and protonolysis or vice versa (Scheme 9; anionic iodide ligands are omitted for clarity) [64].     Copper-promoted or -catalyzed cyclization of S-containing alkyne derivatives to give thiophenes has also been reported. Thus, (Z)-1-en-3-ynyl(butyl)sulfanes 25 were converted into the corresponding substituted 3-halothiophenes 27 (X = Cl or Br) when treated with 2 equiv of CuX2 in MeCN (X = Cl) or THF (X = Br) as the solvent (Scheme 10) [66]. The process is believed to proceed through CuX2-promoted 5-endo-dig S-cyclization, to give the sulfonium salt 26, followed by reductive elimination with simultaneous nucleophilic attack by the X − anion to the butyl group bonded to the sulfur atom of 26 (Scheme 10) [66]. In a strictly related process, 2-aryl-3-halothiophenes 30 were obtained in moderate yields from but-3-ynyl(butyl)sulfanes 28, when working in the presence of 4 equiv of CuX2 (X = Cl, Br) in DMA under air at 100 °C for 12 h, through the intermediate formation of dihydrothiophenes 29 (Scheme 11) [67]. Scheme 11. Synthesis of 2-aryl-3-halothiophenes 30 from but-3-ynyl(butyl)sulfanes 28 by CuX2-mediated 5-endo-dig S-cyclization, elimination of BuX and Cu(0), and in situ oxidation of dihydrothiophene intermediates 29 [67]. The Cu(I)-catalyzed tandem addition of terminal alkynes to 1-phenylsulfonylalkylidenethiiranes 31/cycloisomerization has allowed a convenient synthesis of functionalized thiophenes 33 (Table 4) [68].

Synthesis of Thiophene Derivatives by Iodocyclization of S-Containing Alkyne Substrates
The iodocyclization of suitably functionalized alkynes is a very important synthetic tool for the direct preparation of iodine-containing carbo-and heterocycles starting from readily available starting materials [71][72][73][74][75][76][77][78][79]. The utility of the method is further demonstrated by the possibility to elaborate the final products through various cross-coupling reactions (such as Heck, Suzuki-Miyaura, and Sonogashira reactions). The process is usually carried out under mild conditions, and takes place trough intramolecular nucleophilic attack of the nucleophilic group of the substrate to the iodonium ion formed by the reaction between the triple bond and the electrophilic iodine species (indicated with I + ); both exo and endo cyclization modes are possible, as shown in Scheme 15. The process is usually carried out in the presence of a base, to buffer the acid generated during the process.

(91%) I
As concerns the mechanism leading to 44, as shown in Scheme 17, the initial iodocyclization is followed by nucleophilic attack by the iodide anion on the benzyl group of the sulfonium intermediate 43.

Synthesis of Thiophene Derivatives by Carbocyclization of S-Containing Alkyne Substrates
Only a few methods have been reported so far in the literature for the synthesis of thiophenes through carbocyclization of S-containing acetylenes. To the best of our knowledge, the first catalytic example of such an approach was reported by our research group in 1999 [93]. It involved the PdI2/KI-catalyzed carbonylative carbocyclization of dipropargyl sulfide (57) to afford a mixture of 3,4-bis(methoxycarbonylmethylene)tetrahydrothiophene (58, 39%, Z,Z:E,E ca. 1:1) and 3,4-bis-(methoxycarbonylmethyl)thiophene (59, 3%), which could be treated directly, without further purification, with Et3N in CH2Cl2 at 60 °C for 3 h to selectively give the novel thiophene derivatative 59 in 40% isolated yield based on starting 57 (Scheme 21). The carbonylation reaction was carried out in MeOH as the solvent at 40 °C and under 20 atm of a 3:1 mixture of CO-air, in the presence of 0.5 mol % of PdI2 and 5 mol % of KI for 5 h [93]. (59) by PdI2-catalyzed oxidative carbonylative carbocyclization of dipropargyl sulfide 57 followed by base-promoted isomerization [93]. The carbonylative carbocyclization process started with the formation of a methoxycarbonylpalladium iodide intermediate 60 from the reaction between PdI2, CO, and MeOH [49,[94][95][96][97][98][99][100], followed by the insertion of the triple bond of 57 into the palladium-carbon bond to give complex 61, stabilized by the chelation from the second triple bond (Scheme 22; anionic iodide ligands are omitted for clarity). Further insertion of the triple bond leads to the carbocyclized vinylpalladium intermediate 62, from which the final product 58 is obtained from nucleophilic displacement by MeOH. In the last step, Pd(0) was generated, which is then reoxidized back to PdI2 according to a mechanism involving initial oxidation of 2 mol of HI (also ensuing from the carbonylation process) to give I2, followed by oxidative addition of I2 to Pd(0) [49,[94][95][96][97][98][99][100] (Scheme 22).
Mechanistically, the reaction leading to 75 is believed to occur via an initial double [2,3]-sigmatropic rearrangement to give diallenyl disulfides 77, which may then undergo a [3,3]-sigmatropic rearrangement to give 2,3-dimethylene-1,4-dithione 78, followed by a double conjugate addition of the sulfur atoms to the double bonds of 78, to give 1,4-dihydrothieno [3,4-c]thiophene 79, and isomerization (Scheme 26, path a). On the other hand, 76 may be formed by dimerization of the thiyl radical intermediate 80, formed in its turn from 79 by the action of O2 (Scheme 26, path b). Accordingly, the formation of 76 could be minimized working in the absence of air under argon atmosphere (entry 2, Table 8) [103].

Synthesis of Thiophene Derivatives by Miscellaneous Methods Starting from Functionalized Alkyne Substrates
Miscellaneous methods that cannot be classified into the previous categories are reviewed here. Acetylenic esters can be useful precursors for the construction of the thiophene ring. Thus, ethyl 2-(2-(dimethylamino)thiophen-3-yl)-2-oxoacetate derivatives 84 have been conveniently synthesized through a multicomponent approach, employing acetylenic esters 81, tetramethylthiourea 82, and ethyl bromopyruvate 83 as starting materials [104]. Reactions were carried out in CH2Cl2 at rt using equimolar amounts of 81, 82, and 83, to afford the corresponding thiophenes 84 in good to high yields (Table 8) [104].
Another useful utilization of acetylenic diesters for the thiophene synthesis has been reported recently. It involves the reaction between β-oxodithioesters 94 and dialkyl acetylenedicarboxylates 89 (1:1 molar ratio) carried out in the presence of an equimolar amount of dimethylaminopyridine (DMAP) in CH2Cl2 at rt for 3-5 min (Scheme 29) [106]. The process takes place through α-deprotonation of 94 by DMAP and intermolecular conjugate addition (from nucleophilic attack by the sulfur atom to the triple bond of 89, to give anionic intermediate 95), followed by intramolecular conjugate addition to give dihydrothiophene 96, and elimination of Me2S, eventually leading to dialkyl thiophene-2,3-dicarboxylate derivatives 97 (Scheme 29) [106].

Conclusions
The development of novel, efficient and selective methods for the construction of the thiophene ring starting from acyclic precursors is a very important target in current organic synthesis, in view of the high significance of the products obtained and of the more and more stringent requirements in the direction of a sustainable chemistry. In this regard, the synthesis of thiophene derivatives by heterocyclization of readily available S-containing alkyne substrates has proved to be a valuable and reliable approach, and it is destined to assume a central role in the next future for the one-step production of this particularly important class of heterocyclic derivatives. Recent progress in organometallic catalysis has also recently opened the way to the use of metal catalysis for promoting S-heterocyclization reactions leading to thiophenes under particularly mild and efficient reaction conditions. Further progress will allow developing other novel synthetic routes characterized by even more efficiency and selectivity under environmentally friendly conditions.