One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

Herein, we describe a novel approach for the practical synthesis of tetrasubstituted thiophenes 8. The developed method was particularly used for the facile preparation of thienyl heterocycles 8. The mechanism for this reaction is based on the formation of a sulfur ylide-like intermediate. It was clearly suggested by (i) the intramolecular cyclization of ketene N,S-acetals 7 to the corresponding thiophenes 8, (ii) 1H NMR studies of Meldrum’s acid-substituted aminothioacetals 9, and (iii) substitution studies of the methoxy group on Meldrum’s acid containing N,S-acetals 9b. Notably, in terms of structural effects on the reactivity and stability of sulfur ylide-like intermediates, 2-pyridyl substituted compound 7a exhibited superior properties over those of others.

As part of our ongoing efforts to discover small molecule modulators of protein-protein interactions (PPIs), we are particularly interested in coplanar compounds that mimic β-strand side-chain distributions [39][40][41][42][43]. Consequently, we are fascinated with thienyl-pyridyl ring systems [43] and have explored facile synthetic procedures to facilitate their production. For the synthesis of heterocyclic-heterocyclic biaryl compounds, numerous studies have been carried out to develop efficient catalytic methods [44][45][46][47][48][49]. In general, Pd-catalyzed Suzuki-Miyaura cross-coupling reactions are the most popular synthetic strategy for aryl-aryl bond-forming reactions [50][51][52]. However, it has been reported that the Suzuki cross-coupling of nitrogen-and sulfur-containing heterocycles is more challenging than those of aryl-aryl derivatives. These difficulties resulted from the special properties of thiopheneboronic acids -the sensitivity to polar reaction media and easy degradation by protodeboronation [53].

Results and Discussion
At first, our efforts focused on the intramolecular cyclization reactions with mild conditions -in the absence of an added base at room temperature. To obtain aminothioacetal 7a, we initially performed the S-alkylation of the intermediate thiolate salt with 2-(bromomethyl)pyridine at room temperature overnight. We interestingly found that the desired 5-(pyridin-2-yl)thiophenes 8a has already been achieved by the intramolecular aldol-type condensation of N,S-acetal 7a ( Figure 2C). Subsequently, we investigated the scope of the reaction using our optimized conditions (Scheme 1).
As shown in Scheme 1, various isothiocyanates containing aryl and alkyl groups were applied, and the desired thiophenes (8aa-ai) were obtained in moderate to excellent yields (47-92%). When different 1,3-diketones were applied, the yields were affected by the keto-enol tautomer ratio. Alkyl substituents (isopropyl and cyclopropyl), which promote the enol forms of the ketones, afforded thiophenes 8aj and 8ak in good to excellent yields (68% and 81%). However, a CF 3 substituent, which is electron-withdrawing and might promote the keto form, provided the desired compound 8al in a low yield (14%). When the enolate was derived from 3-oxo-3-phenylpropanenitrile, 3-cyano-4-phenylthiophene 8am was obtained in a low yield (32%). Starting from malonitrile, compound 8an was also prepared in a moderate yield (50%) via a Thorpe-Ziegler-type cyclization of N,S-acetal 7an. In this case, the intramolecular cyclization reaction was carried out at 100 °C for 3 h. With 5,5dimethylcyclohexane-1,3-dione, thiophene 8ao was obtained in a low yield (25%). X-ray crystal structures of thiophenes 8ad and 8an are illustrated in Figure 3 [68].
Mechanistically, our experimental findings may be attributed to the formation of sulfur ylide-like intermediates. To support this reaction pathway, further studies were performed. By changing the substituent groups on N,S-acetals 7, the effects of the structure on the stability and the reactivity of the intermediates were investigated (Table 1).
In terms of inductive and mesomeric effects, we postulated that the electron rich pyridyl N atom could carry a negative charge at the picolinyl position (Table 1, entries 1 to 5). Interestingly, the 2-pyridyl moiety provided stable and reactive N,S-acetal 7aa, which could be isolated and afforded the desired thio- phene 8aa in an excellent yield (92%, Table 1, entry 1). The substrate containing a 3-pyridyl group only afforded S-alkylated compound 7b, while 4-pyridyl substituted intermediate 7c could be easily transformed into thiophene 8c at 0 °C (Table 1,  entries 2 and 3). Notably, the special properties associated with the 2-and 4-positions of pyridine [69][70][71][72] are evident in this study. In the case of 6-methylpyridine-substituted N,S-acetal 7d, the formation of a resonance stabilized enaminate anion had a smaller contribution and this resulted in a reduced yield (34%, Table 1, entry 4) [70]. To identify the effects of sulfur, a reaction with the corresponding isocyanate was performed to introduce an oxygen atom. As a result, only O-alkylation compound 7e was obtained instead of the desired furan (Table 1, entry 5). It is possible to consider that the d orbitals of the sulfur atom in a sulfide group could possibly stabilize the adjacent carbanion [73,74].
To expand the scope of substituted N,S-acetals that could provide the desired sulfur ylide-like intermediates, various heterocycles were subjected to the reaction (  1, entry 10). Because of a similar result obtained with the N-methylimidazole substituted compound 7k, the difference between 7i and 7j could be explained by the imidazole-like structure of the 5-trifluoromethyloxadiazole Scheme 1: One-pot sequential synthesis of the trisubstituted 5-(pyridine-2-yl)thiophenes 8a. Substrate: a malonitrile; b 5,5-dimethylcyclohexane-1,3dione.    moiety. The reduced inductive effect of the amine might be attributed to the resonance structures of imidazole (Table 1, entry 11) [72].
While further studies are required, we suggest the sulfur ylidelike intermediates 7aa, 7c, 7p, 7i, and 7f,g after considering the literature [69][70][71][72] and McNab's research on the synthesis of 3-hydroxythiophene and thiphene-3(2H)-ones ( Figure 4) [78]. With regards to McNab's work, the dipolar species [R 2 C=S + −CH − −R′] were proposed as reaction intermediates [78]. In our studies, it was shown that the order of reactivity was 7c ≥ 7aa > 7i, 7p ≥ 7f, 7g. The different reactivities of the intermediates were related to the presence of heteroatoms, particularly their inductive and mesomeric effects [69][70][71][72]. For example, 2-pyridyl-substituted ylide-like intermediate 7aa showed the desired properties in terms of both reactivity and stability, whereas the 4-pyridyl group only displayed high reactivity. For alkylpyridines 7aa and 7c, our observations may be explained by Fraser's measurements of the pKa values [69,70,79]: among isomeric benzylpyridines, the 4-isomer is more acidic than the 2-isomer, and the 4-and 2-isomers are much more acidic than the 3-isomer. In the case of the oxadiazole-substituted compound 7i, inductive and mesomeric effects facilitated its sulfur ylide-like intermediate formation [71]. For compounds 7f and 7g, the low reactivity resulted from the decreased mesomeric effect of the furan structure: the higher electronegativity of oxygen facilitated the polarized form [71]. Among various arenes, the 4-nitrophenyl substituent 7p only afforded the desired thiophene 8p in a moderated yield (42%) and, the favorable resonance form is illustrated in Figure 4.
To overcome these difficulties, we prepared N,S-acetals 9a-c since the X-ray crystal structure of Meldrum's acid-based N,Sacetal was reported by Wentrup [84]. In addition, the intramolecular aldol condensation of Meldrum's acids did not occur due to the ketone structures.   The 2-pyridyl group caused a downfield shift of 0.13 to 0.14 ppm compared to phenyl and 3-pyridyl groups (

Conclusion
In conclusion, we have developed a new synthetic pathway for the preparation of 2-amino-5-(heterocyclic)thiophenes 8. We have also shown that sulfur ylide-like intermediates 7, which are easily converted into the desired thiophenes 8, can be generated in situ by S-alkylation of the intermediate thiolate salts. By 1 H NMR analysis of N,S-acetals 9 and methoxy group substitution of 9b, the formation of sulfur ylide-like intermediates was successfully demonstrated. The transformation of ylide-like intermediates into the corresponding thiophenes was affected by their electronic properties. Among the various tested residues, the 2-pyridyl motif provided the desired reactivity and stability. This approach could be considered a powerful strategy for the preparation of biologically important thienyl heterocycles. Subsequent studies shall focus on applying this chemistry in other reactions that require sulfur ylides, and the biological activities of thiophenes 8 will also be reported in due course.

Supporting Information
Supporting Information File 1 Experimental part.