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.

Introduction

Since the discovery of stable sulfonium ylides 1 in 1930 [1] and the pioneering work of several research groups during the 1960s (2 and 3) [2-9], these carbene precursors have been played an important role in organic chemistry [10-22]. As shown in Figure 1, sulfur(IV) and sulfur(VI) ylides are stable. The stability of sulfonium ylides is determined by the electron delocalization of the carbanionic center and the substituents on the sulfur atom [10]. In general, these reagents are often applied in the preparation of simple small rings [13], such as epoxides [14-18], cyclopropanes [19-22], aziridines [23], indoles [24], pyrroles [24], and indolines [25]. In addition, other reactions involving sulfonium and sulfoxonium ylides have been reported recently [26-32]. For example, Shen and co-workers reported the use of trifluoromethyl-substituted sulfonium ylide 5 in electrophilic trifluoromethylation reactions [33-34]. Moreover, Maulide and co-workers reported an effective ylide transfer reagent, which led to sulfonium ylide 6 [35-38].

Figure 1

The selected examples of sulfur(IV) and sulfur(VI) ylides 1 [1], 2 [5–7], 3 [6–79], 4 [11–12], 5 [33–34], 6 [35–38].

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 [39-43]. 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 [44-49]. In general, Pd-catalyzed Suzuki–Miyaura cross-coupling reactions are the most popular synthetic strategy for aryl–aryl bond-forming reactions [50-52]. 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].

As a recent example of a metal-free synthesis of the targeted thienylpyridines (Figure 2A and 2B), Al-Showiman and co-workers reported a trisubstituted 5-(pyridin-2-yl)thiophene, obtained from the reaction of 5-(enaminone)thiophene with 2,4-pentanedione in glacial acetic acid in the presence of ammonium acetate [54-55]. Ila and co-workers reported the synthesis of tri- and tetrasubstituted thiophenes via the intramolecular cyclization of S-alkylated heterocyclic–aryl dithioesters [56]. However, these approaches are limited by the multistep synthesis (Figure 2A) [54-55] and the complicated dithioester preparation (Figure 2B) [56]. In general, tetrasubstituted thiophenes have primarily been prepared by base-catalyzed intramolecular Dieckmann-, Thorpe–Ziegler, and aldol-type condensations of the corresponding ketene-N,S-acetals [57-67]. These methods are still need strong bases [60], high temperatures [62,64-65], and are generally low yielding [57,62]. Thus, a new mild synthetic route for the synthesis of 5-(pyridyl)thiophenes is required. We therefore investigated the synthesis of thienylpyridines using a metal-free approach.

Figure 2

Metal-free synthesis of thiophene-based heterocycles (A) [54–55], (B) [56].

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).

Scheme 1

One-pot sequential synthesis of the trisubstituted 5-(pyridine-2-yl)thiophenes 8a. Substrate: amalonitrile; b5,5-dimethylcyclohexane-1,3-dione.

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 CF3 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 5,5-dimethylcyclohexane-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].

Figure 3

X-ray crystal structures of 8ad and 8an [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).

Table 1

Examination of N,S-acetals substituted with a heterocycle (7aa–k) or an arene (7l–p).

Entry	Substrates	X	Y	Products	Yield (%)a,b
1	7aa	S		8aa	92
2	7b	S		8b	–c
3d	7c	S		8c	80
4	7d	S		8d	34
5	7e	O		8e	–c
6	7f	S		8f	33
7	7g	S		8g	20
8	7h	S		8h	–c
9	7i	S		8i	47
10	7j	S		8j	–c
11	7k	S		8k	8
12	7l	S		8l	–c
13	7m	S		8m	–c
14	7n	S		8n	–c
15	7o	S		8o	–c
16	7p	S		8p	42

aR3 = 3-methoxyphenyl, one-pot sequential reactions to thiophenes 8: a) ethyl acetoacetate (1 equiv), K2CO3 (1 equiv), DMF, rt, 2 h; b) 3-methoxyphenyl isothiocyanate (1 equiv), DMF, 60 °C, 2 h; c) the corresponding halomethylarenes or halomethyl heterocycles (1 equiv), DMF, 60 °C, 3 h; bAfter column chromatography; cno desired reaction; dbecause N,S-acetal 7c readily transfer to the corresponding thiophene 8c at 0 °C, the substrate 7c could not be isolated.

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 thiophene 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 [69-72] 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 (Table 1, entries 6–11). The desired thiophenes 8f and 8g were obtained in low yields from the respective furans (33% and 20%, Table 1, entries 6 and 7). With thiophene, however, only N,S-acetal compound 7h was obtained. Thiophene could not generate the desired intermediate because of the lower electronegativity and a weaker inductive effect of sulfur (Table 1, entry 8). Among 1,2,4-oxadiazole moieties, the 3-trifluoromethyloxadiazole group afforded the desired thiophene 8i (Table 1, entry 9), whereas the 5-trifluoromethyloxadiazole substituent was not a viable substrate (Table 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 moiety. The reduced inductive effect of the amine might be attributed to the resonance structures of imidazole (Table 1, entry 11) [72].

To determine the influence of substituents on the phenyl group, various arene(methyl)sulfanes 7l–p were tested (Table 1, entries 12–16,). Simple phenyl and electron-donating compounds 7l and 7m did not provide the desired thiophenes 8l and 8m. Although electron-withdrawing groups such as CN and SF5 did not show any effect (Table 1, entries 14 and 15), NO2, the strongest electron-withdrawing group [75-77], provided the desired thiophene 8p in a moderate yield (42%).

While further studies are required, we suggest the sulfur ylide-like intermediates 7aa, 7c, 7p, 7i, and 7f,g after considering the literature [69-72] 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 [R2C=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 [69-72]. 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 [69-7079]: 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.

Figure 4

The proposed structure of sulfur ylide-like intermediates; resonance contributors (mesomeric structures) [69–7278].

According to the recent reports on the multiple isomeric structures of ketene N,S-acetals [80-83], structural assignments of the ketene N,S-aminothioacetals 7 by 1H NMR are not facile. To overcome these difficulties, we prepared N,S-acetals 9a–c since the X-ray crystal structure of Meldrum’s acid-based N,S-acetal was reported by Wentrup [84]. In addition, the intramolecular aldol condensation of Meldrum’s acids did not occur due to the ketone structures. Table 2 displays the 1H NMR result of the sulfur ylide-like intermediate 9b, and demonstrates the effect of increasing electronegativity on the CH2 proton. The 2-pyridyl group caused a downfield shift of 0.13 to 0.14 ppm compared to phenyl and 3-pyridyl groups (Table 2, entry 2).

Table 2

1H NMR studies of Meldrum’s acid-based N,S-acetals 9a–ca,b [84].

Entry	N,S-Acetalsc,d	Structure	-SCH2Y 1H NMR (ppm)e
1	9a		4.02
2	9b		4.15
3	9c		4.01

aR3 = 3-methoxyphenyl; bS-alkylation of the thiolate with 4-(bromomethyl)pyridine hydrobromide was not successful; cone-pot sequential reactions to N,S-acetals 9: a) Meldrum’s acid (1 equiv), K2CO3 (1 equiv), DMF, rt, 2 h; b) 3-methoxyphenyl isothiocyanate (1 equiv), DMF, 60 °C, 2 h; c) the corresponding benzyl bromide or bromomethylpyridine (1 equiv), DMF, 60 °C, 3 h; dAfter column chromatography; ein CDCl3.

Further 1H NMR studies of pyridin-2-ylmalononitrile 7an, pyridine-2-ylmethyl methanimidothioate 7ao, and time dependent experiments of the intramolecular aldol condensation of N,S-acetal 7aa to 8aa in N,N-dimethylformamide-d7 at room temperature confirmed the formation of the stable sulfur ylide-like intermediates, thus indicating the successful transformation into thiophenes 8an, 8ao, and 8a (see Supporting Information File 1).

In addition to the spectroscopic studies, we attempted to gain additional evidence to support the formation of sulfur ylide-like intermediates via another approach. We selected stable Meldrum’s acid containing N,S-acetals 9a and 9b for further investigation. Based on previous reports regarding carbene generation from sulfonium ylides [6,85-86], compounds 9a and 9b were reacted with excess MeOH (Scheme 2). Interestingly, 2-pyridyl-substituted N,S-acetal 9b only provided N,O-acetal 9ba via a 1,4-Micheal addition, whereas N,S-acetal 9a was completely recovered after the reaction. We believed that these results support the existence of sulfur ylide-like intermediates (Scheme 2) [87].

Scheme 2

The substitution reaction with MeOH.

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 1H 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.

Experimental part.