Copper-catalyzed domino synthesis of benzo[b]thiophene/imidazo[1,2-a]pyridines by sequential Ullmann-type coupling and intramolecular C(sp²)–H thiolation

Abstract

The copper-catalyzed double C–S bond formation via Ullmann-type S-arylation and C–H thiolation using K₂S as a sulfur source is described. This novel one-step sulfur-incorporation method provides a straightforward avenue to benzo[b]thiophene and imidazo[1,2-a]pyridine frameworks.

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Seeking efficient and convenient methods for the construction of C–S bonds is of fundamental research interest in organic chemistry, since sulfur-containing architectures are prevalent in natural products, drugs, bioactive molecules, and materials.¹ Generally, cross-coupling reactions are established to be very useful tools for the formation of C–S bonds. In the past few years, with the renaissance of Ullmann-type reactions,² the copper-catalyzed cross-couplings of aryl halides with thiols have been demonstrated to be a versatile method for constructing C(sp²)–S bonds.³ Meanwhile, metal sulfides as abundant inorganic substances are also used as a sustainable thiol source, and have been widely used for introducing sulfur atoms into organic molecules.⁴ In 2010, Xi and co-workers reported an elegant copper-catalyzed one-pot synthesis of thiophenes from 1,4-diiodo-1,3-dienes and potassium sulphide (Scheme 1a).⁵ In the same year, Li's group developed an efficient CuI-catalyzed double thiolation reaction of 1,4-dihalides with sulfides leading to 2-trifluoromethyl benzothiophenes under mild conditions (Scheme 1b).⁶ Although great achievements have been made using these methods, the substrates involved in these transformations could be mainly limited to aryl halides. Over the past few decades, direct transformation of inert C–H bonds has emerged as an economical and environmentally friendly alternative to traditional synthetic methods.⁷ However, a literature survey indicates that such a synthetic strategy for the formation of C–S bonds remains rather limited,^1d,g,8 and especially the substrates were mainly electron-rich arenas. In this respect, several examples using thiols, diaryl disulfides, 1-(substituted phenylthio)pyrrolidine-2,5-dione, and sulfonyl hydrazide as thiolation reagents under Cu,⁹ Fe,¹⁰ Pd,¹¹ and metal-free¹² conditions have been reported. Very recently, Shi and co-workers developed an elegant copper-mediated C–S/N–S bond-forming reaction via C–H activation using elemental sulfur as a sulfuration agent (Scheme 1c).¹³ From these wonderful studies, it is thereby expected that combining the two coupling partners C(sp²)–X and C(sp²)–H to access the C–S bonds using metal sulfides under copper-catalytic conditions might be more practical and economical (Scheme 1d).

Scheme 1 Strategies for the construction of C–S bonds.

The benzo[b]thiophene skeleton is the core unit of natural products, and its derivatives show remarkable biological and medicinal properties.¹⁴ For example, they are found in numerous clinically important drugs, such as raloxifene,¹⁵ arzoxifene,¹⁶ zileuton,¹⁷ and clopidogrel.¹⁸ In addition, benzo[b]thiophene derivatives are also widely applied in the field of materials science because of their excellent optical properties.¹⁹ On the other hand, imidazo[1,2-a]pyridine fragments widely exist in many commercially available drugs, such as zolimidin (to treat peptic ulcer),²⁰ minodronic acid (to treat osteoporosis),²¹ zolpidem (to treat insomnia),²² and olprinone (to treat heart failure).²³ However, synthesis of the combined motifs of benzo[b]thiophene and imidazo[1,2-a]pyridine frameworks (Fig. 1) has not been explored thus far. Therefore, we wish to synthesize this new kind of fused sulfur-containing N-heterocycle which could possibly possess biological activity and optical properties. With our growing interest in sulfur-containing organic compounds synthesis,²⁴ we herein report a novel and efficient copper-catalyzed one-pot synthesis of benzo[b]thiophene/imidazo[1,2-a]pyridines by sequential Ullmann-type coupling and aerobic oxidative intramolecular C–H thiolation. To the best of our knowledge, this method is the first example of copper-catalyzed direct double C–S bond formation in one step via Ullmann-type S-arylation and C–H thiolation using metal sulfides as a sulfur source.

Fig. 1 Structure of a conjugate containing benzo[b]thiophene and imidazo[1,2-a]pyridine frameworks.

We commenced our study by examining the reaction between 2-(2-bromophenyl)imidazo[1,2-a]pyridine 1a and K₂S 2 to investigate experimental conditions including the optimization of catalysts, ligands, solvents and temperature under an air atmosphere. As shown in Table 1, eight copper catalysts (entries 1–8) were examined at 120 °C in the presence of 0.1 equiv. of 1,10-phenanthroline (A) as the ligand (relative to the amount of 1a) in DMF, and CuI showed the highest reaction activity (entry 3). Only trace amounts of the target product 3a were observed in the absence of catalyst (entry 9). Furthermore, different ligands were tested (entries 3, 10–13), and 1,10-phenanthroline (A) exhibited the highest efficiency (entry 3). We also tested various solvents (entries 3, 14–19), and DMF showed the best result (entry 3). The effect of temperature was also investigated (entries 20–22), and the yields reached the maximum when the temperature was raised from 110 °C to 130 °C. Interestingly, when Na₂S was used as the partner of 1a, only 14% of yield was obtained (entry 23). Notably, only 12% yield of the desired product was obtained under a nitrogen atmosphere, indicating that dioxygen is essential in the present transformation (entry 24).

Table 1 Optimization of the conditions ^a

Entry	Cat.	Ligand	Solvent	Yield^b [%]
a Reaction conditions: 2-(2-bromophenyl)imidazo[1,2-a]pyridine (1a) (0.3 mmol), K2S (2) (0.6 mmol), catalyst (0.03 mmol), ligand (0.03 mmol), solvent (2 mL), 120 °C, reaction time (24 h), under air. b Isolated yield. c 110 °C. d 120 °C. e 130 °C. f Na2S was used. g Under a nitrogen atmosphere (extrusion of air).
1	CuCl	A	DMF	69
2	CuBr	A	DMF	72
3	CuI	A	DMF	81
4	CuSO4	A	DMF	67
5	Cu(OAc)2	A	DMF	74
6	Cu(NO3)2	A	DMF	66
7	Cu(OTf)2	A	DMF	63
8	Cu2O	A	DMF	69
9	None	A	DMF	Trace
10	CuI	B	DMF	Trace
11	CuI	C	DMF	Trace
12	CuI	D	DMF	63
13	CuI	E	DMF	57
14	CuI	A	DMSO	66
15	CuI	A	NMP	Trace
16	CuI	A	1,4-Dioxane	26
17	CuI	A	DCE	Trace
18	CuI	A	CH3CN	11
19	CuI	A	H2O	0
20	CuI	A	DMF	78^c
21	CuI	A	DMF	72^d
22	CuI	A	DMF	81^e
23	CuI	A	DMF	14^f
24	CuI	A	DMF	12^g

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Next, the substrate scope for the copper-catalyzed synthesis of benzo[b]thiophene/imidazo[1,2-a]pyridines (3) was investigated under the optimized conditions (using 10 mol% CuI as the catalyst, 10 mol% 1,10-phenanthroline as the ligand, two equiv. of K₂S as the thiol source, DMF as the solvent at 120 °C under air). As shown in Table 2, the corresponding benzo[b]thiophene/imidazo[1,2-a]pyridines were obtained in moderate to good yields for the examined substrates at 120 °C. Generally, for R¹ and R² substituents, the substrates bearing electron-donating or electron-withdrawing groups were found to show no obvious difference in the transformation. However, a strong electron-withdrawing group such as nitro was not tolerated under the standard conditions (3s). The reason should be that the weak coordination of Cu(I) with sulfur made Cu(I) species unreactive in the present transformation owing to the much more stronger electron-withdrawing properties of the nitro group (see Scheme 3, formation mechanism, the intermediate V). In addition, various functional groups such as methyl, ether, halogen, and trifluoromethyl were well-tolerated under the optimized conditions. Reaction of 6-bromo-2-(2-bromophenyl)imidazo[1,2-a]pyridines with K₂S only took place on the ortho-site C–Br bond of the imidazole group, whereas the 6-site C–Br bond remained intact, thus showing the ortho-substituent effect of the imidazole group during S-arylations (3h and 3r). Furthermore, the application of our present protocol for thiolation of other heterocyclic compounds was explored. To our delight, substituted 6-(2-bromophenyl)imidazo[2,1-b]thiazoles also gave moderate yields of the thiolation products in 62–67% yields (3t–3v).

Table 2 Scope of 2-(2-bromophenyl)imidazo[1,2-a]pyridines for the synthesis of benzo[b]thiophene/imidazo[1,2-a]pyridines (3)^a,b

a Reaction conditions: 2-(2-bromophenyl)imidazo[1,2-a]pyridines (1) (0.3 mmol), K₂S (2) (0.6 mmol), CuI (0.03 mmol), 1,10-phen (0.03 mmol), solvent (2 mL), reaction temperature (120 °C) under air. b Isolated yield.

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Although this transformation was efficient, unfortunately not all the N-heterocycles were compatible with K₂S under the standard conditions. For example, when 2-(2-bromophenyl)-1-methyl-1H-indole and 1-(2-bromophenyl)-1H-pyrrole were used as the substrates under the optimal reaction conditions, no desired product was obtained (Scheme 2). Thus, further investigations to explore more powerful catalysts and ligands are required.

Scheme 2 Substrate scope of heterocyclic compounds.

It is interesting to know the optical properties of the synthesized 3a and derivatives. Therefore, 3a and some selected derivatives were analyzed by UV–vis and photoluminescence (PL) spectroscopy in solution. As shown in Fig. 2, the UV–vis spectra of naked 3a and substituted derivatives 3c, 3l, 3j and 3r have high-intensity absorption between 240 and 270 nm, and lower-intensity bands between 320 and 370 nm. Their emission maxima are observed within the range of 380–430 nm. Compared to naked 3a, substituted derivatives 3c, 3l, 3j and 3r have bathochromic shifts or hypochromatic shifts in both absorption and emission spectra to some extent. Apparently, when there is an electron-donating group attached to the pyridine ring or an electron withdrawing group attached to the benzene ring, a hypochromatic shift could occur.

Fig. 2 Normalized UV–vis (a) and photoluminescence (PL) (b) spectra of selected derivatives 3 in DCM (5.0 × 10⁻⁵ M); (S1: 3a; S2: 3c; S3: 3l; S4: 3j; S5: 3r).

According to the results above and the related literature,²⁵ a possible mechanism for this domino thiolation is thus outlined in Scheme 3. Reaction of CuX with a ligand produces a chelated Cu(I) complex (I), and the subsequent oxidative addition of the chelate with 1 provides the intermediate (II), in which the nitrogen of the imidazole group may coordinate to Cu to provide additional stabilization. Treatment of K₂S (2) with (II) forms the complex (III), and then reductive elimination of (III) leads to the S-arylation product (IV). Reaction of (IV) with LCuX gives the “S–Cu–L” complex (V), then (V) furnishes (VI) under air (O₂). Reductive elimination of (VI) leads to the target product 3 and regenerates the catalyst, LCuX.

Scheme 3 A proposed mechanism for the direct transformation.

In summary, we have developed a novel and efficient copper-catalyzed one-pot method for the synthesis of benzo[b]thiophene/imidazo[1,2-a]pyridines. The corresponding products were obtained in moderate to good yields with excellent functional group tolerance. Some important features of the present protocol involve the use of inexpensive CuI/1,10-phen as the catalyst/ligand system, readily available substituted 2-(2-bromophenyl)imidazo[1,2-a]pyridines and K₂S as the starting materials, and environmentally friendly air (O₂) as the sole oxidant. Further investigations on the practical application of this method are ongoing in our laboratory.

The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21302110, 21302109 and 21375075), the Scientific Research Foundation of Qufu Normal University (BSQD 2012021), the Taishan Scholar Foundation of Shandong Province, the Natural Science Foundation of Shandong Province (ZR2013BQ017 and ZR2013M007), and the Project of Shandong Province Higher Educational Science and Technology Program (J13LD14). We thank Pengfei Sun in this group for reproducing the results of 3a and 3u.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00311c

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