Synthesis of heteroaryl containing sulfides via enaminone ligand assisted, copper-catalyzed C–S coupling reactions of heteroaryl thiols and aryl halides

Abstract

The C–S cross coupling reactions between electron deficient heteroaryl thiols and aryl halides have been smoothly performed to provide various heteroaryl containing sulfides in the presence of copper catalyst and enaminone ligand.

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Introduction

Sulfur containing organic compounds prevalently present in the fine chemicals, pharmaceuticals, materials, agrochemicals and natural products.^1–5 Therefore, the construction of C–S bonds is an issue of considerable research interest in organic synthesis. At present, transition metal-catalyzed coupling reactions of thiols with aryl/vinyl halides are predominantly employed for the synthesis of C–S bond containing organic molecules such as thiols, sulfides, S-containing heterocycles.^6–9 Among the various transition metal-catalyzed methods for C–S coupling reactions, the copper-catalyzed version, also known as Ullmann C–S coupling reaction, has been known as the most atom economical option. Numerous efforts have been devoted to establish improved protocols on C–S coupling reactions between thiols and aryl/vinyl halides based on copper catalysis, which leads to significant progress on the chemistry of C–S coupling reactions by discovering new ligands, recyclable copper catalysts, renewable sulfur sources as well as reactions in green media.^10–23

However, in contrast to the overwhelming reports on the catalytic research of C–S coupling reaction, synthetic methods towards product diversity, for example, the systematic synthesis of heteroaryl containing sulfides are still rare probably because of the low nucleophilicity of most available heteroaryl thiols.^24,25 In a previous study, we have disclosed that thiophenols 4 and (hetero)aryl halides 2 undergo tandem C–S cross coupling/C–H functionalization to provide hydroxyl functionalized sulfides 5 in the presence of copper catalyst and an enaminone ligand (Scheme 1).²⁶ On the basis of this interesting transformation, we have recently conducted extensive investigation on enaminone-based ligand assisted Ullmann C-heteroatom and C–C coupling reactions in order to expand the application scope of this kind of ligands for the synthesis of structurally diverse organic products.^27–30 Based on the structure of products 3, the C–H hydroxylation may possibly happen in either the aryl backbone in the thiophenols or the halides. While the examples using aryl and heteroaryl halides both provide hydroxylated sulfides 3 in the previous work, however, the reactions using heteroaryl thiols 4 have not been examined. Therefore, in order to explore the reaction more comprehensively and synthesize sulfides with higher diversity, we are inspired to investigate the coupling reactions of heteroaryl thiols 4 with aryl halides 2. Herein, we report the results from the systematic investigation on electron deficient thiol-based C–S coupling, which leads to selective production of heteroaryl sulfides 5 with broad application scope.

Scheme 1 Selective synthesis of different sulfides with different thiol substrates.

Results and discussion

Initially, the coupling of 2-mercaptobenzothiazole 4a and iodobenzene 2a was employed as a model reaction. In the presence of CuI catalyst and enaminone ligand L1 using DMSO as medium, the S-arylated product 5a was obtained as the only product from the reaction, suggesting that α-hydroxylation in the sulfide product only occurs when the substrates have a position available for this process. Based on the selective production of heteroaryl sulfide 5a, we consequently conducted optimization on this reaction. As shown in Table 1, the original screening of different copper catalysts, including Cu(I) and Cu(II) catalysts, displayed that Cu(OAc)₂ was the best copper catalyst (entries 1–5, Table 1). Subsequently, a class of enaminone-based ligand L2–L4 and other frequently employed ligand L-proline L5, 8-hydroxylquinoline L6 were compared, which revealed that the enaminone-based ligand L3 was the best partner of the copper catalyst (entires 6–10, Table 1). Following these results, different bases including both organic and inorganic ones were then assayed. Among these tested bases such as K₂CO₃, t-BuOK, DMAP, Cs₂CO₃ was found as the most favorable one (entries 11–14, Table 1). Further efforts in varying different solvents also gave just inferior yields of target product (entries 15–18, Table 1). Finally, lowering the temperature led to sharp decrease in the yield of 5a (entry 19, Table 1).

Table 1 Optimization on reaction conditions^a

Entry	Catalyst	Ligand	Base	Solvent	T (°C)	Yield^b (%)
a General conditions: 4a (0.5 mmol), 2a (0.6 mmol), copper catalyst (0.05 mmol), ligand (0.05 mmol) and base (1.0 mmol) in DMSO (2 mL), stirred for 12 h.b Yield of isolated product.c All Cu(OAc)2 refers to the commercially available reagent Cu(OAc)2·H2O.
1	CuI	L1	Cs2CO3	DMSO	100	60
2^c	Cu(OAc)2	L1	Cs2CO3	DMSO	100	83
3	CuSO4	L1	Cs2CO3	DMSO	100	80
4	Cu2O	L1	Cs2CO3	DMSO	100	70
5	CuBr	L1	Cs2CO3	DMSO	100	80
6	Cu(OAc)2	L2	Cs2CO3	DMSO	100	79
7	Cu(OAc)2	L3	Cs2CO3	DMSO	100	95
8	Cu(OAc)2	L4	Cs2CO3	DMSO	100	81
9	Cu(OAc)2	L5	Cs2CO3	DMSO	100	72
10	Cu(OAc)2	L6	Cs2CO3	DMSO	100	83
11	Cu(OAc)2	L3	K2CO3	DMSO	100	16
12	Cu(OAc)2	L3	NaOH	DMSO	100	53
13	Cu(OAc)2	L3	DMAP	DMSO	100	80
14	Cu(OAc)2	L3	t-BuOK	DMSO	100	71
15	Cu(OAc)2	L3	Cs2CO3	Toluene	100	20
16	Cu(OAc)2	L3	Cs2CO3	EtOH	Reflux	41
17	Cu(OAc)2	L3	Cs2CO3	THF	Reflux	15
18	Cu(OAc)2	L3	Cs2CO3	Dioxane	100	21
19	Cu(OAc)2	L3	Cs2CO3	DMSO	90	31

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With the optimized conditions in hand, we consequently turned to investigate the catalytic C–S coupling of different aryl halides and a variety of heteroaryl thiols for the sake of establishing a generally applicable methodology. The results in synthesizing heteroaryl sulfides of diverse structures were given in Table 2. According to these results, the present protocol suited for the synthesis of heteroaryl sulfides with broad application scope via the employment of different heteroaryl thiols such as 2-mercaptobenzothiazole (4a), 4,6-dimethylpyrimidine-2-thiol (4b) and pyridinyl-2-thiol (4c) as well as different aryl iodides and bromides. Generally, in the reactions involving 4a, aryl iodides containing electron withdrawing groups were better favored to give corresponding products with moderate to excellent yield, while electron enriched iodide such as p-methoxylphenyl iodide 2i underwent the C–S coupling to provide product 5i with low yield (entry 9, Table 2). However, another electron enriched substrate, the o-iodoaniline 2h coupled with 4a to give corresponding product 5h with much higher yield probably because of the chelating effect of the amino group to copper catalyst, which facilitated the catalysis of copper to the desired coupling (entry 8, Table 2). Similar tendencies were observed also in the reactions using heteroaryl thiols 4b and 4c as generally those aryl halides containing electron withdrawing substituents were coupled successfully to afford related sulfides. Notably, some aryl bromides could also participate the coupling reaction to yield disulfide products with moderate yields although the entry using bromobenzene gave only trace amount of expect transformation (entries 13 and 14, Table 2). As reported previously, this enaminone ligand assisted protocol was not applicable for the synthesis of sulfides using carbonaryl thiols containing α-C–H bond because of the selective transformation of α-hydroxylaiton.²⁶

Table 2 Synthesis of different heteroaryl sulfides via C–S coupling reactions^a

Entry	Thiol	Ar-X	Product	Yield^b (%)
a General conditions: 4 (0.5 mmol), 2 (0.6 mmol), Cu(OAC)2·H2O (0.05 mmol), L3 (0.05 mmol) and Cs2CO3 (1.0 mmol) in DMSO (2 mL), stirred at 100 °C for 12 h.b Yield of isolated product.
1		Iodobenzene 2a		95
2	4a	1,4-Diiodobenzene 2b		42
3	4a	p-Nitroiodobenzene 2c		51
4	4a	p-Chloroiodobenzene 2d		93
5	4a	o-Bromoiodobenzene 2e		54
6	4a	1,3-Diiodobenzene 2f		45
7	4a	1,2-Diiodobenzene 2g		52
8	4a	o-Iodoaniline 2h		63
9	4a	p-Methoxyliodobenzene 2i		34
10		2a		94
11	4b	2c		42
12	4b	2b		29
13	4b	p-Bromoacetophenone 2j		33
14	4b	2,6-Dibromopyridine 2k		31
15		2a		96
16	4c	2c		84
17	4c	2b		57
18	4c	2e		36
19	4c	2d		49
20	4c	p-Tolyliodide 2l		45

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Conclusions

In summary, we have illustrated a copper-based catalytic protocol for the C–S coupling reactions of electron deficient heteroaryl thiols with aryl halides. This work expands the scope of known methods for the synthesis of these heteroaryl sulfides, the results are therefore useful as a complementary option in the synthesis of heteroaryl sulfides via simple starting materials.

Acknowledgements

The authors thank NSFC of China (no. 21202064) and a Sponsored Program for Cultivating Youths of Outstanding Ability in Jiangxi Normal University (Y. Liu) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General experimental information, full characterization data, ¹H and ¹³C NMR spectra of all products. See DOI: 10.1039/c4ra07187e

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