DBDMH-Mediated Regioselective C3-Methylthiolation of Imidazo[1,2-a]pyridines in Dimethyl Sulfoxide

doi:10.6023/cjoc202510021

Abstract

An efficient 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) mediated regioselective C3-methylthiolation of imidazo[1,2-a]pyridines was developed using dimethyl sulfoxide (DMSO) as the methylthio source and solvent. This method exhibits excellent functional group tolerance and offers a metal-free, simple, and efficient approach for the C3-methylthiolation of variously substituted imidazo[1,2-a]pyridines. Diethyl sulfoxide and dibenzyl sulfoxide can also be used as alkyl sulfur sources for this conversion. Under optimized conditions, the scope of this method was successfully extended to 25 target compounds, with yields of up to 88%.

Key words: imidazo[1,2-a]pyridines, methylthiolation, 1,3-dibromo-5,5-dimethylhydantoin, dimethyl sulfoxide

Cite this article

Kai Yang, Xinlei Fu, Longhui Wu, Shuqin Yu, Xue Zhu, Zhaowen Liu, Zhiqin Huang. DBDMH-Mediated Regioselective C3-Methylthiolation of Imidazo[1,2-a]pyridines in Dimethyl Sulfoxide[J]. Chinese Journal of Organic Chemistry, 2026, 46(10): 4152-4161.

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Fig. & Tab. 9

Figure 1. Examples of methylsulfide-containing drugs and natural products

Scheme 1. C3-Methylthiolation of imidazo[1,2-a]pyridines using DMSO

Entry	Variation of standard conditions	Yield^b/%
Entry	Variation of standard conditions	3a	3a'
1	None	86		Trace
2	0.6 equiv. DBDMH	52		17
3	0.8 equiv. DBDMH	81		8
4	1.2 equiv. DBDMH	86		Trace
5	NBS instead of DBDMH	Trace		68
6	110 ℃ instead of 100 ℃	85		Trace
7	80 ℃ instead of 100 ℃	62		32
8	50 ℃ instead of 100 ℃	26		73
9	DMSO/Dioxane (V∶V=1∶1) instead of DMSO	18		65
10	DCE instead of DMSO and 50 ℃ instead of 100 ℃	None		88

Table 1. Optimization of the reaction conditions

Table 2. Substrate scope of various imidazo[1,2-a]pyridines

Scheme 2. Substrate scope of various sulfoxides

Scheme 3. Control experiments

Scheme 4. Proposed mechanism

Scheme 5. Derivatizations of methylthio product

Scheme 6. Synthesis of substrates 1a~1x

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DBDMH诱导咪唑并[1,2-a]吡啶在DMSO中C3选择性甲硫基化反应