DBDMH诱导咪唑并[1,2-a]吡啶在DMSO中C3选择性甲硫基化反应

doi:10.6023/cjoc202510021

摘要/Abstract

以1,3-二溴-5,5-二甲基海因(DBDMH)为诱导剂, 二甲基亚砜(DMSO)为甲硫化试剂和溶剂, 实现咪唑并[1,2-a]吡啶的C3甲硫基化反应. 该方法表现出优异的官能团耐受性, 为各种取代的咪唑并[1,2-a]吡啶的甲硫化提供了一种无金属、简捷和高效的方法. 二乙基亚砜和二苄基亚砜也可作为烷硫基源应用于该转化. 在最优条件下, 合成了25种目标化合物, 最高产率达88%.

关键词: 咪唑并[1,2-a]吡啶, 甲硫基化反应, 1,3-二溴-5,5-二甲基海因, 二甲基亚砜

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

引用此文

杨凯, 付鑫磊, 吴龙辉, 余树琴, 朱雪, 刘昭文, 黄志勤. DBDMH诱导咪唑并[1,2-a]吡啶在DMSO中C3选择性甲硫基化反应[J]. 有机化学, 2026, 46(10): 4152-4161.

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.

导出引用 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

分享此文

图/表 9

图1. 含甲基硫的药物和天然产物的例子

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

图式1. 基于DMSO的咪唑并[1,2-a]吡啶的C3甲硫基化反应

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

表1. 反应条件的优化a

Table 1. Optimization of the reaction conditions

表2. 咪唑并[1,2-a]吡啶的底物扩展a,b

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

图式2. 亚砜化合物的底物适用性研究

Scheme 2. Substrate scope of various sulfoxides

图式3. 控制实验

Scheme 3. Control experiments

图式4. 可能的反应机理

Scheme 4. Proposed mechanism

图式5. 甲硫基化产物的衍生化

Scheme 5. Derivatizations of methylthio product

图式6. 底物1a~1x的合成

Scheme 6. Synthesis of substrates 1a~1x

参考文献 17

[1]	(a) Feng M.; Tang B.; Liang S. H.; Jiang X. Curr. Top. Med. Chem. 2016, 16, 1200. doi: 10.2174/1568026615666150915111741 pmid: 27413802
	(b) Conroy S.; Kindon N.; Kellam B.; Stocks M. J. J. Med. Chem. 2016, 59, 9981. pmid: 27413802
	(c) Park S. Y.; Hwang I.-S.; Lee H.-J.; Song C. E. Nat. Commun. 2017, 8, 14877. doi: 10.1038/ncomms14877 pmid: 27413802
	(d) Zhang Y.; Ren Y.; Zhang J.; Liu S.; Li H. Chin. J. Chem. 2023, 41, 3045. doi: 10.1002/cjoc.v41.22 pmid: 27413802
	(e) Yang L.; Li B.; Shu C. Acta Chim. Sinica 2024, 82, 171 (in Chinese). doi: 10.6023/A23100435 pmid: 27413802
	(杨铃悦, 李赟婷, 舒超, 化学学报, 2024, 82, 171.) pmid: 27413802
	(f) Zhou Q.; Jiang J.; Luo N.; Huang J. Acta Chim. Sinica 2025, 83, 274 (in Chinese). doi: 10.6023/A25010015 pmid: 27413802
	(周泉, 蒋佳怡, 罗年华, 黄家翩, 化学学报, 2025, 83, 274.) pmid: 27413802
	(g) Du Y.; Li S.; Cheng S.; Jia H.; Wang Z.; Han L.; Zhu N. Acta Chim. Sinica 2026, 84, 93 (in Chinese). doi: 10.6023/A25060234 pmid: 27413802
	(杜云哲, 李曙懿, 程思柳, 贾慧劼, 王政, 韩利民, 竺宁, 化学学报, 2026, 84, 93.) pmid: 27413802
[2]	(a) Chen Y.; Zhou J.; Wang H.; Xia Y.; Yang Z. Y.; Xia P. Chin. Chem. Lett. 2008, 19, 925. doi: 10.1016/j.cclet.2008.05.043 pmid: 28418240
	(b) Giannetti A. M.; Wong H.; Dijkgraaf G. J. P.; Dueber E. C.; Ortwine D. F.; Bravo B. J.; Gould S. E.; Plise E. G.; Lum B. L.; Malhi V.; Graham R. A. J. Med. Chem. 2011, 54, 2592. doi: 10.1021/jm1008924 pmid: 28418240
	(c) Dunbar K.L.; Scharf D.H.; Litomska A.; Hertweck C. Chem. Rev. 2017, 117, 5521-5577. doi: 10.1021/acs.chemrev.6b00697 pmid: 28418240
	(d) Wang R.; Lu L.; Shen Q. Chin. J. Chem. 2023, 41, 2317. doi: 10.1002/cjoc.v41.18 pmid: 28418240
	(e) Zheng J.; Lin J.; Xiao J. Acta Chim. Sinica 2024, 82, 115 (in Chinese). doi: 10.6023/A23080384 pmid: 28418240
	(郑剑, 林锦鸿, 肖吉昌, 化学学报, 2024, 82, 115.) doi: 10.6023/A23080384 pmid: 28418240
[3]	(a) Tashrifi Z.; Khanaposhtani M. M.; Larijani B.; Mahdavi M. Adv. Synth. Catal. 2020, 362, 65. doi: 10.1002/adsc.201901021
	(b) Wu X.-F.; Natte K. Adv. Synth. Catal. 2016, 358, 336. doi: 10.1002/adsc.v358.3
[4]	(a) Natarajan P.; Basaka A.; Metin O. Green Chem. 2023, 25, 3187. doi: 10.1039/D3GC00187C
	(b) Tian Y.; Zhang J.; Gao W.; Chang H. Chin. J. Org. Chem. 2023, 43, 2391 (in Chinese). doi: 10.6023/cjoc202211026
	(田钰, 张娟, 高文超, 常宏宏, 有机化学, 2023, 43, 2391.) doi: 10.6023/cjoc202211026
	(c) Chen X.-H.; Lhazom T.; Cui H.-L. J. Org. Chem. 2023, 88, 13598. doi: 10.1021/acs.joc.3c01302
	(d) Qi Z.; Wang H.; Ren Y.; Niu Y.; Jiang Y.; Yan R. Chem. Commun. 2020, 56, 15627. doi: 10.1039/D0CC07002E
	(e) Shu W.-M.; He J.-X.; Zhang X.-F.; Wang S.; Wu A.-X. J. Org. Chem. 2019, 84, 2962. doi: 10.1021/acs.joc.8b02755
	(f) Zhu X.; Li W.; Luo X.; Deng G.; Liang Y.; Liu J. Green Chem. 2018, 20, 1970. doi: 10.1039/C8GC00477C
	(g) Xu X.; Yang Y.; Zhang X.; Yi W. Org. Lett. 2018, 20, 566. doi: 10.1021/acs.orglett.7b03673
[5]	(a) Chang M.-Y.; Chen H.-Y.; Tsai Y.-L. Org. Lett. 2019, 21, 1832. doi: 10.1021/acs.orglett.9b00422
	(b) Huang M.-H.; Zhu C.-F.; He C.-L.; Zhu Y.-L.; Hao W.-J.; Wang D.-C.; Tu S.-J.; Jiang B. Org. Chem. Front. 2018, 5, 1643. doi: 10.1039/C8QO00098K
	(c) Zhao P.; Wu X.; Geng X.; Wang C.; Zhou Y.; Wu Y.-D.; Wu A.-X. J. Org. Chem. 2019, 84, 8322. doi: 10.1021/acs.joc.9b01160
	(d) Xu N.; Zhang Y.; Chen W.; Li P.; Wang L. Adv. Synth. Catal. 2018, 360, 1199. doi: 10.1002/adsc.v360.6
	(e) Vaitla J.; Hopmann K. H.; Bayer A. Org. Lett. 2017, 19, 6688. doi: 10.1021/acs.orglett.7b03413
[6]	(a) Toyoda S.; Iizumi K.; Yamaguchi J. Chem. Sci. 2025, 16, 11559. doi: 10.1039/D5SC01428J pmid: 36069536
	(b) Li X.; Sun F.; He J.; Shi H.; Zhang S.; Du Y. J. Org. Chem. 2025, 90, 9928. doi: 10.1021/acs.joc.5c00953 pmid: 36069536
	(c) Zhou Y.-J.; Fang Y.-G.; Yang K.; Lin J.-Y.; Li H.-Q.; Chen Z.-J.; Wang Z.-Y. Molecules 2023, 28, 5635. doi: 10.3390/molecules28155635 pmid: 36069536
	(d) Mamedov V. A.; Algaeva N. E.; Syakaev V. V.; Mustakimova L. V.; Khafizova E. A.; Shamautdinova L. R.; Rizvanov I.; Gubaidullin A.T. J. Org. Chem. 2022, 87, 12072. doi: 10.1021/acs.joc.2c01158 pmid: 36069536
	(e) Li X.; Wang X.; Li Y.; Xiao J.; Du Y. Org. Biomol. Chem. 2022, 20, 4471. doi: 10.1039/D2OB00570K pmid: 36069536
	(f) Wu Y.; Wang N.-X.; Zhang T.; Yan Z.; Xu B.-C.; Inoa J.; Xing Y. Adv. Synth. Catal. 2019, 361, 3008. doi: 10.1002/adsc.v361.12 pmid: 36069536
	(g) Xiao Y.; Wang S.; Liu J.; Zhang H.; Xu Y. Tetrahedron Lett. 2019, 60, 1317. doi: 10.1016/j.tetlet.2019.03.067 pmid: 36069536
	(h) Hu L.; Chen X.; Yu L.; Yu Y.; Tan Z.; Zhu G.; Gui Q. Org. Chem. Front. 2018, 5, 216. doi: 10.1039/C7QO00717E pmid: 36069536
	(i) Cao L.; Luo S.-H.; Wu H.-Q.; Chen L.-Q.; Jiang K.; Hao Z.-F.; Wang Z.-Y. Adv. Synth. Catal. 2017, 359, 2961. doi: 10.1002/adsc.v359.17 pmid: 36069536
	(j) Sharma P.; Rohilla S.; Jain N. J. Org. Chem. 2015, 80, 4116. doi: 10.1021/acs.joc.5b00443 pmid: 36069536
	(k) Gao X.; Pan X.; Gao J.; Jiang H.; Yuan G.; Li Y. Org. Lett. 2015, 17, 1038. doi: 10.1021/acs.orglett.5b00170 pmid: 36069536
	(l) Yuan G.; Zheng J.; Gao X.; Li X.; Huang L.; Chen H.; Jiang H. Chem. Commun. 2012, 48, 7513. doi: 10.1039/c2cc32964f pmid: 36069536
	(m) Luo F.; Pan C.; Li L.; Chen F.; Cheng J. Chem. Commun. 2011, 47, 5304. doi: 10.1039/c1cc10795j pmid: 36069536
	(n) Chu L.; Yue X.; Qing F.-L. Org. Lett. 2010, 12, 1644. doi: 10.1021/ol100449c pmid: 36069536
	(o) Zhang J.; Wang Y.; Tian Y.; Gao W.; Chang H.; Meng F.; Yang B. Chin. J. Org. Chem. 2024, 44, 1576 (in Chinese). doi: 10.6023/cjoc202310026 pmid: 36069536
	(张娟, 王奕森, 田钰, 徐晶, 高文超, 常宏宏, 孟凡会, 杨朋, 有机化学, 2024, 44, 1576.) doi: 10.6023/cjoc202310026 pmid: 36069536
[7]	(a) Devi N.; Singh D.; Rawal R. K.; Bariwal J.; Singh V. Curr. Top. Med. Chem. 2016, 16, 2963. doi: 10.2174/1568026616666160506145539
	(b) Samanta S.; Kumar S.; Aratikatla E. K.; Ghorpade S. R.; Singh V. RSC Med. Chem. 2023, 14, 644. doi: 10.1039/D3MD00019B
[8]	(a) Abe Y.; Kayakiri H.; Satoh S.; Inoue T.; Sawada Y.; Inamura N.; Asano M.; Aramori I.; Hatori C.; Sawai H.; Oku T.; Tanaka H. J. Med. Chem. 1998, 41, 4587. pmid: 9804698
	(b) Okubo T.; Yoshikawa R.; Chaki S.; Okuyama S.; Nakazato A. Bioorg. Med. Chem. 2004, 12, 423. pmid: 9804698
	(c) Ismail M. A.; Arafa R. K.; Wenzler T.; Brun R.; Tanious F. A.; Wilson W. D.; Boykin D. W. Bioorg. Med. Chem. 2008, 16, 683. doi: 10.1016/j.bmc.2007.10.042 pmid: 9804698
	(d) Shukla N. M.; Salunke D. B.; Yoo E.; Mutz C. A.; Balakrishna R.; David S. A. Bioorg. Med. Chem. 2012, 20, 5850. doi: 10.1016/j.bmc.2012.07.052 pmid: 9804698
	(e) Kim O.; Jeong Y.; Lee H.; Hong S.-S.; Hong S. J. Med. Chem. 2011, 54, 2455. doi: 10.1021/jm101582z pmid: 9804698
	(f) Feng S.; Hong D.; Wang B.; Zheng X.; Miao K.; Wang L.; Yun H.; Gao L.; Zhao S.; Shen H. C. ACS Med. Chem. Lett. 2015, 6, 359. doi: 10.1021/acsmedchemlett.5b00008 pmid: 9804698
[9]	(a) Bagdi A. K.; Santra S.; Monir K.; Hajra A. Chem. Commun. 2015, 51, 1555. doi: 10.1039/C4CC08495K
	(b) Patel O. P. S.; Nandwana N. K.; Legoabe L. J.; Das B. C.; Kumar A. Adv. Synth. Catal. 2020, 362, 4226. doi: 10.1002/adsc.v362.20
	(c) Liu X.; Li W.; Liu H.; Cao H. Chin. J. Org. Chem. 2021, 41, 1759 (in Chinese).
	(刘想, 李文, 刘环宇, 曹华, 有机化学, 2021, 41, 1759.) doi: 10.6023/cjoc202012026
	(d) Tali J. A.; Kumar G.; Sharma B. K.; Rasool Y.; Sharma Y.; Shankar R. Org. Biomol. Chem. 2023, 21, 7267. doi: 10.1039/D3OB00849E
	(e) Zhang Z.; Guo Y.; Yang J.; Wang D.; Wang J.; Hong X.; Cai P.; Rong L. Chin. J. Org. Chem. 2023, 43, 2104 (in Chinese).
	(张周, 郭钰, 羊静, 吴丹, 王佳昕, 洪欣玥, 蔡佩君, 荣良策, 有机化学, 2023, 43, 2104.) doi: 10.6023/cjoc202212014
	(f) Gao J.; Fu X.; Yang K.; Liu Z.-W. Molecules 2025, 30, 607. doi: 10.3390/molecules30030607
[10]	(a) Yuan Y.; Cao Y.; Qiao J.; Lin Y.; Jiang X.; Weng Y.; Tang S.; Lei A. Chin. J. Chem. 2019, 37, 49. doi: 10.1002/cjoc.v37.1
	(b) Wen J.; Niu C.; Yan K.; Cheng X.; Gong R.; Li M.; Guo Y.; Yang J.; Wang H. Green Chem. 2020, 22, 1129. doi: 10.1039/C9GC04068D
[11]	Patil S. M.; Kulkarni S.; Mascarenhas M.; Sharma R.; Roopan S. M.; Roychowdhury A. Tetrahedron 2013, 69, 8255. doi: 10.1016/j.tet.2013.07.017
[12]	(a) Ravi C.; Mohan D. C.; Adimurthy S. Org. Biomol. Chem. 2016, 14, 2282. doi: 10.1039/C5OB02475G
	(b) Zhang L.-Y.; Wu Y.-H.; Wang N.-X.; Gao X.-W.; Yan Z.; Xu B.-C.; Liu N.; Wang B.-Z.; Xing Y. Eur. J. Org. Chem. 2021, 1446.
[13]	Feng Z.; Fan Y.; Qiang C.; Liu P.; Sun P. Green Chem. 2024, 26, 3517. doi: 10.1039/D4GC00314D
[14]	(a) Yang K.; Luo S.; Chen S.; Cao X.; Zhou Y.; Lin J.; Huo Y.; Wang Z.-Y. Org. Biomol. Chem. 2021, 19, 8133. doi: 10.1039/d1ob01424b pmid: 34545907
	(b) Yang K.; Chen Z.; Zhou Y.; Chen Q.; Yu S.; Luo S.; Wang Z.-Y. Org. Chem. Front. 2022, 9, 1127. doi: 10.1039/D1QO01753E pmid: 34545907
	(c) Gao J.; Liu Z.; Guo X.; Wu L.; Chen Z.; Yang K. Molecules 2023, 28, 7522. doi: 10.3390/molecules28227522 pmid: 34545907
	(d) Fu X.; Wu L.; Guo X.; Yang K.; Liu Z. J. Saudi Chem. Soc. 2024, 28, 101883. doi: 10.1016/j.jscs.2024.101883 pmid: 34545907
	(e) Liu Z.; Guo X.; Chen Z.; Wu L.; Yang K. Synthesis 2024, 56, 1756. doi: 10.1055/a-2254-0907 pmid: 34545907
[15]	(a) Fu D.; Dong J.; Wang J.; Wang J.; Xu J. Asian J. Org. Chem. 2021, 10, 1756. doi: 10.1002/ajoc.v10.7
	(b) Ma C.-H.; Chen M.; Feng Z.-W.; Zhang Y.; Wang J.; Jiang Y.-Q.; Yu B. New J. Chem. 2021, 45, 9302. doi: 10.1039/D1NJ00704A
[16]	Lu R.; Tao Q.; Qian Q.; Li B.; Zhang Y.; Gao Y. Adv. Synth. Catal. 2024, 366, 4084. doi: 10.1002/adsc.v366.19
[17]	Chen Z.; Cao G.; Zhang F.; Li H.; Xu J.; Miao M.; Ren H. Synlett 2017, 28, 1795. doi: 10.1055/s-0036-1588419