无过渡金属参与杂环甲基化合物与醇的选择性有氧碳-烷基化反应

doi:10.6023/cjoc202204043

摘要/Abstract

研究发现, 使用适当的碱并将反应在空气下进行, 不使用任何外加催化剂即可高效实现杂环甲基化合物与各种醇的选择性脱水碳-烷基化反应. 控制实验说明该反应的确不需要过渡金属催化剂, 机理研究也显示了碱和空气在反应中的关键作用: 该反应实际上通过碱促进下空气将醇氧化为羰基化合物的方式启动, 生成的羰基化合物中间体进而催化烷基化反应的顺利进行、从而选择性地得到烷基化产物, 羰基化合物可在反应中再生、回收、完成催化循环. 该方法具有底物适用范围广、无需过渡金属催化剂及配体、无需惰性气体保护、操作简单、成本较低、产物无过渡金属残留等优点, 因此是一种较为实用的杂环化合物的官能团化方法.

关键词: 醇, 烷基化反应, 杂环甲基化合物, 无过渡金属参与

By performing the reaction under air using a suitable base, selective C-alkylation of methyl N-heteroarenes with various alcohols can be effectively achieved without using any external catalyst. Control experiments reveal that transition metal catalysts are indeed not needed in the reaction. Mechanistic studies reveal that base and air can play crucial roles, so that the reaction is in effect initiated by base-promoted aerobic oxidation of the alcohols to carbonyl intermediates, which can then catalyze the C-alkylation reaction to selectively afford the alkylated N-heteroarenes, and be regenerated and recovered to furnish the catalytic cycle. This method has obvious advantages of broad substrate scope, requiring no transition metal catalysts/ligands and inert conditions, simple operation, low cost, no transition metal residue contaminant in the products, and is thus a practical way for functionalization of the N-heteroarene compounds.

Key words: alcohols, alkylation, methyl N-heteroarenes, transition metal-free

引用此文

陈天煜, 韩峰, 李双艳, 刘建平, 陈建辉, 徐清. 无过渡金属参与杂环甲基化合物与醇的选择性有氧碳-烷基化反应[J]. 有机化学, 2022, 42(9): 2914-2924.

Tianyu Chen, Feng Han, Shuangyan Li, Jianping Liu, Jianhui Chen, Qing Xu. Transition Metal-Free Selective Aerobic C-Alkylation of Methyl N-Heteroarenes with Alcohols[J]. Chinese Journal of Organic Chemistry, 2022, 42(9): 2914-2924.

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Entry	Base (equiv.)	T, t	Conv.^b/% of 1a	3aa/4a ratio^b	Yield^c/% of 3a
1	KOH (0.5)	120 ^oC, 15 h	51	64/36	33
2^d	KOH (0.5)	120 ^oC, 24 h	59	8/92	5
3^e	KOH (0.5)	120 ^oC, 24 h	59	<1/99	Trace
4	KOH (1.0)	120 ^oC, 24 h	66	68/32	45
5	KOH (0.5)	140 ^oC, 12 h	62	65/35	40
6	KOH (1.0)	140 ^oC, 12 h	93	98/2	91 (83)
7	CsOH (1.0)	140 ^oC, 12 h	89	98/2	87 (80)
8	NaOH (1.0)	140 ^oC, 12 h	50	18/82	9
9	t-BuONa (1.0)	140 ^oC, 12 h	15	<1/99	Trace
10	t-BuOK (1.0)	140 ^oC, 12 h	84	92/8	77
11^f	KOH (1.0)	140 ^oC, 12 h	—	—	0~Trace
12^g	KOH (1.0)	140 ^oC, 12 h	—	—	Trace
13^h	KOH (1.0)	140 ^oC, 24 h	90	90/10	81 (71)
14ⁱ	KOH (1.0)	140 ^oC, 12 h	86~98	67/33~87/13	57~85
15^j	KOH (1.0)	140 ^oC, 12 h	16~28	>99/1	16~28
16^k	KOH (1.0)	140 ^oC, 12 h	13	>99/1	13^[15-16]
17^l	KOH (1.0)	140 ^oC, 12 h	64	98/2	63 (55)
18^m	KOH (1.0)	140 ^oC, 12 h	98	94/6	92 (92)

Entry	Base (equiv.)	T, t	Conv.^b/% of 1a	3aa/4a ratio^b	Yield^c/% of 3a
1	KOH (0.5)	120 ^oC, 15 h	51	64/36	33
2^d	KOH (0.5)	120 ^oC, 24 h	59	8/92	5
3^e	KOH (0.5)	120 ^oC, 24 h	59	<1/99	Trace
4	KOH (1.0)	120 ^oC, 24 h	66	68/32	45
5	KOH (0.5)	140 ^oC, 12 h	62	65/35	40
6	KOH (1.0)	140 ^oC, 12 h	93	98/2	91 (83)
7	CsOH (1.0)	140 ^oC, 12 h	89	98/2	87 (80)
8	NaOH (1.0)	140 ^oC, 12 h	50	18/82	9
9	t-BuONa (1.0)	140 ^oC, 12 h	15	<1/99	Trace
10	t-BuOK (1.0)	140 ^oC, 12 h	84	92/8	77
11^f	KOH (1.0)	140 ^oC, 12 h	—	—	0~Trace
12^g	KOH (1.0)	140 ^oC, 12 h	—	—	Trace
13^h	KOH (1.0)	140 ^oC, 24 h	90	90/10	81 (71)
14ⁱ	KOH (1.0)	140 ^oC, 12 h	86~98	67/33~87/13	57~85
15^j	KOH (1.0)	140 ^oC, 12 h	16~28	>99/1	16~28
16^k	KOH (1.0)	140 ^oC, 12 h	13	>99/1	13^[15-16]
17^l	KOH (1.0)	140 ^oC, 12 h	64	98/2	63 (55)
18^m	KOH (1.0)	140 ^oC, 12 h	98	94/6	92 (92)