碱促进脱氟[3＋3]环化反应: 6-氟-1,4-二氢嘧啶类化合物的模块化合成

doi:10.6023/cjoc202603015

摘要/Abstract

报道了一种无过渡金属参与的脱氟[3＋3]环加成反应. 该反应以N-苯基芳基甲脒和β-三氟甲基-1,3-烯炔为原料, 高效合成了一系列结构多样化的6-氟-1,4-二氢嘧啶类化合物(DHPs). 此方法具有广泛的底物适用性(涵盖36种底物实例)、优异的区域选择性及高原子经济性, 目标产物收率最高可达94%. 机理研究以及相关文献表明, 该反应历程先后涉及碱促进的去质子化、亲核加成/原位亲核取代、选择性C—F键断裂以及分子内S_NV环化等分步过程. 放大实验表明, 该反应体系具有良好的可扩展性, 所得产物亦具备优异的后期官能化潜力, 充分证实了本策略的重要合成价值.

关键词: β-三氟甲基-1,3-烯炔, [3＋3]环化, α,γ-双选择性脱氟, 6-氟-1,4-二氢嘧啶

A defluorinative [3＋3] annulation between N-phenyl arylformamidines and β-trifluoromethyl-1,3-enynes was reported, enabling direct access to structurally diversified 6-fluoro-1,4-dihydropyrimidines (DHPs) with yields up to 94% across 36 examples under transition-metal-free conditions. This protocol features broad substrate generality, excellent regioselectivity, and high atom economy. Mechanistic studies and related literature support a sequence base-promoted deprotonation, nucleophilic addition/in situ nucleophilic substitution, selective C—F bond cleavage, and an intramolecular S_NV cyclization. The scalability and broad potential for late-stage functionalization of the products further attest to the synthetic value of this protocol.

Key words: β-trifluoromethyl-1,3-enynes, [3＋3] annulation, α,γ-dual selective defluorination, 6-fluoro-1,4-dihydropyrimi-dines

引用此文

李琰琦, 皮超, 高宁, 吴养洁, 崔秀灵. 碱促进脱氟[3＋3]环化反应: 6-氟-1,4-二氢嘧啶类化合物的模块化合成[J]. 有机化学, 2026, 46(10): 3989-4001.

Yanqi Li, Chao Pi, Ning Gao, Yangjie Wu, Xiuling Cui. Base-Promoted Defluorinative [3＋3] Annulation: Modular Access to 6-Fluoro-1,4-dihydropyrimidines[J]. Chinese Journal of Organic Chemistry, 2026, 46(10): 3989-4001.

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图/表 8

Figure 1. Selected bioactive compounds containing 1,4-dihydropyrimidine skeleton

Scheme 1. Previous reports and our design for the preparation of 1,4-dihydropyrimidines

Entry	Base	Solvent	Yield^b/%
1	Cs₂CO₃	MeCN	29
2	KO^tBu	MeCN	31
3	LiO^tBu	MeCN	27
4	KOH	MeCN	66
5	NaOH	MeCN	69
6	DBU	MeCN	nr
7	DMAP	MeCN	Trace
8	TMG	MeCN	nr
9	NaOH	DCE	nr
10	NaOH	THF	22
11	NaOH	DMF	27
12	NaOH	Toluene	Trace
13^c	NaOH	MeCN	57
14^d	NaOH	MeCN	71
15^e	NaOH	MeCN	85

Table 1. Optimization of the reaction conditionsa

Scheme 2. Scope of the defluorocyclization with N-phenyl arylformamidines Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), NaOH (0.3 mmol), and MeCN (1 mL), 50 ℃, 12 h under air.

Scheme 3. Scope of the defluorocyclization with β-trifluoromethyl alkenes Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), NaOH (0.3 mmol), and MeCN (1 mL), 50 ℃, 12 h under air.

Scheme 4. Scale-up synthesis and synthetic application Reaction conditions: (a) TBAF, tetrahydrofuran (THF), 0 ℃, 15 min; (b) NiCl2•6H2O, CuI, TMEDA, Et3N, THF, r.t., 12 h.

Scheme 5. Control experiments: (a) absence of base; (b) absence of alkynyl group; (c) capture intermediate

Scheme 6. Possible reaction pathways

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