Transition-Metal-Free Direct gem-Difluoroallylation of β,γ-Unsatu- rated α-Amino Nitrile Derived Lithium Reagents

doi:10.6023/cjoc202605002

Chinese Journal of Organic Chemistry ›› 2026, Vol. 46 ›› Issue (9): 3676-3687.DOI: 10.6023/cjoc202605002 Previous Articles Next Articles

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非过渡金属条件下β,γ-不饱和α-胺基腈锂试剂的直接偕二氟烯丙基化反应

黄明琛, 赵海洋, 张新刚^*()

中国科学院上海有机化学研究所先进氟氮材料全国重点实验室上海 200032

收稿日期:2026-05-02 修回日期:2026-06-16 发布日期:2026-07-14
通讯作者: 张新刚
基金资助:
国家重点研发计划(2025YFA1511100); 国家自然科学基金(22301307); 中国科学院基础与交叉前沿科研先导专项(XDB0590000)

Transition-Metal-Free Direct gem-Difluoroallylation of β,γ-Unsatu- rated α-Amino Nitrile Derived Lithium Reagents

Mingchen Huang, Haiyang Zhao, Xingang Zhang^*()

State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032

Received:2026-05-02 Revised:2026-06-16 Published:2026-07-14
Contact: Xingang Zhang
About author:
Dedicated to the 100th anniversary of the birth of Professor Xikui Jiang.
Supported by:
National Key R&D Program of China(2025YFA1511100); National Natural Science Foundation of China(22301307); Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0590000)

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Abstract

A transition-metal-free protocol for the direct gem-difluoroallylation of β,γ-unsaturated α-amino nitrile-derived lithium reagents was reported. The reaction proceeds via the in situ generation of β,γ-unsaturated α-amino nitrile lithium species, which react with gem-difluoroallylic ammonium salts with high regioselectivity. This selectivity is governed by the hard- soft acid-base (HSAB) principle, wherein the softness of the nucleophile is matched with that of the electrophile. The resulting products can be readily transformed into a diverse array of β-gem-difluoroallyl-substituted carboxylic acid derivatives. Notable features of this reaction include the absence of transition metals, the synthetic simplicity inherent in organolithium reagents, scalability to gram quantities, and good functional-group compatibility. This strategy offers an efficient approach to the synthesis of gem-difluoroallyl compounds.

Key words: β,γ-unsaturated α-aminonitriles, organolithium reagents, gem-difluoroallylic ammonium salts, gem-difluoro- allylation

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Mingchen Huang, Haiyang Zhao, Xingang Zhang. Transition-Metal-Free Direct gem-Difluoroallylation of β,γ-Unsatu- rated α-Amino Nitrile Derived Lithium Reagents[J]. Chinese Journal of Organic Chemistry, 2026, 46(9): 3676-3687.

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Fig. & Tab. 4

Scheme 1. (a) Advantages of organolithium reagents and their classical reaction types; (b) Reactions involving Gilman reagents; (c) Nickel-catalyzed difluoroalkylation of heteroatom-stabilized organolithium reagents; (d) transition-metal-free direct gem-difluoroallyla- tion of β,γ-unsaturated α-amino nitrile-derived lithium reagents

Entry	3	x/equiv.	y/equiv.	T₁/℃	T₂/℃	Yield^b/%
Entry	3	x/equiv.	y/equiv.	T₁/℃	T₂/℃	4a		5a
1	3a	1.0	1.0	－78	－78	N.D.	54
2	3b	1.0	1.0	－78	－78	N.D.	67
3	3c	1.0	1.0	－78	－78	63	N.D.
4	3c	1.2	1.0	－78	－78	80	N.D.
5	3c	1.5	1.0	－78	－78	80	N.D.
6	3c	1.2	1.2	－78	－78	96	N.D.
7	3c	1.2	1.5	－78	－78	96	N.D.
8	3c	1.2	1.2	0	－78	96 (82^c)	N.D.
9	3c	1.2	1.2	0	0	N.D.	N.D.

Table 1. Optimization of the gem-difluoroallylation of β,γ-unsaturated α‑amino nitrile derived lithium reagents

Scheme 2. Direct gem-difluoroallylation of β,γ-unsaturated α-amino nitrile derived lithium reagents a Reaction conditions: 1 (0.6 mmol, 1.2 equiv.), LiHMDS (0.6 mmol, 1.2 equiv.), THF (5.0 mL), 0 ℃, 30 min; 3 (0.5 mmol, 1.0 equiv.), －78 ℃ to r.t., 1 h, THF (3.0 mL); 2 mol/L HCl (5.0 mL), 80 ℃, 12 h. All yields are isolated yields. b Reaction conditions: 1 (0.48 mmol, 1.2 equiv.), LiHMDS (0.48 mmol, 1.2 equiv.), THF (4.0 mL), 0 ℃, 30 min; 3 (0.4 mmol, 1.0 equiv.), −78 ℃ to r.t., 1 h, THF (3.0 mL); 2 mol/L HCl (5.0 mL), 80 ℃, 12 h. All yields are isolated yields. c Reaction conditions: 1 (1.2 mmol, 1.2 equiv.), LiHMDS (1.2 mmol, 1.2 equiv.), THF (10.0 mL), 0 ℃, 30 min; 3 (1.0 mmol, 1.0 equiv.), −78 ℃ to r.t., 1 h, THF (3.0 mL); 2 mol/L HCl (5.0 mL), 80 ℃, 12 h. All yields are isolated yields.

Scheme 3. Gram-scale reaction and applications Reaction conditions for gram-scale reaction and applications: (a) (1) 6a (0.2 mmol, 1.0 equiv.), H2SO4 (one drop), MeOH (2.0 mL), 80 ℃; (2) K2Os(OH)4 (0.01 mmol, 5 mol%), NMO (0.2 mmol, 1.0 equiv.), acetone (1.25 mL) and H2O (0.25 mL); (b) (1) 6a (0.2 mmol, 1.0 equiv.), H2SO4 (one drop), MeOH (2.0 mL), 80 ℃; (2) 1-bromobutene (0.8 mmol, 4.0 equiv.), second-generation Grubbs catalyst (0.02 mmol, 10 mol%), dichloromethane (DCM) (0.2 mL); (c) 6a (0.2 mmol, 1.0 equiv.), PPDP (0.32 mmol, 1.6 equiv.), Tf-PPDP (0.34 mmol, 1.7 equiv.), HBpin (0.22 mmol, 1.1 equiv.), DCM (1.0 mL), r.t.; (d) 9 (0.06 mmol, 1.0 equiv.), NaBH4 (0.12 mmol, 2.0 equiv.), MeOH (1.0 mL), r.t.

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非过渡金属条件下β,γ-不饱和α-胺基腈锂试剂的直接偕二氟烯丙基化反应

Transition-Metal-Free Direct gem-Difluoroallylation of β,γ-Unsatu- rated α-Amino Nitrile Derived Lithium Reagents

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