Stereoselective Cross-Coupling between Allylic Alcohols and Aldimines

Abstract

A cross-coupling reaction between an allylic alcohol and an imine is described for stereoselective allylation of aromatic and aliphatic imines. This method provides operationally simple, enantioselective access to functionalized homoallylic amines. Particularly noteworthy is direct use of a functionalized allylic alcohol as an allylating reagent without pre-derivatization, which obviates the use of preformed organometallic reagents or activated imine derivatives.

Addition of organometallic reagents to imines provides a useful method for the stereoselective preparation of amines.¹ An enantioselective allylation/crotylation reaction to aldimines is a valuable tool in organic synthesis, as homoallylic amines are useful building blocks in natural product synthesis and medicinal chemistry.^2,3 Imines are less electrophilic than carbonyl groups, and addition of organometallic reagents to imines can be complicated by accompanying enolization, reduction, or dimerization.⁴ This reactivity issue requires a judicious choice of an allylic metal reagent and/or activation of an imine by a suitable Lewis acid. Additionally, there is a paucity of convenient methods for generating functionalized allylic nucleophiles despite impressive advances in this field.⁵ Direct use of an allylic alcohol as an allylating reagent is particularly attractive, as it obviates pre-derivatization of an allylic alcohol substrate. We report herein regio- and stereoselective cross-coupling between an allylic alcohol and an imine by the action of the Kulinkovich reagent.

A cross-coupling reaction between an allylic alcohol and a vinylsilane (or a styrene) was recently developed by use of the Kulinkovich reagent, in which directing effects of an allylic alkoxide were exploited via a temporary linker.^6,7 An imine was already shown by the Sato group to react with an alkyne–Kulinkovich reagent complex to afford an allylic amine.⁸ Thus, we reasoned that the use of an aldimine in place of a vinylsilane could provide a new approach to regio- and stereoselectively preparing homoallylic amines. Our study began with the coupling reaction between 2-cyclohexen-1-ol and several imines 1a–h (Table 1). Thus, coupling of 2-cyclohexen-1-ol and 1a under previously reported conditions afforded homoallylic amine 2a in 90% yield in >20:1 diastereoselectivity (entry 1). A broad scope with respect to imines (i.e., different R¹ and R²) can be seen from entries 1–8: not only aromatic, but also aliphatic imines are amenable to cross-coupling. The resulting homoallylic amines 2a–h were obtained as virtually single isomers. In the case of imine 1g having an isopropyl branch, a 4:1 mixture of 2g and the by-product (structure not shown) from addition of the cyclopentyl Grignard reagent to the imine was obtained (entry 7). This result could be attributed to steric effects.

Table 1.

Cross-Coupling between 2-Cyclohexen-1-ol and Imines

entry	imine	R1	R2	product	yield
1	1a	Ph	Ph	2a	90%
2	1b		p-MeOC6H4	2b	75%
3	1c		Bn	2c	78%
4	1d		CH2-o-MeOC6H4	2d	69%
5	1e		n-Bu	2e	76%
6	1f	2-furyl	Bn	2f	55%
7	1g	i-Pr	Bn	2g	40%
8	1h	n-C7H15	Bn	2h	60%

Coupling of acyclic Z-allylic alcohols 3 and 4 with imines 1a–c,e was next examined (Table 2). As was the case with cross-coupling with vinylsilanes or styrenes,⁶ high levels of diastereocontrol was achieved to provide E-homoallylic amines 5a–c,e and 6a–c,e. Full compatibility with the presence of an allylic ether is clearly seen with allylic alcohol 4 (entries 5–8).

Table 2.

Cross-Coupling between (Z)-Allylic Alcohols and Imines

entry	imine	R1	R2	product	yield
1	1a	Ph	Ph	5a	78%
2	1b		p-MeOC6H4	5b	72%
3	1c		Bn	5c	74%
4	1e		n-Bu	5e	72%
entry	imine	R1	R2	product	yield
5	1a	Ph	Ph	6a	62%
6	1b		p-MeOC6H4	6b	64%
7	1c		Bn	6c	68%
8	1e		n-Bu	6e	57%

Complete chirality transfer was established by the use of enantiopure allylic alcohols 7–11 (Table 3). Coupling of (S)-7 with 1a and 1c proceeded diastereo- and enantioselectively to afford amines 12 and 13 in 60% and 68% yield, respectively (entries 1 and 2). Similarly, 14 and 15 were obtained from 8 and 9, respectively (entries 3 and 4). Comparative evaluation of E-allylic alcohols 10 and 11 was undertaken next for additional stereochemical studies. As expected by analogy to ethylation and cross-coupling with vinylsilanes,⁶ these E-allylic alcohol substrates produced a mixture of two diastereomers: 10 gave a 1.3:1 separable mixture of 16 and 15 in 71% yield (entry 5), whereas a 1.2:1 mixture of 17 and 14 was obtained from 11 (entry 6). The unequivocal determination of the absolute and relative stereochemistry of the homoallylic amine products 12–17 was possible by these correlation studies, as well as an independent synthesis of 13.⁹

Table 3.

Enantioselective Synthesis of Homoallylic Amines

entry	imine	allylic alcohol	product	yield (%)
1	1a	(S)-7	12: R = Ph	60
2	1c	(S)-7	13: R = Bn	68
3	1c	8	14	68
4	1c	9	15	65
5	1c	10		71 1.3:1 dr
6	1c	11		69 1.2:1 dr

The observed stereochemical outcome can be rationalized by formation of a temporary alkoxide tether and subsequent syn addition/syn β-elimination for the 1,3-transpositive cross-coupling reactions of acyclic and cyclic allylic alcohols. High diastereoselectivity displayed by Z-allylic alcohols is in accord with the involvement of conformer A to minimize A^(1,3) strain (Scheme 1). The lack of selectivity for E-allylic alcohols and the attendant formation of both E- and Z-alkenes suggest the co-involvement of both conformers B and C.⁶

Scheme 1.

In conclusion, we have developed convenient cross-coupling reactions between allylic alcohols and imines for stereoselective allylation of aromatic and aliphatic imines. Particularly noteworthy is direct use of a functionalized allylic alcohol as an allylating reagent without pre-derivatization. This convenient method obviates the use of preformed organometallic reagents or activated imine derivatives.¹⁰