Enantioselective synthesis of arylamines through Zr-catalyzed addition of dialkylzincs to imines. Reaction development by screening of parallel libraries
Enantioselective synthesis of arylamines through Zr-catalyzed addition of dialkylzincs to imines. Reaction development by screening of parallel libraries
复制标题
DOI：
10.1021/ja003747y
复制
发表时间：
2001-02-07
影响因子：
15
通讯作者：
Snapper, ML
中科院分区：
文献类型：
--
作者：
Porter, JR;Traverse, JF;Snapper, ML
高效、不对称地制备胺类化合物是有机合成中的一个重要目标。因此，已有无数的手性助剂和配体（化学计量）3被报道，它们允许烷基金属对映选择性加成到CdN键上。Denmark4和Tomioka5小组已经完成了烷基锂对亚胺的催化加成，其中在10-20 mol%的胺手性配体存在下检测到相当水平的对映选择性（高达82% ee）。我们对催化不对称方法在亚胺上加成二烷基锌的可能性很感兴趣（eq 1）。6我们对烷基锌的偏爱部分是因为它们的官能团耐受性。上述属性的一个优点是，基于模块化肽的配体（例如，1，下文）可用于影响对映选择性催化。在此，我们揭示了由肽基手性配体促进的zr催化的高效亚胺烷基化反应，该反应提供84-98%的ee和60-98%的分离收率。通过构建平行文库来确定合适的反应参数。由苯甲醛和苄胺、氨基二苯基甲烷、苯胺、2-氨基酚、邻氨基苯胺和2,4 -二甲氧基苯胺缩合而成的亚胺构成了最初的底物池。选择甲苯作为溶剂，因为它的低挥发性使得配体筛选的数据更可靠（文库样品的浓度变化最小）。采用市售的Et2Zn作为烷基化剂。筛选的金属盐有：CuCN、Cu (OAc) 2、CuOTf、Ti (Oi-Pr) 4、Zr (Oi-Pr) 4、HOi-Pr、BF3、Et2O、ZnCl2、AlBr3、Sc (OTf) 3。由于我们的研究中包含了早期和晚期过渡金属，因此从萘醛(1)和（2-二苯基膦）苯甲醛8(2)衍生的酚基希夫碱作为初步的手性配体（这两种醛都是市售的）。L-Val位于AA1位点，L-Phe作为AA2位点，因为这两种氨基酸相对便宜。我们判断，如果有必要，将在Schiff碱基和AA1、AA2位点进行位置优化，以增强对映选择性。7中
Efficient and asymmetric preparation of amines is an important objective in organic synthesis. 1 Myriad chiral auxiliaries2 and ligands (stoichiometric) 3 have thus been reported that allow the enantioselective addition of alkylmetals to CdN bonds. The groups of Denmark4 and Tomioka5 have accomplished the catalytic addition of alkyllithiums to imines, where appreciable levels of enantioselectivity are detected (up to 82% ee) in the presence of 10-20 mol% of amine chiral ligands. We are interested in the possibility of a catalytic asymmetric approach to the addition of dialkylzincs to imines (eq 1). 6 Our preference for alkylzincs is partly because of their functional group tolerance. An advantage of the above attribute is that modular peptide-based ligands (eg, 1, below) can be used to effect enantioselective catalysis. 7 Herein, we disclose efficient Zr-catalyzed imine alkylations promoted by peptide-based chiral ligands that afford arylimines in 84-98% ee and 60-98% isolated yield.Parallel libraries were constructed to establish the appropriate reaction parameters. Imines derived from condensation of benzaldehyde and benzylamine, aminodiphenylmethane, aniline, 2-aminophenol, o-anisidine, and 2, 4-dimethoxyaniline constituted the initial substrate pool. Toluene was chosen as the solvent, since its low volatility leads to more reliable data from ligand screening (minimum concentration variation of library samples). Commercially available Et2Zn was used as the alkylating agent. The following metal salts were screened: CuCN, Cu (OAc) 2, CuOTf, Ti (Oi-Pr) 4, Zr (Oi-Pr) 4 ‚HOi-Pr, BF3 ‚Et2O, ZnCl2, AlBr3, Sc (OTf) 3. Since both early and late transition metals were incorporated within our search, the phenol-based Schiff base derived from naphthaldehyde (1) and (2-diphenylphosphino) benzaldehyde8 (2) served as preliminary chiral ligands (both aldehydes are commercially available). L-Val was positioned at the AA1 site, and L-Phe served as the AA2, as these two amino acids are relatively inexpensive. We judged that, if necessary, positional optimization would be carried out at the Schiff base and AA1 and AA2 sites for enhanced enantioselectivities. 7b-e