(S)-N,N-Dimethyl-N-(1-t-butoxy-3-methyl-2-butyl)formamidine1,2

(E)-(S)

[114318-94-4]  · C12H26N2O  · (S)-N,N-Dimethyl-N-(1-t-butoxy-3-methyl-2-butyl)formamidine  · (MW 214.40) (S)

[66919-83-3] (R)

[90482-06-7]

(chiral auxiliary for derivatization, directed lithiation, and asymmetric alkylation adjacent to nitrogen of benzylic or allylic secondary amines by formamidine exchange, metalation, alkylation, and hydrolysis1,2)

Physical Data: bp 55-65 °C/0.05 mmHg; [a]D -59.6° (c 3.5, EtOH).2

Preparative Methods: easily prepared from (S)-valinol in a high yielding four-step procedure (eq 1).2 Other chiral formamidines can be prepared and used successfully in the methodology outlined here (eq 2).2,3

Handling, Storage, and Precautions: store under argon at rt; use in a fume hood.

Introduction.

In the equations, VBE will be used to depict the valinol t-butyl ether portion of the formamidine, while the t-leucinol methyl ether portion will be abbreviated LME.

Upon heating the title formamidine with a secondary amine, dimethylamine is extruded, affording a chiral formamidine derivative of the original amine (eq 3).4a

Deprotonation and alkylation followed by formamidine removal allows entry to a host of isoquinoline alkaloids (eq 4).3b,4

This protocol has also been an avenue to a variety of indole alkaloids (eq 5).5

Chiral 1-alkyl-2-benzazepines can be formed by utilization of the same method (eq 6).3a

This strategy also works well for the asymmetric alkylation of 3-pyrrolines (eq 7)6 and tetrahydropyridines (eq 8).7

The mechanistic process of these asymmetric alkylations and the configurational stability of the chiral lithioformamidines have been investigated.8 A limitation of this strategy is that saturated, cyclic, secondary amines (e.g. pyrrolidines and piperidines) cannot be successfully alkylated in an asymmetric fashion.

Related Reagents.

N-t-Butoxycarbonyl-N-methylaminomethyllithium; N-t-Butyl-N,N-dimethylformamidine; N-t-Butyl-N-methyl-N-trimethylsilylmethylformamidine; N,N-Dimethylformamide Diethyl Acetal; (R)-Methyl 2-t-Butyl-3(2H)-oxazolecarboxylate; N-Nitrosodimethylamine.


1. (a) Meyers, A. I. T 1992, 48, 2589. (b) Meyers, A. I.; Highsmith, T. K. In Advances in Heterocyclic Natural Product Synthesis; Pearson, W. H., Ed.; JAI Press: Greenwich, CT, 1990. (c) Meyers, A. I. Aldrichim. Acta 1985, 18, 59. (d) Meyers, A. I. H 1984, 21, 360.
2. (a) Dickman, D. A.; Boes, M.; Meyers, A. I. OSC 1993, 8, 204. (b) Meyers, A. I.; Boes, M.; Dickman, D. A. OSC 1993, 8, 573.
3. (a) Meyers, A. I.; Hutchings, R. H. T 1993, 49, 1807. (b) Meyers, A. I.; Elworthy, T. R. JOC 1992, 57, 4732.
4. (a) Meyers, A. I.; Dickman, D. A.; Boes, M. T 1987, 43, 5095. (b) Meyers, A. I.; Sielecki, T. M.; Crans, D. C.; Marshman, R. W.; Nguyen, T. H. JACS 1992, 114, 8483. (c) Sielecki, T. M.; Meyers, A. I. JOC 1992, 57, 3673. (d) Guiles, J. W.; Meyers, A. I. JOC 1991, 56, 6873. (e) Meyers, A. I.; Sielecki, T. M. JACS 1991, 113, 2789. (f) Gottlieb, L.; Meyers, A. I. JOC 1990, 55, 5659. (g) Meyers, A. I.; Guiles, J. H 1989, 28, 295.
5. (a) Meyers, A. I.; Highsmith, T. K.; Buonora, P. T. JOC 1991, 56, 2960. (b) Beard, R. L.; Meyers, A. I. JOC 1991, 56, 2091.
6. (a) Meyers, A. I.; Dupre, B. H 1987, 25, 113. (b) Warmus, J. S.; Dilley, G. J.; Meyers, A. I. JOC 1993, 58, 270.
7. Meyers, A. I.; Dickman, D. A.; Bailey, T. R. JACS 1985, 107, 7974.
8. (a) Castonguay, L. A.; Guiles, J. W.; Rappé, A. K.; Meyers, A. I. JOC 1992, 57, 3819. (b) Meyers, A. I.; Warmus, J. S.; Gonzalez, M. A.; Guiles, J.; Akahane, A. TL 1991, 32, 5509. (c) Meyers, A. I.; Guiles, J.; Warmus, J. S.; Gonzalez, M. A. TL 1991, 32, 5505. (d) Meyers, A. I.; Gonzalez, M. A.; Struzka, V.; Akahane, A.; Guiles, J.; Warmus, J. S. TL 1991, 32, 5501.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.