N-t-Butyl-N,N-dimethylformamidine1

[3717-82-6]  · C7H16N2  · N-t-Butyl-N,N-dimethylformamidine  · (MW 128.22)

(lithiation of the title reagent generates an aminomethyl carbanion equivalent which reacts with electrophiles to give, after hydrolysis, homologated N-methylamines; exchange with a secondary amine allows for its subsequent lithiation and alkylation)

Physical Data: bp 133-134 °C.

Preparative Method: condensation of t-Butylamine with either N,N-dimethylformimidate salts or with dimethylformamide dimethyl acetal cleanly affords N-t-butyl-N,N-dimethylformamidine (eq 1).1,2a,b

Handling, Storage, and Precautions: store under an inert atmosphere.

Synthetic Utility.

Deprotonation of N-t-butyl-N,N-dimethylformamidine produces a dipole-stabilized carbanion.1,2c Treatment of this species with electrophiles followed by hydrolysis of the formamidine affords the corresponding a-substituted amine (eq 2).2a,d

The related N-n-butyl- and N-cyclohexylformamidines (1) and (2) are also effective in the above procedure.2a,3

When the title formamidine (or the n-butyl or cyclohexyl analog) is heated in the presence of a secondary amine, dimethylamine is displaced producing a new formamidine derivative of the secondary amine. Deprotonation and alkylation followed by formamidine hydrolysis allows entry into a host of 1-substituted amines.1 For example, a variety of 1-substituted tetrahydroisoquinolines (eq 3) can be prepared by this method.

In addition to the exchange method with the title reagent, the t-butylformamidines of secondary amines can be prepared by aminolysis of O-ethyl formimidate salts (eq 4).4

This route has been used to alkylate indolines (eq 5),4a tetrahydroquinolines,4a dihydroisoindoles,4b and N-methylanilines.4a

Exchange of the title reagent with tetrahydro-b-carbolines followed by lithiation and alkylation gives access to a variety of indole alkaloids.5 Piperidines,2b,6,7 pyrrolidines,2b,7 perhydroazepines (eq 6)2b and cis- and trans-decahydroquinolines,8 as well as others,7f can also be alkylated via their formamidine derivatives.

a-Arylpyrrolidines and -piperidines can be accessed by bridging dialkylations of N-benzyl-N-methylamines with 1,3- or 1,4-dihalides.9 Other amine heterocycles, such as thiazolidine and 1,3-thiazine, may be alkylated at the carbon between the nitrogen and sulfur.2b

Unsaturated cyclic formamidines can be prepared by the sequence of formamidine exchange, metalation, selenation, and selenoxide elimination (eq 7).10

These unsaturated formamidines can be alkylated by the formamidine methodology. Metalation causes deprotonation of the alkenic proton adjacent to the ring nitrogen (eq 8).10

Nucleophilic additions adjacent to nitrogen have also been effected by using a-methoxyformamidines. In this case the methoxyformamidines were not prepared from the title reagent and the formamidine is serving as a protecting and stabilizing group for the a-amino ether (eq 9).11

Various achiral formamidines that contain a chelating group have also been successfully utilized.12 Thus by incorporation of a methoxy group on the formamidine, spiroisoquinolines (eq 10)12a and fused annulated isoquinolines can be prepared efficiently using the above methodology.

Conversion of the title reagent to N-t-Butyl-N-methyl-N-trimethylsilylmethylformamidine (eq 11) allows for the one-carbon homologation of carbonyl compounds to nitriles, amines, aldehydes, and ketones.13

Formamidines form higher order cyanocuprates which add in a 1,4 fashion to Michael acceptors.14 Incorporation of a chiral auxiliary in the formamidine results in high levels of asymmetric induction (see the chiral enantiopure (S)-N,N-Dimethyl-N-(1-t-butoxy-3-methyl-2-butyl)formamidine).1,15


1. (a) Meyers, A. I. Aldrichim. Acta 1985, 18, 59. (b) Meyers, A. I.; Fuentes, L. M.; Bös, M.; Dickman, D. A. CS 1985, 25, NS25. Meyers, A. I. H 1984, 21, 360.
2. (a) Meyers, A. I.; Ten Hoeve, W. JACS 1980, 102, 7125. (b) Meyers, A. I.; Edwards, P. D.; Rieker, W. F.; Bailey, T. R. JACS 1984, 106, 3270. (c) Meyers, A. I.; Rieker, W. F.; Fuentes, L. M. JACS 1983, 105, 2082. (d) Solladié-Cavallo, A.; Bencheqroun, M. TL 1990, 31, 2157.
3. Meyers, A. I.; Hellring, S.; Ten Hoeve, W. TL 1981, 22, 5115.
4. (a) Meyers, A. I.; Hellring, S. TL 1981, 22, 5119. (b) Beeley, L. J.; Rockell, C. J. M. TL 1990, 31, 417.
5. (a) Meyers, A. I.; Miller, D. B.; White, F. H. JACS 1988, 110, 4778. (b) Meyers, A. I.; Loewe, M. F. TL 1984, 25, 2641. (c) Meyers, A. I.; Hellring, S. JOC 1982, 47, 2229.
6. Shawe, T. T.; Meyers, A. I. JOC 1991, 56, 2751.
7. (a) Edwards, P. D.; Meyers, A. I. TL 1984, 25, 939. (b) Thurkauf, A.; Mattson, M. V.; Richardson, S.; Mirsadeghi, S.; Ornstein, P. L.; Harrison, E. A.; Rice, K. C.; Jacobson, A. E.; Monn, J. A. JMC 1992, 35, 1323. (c) Heintzelman, G. R.; Parvez, M.; Weinreb, S. M. SL 1993, 551. (d) Bolster, J. M.; Ten Hoeve, W.; Vaalburg, W.; Van Dijk, T. H.; Zijlstra, J. B.; Paans, A. M. J.; Wynberg, H.; Woldring, M. G. Int. J. Appl. Radiat. Isot. 1985, 36, 339. (e) Sanner, M. A. TL 1989, 30, 1909. (f) Monn, J. A.; Thurkauf, A.; Mattson, M. V.; Jacobson, A. E.; Rice, K. C. JMC 1990, 33, 1069.
8. Meyers, A. I.; Milot, G. JACS 1993, 115, 6652.
9. Meyers, A. I.; Marra, J. M. TL 1985, 26, 5863.
10. Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; Jagdmann, G. E. JOC 1985, 50, 1019.
11. (a) Meyers, A. I.; Shawe, T. T.; Gottlieb, L. TL 1992, 33, 867. (b) Gottlieb, L.; Meyers, A. I. TL 1990, 31, 4723.
12. (a) Meyers, A. I.; Du, B.; Gonzalez, M. A. JOC 1990, 55, 4218. (b) Gonzalez, M. A.; Meyers, A. I. TL 1989, 30, 47. (c) Gonzalez, M. A.; Meyers, A. I. TL 1989, 30, 43.
13. For example, see: Santiago, B.; Meyers, A. I. TL 1993, 34, 5839.
14. Dieter, R. K.; Alexander, C. W. TL 1992, 33, 5693.
15. (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: Greenwich, CT, 1990. (c) Dickman, D. A.; Boes, M.; Meyers, A. I. OSC 1993, 8, 204. (d) Meyers, A. I.; Boes, M.; Dickman, D. A. OSC 1993, 8, 573.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA



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