N-t-Butyl-N-methyl-N-trimethylsilylmethylformamidine

[80376-66-5]  · C10H24N2Si  · N-t-Butyl-N-methyl-N-trimethylsilylmethylformamidine  · (MW 200.40)

(conveniently effects the transformation of ketones and aldehydes to homologated nitriles,1 amines,2 aldehydes,2 and ketones3)

Alternate Name: TMS-Form.

Physical Data: bp 78-80 °C/7 mmHg.

Preparative Methods: easily synthesized by a two-step procedure (eq 1).2 Initially, the condensation of t-Butylamine with either N,N-Dimethylformamide or dimethylformamide dimethyl acetal cleanly affords N-t-Butyl-N,N-dimethylformamidine. Subsequent lithiation and silylation with Chlorotrimethylsilane results in a 70% overall yield of the purified title reagent.

Handling, Storage, and Precautions: the reagent should be handled in a fume hood. Refrigeration should be used for prolonged storage.

Synthetic Utility.

The synthetic utility of TMS-Form has been demonstrated by the one-carbon homologation of a wide variety of ketones and aldehydes. The title compound is deprotonated with s-Butyllithium and then treated with a ketone to form an enamine by the Peterson alkenation (eq 2). A mixture of geometric isomers usually results; however, subsequent hydrolysis of the formamidine moiety affords a single compound. By varying the conditions under which the formamidine unit is destroyed, the corresponding homologated nitriles,1 amines,2 aldehydes,2 and ketones3 are obtained.

Homologation Processes.

The title reagent has recently been used for the homologation of ketones and aldehydes to nitriles.1 The alkene formed from the previously described Peterson alkenation between the carbonyl compound and the anion of the title compound is treated with N,N-Dimethylhydrazine to form the corresponding hydrazone (eq 3). Quaternization with Iodomethane followed by methoxide-induced elimination affords the nitrile (65-89%).1 Moreover, these nitriles can be prepared without purification or isolation of any intermediates. Thus 2-cyclohexen-1-one is transformed to the corresponding homologated nitrile in 66% yield (eq 4).

Alternatively, treatment of the intermediate hydrazone with Copper(II) Acetate easily affords the homologated aldehyde (55-84% from TMS-Form).2 For example, a-tetralone is converted to the homologated aldehyde in 66% yield (eq 5).

Reduction of the N-vinylformamidine with Sodium Borohydride in acidic media reduces both the imine and the enamine functionalities. The resulting aminal is then hydrolyzed to give the N-methylamine (52-70% from TMS-Form). For example, veratraldehyde affords the corresponding homologated N-methylamine in 67% yield (eq 6). In addition, homologated N-alkylamines are prepared by reaction of the initial N-t-butyl-N,N-dimethylformamidine anion with an electrophile and then utilizing this newly prepared compound in the outlined protocol (eq 7).

In a similar vein, the analogous N-butyl-N-(trimethylsilylmethyl)formamidine is converted to an alkene by the standard method (eq 8). Treatment with t-Butyllithium then forms the a-lithio enamine, which can be alkylated by a host of electrophiles. Hydrazinolysis of the formamidine furnishes the homologated ketone or aldehyde. Some examples of this homologating nucleophilic acylation method are illustrated in Table 1.4

Related Reagents.

t-Butylamine; N-t-Butyl-N,N-dimethylformamidine; Chlorotrimethylsilane; Diethyl N-Benzylideneaminomethylphosphonate; Diethyl Isocyanomethylphosphonate; Diethyl Morpholinomethylphosphonate; (S)-N,N-Dimethyl-N-(1-t-butoxy-3-methyl-2-butyl)formamidine; p-Tolylsulfonylmethyl Isocyanide.


1. Santiago, B.; Meyers, A. I. TL 1993, 34, 5839.
2. Meyers, A. I.; Jagdman, G. E. JACS 1982, 104, 877.
3. Meyers, A. I.; Edwards, P. D.; Bailey, T. R.; Jagdman, G. E. JOC, 1985, 50, 1019.
4. Review on homologation of carbonyl compounds: Martin, S. F. S 1979, 633.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA



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