(R = t-Bu)

[2425-74-3]  · C5H11NO  · N-t-Butylformamide  · (MW 101.15) (R = H)

[75-12-7]  · CH3NO  · Formamide  · (MW 45.04)

(amidation of alkenes; amidation of heterocycles; synthesis of secondary amines)

Physical Data: N-t-butylformamide: mp 16 °C; bp 202 °C; d 0.903 g cm-3. Formanide: mp 2 °C; bp 111 °C/20 mmHg; d 1.133 g cm-3.

Solubility: N-t-butylformamide is miscible with most common organic solvents and with water.

Form Supplied in: commercially available in 98% purity.

Preparative Method: N-t-butylformamide is prepared from t-Butylamine and ethyl formate.1

Purification: by distillation.

Hydroamidation of Alkenes.

t-Butylformamide adds across the double bond of alkenes in a Markovnikov fashion using 1,1-Di-t-butyl Peroxide as the radical initiator (eq 1).2 Dimerization of t-butylformamide occurs under these conditions in the absence of an alkene. The related reagent formamide undergoes similar reactions with alkenes (eq 2) and these reactions have been initiated both photochemically and by peroxides.3-5

Amidation of Pyridines.

Pyridines undergo amidation when combined with t-butylformamide and t-Butyl Hydroperoxide and FeII but the reactions show little regioselectivity and the yields are poor. Higher yields and good regiochemical control are obtained with formamide (eq 3).6

Numerous heteroaromatic bases, mostly substituted quinolines and pyridines, have been amidated with formamide under radical conditions (eq 4).7 The radicals for these amidations have been generated from formamide by a variety of means, usually from Hydrogen Peroxide-Iron(II) Sulfate, but also from decomposition of Hydroxylamine-O-sulfonic Acid,8 or from Iodosylbenzene and Sodium Azide.9 These amidations and related reactions with nitrogen heterocycles have been reviewed.10 Amidations under these conditions provide a useful method for acylating pyridines, quinolines, and related compounds that cannot ordinarily be acylated under conventional Friedel-Crafts conditions.

Synthesis of Secondary Amines.

t-Butylformamide is alkylated under phase transfer conditions to yield N,N-dialkylformamides in good yield. Hydrolysis provides secondary amines. This reaction provides an alternative to the Ritter reaction and works with a variety of tertiary amines (eq 5).11

1. Ugi, I.; Meyr, R.; Lipinski, M.; Bodesheim, F.; Rosendahl, F. OSC 1973, 5, 300.
2. Friedman, L.; Schechter, H. TL 1961, 238.
3. Elad, D.; Rokach, J. JOC 1964, 29, 1855.
4. Rieche, A.; Schmitz, E.; Grundemann, E. AG 1961, 73, 621.
5. Elad, D.; Rokach, J. JCS 1965, 800.
6. Langhals, E.; Langhals, H.; Ruchardt, C. LA 1982, 930.
7. Arnone, A.; Cecere, M.; Galli, R.; Minisci, F.; Perchinunno, M.; Porta, O.; Gardini, G 1973, 13.
8. Citterio, A.; Gentile, A.; Minisci, F.; Serravalle, M.; Ventura, S. CC 1983, 916.
9. Fontana, F.; Minisci, F.; Yan, Y. M.; Zhao, L. TL 1993, 34, 2517.
10. Minisci, F. Top. Curr. Chem. 1976, 62, 1.
11. Gajda, T.; Koziara, A.; Zawadzki, S.; Zwierzak, A. S 1979, 549.

Kevin E. Henegar

The Upjohn Company, Kalamazoo, MI, USA

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