[26939-18-4]  · C8H15NO  · 5,6-Dihydro-2,4,4,6-tetramethyl-1,3(4H)-oxazine  · (MW 141.21)

(a-carbanion serves as acetate or acetaldehyde enolate equivalent for synthesis of a,b-unsaturated aldehydes, aliphatic aldehydes, a-amino ketones, unsymmetrical ketones, and substituted carboxylic acids)

Physical Data: bp 47-49 °C/17 mmHg.

Preparative Method: prepared by the acid-catalyzed condensation of Acetonitrile and 2-methyl-2,4-pentanediol in 65% yield (eq 1).2

Handling, Storage, and Precautions: no special precautions required; this reagent can be stored for months at rt under an inert atmosphere.

Synthetic Utility.

The lithio anion, or the potassio anion generated using Potassium-Graphite,3 of this reagent can be alkylated with a variety of electrophiles to form a-substituted oxazines.2 Reduction of the oxazine with Sodium Borohydride followed by hydrolysis with Oxalic Acid affords the corresponding aldehyde. However, the oxazine could not be hydrolyzed by this procedure when the electrophile was a nitrile or ester.4 Thus aliphatic aldehydes can be readily prepared via this protocol (isolation of the intermediates is not necessary) (eq 2, Table 1).2,5 By substituting NaBD4 or NaBT4 for NaBH4 in the reduction, the corresponding C1 deuterated and tritiated aldehydes are obtained.6

Retreatment of the initially alkylated oxazine with t-Butyllithium and alkylation with a second electrophile forms, after reduction and hydrolysis, a,a-disubstituted aldehydes. Cycloalkanecarbaldehydes are produced by a,a-dialkylation with 1,n-dihalides (eq 3).2,7

Acid-catalyzed hydrolysis of the oxazine allows for the formation of functionalized carboxylic acids (eq 4).8

The N-methyloxazinium salts formed by alkylation of the dihydro oxazines with Iodomethane undergo Grignard addition to the iminium double bond. Aqueous hydrolysis affords unsymmetrical ketones (eq 5).9

The lithio anion of the title reagent adds in a 1,2-fashion to carbonyl compounds. Reduction of the oxazine followed by hydrolysis and dehydration affords the a,b-unsaturated aldehydes (eq 6).2,10

Improved (E)/(Z) ratios can be obtained by using oxazine phosphonates (1)11 and phosphonium ylides (2)11 and Peterson-type a-trimethylsilyl oxazines (3) and (4).12

The title reagent can also be used as a precursor to a-amino ketones.13 In addition, the N-oxide of the title reagent cycloadds with dipolarophiles in 1,3-dipolar cycloadditions.14

Related Reagents.

Acetaldehyde N-t-Butylimine; Dilithioacetate; Ethyl Lithioacetate; (4S,5S)-4-Methoxymethyl-2-methyl-5-phenyl-2-oxazoline; 2-Methylbenzothiazole; 2-Methyl-2-thiazoline; 2,4,4-Trimethyl-2-oxazoline.

1. Collington, E. W. CI(L) 1973, 987.
2. Meyers, A. I.; Nabeya, A.; Adickes, H. W.; Politzer, I. R.; Malone, G. R.; Kovelesky, A. C.; Nolen, R. L.; Portnoy, R. C. JOC 1973, 38, 36.
3. Savoia, D.; Trombini, C.; Umani-Ronchi, A. JOC 1978, 43, 2907.
4. Malone, G. R.; Meyers, A. I. JOC 1974, 39, 713.
5. Adickes, H. W.; Politzer, I. R.; Meyers, A. I. JACS 1969, 91, 2155.
6. (a) Herbert, R. B.; Kattah, A. E.; Knagg, E. T 1990, 46, 7119; (b) Meyers, A. I.; Nabeya, A.; Adickes, H. W.; Politzer, I. R. JACS 1969, 91, 763.
7. (a) Meyers, A. I.; Adickes, H. W.; Politzer, I. R.; Beverung, W. N. JACS 1969, 91, 765. (b) Politzer, I. R.; Meyers, A. I. OSC 1988, 6, 905.
8. Meyers, A. I.; Politzer, I. R.; Bandlish, B. K.; Malone, G. R. JACS 1969, 91, 5886.
9. (a) Meyers, A. I.; Smith, E. M. JOC 1972, 37, 4289. (b) Henley-Smith, P.; Whiting, D. A.; Wood, A. F. JCS(P1) 1980, 614.
10. (a) Whittaker, M.; McArthur, C. R.; Leznoff, C. C. CJC 1985, 63, 2844. (b) Meyers, A. I.; Nabeya, A.; Adickes, H. W.; Fitzpatrick, J. M.; Malone, G. R.; Politzer, I. R. JACS 1969, 91, 764. (c) Meyers, A. I.; Collington, E. W. T 1971, 27, 5979.
11. Malone, G. R.; Meyers, A. I. JOC 1974, 39, 623.
12. Sachdev, K. TL 1976, 4041.
13. Talaty, E. R.; Bengtsson, K. C.; Pankow, L. M. SC 1980, 10, 99.
14. Ashburn, S. P.; Coates, R. M. JOC 1984, 49, 3127.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA

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