N,O-Dimethylhydroxylamine1

[1117-97-1]  · C2H7NO  · N,O-Dimethylhydroxylamine  · (MW 61.10) (.HCl)

[6638-79-5]  · C2H8ClNO  · N,O-Dimethylhydroxylamine Hydrochloride  · (MW 97.56)

(used extensively in the formation of N-methoxy-N-methylamides2 and ureas,3 which are valuable acylating agents)

Physical Data: mp -97 °C; bp 43.2 °C. .HCl salt, mp 115-116 °C.

Form Supplied in: commercially available as the HCl salt.

Handling, Storage, and Precautions: the free amine decomposes readily. However, the HCl salt is stable indefinitely.

Formation.

N,O-Dimethylhydroxylamine hydrochloride, although commercially available, can be generated from Ethyl Chloroformate and Hydroxylamine in excellent yield (eq 1).4 The hydrochloride salt can be converted to the distillable free amine by reaction with strong base (eq 2),5 but is generally formed in situ for most reactions.

Preparation of N-Methoxy-N-methylamides.

The widest use of the title compound is in the synthesis of N-methoxy-N-methylamides, which can be prepared from acid chlorides in good to excellent yield (eq 3).6 The amides can also be prepared from carboxylic acids via anhydrides (eq 4)7,8 or by using peptide coupling reagents such as 1,3-Dicyclohexylcarbodiimide (eq 5)9 and others.10 A mild method for the generation of N-methoxy-N-methylamides from carboxylic acids using Carbon Tetrabromide and Triphenylphosphine has been published (eq 6).11 N,O-Dimethylhydroxylamine reacts with cyclic anhydrides to produce amide acids (eq 7).12 Esters can also be converted to their corresponding amides via dialkylaluminum amides, formed by the reaction of N,O-dimethylhydroxylamine or the hydrochloride with trialkylaluminum reagents (eq 8)13 (see also Dimethylaluminum Amide).

Alkylation of N-Methoxy-N-methylamides.

N-Methoxy-N-methylamides have advantages over N,N-dialkylamides in that they give fewer side products in nucleophilic addition reactions, with little or no overaddition. Addition of a nucleophile to an N-methoxy-N-methylamide results in the formation of a stable chelated tetrahedral intermediate that is not susceptible to additional nucleophilic attack. Thus even in the presence of a large excess of a nucleophile, only monoalkylation occurs. The general reaction works well with alkyllithiums and Grignard reagents at low temperatures (eq 9).2 Many nucleophiles have been used with these amides to produce symmetrical and unsymmetrical ketones,2,14 a-amino ketones,15 b-dicarbonyl compounds (eq 10),16 and 1,4- and 1,5-dicarbonyl compounds (eq 11).17,18 It has also been shown that N,N-dimethoxy-N,N-dimethylethanediamides, formed from Oxalyl Chloride, undergo monoalkylation with alkyllithium or Grignard reagents to form a-keto amides (eq 12), which can subsequently be converted to 1,2-diketones.19

Acylation of the enolates of di-, tri-, and tetraketones with N-methoxy-N-methylamides results in high yield of the desired product (eq 13),20 in contrast to acylations using esters which give lower yields and are generally problematic.

The dianions of b-keto esters react with a,b-unsaturated N-methoxy-N-methylamides to give the b,d-diketo ester in moderate yields, with no trace of conjugate addition (eq 14).21

N-Methoxy-N-methylamides have recently been used to prepare regiocontrolled cross-aldol products, by using Zinc powder and Chlorotrimethylsilane to generate the intermediate b-siloxyamides, followed by reaction with a Grignard reagent. This reaction works with both enolizable and nonenolizable carbonyl compounds (eq 15).22

Reductions of N-Methoxy-N-methylamides.

Reduction of N-methoxy-N-methylamides occurs under mild conditions to give high yields of aldehydes, in contrast to N,N-dialkylamides which tend to give considerable quantities of amine and alcohol side products (eqs 16 and 17).2 One area of recent interest involves the formation of N-protected a-amino aldehydes from the corresponding N-methoxy-N-methylamides in high yields without racemization (eq 18).23

Preparation and Uses of N-Methoxy-N-methylureas.

N,O-Dimethylhydroxylamine has also been used in the preparation of ureas by reaction with the appropriate carbonyl compound (eqs 19 and 20).3

The resultant ureas have been used as carbon dioxide equivalents in the formation of a variety of symmetrical and unsymmetrical ketones (eqs 21-23).3


1. Sibi, M. P. OPP 1993, 25, 15.
2. Nahm, S.; Weinreb, S. M. TL 1981, 22, 3815.
3. (a) Hlasta, D. J.; Court, J. J. TL 1989, 30, 1773. (b) Whipple, W. L.; Reich, H. J. JOC 1991, 56, 2911.
4. Goel, O. P.; Krolls, U. OPP 1987, 19, 75.
5. Beak, P.; Basha, A.; Kokko, B.; Loo, D. JACS 1986, 108, 6016.
6. (a) Jacobi, P. A.; Zheng, W. TL 1991, 32, 1279. (b) Bartos, A.; Bliefert, C. CZ 1986, 110, 127.
7. (a) Angelastro, M. R.; Peet, N. P.; Bey, P. JOC 1989, 54, 3913. (b) Angelastro, M. R.; Mehdi, S.; Burkhart, J. P.; Peet, N. P.; Bey, P. JMC 1990, 33, 11.
8. (a) Oppolzer, W.; Cunningham, A. F. TL 1986, 27, 5467. (b) Irako, N.; Hamada, Y.; Shioiri, T. T 1992, 48, 7251.
9. Boumendjel, A.; Nuzillard, J. M.; Massiot, G. BSF 1990, 127, 645.
10. Maugras, I.; Poncet, J.; Jouin, P. T 1990, 46, 2807.
11. Einhorn, J.; Einhorn, C.; Luche, J.-L. SC 1990, 20, 1105.
12. Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. TL 1984, 25, 4859.
13. Garigipati, R. S.; Tschaen, D. M.; Weinreb, S. M. JACS 1985, 107, 7790.
14. Souchet, M.; Clark, R. D. SL 1990, 151.
15. Radunz, H-E.; Eiermann, V.; Schneider, G.; Riethmüller, A. T 1991, 47, 1887.
16. Turner, J. A.; Jacks, W. S. JOC 1989, 54, 4229.
17. Bergman, R.; Nilsson, B.; Wickberg, B. TL 1990, 31, 2783.
18. Gilbreath, S. G.; Harris, C. M.; Harris, T. M. JACS 1988, 110, 6172.
19. Sibi, M. P.; Sharma, R.; Paulson, K. L. TL 1992, 33, 1941.
20. Oster, T. A.; Harris, T. M. TL 1983, 24, 1851.
21. Hanamoto, T.; Hiyama, T. TL 1988, 29, 6467.
22. Palomo, C.; Aizpurua, J. M.; Aurrekoetxea, N.; Lopez, M. C. TL 1991, 32, 2525.
23. (a) Fehrentz, J.-A.; Castro, B. S 1983, 676. (b) Martinez, J.; Bali, J.-P.; Rodriguez, M.; Castro, B.; Magous, R.; Laur, J.; Lignon, M.-F. JMC 1985, 28, 1874.

Steven M. Weinreb & James J. Folmer

The Pennsylvania State University, University Park, PA, USA



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