N-Nitrosodimethylamine1

(R = Me)

[62-75-9]  · C2H6N2O  · N-Nitrosodimethylamine  · (MW 74.10) (R = Et)

[55-18-5]  · C4H10N2O  · N-Nitrosodiethylamine  · (MW 102.16) (R = -(CH2)4-)

[130-55-2]  · C4H8N2O  · N-Nitrosopyrrolidine  · (MW 100.14)

(lithiation of the title reagent and its analogs generates a-amino carbanion equivalents which can be alkylated and denitrosated to form secondary amines, 1,2-amino alcohols, a-amino acids, and related compounds1)

Physical Data: R = Me: bp 154 °C/760 mmHg; d 1.006 g cm-3. R = Et: bp 177 °C/760 mmHg; d 0.943 g cm-3. R = (CH2)4: bp 104-106 °C/20 mmHg; d 1.085 g cm-3.

Form Supplied in: the three nitrosamines shown are commercially available; others may be prepared from secondary amines and ethyl nitrite by transfer of the nitroso group.

Handling, Storage, and Precautions: nitrosodialkylamines are carcinogenic;2 use a fume hood; handling and precautions are described by Seebach and Enders.1

Introduction.

Nitrosodimethylamine and analogous compounds are important for synthesis of 1.1-dialkylhydrazines (being substrates, not reagents for this purpose). Nitrosodimethylamine (1) can be a source of either the dimethylamino group or the nitroso group,3 but due to its carcinogenicity it is no longer a competitor to other sources of these groups. It is, however, very useful for C-C bond formation with carbon electrophiles. By the reaction sequence lithiation (in this case a typical umpolung), action of an electrophile El-X, and denitrosation, the starting amine is converted to another secondary amine with formal substitution of an a-H by the electrophile (eq 1).

Lithiation.

Solutions of the nitrosamine can be used after removal of the ethanol without isolation or purification. Lithiation is carried out with Lithium Diisopropylamide; 5 min at -80 °C is sufficient time for metalation of a methyl group, 1 h at rt is necessary for a methylene group. Kinetically controlled regiospecific lithiation at the methyl group of an unsymmetrical N-nitrosamine can be effected. Hexamethylphosphoric Triamide increases the metallation rate and stabilizes the solutions of the reagents. Metalation yields of simple aliphatic N-nitrosamines often exceed 90%, whereas those of cyclic aliphatic N-nitrosamines with four- to seven-membered rings are in the 50-70% range.

C-Alkylation.

C-Alkylation proceeded smoothly in all investigated cases. Alkylation yields for lithiated N-nitrosodimethylamine with Iodomethane, n-butyl iodide, Allyl Bromide, and Benzyl Bromide were 75, 75, 90, and 95%, respectively. Alkylation of alkyl lithiomethylnitrosamines with the same alkyl halides gave the corresponding products in ca. 90% yields, whereas alkylation of the cyclic N-nitrosamines occurred in ca. 60% yield. Aldehydes and ketones undergo addition to give 1,2-amino alcohols. Thus the pharmaceutically important arylamino alcohols are easily accessible (eq 2). Carboxylations proceed smoothly (eq 3); reaction with acid halides leads to derivatives of a-amino ketones (eq 4). Michael additions to a,b-unsaturated ketones (eq 5) lead to nitrosamines of g-amino ketones. Additions to nitroalkenes are also possible (eq 6).

Nitriles react with subsequent formation of triazoles (eq 7). The following hetero electrophiles also afforded the expected substitution products: Chlorotrimethylsilane, Chlorotrimethylstannane, disulfides, and diselenides.4

Denitrosation.

Denitrosation by acid alone is a very slow reaction,5 and a reducing species must be present. Preference is given to either Hydrogen Bromide/Acetic Acid or Raney Nickel. Catalysis by a copper salt is also reported. The review of the inventors of the method recommends a one-pot procedure combining nitrosation, metalation, alkylation, and denitrosation without isolation of any intermediates.

When the lithiation-alkylation sequence is to be carried out twice, the conformation of the nitrosamino group controls the kinetic position of lithiation.6 The position of entry of the second alkyl group also depends on temperature.

When two alkylations are carried out at the two a-positions of e.g. nitrosopyrrolidine, the steric result depends on the final protonation step,7 and may be controlled by the conditions of protonation.

Related Reagents.

N-t-Butoxycarbonyl-N-methylaminomethyllithium; N-t-Butyl-N,N-dimethylformamidine; Dimethylaminomethyllithium; N-(Diphenylmethylene)methanamine.


1. (a) Seebach, D.; Enders, D. AG(E) 1975, 14, 15. (b) Seebach, D.; Enders, D. CB 1975, 108, 1293.
2. Druckrey, H. AG(E) 1970, 9, 777.
3. FF 1975, 5, 479; 1977, 6, 336.
4. Seebach, D.; Enders, D. JMC 1974, 17, 1225.
5. Zaradnik, R. CCC 1958, 23, 1529.
6. Barton, D. H. R.; Bracho, R. D.; Gunatilaka, A. A. L.; Widdowson, D. A. JCS(P1) 1975, 579.
7. Schmitz, E.; Sonnenschein, H.; Gründemann, Ch. JPR 1980, 322, 261.

Ernst Schmitz

Institut für Angewandte Chemie, Berlin-Adlershof, Germany



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