[100-97-0]  · C6H12N4  · Hexamethylenetetramine  · (MW 140.22)

(oxidation of benzyl and alkyl halides and amines to aldehydes; ammonolysis of alkyl halides to primary amines; electrophilic formylation of aromatics; useful one-carbon unit in heterocyclic synthesis)

Alternate Name: HMTA.

Physical Data: mp 285-295 °C (subl.); d 1.331 g cm-3.

Solubility: sol water, ethanol, ether, chloroform.

Form Supplied in: white solid.

Analysis of Reagent Purity: 1H NMR (CDCl3) sharp singlet at d 4.70.

Purification: sublimation at aspirator pressure.

Handling, Storage, and Precautions: stable, low toxicity.

Oxidation of Benzylic Halides (Sommelet Reaction).2

Treatment of an activated (usually benzylic) halide with HMTA in a protic solvent such as aqueous acetic acid gives the aldehyde, via the Schiff base.3 The reaction involves an intramolecular hydride transfer, as shown in eq 1. Hydrochloric acid is sometimes added at the end of the reaction to speed the hydrolysis of the Schiff base.

The method works well with phenolic (eq 2)4 and heterocyclic (eq 3)5 substrates, for which other methods would probably be unsuitable.

Secondary halides usually give poor yields, while highly hindered substrates such as 2,6-disubstituted benzyl bromides are unreactive, although mononitrobenzyl bromides are oxidized. With unreactive halides it is often better to form the quaternary salt in chloroform, and decompose it in a protic medium.

In a related reaction, HMTA transforms benzylamines into benzaldehydes (eq 4).6

Ammonolysis of Alkyl Halides (Delépine Reaction).7,8

The quaternary salt of HMTA and alkyl halides decomposes under strongly acidic conditions (usually EtOH, concentrated HCl) to give primary amines rather than aldehydes or ketones (eqs 5-7).9-11

As in the Sommelet reaction, the bromide or chloride must be activated in order to react with the HMTA. The Delépine reaction provides a ready synthesis of a-amino acids (eq 8). If the decomposition is performed with HCl gas in dry ethanol, the corresponding ethyl ester is obtained instead.12

The reaction may be combined with the Eschweiler-Clark methylation by heating the quaternary salt in formic acid, the formaldehyde deriving from the decomposition of the HMTA (eq 9).13

HMTA opens epoxides exclusively at the less substituted site. This is of importance because free amines react unselectively (eq 10).14

Overall, HMTA provides a cheap and nonhazardous alternative to Sodium Azide for the synthesis of certain primary amines from their halides.

Electrophilic Formylation of Aromatics (Duff Reaction).15

Electron-rich aromatics (phenols, indoles, etc.) are formylated by HMTA in glacial acetic acid (eqs 11 and 12) or glyceroboric acid (H3BO3 in dry glycerol) (eq 13). Yields are sometimes poor.16-18

With phenols there is a strong tendency to give the ortho product selectively (eq 13). Yields are higher, and para selectivity is observed, when the reaction is conducted in Trifluoroacetic Acid (eq 14).19 Even unactivated aromatics react under these conditions.

Use in Heterocyclic Synthesis.

Treatment of phenanthroquinones with HMTA furnishes the fused imidazoles in good yield (eq 15).20

Benzodiazepines and quinazolines are accessible by treatment of the appropriate chloroacetamides and aminobenzophenones with HMTA (eqs 16 and 17).21

Isatins undergo ring expansion with HMTA in an alcoholic solvent (eq 18).22

1. Blazevic, N.; Kolbah, D.; Belin, B.; Sunjic, V.; Kajfez, F. S 1979, 161.
2. Angyal, S. J. OR 1954, 8, 197.
3. Angyal, S. J.; Tetaz, J. R.; Wilson, J. G. OSC 1963, 4, 690.
4. Gardner, T. S.; Smith, F. A.; Wenis, E.; Lee, J. JOC 1951, 16, 1121.
5. Kilényi, S. N. COS 1991, 7, 653.
6. Angyal, S. J.; Morris, P. J.; Tetaz, J. R.; Wilson, J. G. JCS 1950, 2141.
7. Ackerman, J. H.; Surrey, A. R. OS 1967, 47, 76.
8. Delépine, M. BSF 1895, 13, 352.
9. Galat, A.; Elion, G. B. JACS 1939, 61, 3585.
10. Graymore, J.; Davies, D. R. JCS 1945, 293.
11. Besace, Y.; Marszak-Fleury, A.; Marszak, I. BSF 1971, 1468.
12. Kajfez, F.; Kovac, T.; Mihailic, M.; Belin, B.; Sunjic, V. JHC 1976, 13, 561.
13. Nodiff, E. A.; Hulsizer, J. M.; Tanabe, K. CI(L) 1974, 962.
14. Angyal, S. J.; Penman, D. R.; Warwick, G. P. JCS 1953, 1737.
15. Roth, H. J.; Brandau, A. AP 1959, 292, 761.
16. Ferguson, L. F. CRV 1946, 38, 227.
17. Duff, J. C. JCS 1945, 276.
18. Duff, J. C. JCS 1941, 547.
19. Chatterjee, A.; Biswas, K. M. JOC 1973, 38, 4002.
20. Smith, W. E. JOC 1972, 37, 3972.
21. Kessler, E. M. M 1967, 98, 1512.
22. Blazevic, N.; Sunjic, V.; Crvelin, I.; Kolbah, D.; Kajfez, F. JHC 1972, 9, 531.

S. Nicholas Kilényi

Sanofi Research, Brussels, Belgium

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