HEXAMETHYLENETETRAMINE

1

Hexamethylenetetramine

1

N

N

N

N

[100-97-0]

C

6

H

12

N

4

(MW 140.22)

InChI = 1/C6H12N4/c1-7-2-9-4-8(1)5-10(3-7)6-9/h1-6H2
InChIKey = VKYKSIONXSXAKP-UHFFFAOYAW

(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 Names:

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:

1

H NMR (CDCl

3

) sharp singlet at δ

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.

N

N

N

N

Cl

N

N

N

N

N

N

N

N

N

N

N

N

Me

+

aq AcOH

+

Br

–

CHO

Br

–

+

+

Br

–

ArCH

H

3

O

+

ArCH

2

(1)

77–82%

The method works well with phenolic (eq 2)

4

and heterocyclic

(eq 3)

5

substrates, for which other methods would probably be

unsuitable.

(2)

OH

CHO

Cl

CHO

CHO

OH

HMTA

aq. AcOH

65%

N

HO

Cl

N

CHO

HO

(3)

HMTA

aq. EtOH

34%

Secondary halides usually give poor yields, while highly hin-

dered substrates such as 2,6-disubstituted benzyl bromides are un-
reactive, 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 ben-

zaldehydes (eq 4).

6

NH

2

NH

2

CHO

CHO

(4)

AcOH, aq. HCl

60%

HMTA

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

(5)

Cl

Br

Cl

NH

2

H

3

O

+

74%

HMTA

Cl

NH

2

(6)

66%

Ph

H
N

Ph

Br

O

Ph

H
N

Ph

NH

2

O

(7)

100%

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 α-amino acids (eq 8). If the decompo-
sition is performed with HCl gas in dry ethanol, the corresponding
ethyl ester is obtained instead.

12

(8)

CO

2

H

Br

CO

2

–

+

NH

3

93%

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

N

PhCH

2

N

N

N

(9)

PhCH

2

Cl

+

HMTA

Cl

–

+

PhCH

2

NMe

2

HCO

2

H

HMTA opens epoxides exclusively at the less substituted site.

This is of importance because free amines react unselectively
(eq 10).

14

O

Ph

Ph

NH

2

OH

+

HMTA

(10)

HCl

EtOH

Avoid Skin Contact with All Reagents

2

HEXAMETHYLENETETRAMINE

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
(H

3

BO

3

in dry glycerol) (eq 13). Yields are sometimes poor.

16

–

18

(11)

HMTA

N
H

Ph

N
H

CHO

Ph

AcOH

74%

NMe

2

NMe

2

CHO

(12)

AcOH

38%

HMTA

(13)

HO

HO

CHO

HMTA

H

3

BO

3

, glycerol

25%

With phenols there is a strong tendency to give the ortho

product selectively (eq 13). Yields are higher, and para selectiv-
ity is observed, when the reaction is conducted in Trifluoroacetic
Acid (eq 14).

19

Even unactivated aromatics react under these con-

ditions.

HTMA

CF

3

CO

2

H

CHO

CHO

+

(14)

50%

11%

Use in Heterocyclic Synthesis.

Treatment of phenanthro-

quinones with HMTA furnishes the fused imidazoles in good yield
(eq 15).

20

O

O

R

2

R

1

NH

N

R

2

R

1

(15)

HMTA

R

1

, R

2

= H, Cl, Br, NO

2

NH

4

OAc, AcOH

61–80%

Benzodiazepines and quinazolines are accessible by treatment

of the appropriate chloroacetamides and aminobenzophenones
with HMTA (eqs 16 and 17).

21

H
N

O

Cl

O

Ph

N

N

O

Ph

Cl

(16)

1. HMTA, MeCN

2. EtOH,

∆

X

NH

2

O

Ph

N

N

Ph

CO

2

Et

N

N

Ph

(17)

1. HMTA, MeCN

+

2. BrCH

2

CO

2

Et

Isatins undergo ring expansion with HMTA in an alcoholic sol-

vent (eq 18).

22

N

O

O

Cl

O

X

N

H

N

O

(18)

X

RO

2

C

HMTA

ROH

1.

Blazevic, N.; Kolbah, D.; Belin, B.; Sunjic, V.; Kajfez, F., Synthesis 1979,
161.

2.

Angyal, S. J., Org. React. 1954, 8, 197.

3.

Angyal, S. J.; Tetaz, J. R.; Wilson, J. G., Org. Synth., Coll. Vol. 1963, 4,
690.

4.

Gardner, T. S.; Smith, F. A.; Wenis, E.; Lee, J., J. Org. Chem. 1951, 16,
1121.

5.

Kilényi, S. N., Comprehensive Organic Synthesis 1991, 7, 653.

6.

Angyal, S. J.; Morris, P. J.; Tetaz, J. R.; Wilson, J. G., J. Chem. Soc 1950,
2141.

7.

Ackerman, J. H.; Surrey, A. R., Org. Synth. 1967, 47, 76.

8.

Delépine, M., Bull. Soc. Chem. Fr. 1895, 13, 352.

9.

Galat, A.; Elion, G. B., J. Am. Chem. Soc. 1939, 61, 3585.

10.

Graymore, J.; Davies, D. R., J. Chem. Soc. 1945, 293.

11.

Besace, Y.; Marszak-Fleury, A.; Marszak, I., Bull. Soc. Chem. Fr. 1971,
1468.

12.

Kajfez, F.; Kovac, T.; Mihailic, M.; Belin, B.; Sunjic, V., J. Heterocycl.
Chem. 1976

, 13, 561.

13.

Nodiff, E. A.; Hulsizer, J. M.; Tanabe, K., Chem. Ind. (London) 1974,
962.

14.

Angyal, S. J.; Penman, D. R.; Warwick, G. P., J. Chem. Soc. 1953, 1737.

15.

Roth, H. J.; Brandau, A., Arch. Pharm. (Weinheim, Ger.) 1959, 292, 761.

16.

Ferguson, L. F., Chem. Rev. 1946, 38, 227.

17.

Duff, J. C., J. Chem. Soc. 1945, 276.

18.

Duff, J. C., J. Chem. Soc. 1941, 547.

19.

Chatterjee, A.; Biswas, K. M., J. Org. Chem. 1973, 38, 4002.

20.

Smith, W. E., J. Org. Chem. 1972, 37, 3972.

21.

Kessler, E. M., Monatsh. Chem. 1967, 98, 1512.

22.

Blazevic, N.; Sunjic, V.; Crvelin, I.; Kolbah, D.; Kajfez, F., J. Heterocycl.
Chem. 1972

, 9, 531.

S. Nicholas Kilényi

Sanofi Research, Brussels, Belgium

A list of General Abbreviations appears on the front Endpapers