An efficient synthesis of 2-(methylaminomethyl)-4,5-dialkyl-1H-imidazoles

Article abstract of DOI:10.1055/s-1998-1879

A mild and convenient synthesis of 2-(methylaminomethyl)-4,5-dialkyl-1H-imidazoles is described. The procedure was used in the preparation of 2-(methylaminomethyl)-4,5,6,7-tetrahydro-1H-benzimidazole 1 and 2-(methylaminomethyl)-4,5-dimethyl-1H-imidazole 2

Full text of DOI:10.1055/s-1998-1879

October 1998
SYNLETT
1077
An Efficient Synthesis of 2-(Methylaminomethyl)-4,5-Dialkyl-1H-Imidazoles.
1
Valérie A. Reader
Department of Medicinal Chemistry, Research and Development Division, SmithKline Beecham Pharmaceuticals,
709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406-0939, USA.
Received 3 June 1998
Abstract: A mild and convenient synthesis of 2-(methylaminomethyl)-
4,5-dialkyl-1H-imidazoles is described. The procedure was used in the
The protection of the commercially available N-methylamino
5
acetonitrile hydrochloride
with benzylchloroformate gave
a
3
6
preparation
benzimidazole
imidazole 2.
of
1
2-(methylaminomethyl)-4,5,6,7-tetrahydro-1H-
and 2-(methylaminomethyl)-4,5-dimethyl-1H-
quantitative yield of , which was converted to the thioamide in 70%
4
5
yield by reaction with H S in the presence of excess Et N in DMF at
2
3
room temperature. Treatment of
with methyl iodide in acetone
5
afforded the S-methyl thioimidate which was obtained as a crystalline
6
7
product in 89% yield . Compound
was prepared in 77% yield from
8a
As part of a recent medicinal chemistry program, we required a general
and efficient synthesis of 2-(alkylaminomethyl)-substituted imidazoles.
The method we developed is exemplified in scheme 1 by the synthesis
of 2-(methylaminomethyl)-4,5-dialkyl-1H-imidazoles, specifically 2-
(methylaminomethyl)-4,5,6,7-tetrahydro-1H-benzimidazole 1 and 2-
(methylaminomethyl)-4,5-dimethyl-1H-imidazole 2.
5
commercially available α-hydroxyketal
by catalytic oxidation with
7
8
TPAP/NMO in CH Cl . Subsequent reductive amination of
by
8a
2
2
NaBH CN and excess NH OAc in methanol at pH 6 gave the α-amino
3
4
9
ketal
in 70% yield . The S-methyl thioimidate was then stirred in
6
9a
o
methanol with 50% excess of the α-amino ketal
at 60 C for 3 hours
9a
to give the amidine
. Compound
10a
was then reacted without
10a
Numerous syntheses of 2-(aminomethyl)- and 2-(alkylaminomethyl)-
purification with 6N HCl to give an intermediate which spontaneously
2
4,5-dialkyl-1H-imidazoles have been reported . The methods we tried
cyclized to give the 2,4,5- trisubstituted imidazole
in an overall
11a
were not reliable for our examples, affording low yields and multiple
products. An excellent method for the synthesis of imidazoles has been
10
yield of 51% (based on
)
after purification by flash chromatography.
Removal of the benzylcarbamate by catalytic hydrogenolysis afforded
6
3
described by Hoff in which an amidine is cyclized with an α-
the 2-(methylaminomethyl)-4,5-disubstituted-1H-imidazole
in 79%
1
substituted-acetal. We have found this method to be equally applicable
yield.
4
with an α-substituted ketal , leading to the desired 2-
10,11
Analogously, the dimethylimidazole
2
was prepared from
(alkylaminomethyl)-substituted imidazoles.
commercially available 3,3- dimethoxy-2-butanone in an overall yield
of 35% (based on 6) after flash chromatography.
The syntheses of the imidazoles 1 and 2 are shown below in Scheme 1.
In summary, we have demonstrated a convenient and mild synthesis of
highly substituted imidazole derivatives. The method is exemplified by
the preparation of the tetrahydrobenzimidazole and the dimethyl
imidazole derivatives and We believe that this route can be applied
2.
1
to a wide range of substituted imidazoles using for example thioamides
derived from amino acids, and a wide range of α-hydroxy ketones.
Acknowledgments : The author would like to thank Dr D. Yamashita
and Dr W. Bondinell for their help and guidance during the writing of
this manuscript.
References and notes
(1) Current Address: Cambridge Combinatorial Ltd. The Merrifield
Centre, Rosemary Lane. Cambridge CB1 3LQ. U.K.
(2) a) Buschauer, A.; Schunack, W. J. Heterocyclic Chem., 1984, 21,
753-757, b) Buschauer, A.; Wegner, K; Schunack, W. Eur. J. Med.
Chem.-Chim. Ther., 1982, 17, 507-8, c) Bastiaansen, L. A. M.;
Godelfroi, E. F. J. Org. Chem., 1978, 43, 1603-4, d) Jun, Y.;
Thurkauf, A. WO 9625411 A1, e) Kuzmierkiewicz, W. Pol. Acta
Pol. Pharm., 1986, 43, 221-6, f) Towliati, H. Chem. Ber., 1970,
103, 3952-3953.
(3) Hoff, D. R. Proc. Internat. Symp. on Drug Res., Montreal,
Canada, 1967, p100.
(4) Lipinski, C. A.; LaMattina, J. L.; Oates P. J. J. Med. Chem, 1986,
29, 2154-2163.
(5) All comercially available compounds were bought from Aldrich
Chemical Company, Inc.
Scheme 1
(6) Thioamide
has been synthesized by Culbertson, T. P.;
5
Domagala, J. M.; Peterson, P.; Bongers, S.; Nichols, J. J.
Heterocyclic Chem. 1987, 24, 1509-1520 using pyridine as the
solvent.

1078
LETTERS
SYNLETT
1
(7) H NMR(400MHz) in CDCl of
δ=7.3-7.5 (m, 5H, Ph), δ=5.20
(11) Typical procedure for the formation of 11a,b : A solution of 2-
amino-3,3-dimethoxy butane 9b (1.05g, 7.89mmol) and N-
(carbobenzyloxy)-N-(methyl)aminomethyl-S-methyl
6 :
3
(s, 2H, C -Ph), δ=4.85 (s, 2H, C -N), δ=3.05 (s, 3H, N-C ),
δ=2.90 (s, 3H, S-C
H
H
H
3
2
2
)
H3
thioacetimidate 6 (2.0g, 5.26mmol) in methanol (30 ml) was
heated at 60 C for 2h, and then concentrated to give a yellow oil.
(8) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis,
1994, 639-666.
o
The crude material was then dissolved in 6N HCl (30 ml) and
stirred at room temperature 1h. The solution was basified to pH 12
(9) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc.,
1971, 93, 2897-2904.
with aqueous NaOH and then extracted with CH Cl . The
2
2
1
(10) H NMR(400MHz) in CD OD of
: δ=7.3-7.5 (m, 5H, Ph),
11a
3
combined organic layers were dried (MgSO ) and concentrated to
4
δ=5.15 (s, 2H, C -Ph), δ=4.4 (s, 2H, C -N), δ=3.05 (s, 3H,
H
H
2
2
give a brown oil. Purification by flash chromatography (silica gel,
C
), δ=2.55 (m, 4H, C
imid.), δ=1.75 (m, 4H, CH (C
)
H -
H
3
- H -
-
2
2
2 2
4% MeOH/CH Cl ) gave N-(carbobenzyloxy)-N-methyl-(4,5-
2
2
CH ).
2
dimethyl-1H-imidazol-2-yl)methylamine 11b as
(0.590g, 41%). MS (ES) m/e 274.0 [M+H] .
a clear oil
1
H NMR(400MHz) in CD OD of
: δ=7.3-7.5 (m, 5H, Ph),
11b
+
3
δ=5.15 (s, 2H, C -Ph), δ=4.35 (s, 2H, C -N), δ=2.95 (s, 3H,
H
H
2
2
C
), δ=2.1 (s, 6H, 2C of the imid.).
H
3
H
3