Facile synthesis of N-dialkylaminomethyl-substituted heterocycles

Article abstract of DOI:10.1021/jo061723p

Iminium ions are generated by treatment of aminals with succinic anhydride. These iminium ions are trapped by heterocycles, giving the corresponding N-dialkylamino-methyl-substituted heterocycles, which are easily separated from the succinic acid monoamid

Full text of DOI:10.1021/jo061723p

SCHEME 1
Facile Synthesis of
N-Dialkylaminomethyl-Substituted Heterocycles
Brian E. Love
Department of Chemistry, East Carolina UniVersity,
GreenVille, North Carolina 27858
TABLE 1. Synthesis and Lithiation of
1-(Dialkylaminomethyl)imidazoles
loVeb@ecu.edu
ReceiVed August 18, 2006
Iminium ions are generated by treatment of aminals with
succinic anhydride. These iminium ions are trapped by
heterocycles, giving the corresponding N-dialkylamino-
methyl-substituted heterocycles, which are easily separated
from the succinic acid monoamide byproducts by means of
an aqueous base wash. The heterocyclic products are obtained
in good yield and in a high state of purity without need of
recrystallization or distillation.
the solution was washed with 6 M NaOH, followed by a
saturated NaCl solution. Evaporation of dichloromethane from
the organic phase led to isolation of good yields of 2
uncontaminated by acylation byproducts. Phthalic, maleic, and
succinic anhydrides were all investigated, and although all three
were successful, succinic anhydride became the anhydride of
choice.4
Extension of this methodology to the synthesis of other
1-(dialkylaminomethyl)imidazoles 4 was also investigated. The
required aminals 3 were easily prepared in high yield by
allowing secondary amines to react with formaldehyde.5 Reac-
tion of these aminals with imidazole and succinic anhydride
produced the corresponding aminomethylated imidazoles 4 in
good yield and in a high state of purity (Table 1).
As part of another project, a facile synthesis of usable
quantities of 1-(N,N-dimethylaminomethyl)imidazole 2 was
required. The standard literature preparation of this compound
is the one reported by Katritzky and co-workers,1 which is a
modification of the procedure of Stocker.2 Although this
procedure provides 2 in 78% yield, the synthesis requires 48 h
and gives a product contaminated with other byproducts
(presumably C-aminomethylated isomers),2 thus requiring pu-
rification by distillation.A shorter, cleaner route to 2 and related
compounds was sought, and the results of that investigation are
reported herein.
One of the principal uses of dialkylaminomethyl groups on
imidazoles is to direct lithiation at C-2, as has been demonstrated
by Katritzky and co-workers.1 Thus, the ease of lithiation of
imidazoles 4 was briefly investigated. Imidazoles 4 were stirred
for 30 min at 0 °C with 1.1 equiv of n-butyllithium, then
quenched with D2O. Percent deuterium incorporation (measured
by NMR) was taken as an indication of the minimum amount
of lithiation. As can be seen in Table 1, all dialkylaminomethyl
groups studied were effective at directing lithiation at C-2.
Because 1-(dialkylaminomethyl)imidazoles could be prepared
quickly and in a high state of purity without need of either
recrystallization or distillation, application of this methodology
to the synthesis of other dialkylaminomethyl heterocycles 6 was
The concept was to allow imidazole to react with the iminium
ion generated by reaction of bis(dimethylamino)methane 1 with
an acylating agent3 (Scheme 1). Acetyl chloride was initially
chosen as the acylating agent, which produced the desired 2
along with an approximately equal amount of N,N-dimethyl-
acetamide. Although the latter compound could be removed by
an aqueous wash, this greatly reduced the yield of 2, owing to
its significant water solubility.
The use of cyclic anhydrides as acylating agents was then
investigated because the byproducts of such reactions contain
a carboxylic acid group and thus can be easily removed by base.
In a typical reaction, a mixture of 1, imidazole, and potassium
carbonate in dichloromethane was treated with the solid
anhydride, and after stirring at room temperature for an hour,
(4) Use of maleic anhydride occasionally resulted in the formation of
other byproducts, and the phthalic acid monoamides formed from some of
the higher molecular weight analogues of 1 had reduced solubility in an
aqueous base.
(5) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron 1997, 53,
2941.
(1) Katritzky, A. R.; Rewcastle, G. W.; Fan, W.-Q. J. Org. Chem. 1988,
53, 5685.
(2) Stocker, F. B.; Kurtz, J. L.; Gilman, B. L.; Forsyth, D. A. J. Org.
Chem. 1970, 35, 883.
(3) Kinast, G.; Tietze, L.-F. Angew. Chem., Int. Ed. 1976, 15, 239.
10.1021/jo061723p CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/23/2006
630
J. Org. Chem. 2007, 72, 630-632

TABLE 2. Synthesis of Dimethylaminomethyl-Substituted Heterocycles
a Yield ) 62% using workup protocol A; yield ) 91% on 100 mmol scale preparation. b Yield ) 96% on 50 mmol scale preparation. c Yield ) 32%
using workup protocol A.
investigated. The dimethylaminomethyl group has been found
to be a useful lithiation directing group for the synthesis of
heterocycles,1,6-10 including compounds used as ligands for
transition-metal catalysts.11,12 Additionally, some dialkylami-
nomethyl heterocycles have been found to have useful phar-
macological properties.13,14
As can be seen from the data in Table 2, high yields were
obtained for most substrates, though several of the amide-like
heterocycles failed to give the desired products. As with the
imidazole derivatives, the products were obtained in a high state
of purity using the aqueous base wash as the only purification
step. With these substrates, two workup protocols were em-
ployed. For most reactions, the dichloromethane solution of the
crude product was washed with two 25 mL portions of 1 M
NaOH, followed by 10 mL of saturated NaCl (“workup A”).
For products which had comparatively high water solubility,
the two 1 M NaOH washes were replaced with one wash with
10 mL of 6 M NaOH ( “workup B”).15
Bis(dimethylamino)methylation could also be achieved simply
by combining 2 equiv each of aminal 1, potassium carbonate,
and succinic anhydride with 1 equiv of a suitable diprotic
heterocycle (Table 3). Treatment of indole with just 1 equiv of
the aminomethylating reaction mixture produced a mixture of
gramine, isogramine, and 1,3-bis[(dimethylamino)methyl]indole
7a, as well as some unreacted indole. Use of 2 equiv gave a
3:1 mixture of 7a/isogramine, the crude yield of 7a in this
mixture being approximately 70%. Interestingly, benzimidazole
derivatives 7c and 7d were obtained in good yield, even though
indigo failed to give the desired product, consistent with the
failure of other amide-like heterocycles to undergo this trans-
formation. All of these reactions were worked up using
workup A.
(6) Katritzky, A. R.; Rewcastle, G. W.; Vazquez de Miguel, L. M.
J. Org. Chem. 1988, 53, 794.
(7) Katritzky, A. R.; Lue, P.; Chen, Y. X. J. Org. Chem. 1990, 55, 3688.
(8) Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron
Lett. 1990, 31, 5779.
(9) Granier, T.; Vasella, A. HelV. Chim. Acta 1995, 78, 1738.
(10) Huang, L.-F.; Bauer, L. J. Heterocycl. Chem. 1997, 34, 1123.
(11) Berens, U.; Brown, J. M.; Long, J.; Selke, R. Tetrahedron:
Asymmetry 1996, 7, 285.
(12) Yu, J. O.; Lam, E.; Sereda, J. L.; Rampersad, N. C.; Lough, A. J.;
Browning, C. S.; Farrar, D. H. Organometallics 2005, 24, 37.
(13) Harmenberg, J.; Wahren, B.; Bergman, J.; Aakerfeldt, S.; Lundblad,
L. Antimicrob. Agents Chemother. 1988, 32, 1720.
In many instances, yields using the present method are
superior to those obtained by “traditional” Mannich conditions
(15) “Workup B” was used for all reactions shown in Table 1. When
“Workup A” was applied to the synthesis of imidazole 4a, the yield dropped
from 75% to 60%.
(16) Zinner, H.; Spangenberg, B. Chem. Ber. 1958, 91, 1432.
(17) The reaction is exothermic but requires no external cooling when
run on this scale.
(14) Fadda, A. A.; Etman, H. A.; Ali, M. M. Pharmazie 1991, 46, 52.
J. Org. Chem, Vol. 72, No. 2, 2007 631

TABLE 3. Synthesis of Bis(dimethylaminomethyl)-Substituted
Heterocycles
ability to obtain products of high purity without need of
recrystallization or distillation.
Experimental Section
Typical Small-Scale Synthesis. The starting heterocycle (ca.
2-3 mmol)17 was combined with 1.1 equiv of the aminal and 1.1
equiv of K2CO3 in 15 mL of CH2Cl2 and stirred while 1.1 equiv of
succinic anhydride was added in one portion. The flask was lightly
stoppered, and the mixture was stirred at room temperature for 1
h. The reaction mixture was diluted with 50 mL of CH2Cl2 and
washed with either two 25 mL portions of 1 M NaOH (workup A)
or one 10 mL portion of 6 M NaOH (workup B) followed by
10 mL of saturated NaCl solution. The organic layer was dried
over MgSO4, and the solvent was removed under reduced pressure,
affording the product in a high state of purity.
Example of a Larger-Scale Synthesis. An 8.21 g (100 mmol)
sample of 2-methylimidazole was combined with 11.40 g (111.8
mmol) of bis(dimethylamino)methane 1 and 15.21 g (110.2 mmol)
of K2CO3 and taken up in 50 mL of CH2Cl2. The mixture was
cooled in an ice bath and stirred as 11.04 g (110.4 mmol) of succinic
anhydride was added. The temperature of the reaction mixture rose
to 25 °C, and when it had dropped to 20 °C, the flask was removed
from the ice bath and allowed to come to room temperature over
1 h. The reaction mixture was diluted with 150 mL of CH2Cl2 and
washed with 100 mL of 3 M NaOH, 50 mL of 6 M NaOH, and
25 mL of saturated NaCl solution. The organic layer was dried
over MgSO4, and the solvent was removed under reduced pressure,
affording 12.58 g (91%) of 1-(dimethylamino)methyl-2-methylimi-
dazole 6a in a high state of purity. (Note: when a 50 mmol scale
preparation of 6f was carried out under similar conditions, only a
5 °C increase in reaction mixture temperature was observed upon
addition of the succinic anhydride.)
Typical Lithiation Procedure. The starting heterocycle (ca. 2
mmol) was dissolved in 10 mL of freshly distilled THF and cooled
in an ice bath under nitrogen. A portion of 1.1 equiv of 1.9 M
n-BuLi in hexane was added, and the solution was stirred in the
bath for 30 min. Then the reaction was quenched by addition of
0.5 mL of D2O. The solution was removed from the bath and
allowed to come to room temperature and then diluted with 50 mL
of ether and washed with 10 mL of 6 M NaOH followed by
10 mL of saturated NaCl solution. The organic layer was dried
over MgSO4, and the solvent was removed under reduced pressure.
a Impure (see text).
(direct reaction of the heterocycle with aqueous amine and
aqueous formaldehyde). For example, the literature6 synthesis
of 6k requires 12 h of heating at reflux and gives 6k in 51%
yield (compared to 89% yield under these conditions). Similarly,
the literature16 synthesis of 7d requires 3 days of stirring at room
temperature and gives 7d in 28% yield after distillation, whereas
the present method allows isolation of this compound in 86%
yield.
In summary, an operationally simple procedure has been
developed that allows the preparation of a wide variety of
heterocycles substituted with dialkylaminomethyl groups. Ad-
vantages of this method include short reaction times and the
Supporting Information Available: 1H and 13C NMR spectra
and characterization data for compounds 4, 6, and 7. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO061723P
632 J. Org. Chem., Vol. 72, No. 2, 2007