N-alkylation of N-trimethylsilylimidazole

Article abstract of DOI:10.1134/S1070363207060230

The reaction of N-trimethylsilylimidazole with alkyl chloroacetates is studied. This process yields a mixture of N-alkylation and quarternization products in the ratio dependent on the reaction conditions. The reaction mechanism is discussed. ¹H NMR data show that high melting point and low solubility of 1-imidazolylacetic acid in organic solvents are evidently caused by the formation of strong intermolecular hydrogen bonds, whereas in water zwitterionic structures with the protonation of both nitrogen atoms are formed.

Full text of DOI:10.1134/S1070363207060230

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 6, pp. 1086 1088.
Pleiades Publishing, Ltd., 2007.
Original Russian Text A.V. Lebedev, V.D. Sheludyakov, A.B. Lebedeva, A.Yu. Frolov, V.V. Shatunov, O.L. Ustinova, E.A. Kovaleva, 2007, published in
Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 6, pp. 998 1001.
N-Alkylation of N-Trimethylsilylimidazole
A. V. Lebedev, V. D. Sheludyakov, A. B. Lebedeva, A. Yu. Frolov,
V. V. Shatunov, O. L. Ustinova, and E. A. Kovaleva
State Research Institute of Chemistry and Technology of Organoelement Compounds,
shosse Entuziastov 38, Moscow, 111123 Russia
Received December 25, 2006
Abstract The reaction of N-trimethylsilylimidazole with alkyl chloroacetates is studied. This process
yields a mixture of N-alkylation and quarternization products in the ratio dependent on the reaction conditions.
1
The reaction mechanism is discussed. H NMR data show that high melting point and low solubility of
1
-imidazolylacetic acid in organic solvents are evidently caused by the formation of strong intermolecular
hydrogen bonds, whereas in water zwitterionic structures with the protonation of both nitrogen atoms are
formed.
DOI: 10.1134/S1070363207060230
Data on alkylation of aminosilanes of the formula
RNHSiMe or R NSiMe with haloalkanes are prac-
chloroacetate IIc, giving silyl ester of 1-imidazolyl-
acetic acid Vc in 63% yield, was also described [3].
In this connection, it seemed promising to study in
detail the alkylation of silyl derivative I with alkyl
chloroacetates as a possible route to 1-imidazolyl-
acetic acid derivatives, which are the starting com-
pounds in the production of zoledronic acid drug [4].
3
2
3
tically lacking. This is evidently due to low nucleo-
philicity of the nitrogen center of the molecule and
steric effect of the silyl substituent. At the same time,
formally similar reactions of N-alkylation of N-silyl-
substituted pyrazoles with R Cl alkylating reagents
containing an active C Cl bond have been reported
[
1]. Preparative acylation of N-silyl-substituted di-
We found that N-trimethylsilylimidazole I reacts
with alkyl chloroacetates IIa IIc at elevated tem-
peratures without a solvent to form derivatives IVa
IVc and Va Vc, which are readily hydrolyzed with
hot water to give acids IVd and Vd.
azoles with phosgene, cyanogen chloride, acylcar-
bamoyl chlorides [2], and chloroformates [3] gives
the desired products in high yields. Direct alkylation
of N-trimethylsilylimidazole I with trimethylsilyl
+
N CH COOR
N CH2COOR
2
N
> |
_
+
ClCH COOR
+
N
2
Cl
N
N
.
.
SiMe3
SiMe3
SiMe3
I
IIa IIc
III
+
N
N CH COOR
2
+
II
Cl
Me SiCl
Me SiCl
N
3
3
N
CH COOR
2
CH COOR
2
IVa IVc
Va Vc
+
H O ROH
+
H O ROH
2
2
IVd
Vd
R = Et (a); Me (b); SiMe3 (c); H (d).
086
1

N-ALKYLATION OF N-TRIMETHYLSILYLIMIDAZOLE
1087
Note that no silyl interchange product, N-chloro-
methylcarbonylimidazole, was detected in the reaction
mixture, although the related transformation is charac-
teristic of pyrazole derivatives [1].
signals of the imidazole ring are revealed at 7.64
and 7.65 ppm, whereas the proton in position 2 gives
two low-field signals of equal intensity at 8.88 and
8.97 ppm which are strongly shifted downfield as
compared to the spectrum in DMSO-d . So large
6
N
N
downfield shift of the signals of the imidazole ring
protons is observed only in the case of quarternization
of the nitrogen atom. For example, for compound IVd
+
ClCH COOR
2
N
Me3SiOR
N
2
SiMe3
O=CCH Cl
2
containing a quarternary nitrogen atom, the H signal
1
in the H NMR spectrum is observed at 9.18 ppm
The structure of compounds IVd and Vd was
determined by elemental analysis, mass spectrometry,
and H NMR spectroscopy. Note that 1-imidazolyl-
acetic acid Vd has high melting point and low solu-
bility in organic solvents owing to the formation of
strong intermolecular hydrogen bonds, rather than to
its existence in the betaine form, as could be expected
from the presence of a carboxy group and two nitro-
gen atoms with free unshared electron pairs. Indeed,
the H NMR spectrum of Vd in DMSO-d contains
in DMSO-d and at 8.90 ppm in D O. For the hydro-
6
2
1
chloride of Vd, the low-field signal in the H NMR
spectrum in DMSO-d is observed at 9.10 ppm.
Thus, the signal of the H proton in the imidazole ring
1
6
2
in D O is shifted downfield as compared to that in
2
DMSO-d . This fact suggests the formation of the
6
zwitterionic structure of V only in water. The ap-
2
pearance of two downfield signals of the H proton
1
suggests the existence of two types of the betaine
structure with the protonation of both nitrogen atoms
according to the following scheme:
6
three signals of the imidazole ring protons at 6.92,
.15, and 7.69 ppm. At the same time, in D O the
7
2
N
N
N CH2COO + H3O+
N CH COOH + H2O
2
+
HN
N
N CH COO + H O
NHCH2COO + H2O
2
2
When considering the mechanism of alkylation of
The multiplicity of the N Si bond in intermediate
III is decreased because of the effect of the CH2
COOR group and the resonance stabilization of the
cation. Hence, it can react further with the internal
the silylated imidazole, it should be noted that the
direct attack of alkyl halides IIa IIc on the N-tri-
methylsilylimidazole nitrogen atom bound with sil-
icon is impossible because of its low nucleophility
arising from the partial double bonding with silicon
and steric hindrance. The reactions of I with IIa IIc
start only at about 70 C and occur primarily at the
pyridinium nitrogen atom of the imidazole ring to
form intermediate III. The similar reaction pathway
with the shift of the reaction center was found pre-
viously for the reaction of silylpyrazoles with an ac-
tive halomethylsilane ClCH Si(OEt) [1]. The results
elimination of the Me SiCl molecule and the forma-
3
tion of the alkylation products, alkyl 1-imidazolyl-
acetates Va Vc. The reaction with the second mole-
cule of chloroacetates IIa IIc leads to the formation
of the symmetric alkylation and quaternization prod-
ucts IVa IVc. The ratio of the products of the com-
peting strongly exothermic reactions does not depend
on the nature of substituent R in esters IIa IIc, but
is determined by the reaction conditions. When the
reaction temperature is maintained in the range 68
2
3
of the reaction in nonpolar toluene count in favor of
the initial quaternization. The reaction is significantly
decelerated at threefold dilution of the reaction mix-
ture with toluene. After the tenfold dilution, it is com-
pletely inhibited even at the toluene boiling point.
7
0 C, the subsequent hydrolysis gives 1:3 ratio of
the products IVd and Vd. Self-heating of the reaction
mixture to 90 100 C without external cooling leads to
the 4:1 product ratio, which is characteristic of the
quarternization.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 6 2007

1
088
LEBEDEV et al.
In all the cases the yield of the released trimethyl-
with 200 ml of hot water, and the reaction products
IVd and Vd were separated by fractional crystalliza-
tion from water.
chlorosilane did not exceed 80% based on silylimida-
zole I taken into in the reaction. Therefore, the separa-
tion of the reaction mixture involved vacuum distilla-
tion of the unchanged compound I and the subsequent
distillation of esters Va Vc. Another procedure in-
volved fractional crystallization of acids IVd and Vc,
among which the first one is poorly soluble in water.
The preparative yield of 1-imidazolylacetic acid does
not exceed 60% based on silylimidazole I. It decreases
with an the increase in the amount of the starting
compounds, because maintaining the minimum neces-
sary temperature for the synthesis becomes more
difficult.
1
,3-Bis(carboxymethyl)imidazolium chloride
IVd: decomposition point 222 223 C (MeOH/H O
2
1
1
:1). H NMR spectrum (DMSO-d ), , ppm: 5.22 s
6
(
4H, 2CH ), 7.759 s (1Harom), 7.764 (1Harom), 9.18 s
2
1
(1Harom). H NMR spectrum (D O), , ppm: 5.07 s
2
4H, 2CH ), 7.571 s (1Harom), 7.577 s (1Harom), 8.90 s
2
7
9
2
4
Calculated, %: C 38.11, H 4.11.
Ethyl 1-imidazolylacetate Va: bp 108 110 C
1
(2 mm Hg). H NMR spectrum (CDCl ), , ppm:
3
1
.41 t (3H, CH ), 3.95 q (2H, OCH ), 4.67 s (2H,
3 2
EXPERIMENTAL
CH ), 6.89 s (1Harom), 6.99 s (1Harom), 7.43 s(1Harom).
2
1
1-Imidazolylacetic acid Vd: decomposition point
The H NMR spectra were taken on a Bruker AM-
1
2
4
7
5
8
66 269 C. H NMR spectrum (DMSO-d ), , ppm:
6
3
60 spectrometer (360.14 MHz) in CDCl , DMSO-d ,
or D O. The mass spectra were measured on an MAT-
11A mass spectrometer at the ionizing electron
energy of 70 eV, with direct sample inlet.
3 6
.83 s (2H, CH ), 6.92 s (1Harom), 7.15 s (2Harom),
2
2
1
.69 s (1Harom). H NMR spectrum (D O), , ppm:
2
3
.12 s (2H, CH ), 7.64 s (1Harom), 7.65 s (1Harom),
2
.88 s/8.97 s (1/1, 1Harom). Mass spectrum (m/z): 126
+
Reaction of N-trimethylsilylimidazole I with
alkyl chloroacetates. Compound I, 0.4 mol, was
treated with 0.4 mol of appropriate ester IIa IIc. The
reaction mixture was heated with stirring to 75 80 C.
The released trimethylchlorosilane was distilled off
from the reaction mixture using a descending con-
denser. The reaction temperature was maintained in
the range 67 70 C by boiling and external cooling,
or the mixture was allowed to warm up to 90 100 C.
After the complete distillation of chlorosilane, which,
according to mass spectra, did not contain alkoxytri-
methylsilanes and noticeable amounts of hexamethyl-
disiloxane, the unchanged imidazole I and esters Va
Vc were successively distilled in a vacuum from the
reaction mixture. The residue containing mainly salts
IVa IVc and the distillate consisting of esters Va Vc
were treated with 100 ml of water, and the mixtures
obtained were evaporated until the distillation of
water ethanol azeotrope, methanol, or hexamethyldi-
siloxane, respectively, was complete. The residues
were cooled, treated with 30 ml of acetone and 150 ml
of methanol, stirred, and filtered. Pure compounds
IVd and Vd, respectively, were obtained. When the
syntheses were carried out without distillation of
esters Va Vc, the reaction mixture was hydrolyzed
([M] ). C H N O . Calculated: molecular mass
5
6
2
2
126.1138.
1-Imidazolylacetic acid hydrochloride Vd HCl.
Compound Vd (1 g) and 1 ml of concentrated hydro-
chloric acid were refluxed for 15 min. Excess acid
was removed in a vacuum, and the residue was re-
crystallized from water methanol mixture. Hydro-
chloride of Vd, 1.02 g, was obtained. H NMR spec-
trum (DMSO-d ), , ppm: 5.15 s (2H, CH ), 7.65 s
1
6
2
(1Harom), 7.71 s (1Harom), 9.10 s (1Harom).
REFERENCES
1
2
3
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va, M.G., Silkina, N.N., and Mironov, V.F., Zh.
Obshch. Khim., 1980, vol. 50, no. 4, p. 375.
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1
960, vol. 93, p. 2804.
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