Reaction of imidazoles with cyanogen bromide: Cyanation at N 1 or bromination at C 2?

Article abstract of DOI:10.1071/C98105

The reaction in acetonitrile solution of a number of imidazoles (1H-, 1-methyl-, 2-methyl-, 4-methyl-, 1,2-, 1,4- and 1,5-dimethyl-, 1-ethyl-, 1-benzyl- and 1-butyl-imidazole) and imidazole complexes ([Co(NH₃)₅(imH)](ClO₄)₃, [Co(NH₃)₅(im)] (ClO₄)₂ and [Co(NH₃)₅(1-Meim)] (ClO₄)₃) with BrCN has been studied. Those imidazoles bearing an N-alkyl substituent and having a hydrogen at C2 react to give the 2-bromo products, while the N-H imidazoles react to give W-cyano derivatives. The product(s) from the reaction of 1,2-dimethylimidazole with BrCN could not be characterized. Of the complexes, only [Co(NH₃)₅(im)] (ClO₄)₂ reacts, giving the 2-bromo product. Our observations suggest a lone pair on a ring nitrogen atom is necessary for an imidazole to react with BrCN, and a possible mechanism is suggested. The X-ray structure of 2-methylimidazole-1-carbonitrile is reported. Crystal data (-143°C) for C₅H₅N₃: monoclinic, P2₁/c, a 10.201(5), b 7.110(3), c 7.227(3) A, β 100.47(2)°, V 515.4(4) A³, Z 4, d_calcd 1-380 g cm^-3. Refinement of the structure converged with R₁ 0.0444 for 1183 reflections with F_o > 4F(F_o) and ωR₂ 0.1259 for all 1278 data.

Full text of DOI:10.1071/C98105

C S I R O P U B L I S H I N G
Australian Journal
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Volume 52, 1999
©
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Aust. J. Chem., 1999, 52, 159–165
.
Reaction of Imidazoles with Cyanogen Bromide:
Cyanation at N 1 or Bromination at C 2?
A
A,B
M. Ross Grimmett A,B and
Peter B. W. McCallum, Rex T. Weavers,
Allan G. Blackman
A,B
A
Department of Chemistry, University of Otago, Dunedin, New Zealand.
Authors to whom correspondence should be addressed.
B
The reaction in acetonitrile solution of a number of imidazoles (1H -, 1-methyl-, 2-methyl-, 4-methyl-,
,2-, 1,4- and 1,5-dimethyl-, 1-ethyl-, 1-benzyl- and 1-butyl-imidazole) and imidazole complexes
[Co(NH3)5(imH)] (ClO4)3, [Co(NH3)5(im)] (ClO4)2 and [Co(NH3)5(1-Meim)] (ClO4)3) with BrCN has
1
(
been studied. Those imidazoles bearing an N -alkyl substituent and having a hydrogen at C 2 react
to give the 2-bromo products, while the N–H imidazoles react to give N -cyano derivatives. The
product(s) from the reaction of 1,2-dimethylimidazole with BrCN could not be characterized. Of the
complexes, only [Co(NH3)5(im)] (ClO4)2 reacts, giving the 2-bromo product. Our observations suggest
a lone pair on a ring nitrogen atom is necessary for an imidazole to react with BrCN, and a possible
mechanism is suggested. The X-ray structure of 2-methylimidazole-1-carbonitrile is reported. Crystal
�
�
�
�
data (� 143 C) for C5H5N3: monoclinic, P 21/c, a 10�201(5), b 7�110(3), c 7�227(3) A, � 100�47(2) ,
3
� 3
V 515�4(4) A , Z 4, dcalcd 1�380 g cm . Re�nement of the structure converged with R1 0�0444 for
183 re�ections with Fo > 4F(Fo) and wR2 0�1259 for all 1278 data.
1
Introduction
given somewhat con�icting results. Giesemann showed
that both imidazole and 4-methylimidazole reacted with
BrCN in ether to give respectively 1-cyanoimidazole and
�
The reaction of imidazoles with bromine in aqueous
and non-aqueous solution usually proceeds rapidly to
give bromination at all available carbon sites. Studies
a mixture of 1-cyano-4-methylimidazole and 1-cyano-5-
1
7
methylimidazole, while Purygin and Pan’kov recently
of such reactions have shown that the 2-position is
invariably the least reactive towards bromine (and
other electrophilic brominating reagents) and, indeed,
electrophilic bromination at C 2 without concomitant
reported the synthesis of 1-cyano-2-methylimidazole
from the reaction of 2-methylimidazole with BrCN in
re�uxing benzene. Although N -cyanoazoles are rela-
8
tively rare, they are currently of interest due to their
2
+
9
bromination at the other carbon sites is impossible.
capacity to act as CN transfer agents and as reagents
10
This usually necessitates the use of indirect methods to
for non-enzymic ligation of double-helical DNA, and
3
prepare 2-bromoimidazoles. Given the current interest
new routes to the synthesis of such compounds are being
4
11,12
in the synthesis of 2-substituted imidazoles and the
sought.
To date, no N -cyanoazoles have been struc-
use of 2-bromoimidazoles as starting materials in the
synthesis of such compounds, it is surprising that
turally characterized. Recently, it was reported that
reaction of imidazole with BrCN gave diimidazole imine
5
the early (1928) work of Langenbeck concerning the
reaction of imidazoles with cyanogen bromide (BrCN)
has not received further attention. He reported that
1
,4-dimethylimidazole reacted with BrCN to give 2-
bromo-1,4-dimethylimidazole (Scheme 1) while both
pilocarpine and isopilocarpine reacted similarly to give
the 2-bromo derivatives. However, the few subsequent
6
studies of reactions of imidazoles with BrCN have
�
Under IUPAC recommendation R-4.1, the systematic name should be imidazole-1-carbonitrile. Such names will be used in the
Experimental section.
Manuscript received 16 June 1998
᭧ CSIRO 1999
10.1071/CH98105
0004-9425/99/030159$ 05.00

1
60
P. B. W. McCallum et al.
1
3
14
(
1) and 1-carbamoylimidazole, presumably via the
of the reaction of 1,4-dimethylimidazole with BrCN, in
order to con�rm unequivocally Langenbeck’s original
intermediacy of 1-cyanoimidazole, while Whitten and
coworkers showed that treatment of a number of imida-
zoles with a mixture of BrCN/dimethylaminopyridine
gave the corresponding 2-cyanoimidazoles. During our
studies of the bromination of cobalt(III)-coordinated
imidazoles, we became interested in the mechanism
of the reaction of BrCN with imidazoles, as the vari-
ety of products and the orientation of bromination
preclude a simple electrophilic mechanism. In this
paper, we report the results of our studies of the
reaction of a number of imidazoles with BrCN to
give both C-brominated and N -cyanated products,
and present a reaction mechanism which accounts for
the observed experimental data. We also report the
crystal structure of 1-cyano-2-methylimidazole, the �rst
structurally characterized 1-cyanoazole.
6
assignment of this as 2-bromo-1,4-dimethylimidazole.
1
The H n.m.r. spectrum of the product showed only one
15
signal in the aromatic region at 6�67 ppm, irradiation
of which resulted in enhancement of both methyl signals
at 3�55 and 2�17 ppm. The signal at 6�67 ppm must
therefore be due to H 5 and this requires substitution at
C 2. N -Cyanation of imidazole and 2-methylimidazole
resulted in loss of symmetry and resulted in three
and two peaks respectively in the aromatic region of
1
6
1
1
the H n.m.r. spectrum. The H n.m.r. spectrum
of 1-cyanoimidazole is worthy of note, comprising a
broad singlet (7�98 ppm, H 2), triplet (7�33 ppm) and
broad doublet (7�18 ppm). Homonuclear decoupling
experiments show that H 2 is coupled to both H 4
and H 5, but this coupling is unresolved, presumably
due to the two adjacent quadrupolar nitrogen atoms.
13
The C n.m.r. spectrum of both 1-cyanoimidazoles
showed the cyano carbon resonance at c. 105 ppm.
N -Cyanation of imidazole and 2-methylimidazole was
also con�rmed by the appearance of a C� N band in
�
1
the i.r. spectrum at approximately 2250 cm
.
Results and Discussion
Synthesis and Characterization
Reactions of imidazoles with excess BrCN were car-
ried out in acetonitrile solution at room temperature
in the absence of light for times ranging from 3 h
to 3 days. Workup procedures di�ered depending
on the nature of the products. 1-Cyanoimidazoles
were found to hydrolyse in aqueous solution and
therefore non-aqueous conditions were used to isolate
these following removal of solvent under reduced pres-
sure. 1-Cyanoimidazole was crystallized from CHCl3
while 1-cyano-2-methylimidazole was isolated by vac-
uum sublimation following chromatography on neutral
alumina. Although the products of the reaction of
4
-methylimidazole and BrCN could not be separated,
1
the H n.m.r. spectrum of the crude reaction mixture
was consistent with the presence of both 1-cyano-4-
methylimidazole and 1-cyano-5-methylimidazole. The
brominated imidazoles were isolated by extraction of
an aqueous solution of the crude material with CHCl3,
with those requiring further puri�cation being distilled
under reduced pressure and/or chromatographed on
neutral alumina using CHCl3 as eluent. The bromi-
nated complex [Co(NH3)5(2-BrimH)] Br3 was puri�ed
by column chromatography on Dowex 50W� 2 cation
exchange resin and was crystallized as the bromide salt.
Characterization of the products was achieved in
Fig. 1. ORTEP diagram of 1-cyano-2-methylimidazole, with
thermal ellipsoids drawn at the 50% probability level.
Table 1. Bond lengths and angles for
1
-cyano-2-methylimidazole
Angles (degrees)
C(7)–N(1)–C(2)
Distances ( �A )
N(1)–C(7)
N(1)–C(2)
N(1)–C(5)
C(6)–C(2)
C(2)–N(3)
N(3)–C(4)
C(4)–C(5)
N(8)–C(7)
1�3367(18)
1�3858(19)
1�3908(19)
1�472(2)
126�71(13)
125�69(13)
107�56(12)
109�74(14)
128�00(14)
122�26(13)
106�98(12)
111�12(13)
104�60(12)
179�30(16)
1
13
C(7)–N(1)–C(5)
C(2)–N(1)–C(5)
N(3)–C(2)–N(1)
N(3)–C(2)–C(6)
N(1)–C(2)–C(6)
C(2)–N(3)–C(4)
C(5)–C(4)–N(3)
C(4)–C(5)–N(1)
N(8)–C(7)–N(1)
the �rst instance by H and C n.m.r. spectroscopy.
Bromination at C 2 was accompanied by loss of the
1
lowest �eld proton signal in the H n.m.r. spectrum,
1�2892(19)
1�381(2)
1
3
while in the C n.m.r. spectrum the peak in the
starting material corresponding to C 2 was found to
decrease in intensity and move 10–20 ppm up�eld in
the spectrum of the brominated product. N.O.e. and
HETCOR data were also used to characterize the product
1�339(2)
1�137(2)

Reaction of Imidazoles with Cyanogen Bromide
161
Crystal Structure of 1-Cyano-2-methylimidazole
Bromination or Cyanation? The Reaction Mechanism
Fig. 1 shows a representation of the molecule, while
Table 1 gives bond lengths and angles. The imidazole
ring is essentially planar, with the mean deviation of the
ring atoms from the plane de�ned by N(1)–C(2)–N(3)–
The imidazoles in this study were found to undergo
one of two reactions with BrCN in acetonitrile solu-
tion, with the reactivity of the imidazoles apparently
dictated by the nature of the substituent at N 1. Imid-
azoles protonated at N 1 gave the N -cyano derivatives
(Scheme 2), while N -alkylimidazoles having a hydrogen
at C 2 gave the 2-bromo derivatives (Scheme 3). Thus
reaction of N–H imidazoles with BrCN allows facile
synthesis of the novel N -cyanoimidazoles in a one-step
procedure and, while other syntheses involving ring
contraction of pyrazines and tetrazolopyrimidines, and
reaction of an �-cyaniminocarbene with acetonitrile,
�
C(4)–C(5) being 0�001 A. Cyanation of N 1 appears to
in�uence the bond lengths within the imidazole ring,
with the N(1)–C(2) and N(1)–C(5) bonds being most
a�ected. The N(1)–C(2) and N(1)–C(5) bond distances
�
of 1�3858(19) and 1�3908(19) A respectively are slightly
longer than the analogous distances in other structurally
17
characterized 1,2-disubstituted imidazoles, while the
�
N(1)–C(7) bond (1�3367(18) A) is very short for a
12
formal single bond. We believe that these observations
are indicative of �-electron donation from the imida-
zole ring to the cyano group, thus lengthening the
ring bonds adjacent to the N -cyano substituent and
resulting in signi�cant multiple-bond character for the
N(1)–C(7) bond. Similarly short N–C ‘single’ bonds
have also been observed in structurally characterized
have been reported, this should be considered the
method of choice for the preparation of such com-
pounds. The reaction of N -alkylimidazoles with BrCN
similarly allows a one-step synthesis of 2-bromo-N -
alkylimidazoles which hitherto have been prepared
by alkylation of 2-bromoimidazole (itself prepared by
20
a multistep synthesis ) or by lithiation of the N -
18
21
N -cyanoindole derivatives.
-Cyano-2-methylimidazole crystallizes as layers of
alkylimidazole followed by treatment with Br2
or
5
1
1,2-dibromoethane. Bromination at C 2 does not occur
on treatment of 1,2-dimethylimidazole with BrCN as
such a reaction would necessarily involve loss of the
methyl group at C 2. We believe that some con-
jugated ring-opened product may have formed, as
evidenced by the deeply coloured products. Such
ring-opening reactions are well known for pyridine and
in�nite two-dimensional sheets, with the individual
molecules within these sheets held in close proximity
by extensive hydrogen bonding interactions. Fig. 2
shows the hydrogen bonds which occur between H(5)
�
�
and N(8) (2�542 A) and H(4) and N(3) (2�527 A)
of adjacent molecules in these sheets. The methyl
group is not involved in any hydrogen bonding. The
22
its derivatives.
�
intersheet distance of approximately 3�35 A suggests
that there may be �-type interactions between the
sheets, and this is further supported by the observation
that individual molecules in adjacent sheets do not
lie directly above one another, but are instead o�set
�
by approximately 1�5 A with respect to one another.
Such an o�set has been suggested to be indicative of
19
�
-stacking interactions.
Coordination of both imidazole (imH) and N -
3+
methylimidazole (N -Meim) to Co(NH3)5
markedly
changes their reactivity towards BrCN (Scheme 4).
While imidazole and N -methylimidazole gave N -
cyanoimidazole and 2-bromo-N -methylimidazolerespec-
tively on treatment with BrCN, the corresponding
complexes[Co(NH3)5(imH)] (ClO4)3 and [Co(NH3)5(N -
Meim)] (ClO4)3 were unreactive towards BrCN. In these
complexes, the imidazole ligands are bound to the
metal ion via the lone pair on N 3, thus removing the
ability of this lone pair to act as a nucleophile. How-
Fig. 2. Hydrogen-bonding interactions between adjacent 1-
cyano-2-methylimidazole molecules. N(8)–H(5) 2�542 �A , N(3)–
H(4) 2�527 �A .

1
62
P. B. W. McCallum et al.
being determined by the nature of the substituent on
N 1. We are currently investigating the reactivity of
+
N -cyanoimidazoles as CN transfer agents.
Experimental
All reagents were L.R. or A.R. grade. Cyanogen bromide
1
13
(
5�0 M in acetonitrile, Aldrich) was used as received. H and
C
n.m.r. spectra were recorded on a Varian VXR 300 spectrometer
or a Gemini 200 spectrometer in CDCl3 or D2O at 25 C.
�
Chemical shifts (�) are reported in ppm using tetramethyl-
1
13
silane ( H, 0�00 ppm) and CDCl3 ( C, 77�08 ppm) or sodium
1
3
1
-(trimethylsilyl)(2,2,3,3-D4)propionate ( H, 0�00 ppm) and
13
,4-dioxan ( C, 67�8 ppm) as internal reference standards for
3+
ever, deprotonation of [Co(NH3)5(imH)] at N 1 gave
solutions prepared in CDCl3 or D2O respectively. Microanalyses
were performed by the Campbell Microanalytical Laboratory,
University of Otago.
2+
the conjugate base [Co(NH3)5(im)] , which reacted
with BrCN to give the 2-bromo product [Co(NH3)5(2-
BrimH)](ClO4)3. These observations suggest that the
presence of a lone pair on an imidazole ring nitrogen
is essential for any reaction to occur and plays a vital
role in the reaction mechanism. Scheme 5 gives a
possible mechanism for the reaction which explains
both the fact that the substituent on N 1 determines
the product, and that a nitrogen lone pair is required
for reaction to occur. The initial step is nucleophilic
attack of the imidazole on the carbon atom of BrCN,
via the nitrogen lone pair, to form an imidazolium
cation which then undergoes bromination at C 2. The
di�erence in products comes about as a consequence of
the di�erent mechanisms of rearomatization available
to the N–H and N–R species. Imidazoles having an
ionizable N–H proton can rearomatize by loss of HBr
to give the N -cyano product. Such a pathway is not
available to either the N -alkylated and N -metallated
imidazoles, and these must rearomatize by loss of HCN
to give the 2-bromo products.
Table 2. Atomic coordinates and equivalent isotropic displace-
ment parameters for 2-methylimidazole-1-carbonitrile (1-cyano-
2-methylimidazole)
U eq is de�ned as one-third of the trace of the orthogonalized
U ij tensor
4
4
4
3
2
Atom
10 x
10 y
10 z
10 U eq (A )
�
N(1)
C(6)
C(2)
N(3)
C(4)
N(8)
C(5)
C(7)
2059(1)
2996(2)
3096(1)
4085(1)
3711(1)
� 98(1)
2472(1)
890(1)
2620(2)
5856(2)
3794(2)
2802(2)
938(2)
3596(2)
777(2)
3142(2)
4720(2)
5369(2)
5509(2)
6350(2)
6114(2)
2817(2)
5122(2)
3698(2)
17(1)
22(1)
17(1)
18(1)
18(1)
31(1)
18(1)
20(1)
X-Ray Structure of 2-Methylimidazole-1-carbonitrile
X-Ray structural data for 2-methylimidazole-1-carbonitrile
�
were collected at � 143(2) C on a Seimens P4 di�ractometer
with graphite-monochromatized Mo K� radiation (0�71073
�
A).
The crystal (0�50 by 0�30 by 0�24 mm) of 2-methylimidazole-1-
carbonitrile used for data collection was obtained from vacuum
sublimation of impure material (0�5 mmHg, room temperature)
onto a cold �nger. Data were processed and empirical absorp-
tion corrections (� -scans) applied using programs from the
23
SHELXTL package. The unit cell dimensions and orientation
matrices were obtained from 24 accurately centred re�ections.
Systematic absences were consistent with the monoclinic space
group P 21/c and this was con�rmed by subsequent solution
and re�nement of the structure. The structure was solved by
24
direct methods with the TREF option in SHELXS-97 with the
resulting Fourier map revealing the location of all non-hydrogen
2
atoms. Weighted full-matrix re�nement on F was carried out
25
using SHELXL-97 with all non-hydrogen atoms being re�ned
with anisotropic displacement parameters. Hydrogen atoms
were included in calculated positions and re�ned as riding atoms
with individual (or group if appropriate) isotropic displacement
parameters. Final residuals were R1 0�0444 and wR2 0�1193 for
1
0
183 re�ections with Fo > 4F(Fo), and R1 0�0536 and wR2
�1259 for all 1278 data, where R1 = �||Fo| � |Fc||/�|Fo|
2
2
2
2
2
1/2
and wR2 = [�{(wFo � Fc ) }/�{w(Fo ) }]
with w =
2
2
2
2
2
1
/[� (Fo )+(0�0651P) +0�3348P] and P = (Fo +2Fc )/3.
The goodness of �t was 1�038. A �nal di�erence-Fourier map
�
3
� 3
showed the highest peak to be 0�329 e �A (hole � 0�338 e �A ).
In conclusion, we have shown that BrCN is an
e�ective reagent for the one-pot synthesis of other-
wise di� cult-to-prepare 2-bromoimidazoles, while it
can also be used with similar ease to prepare the rare
N -cyanoimidazoles, with the course of the reaction
Further details of the crystals, data collection and structure
re�nement are as follows: empirical formula C5H5N3; for-
mula weight 107�12; unit cell dimensions a 10�201(5), b
�
7
�110(3), c 7�227(3) A, � 90, � 100�47(2), � 90 ; volume
�
3
� 3
515�4(4)
�
; Z 4; calculated density 1�380 g cm ; absorption

Reaction of Imidazoles with Cyanogen Bromide
163
�
1
coe� cient 0�093 mm ; F(000) 224; � range for data col-
and the mixture was stirred at room temperature overnight.
The yellow solution was reduced to dryness, the residue was
dissolved in water (20 ml) and the resulting solution was made
basic by addition of solid sodium carbonate. This was extracted
with CHCl3 (4� 20 ml), the combined extracts were dried over
MgSO4, �ltered and reduced to dryness. The crude product
�
lection 2�03–27�50 ; index ranges � 13 < h < 13, � 9 < k < 0,
0
1
< l < 9; re�ections collected 1278; independent re�ections
183 (Rint = 0�0164); data/restraints/parameters 1183/0/75;
extinction coe� cient 0�052(9). Atomic coordinates are given in
Table 2 and bond lengths and angles are given in Table 1. An
Accessory Publication (anisotropic displacement parameters,
hydrogen atom parameters and a list of structure factors) is
available, until 31 December 2004, from the Australian Journal
of Chemistry, P.O. Box 1139, Collingwood, Vic. 3066.
�
was distilled (Kugelrohr, 65 C/0�3 mmHg) to give the pure
product as a colourless oil which slowly solidi�ed on standing
�
6
�
(0�54 g, 29%), m.p. 52 C (lit. 51–52 C). The product could
also be puri�ed by column chromatography on neutral alumina
with CHCl3 as eluent (Found: C, 34�5; H, 4�1; Br, 45�4;
N, 16�0. Calc. for C5H7BrN2: C, 34�3; H, 4�0; Br, 45�7;
Syntheses
1
N, 16�0%). H n.m.r. (CDCl3): � 6�67, s, 1H; 3�55, s, 3H;
Caution
1
3
2
1
�17, s, 3H. C n.m.r. (CDCl3): � 121�4, 119�5, 118�5, 34�3,
3�7. N.O.e. enhancement of both 3�55 and 2�17 when 6�67
Cyanogen bromide is highly toxic. All work with BrCN was
carried out in an e� cient fume hood. Removal of solvent from
these reaction mixtures was carried out so that all vapours
passed through an aqueous base trap to destroy any excess
BrCN.
irradiated, no enhancement of 2�17 by irradiation at 3�55.
HETCOR: 6�67–119�5; 3�54–34�3; 2�17–13�7.
All reactions were carried out in the absence of light, as
some 1-cyanoimidazoles were found to be photosensitive.
2-Bromo-1,5-dimethylimidazole
To a solution of 1,5-dimethylimidazole (0�87 g) in aceto-
nitrile (40 ml) was added BrCN in acetonitrile (5 M, 2 ml)
and the mixture was stirred at room temperature overnight.
The yellow solution was reduced to dryness, the residue was
dissolved in water (20 ml) and the resulting solution made basic
by addition of solid sodium carbonate. This was extracted
with CHCl3 (4� 20 ml), the combined extracts were dried over
4
Imidazole-1-carbonitrile
To a solution of imidazole (0�68 g) dissolved in acetonitrile
(
30 ml) was added BrCN in acetonitrile (5 M, 2 ml) and the
solution was stirred at room temperature for 3 h. Removal of
solvent under vacuum gave a dark yellow solid. The solid was
extracted with 3� 50 ml aliquots of chloroform and the extracts
were concentrated under vacuum to yield white needle-like
crystals (0�33 g, 35%). The product decomposed on exposure
MgSO , �ltered and reduced to dryness. The crude product
�
was distilled (Kugelrohr, 78 C/0�2 mmHg) to give the pure
product as a colourless oil which slowly solidi�ed on standing
�
7
�
1
�
to light. M.p. 60 C (lit. 59�5–60�5 C). H n.m.r. (CDCl3):
(0�42 g, 27%), m.p. 46–47 C. The product could also be puri�ed
�
7�98, br s, W
2�8 Hz, 1H; 7�33, t, J 1�4 Hz, 1H; 7�18,
by column chromatography on neutral alumina with CHCl as
h/2
3
3
1
d, J 1 Hz, 1H. C n.m.r. (CDCl3): � 138�9, 129�8, 119�8,
eluent (Found: C, 34�7; H, 4�0; Br, 45�9; N, 16�0. C5H7BrN2
�
1
1
1
04�4. �C� N (Nujol) 2259 cm
-Methylimidazole-1-carbonitrile
.
requires C, 34�3; H, 4�0; Br, 45�7; N, 16�0%). H n.m.r.
(
CDCl3): � 6�74, d, J 1 Hz, 1H; 3�48, s, 3H; 2�21, d, J 1 Hz,
13
2
3H. C n.m.r. (CDCl ): � 130�4, 126�9, 118�6, 31�7, 10�4.
3
To a solution of 2-methylimidazole (0�82 g) dissolved in
acetonitrile (40 ml) was added BrCN in acetonitrile (5 M, 2 ml)
and the solution was stirred at room temperature overnight.
Removal of solvent under vacuum gave a dark yellow oil that
solidi�ed on standing. The solid was dissolved in chloroform
and the solution loaded onto an alumina column. The product
was eluted with chloroform and the eluate was concentrated to
give a light yellow solid which was puri�ed by vacuum sublima-
tion (0�5 mmHg, room temperature) onto a water-cooled cold
2
-Bromo-1-ethylimidazole
To a solution of 1-ethylimidazole (0�92 g) in acetonitrile
(
30 ml) was added BrCN in acetonitrile (5 M, 2 ml) and the
solution was stirred at room temperature for 3 days. Distilled
water (40 ml) was then added and the solution was concentrated
under vacuum to half its original volume. The aqueous solution
was extracted with chloroform (3� 30 ml) and concentration
of the combined extracts under vacuum gave the product as
a colourless oil (0�57 g, 34%) (Found: C, 34�0; H, 4�2; Br,
�
nger. Large clear cubic crystals suitable for X-ray structural
�
analysis were formed (0�28 g, 26%) over 2–3 h, m.p. 60–62 C
4
5�9; N, 15�6. C5H7BrN2 requires C, 34�3; H, 4�0; Br, 45�7;
(
Found: C, 56�1; H, 4�6; N, 39�2. C5H5N3 requires C, 56�1;
1
1
N, 16�0%). H n.m.r. (CDCl ): � 6�93, s, 2H; 3�90, q, J
3
H, 4�7; N, 39�2%). H n.m.r. (CDCl3): � 7�17, d, J 1�7 Hz,
13
13
7�2 Hz, 2H; 1�32, t, J 7�2 Hz, 3H. C n.m.r. (CDCl ): �
3
1
�
H; 6�97, d, J 1�7 Hz, 1H; 2�61, s, 3H. C n.m.r. (CDCl3):
149�0, 129�7, 119�6, 105�1, 13�3. �C� N (Nujol) 2256 cm�
1
.
129�7, 121�1, 118�7, 42�6, 15�5.
2
-Bromo-1-methylimidazole
1
-Benzyl-2-bromoimidazole
To a solution of 1-methylimidazole (0�82 g) dissolved in
To a solution of 1-benzylimidazole (1�59 g) in acetonitrile
acetonitrile (40 ml) was added BrCN in acetonitrile (5 M, 2 ml)
and the solution was stirred at room temperature for 3 h.
Distilled water (60 ml) was then added, and the solution was
concentrated under vacuum to about half the original volume
and then extracted with 3� 20 ml aliquots of chloroform. The
combined extracts were dried over MgSO4 and concentrated
under vacuum to give the product as a pale yellow oil (1�03 g,
(
30 ml) was added BrCN in acetonitrile (5 M, 2 ml) and the
solution was stirred at room temperature for 2 days. The solvent
was removed under reduced pressure, the residue suspended
in water (20 ml) and the suspension made basic by addition
of solid sodium carbonate. This was extracted with CHCl3
(
4� 20 ml), the combined extracts were dried over MgSO4
and reduced to dryness. The crude material was distilled
6
4%) (Found: C, 29�8; H, 2�9; Br, 49�5; N, 17�1. C4H5BrN2
�
(
Kugelrohr, 170 C/0�3 mmHg) to give a colourless oil which
1
requires C, 29�8; H, 3�1; Br, 49�6; N, 17�4%). H n.m.r.
was further puri�ed by column chromatography on neutral
13
(
(
CDCl3): � 6�98, s, 1H; 6�96, s, 1H; 3�61, s, 3H. C n.m.r.
CDCl3): � 129�6, 123�0, 120�0, 34�5.
alumina with CHCl3 as eluent (0�94 g, 39%) (Found: C, 50�7;
H, 3�8; Br, 33�7; N, 11�6. C10H9BrN2 requires C, 50�7; H,
1
3
�8; Br, 33�7; N, 11�8%). H n.m.r. (CDCl3): � 7�36–7�31,
2
-Bromo-1,4-dimethylimidazole
m, 3H; 7�18–7�12, m, 2H; 7�04, s, 1H; 6�95, s, 1H; 5�11, s,
1
3
To a solution of 1,4-dimethylimidazole (1�02 g) in aceto-
2H. C n.m.r. (CDCl ): � 130�2, 129�6, 129�5, 129�0, 128�3,
3
nitrile (40 ml) was added BrCN in acetonitrile (5 M, 2 ml)
127�3, 122�2, 51�3.

1
64
P. B. W. McCallum et al.
2
-Bromo-1-butylimidazole
References
1
To a solution of 1-butylimidazole (1�32 g) in acetonitrile
Balaban, I. E., and Pyman, F. L., J. Chem. Soc., 1922,
(
30 ml) was added BrCN in acetonitrile (5 M, 3 ml) and the
1
1
21, 947; Light, L., and Pyman, F. L., J. Chem. Soc.,
922, 121, 2626; Pyman, F. L., and Timmis, G., J. Chem.
solution was stirred at room temperature overnight. To the
solution was added distilled water (40 ml) and the resulting
solution was evaporated under vacuum to half its original
volume. The aqueous solution was extracted with chloroform
Soc., 1923, 123, 494; Balaban, I. E., and Pyman, F. L., J.
Chem. Soc., 1924, 125, 1564; Linda, P., Tetrahedron, 1969,
2
5, 3297; Stensi �o , K. E., Wahlberg, K., and Wahren, R.,
(
3� 30 ml) and the combined extracts were concentrated to give
Acta Chem. Scand., 1973, 27, 2179.
Boulton, B. E., and Coller, B. A. W., Aust. J. Chem.,
2
3
4
5
the product as a yellow oil (0�51 g, 24%) (Found: C, 41�5; H,
5
�3; Br, 39�5; N, 13�8. C7H11BrN2 requires C, 41�4; H, 5�4;
1
974, 27, 2331.
King, H., and Murch, W. O., J. Chem. Soc., 1923, 123,
21.
Grimmett, M. R., ‘Imidazole and Benzimidazole Synthesis’
Academic: San Diego 1997).
Miller, R. D., Lee, V. Y., and Moylan, C. R., Chem. Mater.,
994, 6, 1023.
1
Br, 39�3; N, 13�8%). H n.m.r. (CDCl3): � 6�99, d, J 1�4 Hz,
1
7
H; 6�97, d, J 1�4 Hz, 1H; 3�91, t, J 7�2 Hz, 2H; 1�74, quin, J
13
6
�2 Hz, 2H; 1�34, sext, J 7�2 Hz, 2H; 0�94, t, J 7�2 Hz, 3H.
C
n.m.r. (CDCl3): � 129�7, 121�7, 119�2, 47�4, 32�3, 19�5, 13�5.
(
[
Co(NH3)5(2-BrimH)] Br3.1�5H2O
1
6
7
8
26
Langenbeck, W., J. Prakt. Chem., 1928, 119, 77.
Giesemann, H., J. Prakt. Chem., 1955 1, 345.
Purygin, P. P., and Pan’kov, S. V., Zh. Org. Khim., 1995,
To a solution of [Co(NH3)5(im)] (ClO4)2
(1�89 g) in ace-
tonitrile was added BrCN in acetonitrile (5 M, 1 ml) and the
solution was stirred at room temperature for 3 days. The
solution was �ltered to remove an orange precipitate and the
3
3
1, 934 (English translation: Russ. J. Org. Chem., 1995,
1, 865).
�
ltrate was evaporated to dryness. The resulting solid was
9
0
1
2
Katritzky, A. R., Brzezinski, J. Z., and Lam, J. N., Rev.
Roum. Chim., 1991, 36, 573.
Luebke, K. J., and Dervan, P. B., Nucleic Acids Res., 1992,
dissolved in water and sorbed onto Dowex 50W� 2 cation
exchange resin. This was washed with water and 1 M HCl,
and elution with 2 M HCl produced two bands. The �rst
band contained starting material while the second contained
the brominated product. The eluate containing the second
band was evaporated to dryness and the solid was twice
recrystallized (0�62 g, 24%) from hot water by adding LiBr
and cooling in ice (Found: C, 6�5; H, 3�3; Br, 57�6; N, 17�5.
C3H18Br4CoN7.1�5H2O requires C, 6�5; H, 3�8; Br, 57�3; N,
1
1
1
2
0, 3005; J. Am. Chem. Soc., 1991, 113, 7447.
Hughes, T. V., Hammond, S. D., and Cava, M. P., J. Org.
Chem., 1998, 63, 401.
Watanabe, T., Ueda, I., Hayakawa, N., Kondo, Y., Adachi,
H., Iwasaki, A., Kawamata, S., Mentori, F., Ichikawa, M.,
Yuasa, K., and Ohta, A., J. Heterocycl. Chem., 1990, 27,
1
13
7
11; Watanabe, T., Nishiyama, J., Hirate, R., Uehara, K.,
1
7�6%). H n.m.r. (D2O): � 7�44, d, 1H; 6�96, d, 1H.
C
Inoue, M., Matsumoto, K., and Ohta, A., J. Heterocycl.
Chem., 1983, 20, 1277; Danion, D., Arnold, B., and Regitz,
M., Angew. Chem., Int. Ed. Engl. 1981, 20, 113; Ohta, A.,
Watanabe, T., Nishiyama, J., Uehara, K., and Hirate, R.,
Heterocycles, 1980, 14, 1963; Wentrup, C., and Th �e taz, C.,
Helv. Chim. Acta, 1976, 59, 256.
Ferris, J. P., Huang, C. H., and Hagan, W. A., Nucleosides
Nucleotides, 1989, 8, 407.
Kanaya, E., and Yanagawa, H., Biochemistry, 1986, 25,
n.m.r. (D2O): � 131�3, 124�6, 123�2.
Reaction of 4-Methylimidazole with BrCN
To a solution of 4-methylimidazole (0�82 g) dissolved in
acetonitrile (40 ml) was added BrCN in acetonitrile (5 M, 2 ml)
and the solution was stirred at room temperature for 3 h.
The yellow solution was concentrated to a yellow oil which by
H n.m.r. appeared to be a mixture of two compounds. All
attempts to isolate the pure products were unsuccessful.
13
14
1
7
423.
1
1
5
6
Whitten, J. P., McCarthy, J. R., and Matthews, D. P.,
Synthesis, 1988, 6, 470.
Reaction of 1,2-Dimethylimidazole with BrCN
To a solution of 1,2-dimethylimidazole (0�82 g) in aceto-
nitrile (30 ml) was added BrCN in acetonitrile (5 M, 2 ml). A
rapid colour change to deep orange was observed, and stirring
was continued for 1 h. All attempts to isolate pure products
from the reaction mixture were unsuccessful.
Blackman, A. G., Buckingham, D. A., Clark, C. R., and
Kulkarni, S., Aust. J. Chem., 1986, 39, 1465; Blackman,
A. G., Buckingham, D. A., and Clark, C. R., Aust. J.
Chem., 1991, 44, 981; Blackman, A. G., Buckingham, D.
A., and Clark, C. R., J. Am. Chem. Soc., 1991, 113, 2656;
Blackman, A. G., Buckingham, D. A., Clark, C. R., and
Simpson, J., Inorg. Chem., 1991, 30, 1635; J. Chem. Soc.,
Dalton Trans., 1991, 3031.
Olszak, T. A., Peeters, O. M., Blaton, N. M., and De
Ranter, C. J., Acta Crystallogr., Sect. C, 1994, 50, 761; De
Bondt, H. L., Blaton, N. M., Peeters, O. M., and De Ranter,
C. J., Acta Crystallogr., Sect. C, 1991, 47, 2697; Hallows,
W. A., Carpenter, G. B., Pevear, K. A., and Sweigart,
D. A., J. Heterocycl. Chem., 1994, 31, 899; Ishihara, M.,
Tonogaki, M., Ohba, S., Saito, Y., Okazaki, M., Katoh,
T., and Kamiyama, K., Acta Crystallogr., Sect. C, 1992,
Attempted Reaction of [Co(NH3)5(imH)] (ClO4)3 with BrCN
1
6
To a solution of [Co(NH3)5(imH)] (ClO4)3
(1�25 g) in
17
acetonitrile was added BrCN in acetonitrile (5 M, 1 ml) and the
solution was stirred at room temperature overnight. Following
removal of solvent, i.r. and n.m.r. spectra of the solid material
were identical to those of starting material.
Attempted Reaction of [Co(NH3)5(1-Meim)] (ClO4)3 with BrCN
16
To a solution of [Co(NH3)5(1-Meim)] (ClO4)3
in ace-
tonitrile was added BrCN in acetonitrile (5 M, 2 ml) and the
solution was stirred for 3 days at room temperature. N.m.r.
spectroscopy of the solid following removal of solvent showed
the presence of starting material only.
4
1
8, 184; Kowalski, A., Acta Crystallogr., Sect. C, 1995, 51,
670; 1996, 52, 1784; Jones, R. H., Lothian, A. P., and
Ramsden, C. A., Acta Crystallogr., Sect. C, 1996, 52, 982.
Weeratunga, G., Prasad, G. K. B., Dilley, J., Taylor, N.
J., and Dmitrienko, G. I., Tetrahedron Lett., 1990, 31,
18
Acknowledgments
5
713; Furusaki, A., Matsui, M., Watanabe, T., Omura, S.,
Nakagawa, A., and Hata, T., Isr. J. Chem., 1972, 10, 173;
Mithani, S., Weeratunga, G., Taylor, N. J., and Dimitrienko,
G. I., J. Am. Chem. Soc., 1994, 116, 2209.
Hunter, C. A., and Sanders, J. K. M., J. Am. Chem. Soc.,
1990, 112, 5525.
We thank Professor W. T. Robinson (University of
Canterbury) for X-ray data collection. This work was
supported by a grant from the Division of Sciences,
University of Otago.
19

Reaction of Imidazoles with Cyanogen Bromide
165
2
2
0
1
24
25
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2
2
2
3
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26
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