Tetrahalogenomethanes: Simple reagents for the synthesis of monohalogenated and mixed dihalogenated aromatic heterocycles via metal-halogen exchange from lithium compounds

Article abstract of DOI:10.1016/S0022-328X(00)00068-1

Tetrabromo- or tetrachloromethane and 2-lithio derivatives of aromatic heterocycles rapidly produce the corresponding 2-bromo or 2-chloro derivatives in high yields through a metal-halogen exchange mechanism. This kind of reaction was also used to obtain, in good yields, 5-bromo-2-chlorothiazole and 5-bromo-2-chloro-N-methylimidazole.

Full text of DOI:10.1016/S0022-328X(00)00068-1

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Journal of Organometallic Chemistry 601 (2000) 233–236
Tetrahalogenomethanes: simple reagents for the synthesis of
monohalogenated and mixed dihalogenated aromatic heterocycles
via metal–halogen exchange from lithium compounds
Carla Boga * , Erminia Del Vecchio, Luciano Forlani, Paolo Edgardo Todesco
Dipartimento di Chimica Organica ‘A. Mangini’, 6ia le Risorgimento, I-40136 Bologna, Italy
Received 20 December 1999; accepted 24 January 2000
Abstract
Tetrabromo- or tetrachloromethane and 2-lithio derivatives of aromatic heterocycles rapidly produce the corresponding
2-bromo or 2-chloro derivatives in high yields through a metal–halogen exchange mechanism. This kind of reaction was also used
to obtain, in good yields, 5-bromo-2-chlorothiazole and 5-bromo-2-chloro-N-methylimidazole. © 2000 Elsevier Science S.A. All
rights reserved.
Keywords: Halogenation; Tetrabromomethane; Tetrachloromethane; Lithium compounds; Aromatic heterocycles; Metal–halogen exchange
1. Introduction
rial [2b]. The direct halogenation of thiazole and N-
alkyl imidazoles affords mixtures of mono-, di- or
trihalogenated derivatives [3], and benzothiazole is
brominated in the 2-position only under drastic reac-
tion conditions. In addition, these methods are not
suitable for the preparation of mixed polyhalo deriva-
tives and only a few syntheses of mixed dihaloderiva-
tives of thiazole [4] and imidazole [5] have been
reported so far. An alternative route is the regioselec-
tive metallation of the heterocycle, followed by treat-
ment with different halogen sources [1,6]; in this context
we recently found [7] that 2-chloro derivatives of thi-
azole, N-methylimidazole and their benzo analogues
can be easily obtained, in good yield, via metal–halo-
gen exchange reaction between 2-lithio precursors and
trichloroacetyl compounds.
Haloderivatives of thiazole, imidazole and their ben-
zocondensates are of wide importance in organic chem-
istry as intermediates in the synthesis of many
compounds, most of them of biological interest.
Classical methods to obtain aromatic haloderivatives
[1], such as the Sandmeyer reaction or direct halogena-
tion, often require tedious or drastic conditions, even if
the Sandmeyer reaction on 2-aminothiazoles remains
the preferred route to obtain the corresponding 2-halo
derivatives (with yield depending on the substituents on
the ring [2a]) because of the inexpensive starting mate-
These findings prompted us to perform this reaction
using tetrahalogenomethanes, the reactivity of which
with magnesium or lithium compounds has been exten-
sively studied [8], but scarcely used for the present
synthetic purpose [9].
Scheme 1.
Now we report results showing that tetra-
halogenomethanes are useful ‘positive halogen ion’
donors for performing a simple, efficient and regiospe-
cific halogenation of heterocycles.
* Corresponding author. Tel.: +39-051-2093616; fax: +39-051-
2093654.
E-mail address: boga@ms.fci.unibo.it (C. Boga)
0022-328X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0022-328X(00)00068-1

234
C. Boga et al. / Journal of Organometallic Chemistry 601 (2000) 233–236
Table 1
methylbenzimidazole and dibromocarbene, which arises
from lithio-tribromomethane, according to Scheme 2.
When bromotrichloromethane was used, a mixture of
both bromo- and chloro-derivatives was obtained, in
which the brominated product predominated (5:1).
The results obtained above prompted us to use this
simple and direct halogenation method to synthesize
mixed dihaloderivatives of thiazole and N-methylimid-
azole, the syntheses of which have been reported in few
cases.
Reactions between 2-lithio derivatives of heterocycles 1a–4a and
tetrahalogeno methanes a
Entry
HetH
CX4
Reaction time
(min)
Product
(yield %)
1
2
3
4
5
1a
1a
2a
2a
2a
CBr4
CCl4
CBr4
CCl4
15
30
15
15
30
1b (80) b
1c (90) b
2b (80) c, (75) d
2c (90) b
CBrCl3
2b (35) d,e
2c(7) d,e
2-Chloro-5-bromothiazole (6) and 2-chloro-5-bromo-
N-methylimidazole (7) were obtained as depicted in
Scheme 3.
6
7
8
9
3a
3a
4a
4a
CBr4
CCl4
CBr4
CCl4
15
15
15
15
3b (80)c
3c (75) b
4b (65) b,f
4c (85) b, (76)d
Thiazole (1a) and N-methylimidazole (3a) were
metallated with n-butyl lithium at −70°C and then
treated with tetrachloromethane to give the correspond-
ing 2-chloro derivatives. A successive treatment with
n-butyl lithium, followed by addition of CBr4, gave the
mixed dihalogenoderivatives 6 and 7 in satisfactory
yields.
a Reactions carried out in anhydrous THF, at −70°C.
b Yield from GC–MS.
c Conversion calculated from 1H-NMR spectra.
d Yield from FC.
e 30% of 2a was recovered.
f 10% of 2-(dibromomethyl)-N-methylbenzimidazole (5) was also
recovered.
All the products were characterized by 1H-, 13C-
NMR and MS spectrometry. The structure of com-
1
pound 7 was ascertained by H–1H NOE experiments.
In conclusion, chlorination and bromination of aro-
matic azaheterocycles can be easily performed via
metal–halogen exchange between lithio precursors and
tetrahalogenomethanes. This can be considered as a
simple and efficient alternative to classical methods
for obtaining chloro and bromo heterocycles
regioselectively.
Scheme 2.
3. Experimental
3.1. General
1H, 1H–1H NOE and 13C-NMR spectra were
recorded on a Varian Gemini spectrometer at 300 and
75.46 MHz, respectively, in CDCl3 (l=7.27 ppm for
1H-NMR and 77.20 ppm for 13C-NMR). J values are
given in Hz. IR spectra were recorded on a Perkin–
Elmer spectrophotometer model 1600 FTIR. MS spec-
tra were recorded at an ionization voltage of 70 eV on
a VG 7070 E spectrometer. GC–MS analyses were
performed on a HP-5890 gas chromatograph equipped
with a methyl silicone capillary column and an HP-
5970 mass detector. Chromatographic purifications
were carried out on columns packed with silica gel
Kieselgel (Merck, 230–400 mesh) at medium pressure.
Thin-layer chromatography was performed on Merck
Kieselgel 60 F254. Melting points were measured with a
Bu¨chi apparatus and are uncorrected. THF was dis-
tilled from sodium benzophenone ketyl. All of the
reagents were commercial samples (Aldrich). All the
reactions were performed in a flame-dried apparatus
under a static atmosphere of dry nitrogen. 2-Lithio
derivatives of compounds 1a–4a were prepared as in
Scheme 3.
2. Results and discussion
The reaction between the 2-lithio derivative of thi-
azole (1a), benzothiazole (2a), N-methylimidazole (3a)
and N-methylbenzimidazole (4a) and an equimolar
amount of tetrabromomethane or tetrachloromethane
(Scheme 1) was performed in THF at −70°C to give,
in a few minutes, the corresponding haloderivative in
good yield (Table 1).
The reported results show that the metal–halogen
exchange occurs immediately, giving the chlorinated
and the brominated products in good yields. In the case
of the reaction between 2-lithio-N-methylbenzimidazole
and tetrabromomethane, we also isolated 10% of 2-(di-
bromomethyl)-N-methylbenzimidazole (5), probably
deriving from a side reaction between 2-lithio-N-

C. Boga et al. / Journal of Organometallic Chemistry 601 (2000) 233–236
235
Ref. [3]. The characteristics of compounds 1b, 1c, 2c,
3c, 4c are in agreement with literature data [7,10].
slowly added. After further 30 min, CBr4 (0.48 g, 1.48
mmol), dissolved in THF (2 ml), was added. The reac-
tion was monitored by TLC (eluant: 7:3 petroleum
light–diethyl ether) and GC–MS analyses, then it was
quenched with aqueous saturated solution of NH4Cl,
diluted with diethyl ether, and dried over anhydrous
Na2SO4. After filtration, evaporation of the solvent at
reduced pressure and FC (eluant: 7.5:2.5 light
petroleum–diethyl ether) of the residue, pure 6 (0.08 g,
27%) was obtained.
3.2. Reactions between 2-lithio heterocycles and
tetrahalogenomethanes: typical procedure
To a solution containing 2.5 mmol of 2-lithio-N-
methyl benzimidazole in 5 ml of THF, cooled at
−70°C, CCl4 (0.24 ml, 2.5 mmol) (diluted in 5 ml of
THF) was added. The solution turned immediately
dark and after 15 min, TLC (eluant: 7:3 light
petroleum–diethyl ether) and GC–MS analyses showed
85% conversion. After 15 min, the reaction was
quenched with a saturated aqueous solution of NH4Cl
(2 ml), diluted with diethyl ether and dried over anhy-
drous MgSO4. After filtration, the solvent was removed
at reduced pressure. FC (eluant: dichloromethane) of
the residue gave 0.315 g (76%) of 4c.
1H-NMR (CDCl3):
l
7.51 (s, 1H). 13C-NMR
(CDCl3): l 145.4, 142.8, 109.3. MS (m/e): 201 [M+],
199, 197, 120, 118.
3.3.6. 5-Bromo-2-chloro-N-methylimidazole (7)
compound 7 was obtained in 63% yield from 3c
following the procedure above described for the prepa-
ration of 6.
M.p. 92–94°C. 1H-NMR (CDCl3): l 6.92 (s, 1H),
3.59 (s, 3H, CH3). 13C-NMR (CDCl3): l 131.9, 128.1,
103.7, 32.2. MS (m/e): 198 [M+], 196, 194, 117, 115, 80.
3.3. Physical constants of compounds synthesized
3.3.1. 2-Bromobenzothiazole (2b)
M.p. 39–41°C (lit. [11]: 39.5–40°C). 1H-NMR
(CDCl3): l 7.98 (dd, 1H, J=7.5, J=1.5 Hz, 4-H or
7-H), 7.79 (dd, 1H, J=7.8, J=1.8 Hz, 4-H or 7-H),
7.50–7.35 (m, 2H, 5-H and 6-H). 13C-NMR (CDCl3): l
152.5, 139.0, 137.5, 126.8, 126.0, 123.0, 121.0. MS
(m/e): 215, 213, 134.
Acknowledgements
Investigation supported by University of Bologna
(funds for selected research topics AA. 1997–99), Min-
istero dell’Universita` e della Ricerca Scientifica e Tec-
nologica (MURST, Roma), Consiglio Nazionale delle
Ricerche (CNR, Roma).
3.3.2. 2-Bromo-N-methylimidazole (3b)
1H-NMR (CDCl3): l 6.85 (d, 1H, J=2.1 Hz), 6.72
(d, 1H, J=2.1 Hz), 3.40 (s, 3H, CH3). 13C-NMR
(CDCl3): l 129.0, 122.8, 119.4, 34.2.
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(m, 3H, aromatics), 3.75 (s, 3H, NCH3). 13C-NMR
(CDCl3): l 142.9, 136.0, 130.4, 123.2, 122.6, 119.2,
109.3, 31.7. MS (m/e): 212 [M++2], 210 [M+], 129,
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