Convenient multi-gram scale synthesis of polybrominated imidazoles building blocks

Article abstract of DOI:10.1016/j.tetlet.2006.01.066

The multi-gram scale polybromination of variously substituted imidazoles has been realized using a stoichiometric amount of the Br₂-DMF complex. Good yields have been obtained compared to other methods using large amounts of acetic acid-sodium acetate buffer.

Full text of DOI:10.1016/j.tetlet.2006.01.066

Tetrahedron Letters 47 (2006) 1949–1951
Convenient multi-gram scale synthesis of polybrominated
imidazoles building blocks
a,
a
b
b,
*
*
Mebarek Bahnous, Chabane Mouats, Yves Fort and Philippe C. Gros
a
Laboratoire de Chimie Mol e´ culaire, du Contr oˆ le de l’Environnement et des Mesures Physico-Chimiques,
Universit e´ Mentouri de Constantine, Campus Chabaat-Ersas, 25000 Constantine, Algeria
b
Synth e` se Organom e´ tallique et R e´ activit e´ , UMR CNRS-UHP 7565, Facult e´ des Sciences, Universit e´ Henri Poincar e´ ,
Boulevard des Aiguillettes, BP 239, 54506 Vandoeuvre-l e` s-Nancy, France
Received 6 December 2005; revised 12 January 2006; accepted 16 January 2006
Available online 30 January 2006
Abstract—The multi-gram scale polybromination of variously substituted imidazoles has been realized using a stoichiometric
amount of the Br –DMF complex. Good yields have been obtained compared to other methods using large amounts of acetic
2
acid–sodium acetate buffer.
Ó 2006 Elsevier Ltd. All rights reserved.
Br
FG3
The imidazole ring is a key unit for numerous important
biologically active naturally occurring or synthetic sub-
stances such as Girolline (A) or Carmethizole (B).
n-BuLi
N
N
1
2
Br
Br
FG2
FG1
N
R
N
R
Electrophiles
O
Scheme 1. Polyfunctionalization of bromoimidazoles.
Me
OH
H
N
N
O
O
NHCH
3
NH2
MeS
H N
Such side-reactions drew other authors to use basic
media for the neutralization of hydrogen bromide
formed along the reaction. Indeed using an acetic acid/
sodium acetate buffer, excellent yields have been
obtained. However, the amount of buffer is prohibi-
tive for large scale preparations. For example, the poly-
bromination of 0.2 mol of imidazole with 0.6 mol of
bromine consumed 250 g of sodium acetate in 2 L of
acetic acid.
2
Cl
N
NHCH3
N
O
A
B
8
,9
Imidazoles have also found applications as metal–car-
3
4
bene metathesis catalysts and ionic liquids. The most
efficient synthetic routes to polyfunctional compounds
involve halogen–metal exchanges on iodo- or bromoim-
5
idazoles. The reaction provided a wide range of substi-
tutions on every position of the ring as nicely reported
by Lipshutz and co-workers (Scheme 1).
6
So, the development of efficient methodologies using
low amounts of reagents remains an important subject
for research. Singh and co-workers have disclosed the
mono bromination of activated nitro-imidazoles using
Consequently, the polybromination of the imidazole
ring is of high synthetic interest and efforts have to be
made to develop this reaction. The pioneering works
1
0
a stoichiometric amount of the DMF–Br complex in
2
7
basic medium. From our knowledge, no polybromina-
tion in the unactivated imidazole series has been
described yet. Herein, we report the efficiency of the
by Pyman using bromine in refluxing chloroform only
led to poor yields. This was attributed to the formation
8
of the hydrobromide and subsequent degradations.
DMF–Br complex for the large scale preparation of
2
polybrominated imidazoles.
*
Corresponding authors. Tel.: +33 (0) 3 83 68 49 79; fax: +33 (0) 3 83
47 85 (P.C.G.); e-mail addresses: Bahnous2002@yahoo.fr;
68
The reaction was investigated with a range of variously
substituted imidazoles. The substrates were reacted with
Philippe.Gros@sor.uhp-nancy.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.066

1
950
M. Bahnous et al. / Tetrahedron Letters 47 (2006) 1949–1951
Br
1
/1 mixtures of DMF and Br in the presence of KHCO
Br
Br
2
3
1
1
N
N
N
(
Table 1). As shown, all polyhalogenated products
were obtained in acceptable to good yields. The
Br
Br Br
Me
Br
Ph
N
N
N
DMF–Br reagent led to the tribromo compounds 2a
H
H
H
2
and 2d in acceptable yields similar to those reported in
2
a
2b
2c
the literature with the acetate buffer.
(
CH ) SO (1.5 eq.)
3 2 4
The hydroxymethyl derivative 2f was obtained in poor
yield due to degradations and, in our hands, the acetic
acid/sodium acetate buffer gave a better outcome in this
case. The chloromethyl group in 1g was found more
compatible with the reaction medium leading to 2g in
fair yield. The best results were obtained with 2-substi-
tuted imidazoles 1b and especially 1c. This probably
resulted in an acidifying effect of the phenyl group
enhancing the proton abstraction. The introduction of
substituents on nitrogen led to lower yields probably
aq. NaOH (10%)
5
o
0
C
Br
Br
Br
N
N
N
Br
Br Br
Me
Br
Ph
N
N
N
Me
Me
Me
2
d, 74%
2e, 76%
2h, 78%
Scheme 2. N-Methylation of bromoimidazoles.
a
due to the enhancement of the basicity of this site lead-
ing to the formation of the hydrobromide. The bromina-
tions were performed with only stoichiometric amounts
Table 1. Polyhalogenation of imidazoles
H
Br
N
N
Br -DMF-KHCO
of the Br –DMF complex based on the number of pro-
2
2
3
H
FG2
Br
FG2
tons to be substituted. 1.5 Equiv instead of the normally
required 2 equiv of reagent was used for the dibromina-
tions. Higher amounts were found to be deleterious
leading to complex mixtures from which the target com-
pound was hardly separated.
N
N
0 oC then 100 C, 2-3h
o
FG1
FG1
1a-f
2a-f
b
Imidazole
Product
Yield%
Br
N
Then we examined an alternative way to synthesize the
N-substituted polybromo derivatives with the aim to
improve the yields. So, we investigated the incorpora-
tion of the methyl group on nitrogen after initial poly-
bromination of 1H-imidazoles. The N-methylation of
imidazoles have been reported with several reagents
such as dimethylsulfate in alcoholic solution of sodium
N
c
1
a
2a
64 (68)
N
H
Br
Br
Br
N
H
Br
N
N
1
1
1
b
2b
2c
2d
65 (62)
75 (76)
47 (51)
Me
N
H
13
Me
N
H
hydroxide or treatment with sodium hydride and
6
iodomethane. In our hands, reaction of 2a–c with di-
Br
Br
N
N
methylsulfate in aqueous NaOH gave the best results
N
N
14
c
(Scheme 2).
Ph
N
H
Br
Br
Ph
Br
N
H
The N-methyl derivatives were obtained in good yields
although overall yields based on starting imidazoles
1a–c were found to be similar to those obtained from
the direct process. However, the two-step procedure
remains valuable for the introduction of functional
diversity on nitrogen.
d
d
N
N
Me
Me
Br
Br
N
N
Me 1e
2e
50 (49)
In summary, an efficient multi-gram scale straightfor-
ward access to polybrominated imidazoles has been
performed using stoichiometric amounts of the DMF–
N
Br
Br
Me
N
Me
Me
1
f,
Br complex. This reagent gave yields similar to those
2
N
N
2f, X=OH
X=OH
27 (48)
43 (40)
obtained using large excesses of acetic acid–sodium ace-
tate buffers. The reactivity of the polybromoimidazoles
scaffolds is now under investigation.
f
N
1
g,
N
2g, X=Cl
X
e
Me
X=Cl
X
Me
a
Reactions carried out on 0.1 mol of 1a–g using 3 equiv of Br
with 1a, 1d and 1.5 equiv with 1b, 1c and 1e–g.
Isolated yields. In parentheses, yields obtained in the acetic acid/
2
–DMF
Acknowledgements
b
sodium acetate buffer.
See Ref. 9.
See Ref. 12.
The hydrochloride was used.
Obtained as the hydrobromide.
c
d
e
f
M.B. would like to thank the ‘Minist e` re de l’Enseigne-
ment Sup e´ rieur et de la Recherche Scientifique’ of Alge-
ria for a financial support and F. Lou e¨ rat (Nancy) for
helpful technical assistance.

M. Bahnous et al. / Tetrahedron Letters 47 (2006) 1949–1951
1951
References and notes
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Org. Chem. 1992, 57, 3240–3242.
1
1. Preparation of 2,4,5-tribromoimidazole 2a is given as a
1
. (a) Commercon, A.; Ponsonet, G. Tetrahedron Lett. 1990,
typical procedure for tribromination. Finely powdered
KHCO (30 g, 0.3 mol) was added to a solution of 1H-
3
3
1, 3871–3874; (b) Paris, J. M. Tetrahedron Lett. 1991, 32,
4
905–4906.
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added drop-wise during 1 h. The reaction medium was
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2
3
4
5
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1
3
1
9.5 g (64%) of 2a as a white powder. All products
1 13
obtained by this method were characterized by H,
C
5
NMR and melting points, which were found comparable
to those reported in the literature.
6
7
5
1
1
1
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2
1
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