The first application of an imidazole o-quinodimethane in Diels-Alder reactions leading to the synthesis of benzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2007.01.162

An efficient procedure for the generation of the imidazole-4,5-quinodimethane intermediate 4 from 2-bromo-4,5-bis(bromomethyl)imidazole derivative 3 in boiling toluene in the presence of 18-crown-6 is described. o-Quinodimethane 4 was captured for the fir

Full text of DOI:10.1016/j.tetlet.2007.01.162

Tetrahedron Letters 48 (2007) 2275–2277
The first application of an imidazole o-quinodimethane in
Diels–Alder reactions leading to the synthesis of benzimidazoles
Constantinos Neochoritis, Despina Livadiotou, Julia Stephanidou-Stephanatou
and Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, 54124 Macedonia, Greece
Received 15 December 2006; revised 25 January 2007; accepted 31 January 2007
Available online 3 February 2007
Abstract—An efficient procedure for the generation of the imidazole-4,5-quinodimethane intermediate 4 from 2-bromo-4,5-bis(bromo-
methyl)imidazole derivative 3 in boiling toluene in the presence of 18-crown-6 is described. o-Quinodimethane 4 was captured for
the first time by several symmetrically and unsymmetrically substituted dienophiles to afford the corresponding Diels–Alder benz-
imidazole adducts.
Ó 2007 Elsevier Ltd. All rights reserved.
The heterocyclic analogs of o-quinodimethane (o-QDM)
are of considerable interest both from a theoretical point
of view and for their potential in organic synthesis1 as
useful dienes. Their use in annulations of aromatic sys-
tems has now acquired practical importance and has
been exploited in efficient syntheses of a wide range of
polycyclic natural products.2 The most widely used
routes to these heterocyclic o-QDMs involve flash vac-
uum pyrolysis,3 thermal extrusion of sulfur dioxide from
heteroaromatic fused 3-sulfolenes,4 and 1,4-elimination
of suitable precursors.5
Although a substantial number of heterocyclic o-QDMs
have been explored, very recently some new methods for
their preparation involving MW irradiation,6 allenylan-
ilines,7 and ene-bis(sulfinylallenes)8 have appeared in the
literature. Concerning the imidazole o-QDM, although
the formation of the 1-methylimidazole o-QDM by flash
pyrolysis has been reported,9 all attempts at its trapping
with dienophiles were unsuccessful. Moreover, imidaz-
ole based heterocyclic molecules play important roles
in various biochemical processes.10 The imidazolyl
moiety is used as a building block in developing new
drugs,10b,11 and also has wide-ranging applications in
organometallic catalysis,12 in asymmetric catalysis13
and in coordination chemistry.14 There are several
reports of the synthesis and functionalization of the
imidazole moiety.15 For all these reasons the synthesis
and Diels–Alder reactions of an imidazole o-quinodime-
thane were undertaken.
Flash pyrolytic 1,4-elimination requires very harsh reac-
tion conditions resulting in the formation of polymeric
products, thus precluding trapping of the o-QDM
intermediates except in the most stable cases. However,
heterocyclic fused 3-sulfolenes have been shown to be
useful precursors for generation and trapping4 of hetero-
cyclic o-QDMs, although sometimes fairly harsh reac-
tion conditions are required and the reagents are
heated to high temperatures, up to 200 °C. Similarly,
several heterocyclic o-QDMs have been generated by
1,4-elimination in solution and are efficiently trapped
by various dienophiles to afford5 the corresponding
adducts in good yields.
Our synthetic approach is depicted in Scheme 1. To gen-
erate the required imidazole o-QDM we envisaged NBS
bromination of 1-phenylmethylamino-4,5-dimethylimi-
dazole 1, followed by the formation of the imidazole
o-QDM through 1,4-elimination, and trapping with var-
ious symmetrical and unsymmetrical dienophiles. How-
ever, NBS bromination either in the presence of light or
in the presence of radical initiators [(PhCOO)2 or AIBN]
led preferentially to 1-(4-bromophenyl)-2-bromo-4,5-
dimethylimidazole 2. Thus, bromination was performed
with 6.0 equiv of NBS under reflux in CCl4 solution in
the presence of a 200 W light bulb for 1 h, whereupon
Keywords: Imidazole o-quinodimethanes; Benzimidazoles; Diels–Alder
reactions.
*
Corresponding author. Tel.: +30 2310 997865; fax: +30 2310
997679; e-mail: tsolerid@chem.auth.gr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.162

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C. Neochoritis et al. / Tetrahedron Letters 48 (2007) 2275–2277
MeO2C
CO2Me
MeO2C
H3C
CH3
BrH2C
CH2Br
CO2Me
6 eq. NBS
N
N
N
N
+
N
N
Ar
CCl4, hν
reflux, 1 h
Me
Me
Br
60%
N
N
N
N
N
N
Ar
Ar
3
1
Me
Me
Br
35%
Br
6 44%
NaI/toluene
18-crown-6
2.2 eq. NBS
5
(PhCOO)2
or AIBN
MeO2CC CCO2Me
R
H2C
CH2
N
O
O
R
N
H3C
CH3
N
N
N
N
O
O
Ar
N
N
Me
Ar
Br
Me
Br
N
N
N
Ar
4
2
Me
Br
H2C CHCO2Me
7
8
R = Me 72%
R = Ph 75%
H2C CHCOMe
MeO2C
CO2Me
HC CCO2Me
COMe
MeOC
+
N
N
N
N
N
N
Ar
Ar
Me
Me
Br
Br
+
N
N
N
N
N
10a + 10b
24% (70:30)
N
9a
9b
Ar
Ar
Me
Me
53% (60:40)
Br
Br
12a
55% (50:50)
12b
MeO2C
CO2Me
CO2Me
MeO2C
+
+
N
N
N
N
N
N
N
N
N
N
N
N
Ar
Ar
Ar
Ar
Ar =
Br
Me
Me
Me
Me
Br
11b
Br
Br
10b
24% (60:40)
Br
10a
11a
24% (70:30)
Scheme 1. Bromination of compound 1, preparation and Diels–Alder trapping of o-QDM 4 with symmetrically and unsymmetrically substituted
dienophiles.
the tetrabromo-derivative 3, a suitable o-QDM precur-
sor was formed, in 60% yield.
ence of 18-crown-6, since it was found to give much
better yields.5e
Due to the instability of 3 on silica gel, it was not puri-
fied but instead was treated directly with sodium iodide
in boiling toluene in the presence of 18-crown-6 to afford
imidazole o-QDM 4, which was reacted in situ with
dienophiles. From the reaction with dimethyl acetylene-
dicarboxylate, a mixture of the fully and the partially
aromatized benzimidazole cycloadducts 5 and 6 in
35% and 44% yields, respectively, were obtained.16
Using similar conditions, o-QDM 4 reacted with the
symmetrical dienophiles N-methyl- and N-phenylmalei-
mide, whereupon the initially formed Diels–Alder
cycloadducts were not isolated but, under the reaction
conditions, underwent subsequent oxidation to give aro-
matized products 7 and 8, in 72% and 75% yields,
respectively17 (Scheme 1). A note should be made to
the change of solvent from DMF to toluene in the pres-
To further extend the scope of this method the reactions
of 4 with the asymmetrically substituted dienophiles
methyl acrylate, methyl propiolate, and methyl vinyl
ketone were studied. In all cases, inseparable mixtures
of the two possible regioisomers 9a and 9b (ratio
60:40), 11a and 11b (70:30) and 12a and 12b (50:50) were
isolated in 53%, 24%, and 55% yields, respectively.
However, in the case of methyl acrylate and methyl pro-
piolate, the regioisomeric fully aromatized compounds,
10a and 10b, (24% yield, 60:40 ratio and 24% yield,
70:30 ratio) were also formed.
In conclusion, an efficient route for the synthesis of
imidazole o-quinodimethane 4 and its in situ trapping,
for the first time, with dienophiles yielding benzimid-
azole derivatives has been described. Further applica-

C. Neochoritis et al. / Tetrahedron Letters 48 (2007) 2275–2277
2277
14. Nieto, I.; Cervantes-Lee, F.; Smith, J. M. Chem. Commun.
2005, 3811–3813.
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regioselectivity are being studied.
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1997, 36, 2162–2187; (b) Khramov, D. M.; Bielawski, C.
W. Chem. Commun. 2005, 4958–4960; (c) Majo, V. J.;
Perumal, P. T. J. Org. Chem. 1998, 63, 7136–7142; (d)
Parenty, A. D. C.; Guthrie, K. M.; Song, Y.-F.; Smith, L.
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3´
H
H
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4´
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8.5 Hz, 2H, C(30, 50)), 7.64 (s, 1H, C(7)), 8.18 (s, 1H, C(4)).
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