Synthesis of polycyclic pyrazoles through formation of the first fused heterocyclic o-quinodimethane intermediate

Article abstract of DOI:10.1016/j.tetlet.2005.05.079

1-Benzoyl-4,6-dibromo-3-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (2) was used as a precursor for o-quinodimethane 3, which was trapped by in situ reactions with dienophiles to give bridged pyrazole derivatives.

Full text of DOI:10.1016/j.tetlet.2005.05.079

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4843–4845
Synthesis of polycyclic pyrazoles through formation of the
first fused heterocyclic o-quinodimethane intermediate
Despina Konstantinidou, Marina Papageorgiou, J. Stephanidou-Stephanatou* and
Constantinos A. Tsoleridis
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, 54124 Macedonia, Greece
Received 11 March 2005; revised 10 May 2005; accepted 18 May 2005
Abstract—1-Benzoyl-4,6-dibromo-3-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (2) was used as a precursor for o-quinodi-
methane 3, which was trapped by in situ reactions with dienophiles to give bridged pyrazole derivatives.
Ó 2005 Elsevier Ltd. All rights reserved.
o-Quinodimethane (o-QDM) derivatives are reactive
dienes and can be generated in situ by a number of
methods. The inter- and intramolecular Diels–Alder
reactions of these compounds form the basis of the syn-
thesis of a wide range of target molecules.1 Tradition-
ally, heterocyclic o-QDMs have received much less
attention. However, the generation and synthetic appli-
cations of these materials have been recently reviewed2
and interest in them is growing rapidly. Pyrazoles have
long been of pharmacological interest3 as antianxiety,4,5
antipyretic, analgesic and antiinflammatory drugs,6–8 as
well as antimicrobials.9–13 Agrotechnical and analytical
applications have also been reported for some pyrazole
derivatives.14 Certain hydroxy phenylpyrazoles can act
as ultraviolet stabilizers15 and as analytical reagents in
the complexation of transition metal ions.16 3-Benzo-
ylpyrazoles can act as precursors of other important
heterocyclic compounds (e.g., in the preparation of
cizolirtine, a potent analgesic).17,18 This highlights the
potential applications of benzoylpyrazoles and has stim-
ulated the study of their synthesis.
reactive intermediate in Diels–Alder reactions with
dienophiles.
The bromination of 1-benzoylcyclopentapyrazole 1 was
initially attempted with NBS under reflux in carbon tet-
rachloride solution irradiated with a 200 W light bulb,
whereupon the formation of several products was
observed. However, the use of NBS (2.2 equiv) in the
presence of either dibenzoyl peroxide or 2,20-azoisobuty-
ronitrile (AIBN) resulted, after selective bromination, in
the formation of a mixture of syn–anti dibromocyclo-
pentapyrazoles 2. The reaction was followed by TLC
until almost complete disappearance of the starting pyr-
azole 1 (ꢀ10 min). Unfortunately, all attempts to sepa-
rate the bisbromides 2 by chromatography failed,
because of their instability and partial decomposition.
1
However, by studying the H NMR spectrum of the
crude reaction mixture, we concluded that a 1:1 mixture
of the syn–anti isomers had been formed.21
In the next step, the crude bromide mixture 2 was used
for the formation of the o-QDM intermediate 3 through
the action of sodium iodide in dry DMF at 80 °C for
45 min, whereupon in the presence of N-methylmale-
imide a single cycloadduct 4endo was obtained in 31%
overall yield (Scheme 1). The endo stereochemistry was
established by the coupling constants (Table 1) between
protons 1 and 12 (4.60 Hz) and protons 7 and 8
(4.70 Hz) and also on the basis of the NOESY H–H
spectrum, where a correlation signal between the 8 and
12 protons and the 13-syn proton was observed. This
result is in agreement with the results obtained for the
addition of N-methylmaleimide to isoindene.22 In
In continuation of our work on the synthesis of pyrazole
derivatives19 and on heterocyclic o-QDMs,20 we herein
describe the bromination of the cyclopentapyrazole 1,
the generation of the corresponding fused pyrazole
o-quinodimethane 3 and the in situ trapping of this
Keywords: Pyrazoles; o-Quinodimethanes; Diels–Alder reactions.
*
Corresponding author. Tel.: +30 2310 997831; fax: +30 2310
997679; e-mail: ioulia@chem.auth.gr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.079

4844
D. Konstantinidou et al. / Tetrahedron Letters 46 (2005) 4843–4845
H3C
N
Hsyn
H
H
Hanti 13
H
8
H3C
O
N10
6
N
1
O
12
4
N
CO
1
2
CH3
Ph
N
H
N-CH3
O
C
O
Ph
NBS
O
4endo
Br
H
H
H
H3C
N
H3C
H3C
NaI, 80 o
DMF
C
O
O
N
N
N
H
N
N
N
C
Br
Ph
O
N-Ph
CO
CO
O
Ph
Ph
Ph
O
2
3
5endo
+
CH2=CHCOOCH3
O
H
H3C
N
Ph
N
H
H
H
N
H
O
H
H
H3C
N
O
H3C
N
H
H
H
C
O
Ph
+
OCH3
H
OCH3
N
C
5exo
N
C
H
H
H
O
O
Ph
O
Ph
6c,d
6a,b
Scheme 1. Formation of the heterocyclic o-QDM 3 and its reaction with some dienophiles.
contrast, N-phenylmaleimide reacted with 3 to afford a
5endo–5exo (1:1) mixture in 30% overall yield. However,
by successive recrystallizations from ethanol a pure sam-
ple of the 5endo isomer was isolated, hence the NMR
spectral data of the 5exo isomer was also established.23
Finally, in the case of the less reactive dienophile methyl
acrylate, neither regio- nor stereo-selectivity was
observed and a mixture of all four isomers (2:2:1:1)
was isolated in 18% overall yield (Table 1).
In summary, a route leading to a fused N-ben-
zoyl-cyclopentanopyrazole quinodimethane 3 and its
reaction in situ with dienophiles yielding bridged
polycyclic benzoylpyrazole derivatives has been
described.
To our knowledge, this is the first example of the forma-
tion of a heterocyclic quinodimethane formed through
bromination of fused methylene groups. Further appli-
Table 1. NMR dataa (1H, 13C and COLOC C–H) for compound 4endo
Positionb
C
H
COLOCc
1
45.05
4.38 (1H, dddd, J = 4.60, 1.61, 1.53, 1.10)d
129.66, 40.88
2
152.13
147.67
12.68
5
5-CH3
2.22
152.13, 147.67, 129.66
6
129.66
40.88
47.33
7
3.83 (1H, dddd, J = 4.70, 1.63, 1.54, 1.10)
3.55 (1H, dd, J = 7.52, 4.70)
152.13, 45.05
175.47, 129.66
8
9
176.70
24.04
10-CH3
11
12
2.53
176.70, 175.47
175.47
47.70
54.24
3.50 (1H, dd, J = 7.52, 4.60)
syn-2.05 (1H, ddd, J = 9.36, 1.63, 1.61)
anti-2.38 (1H, ddd, J = 9.36, 1.54, 1.53)
176.70, 152.13
152.13, 129.66
13
N3–CO
10
20,60
30,50
40
165.28
131.62
131.41
128.08
132.88
8.04–8.08 (2H, m)
7.40–7.50 (2H, m)
7.56–7.62 (1H, m)
165.28, 132.88
131.62
131.41
a Chemical shifts in ppm relative to TMS in CDCl3 solution; coupling constants J in hertz.
b Primed numbers referred to the C-atoms of the Ph group.
c Long range correlations (2J and 3J) between the H-atom on the left column and the C-atoms stated in this column.
d The spin system consisting of protons H1–H7–H8–H12–H13syn–H13anti has been studied also by simulation (SpinWorks ver. 2.2.0).

D. Konstantinidou et al. / Tetrahedron Letters 46 (2005) 4843–4845
4845
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2.34 (s, 3H), 2.35 (s, 3H), 3.27–3.36 (m, 1H), 3.61–3.69 (m,
2H), 3.79–3.89 (m, 1H), 5.19–5.23 (m, 1H), 5.34–5.41 (m,
1H), 5.58–5.66 (m, 2H), 7.45–7.55 (m, 4H), 7.60–7.66 (m,
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1
Compound 5endo: mp 240–242 °C; H NMR (300 MHz,
CDCl3): d 2.13 (ddd, 1H, J = 9.35, 1.5, 1.5 Hz, H-13anti),
2.29 (s, 3H, CH3), 2.46 (ddd, 1H, J = 9.35, 1.5, 1.5 Hz, H-
13syn), 3.69 (dd, 1H, J = 7.9, 4.6 Hz, H-8), 3.74 (dd, 1H,
J = 7.9, 4.6 Hz, H-12), 3.94 (dddd, 1H, J = 4.6, 1.5, 1.5,
0.8 Hz, H-7), 4.48 (dddd, 1H, J = 4.6, 1.5, 1.5, 0.8 Hz, H-
1), 6.81–6.85 (m, 2H, o-N–Ph), 7.31–7.36 (m, 3H, m, p-N–
Ph), 7.35–7.40 (m, 2H, m-CO–Ph), 7.50–7.57 (m, 1H, p-
CO–Ph), 7.91–7.94 (m, 2H, o-CO–Ph); 13C NMR
(75 MHz, CDCl3): d 12.86 (CH3), 41.28 (C-7), 45.35 (C-
1), 47.70 (C-8), 47.98 (C-12), 54.91 (C-13), 126.41 (o-N–
Ph), 128.00 (m-CO–Ph), 128.69 (p-N–Ph), 129.12 (m-N–
Ph), 130.00 (C-6), 131.35 (o-CO–Ph), 131.43 (i-N–Ph),
131.48 (i-CO–Ph), 132.83 (p-CO–Ph), 147.78 (C-5), 152.52
(C-2), 165.50 (N–CO), 174.49 (C-11), 175.75 (C-9).
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Compound 5exo: 1H NMR (300 MHz, CDCl3): d 2.24
(dd, 1H, J = 8.6, 1.5 Hz, H-13), 2.10 (s, 3H, CH3), 2.70
(dd, 1H, J = 8.6, 1.5 Hz, H-13), 3.75 (dd, 1H, J = 8.3,
5.1 Hz, H-8), 3.92 (dd, 1H, J = 5.1, 1.5 Hz, H-7), 4.43 (d,
1H, J = 8.3 Hz, H-12), 6.25 (d, 1H, J = 3.2 Hz, H-1), 7.07–
7.10 (m, 2H, o-N–Ph), 7.31–7.52 (m, 6H), 7.89–7.92 (m,
2H, o-CO–Ph); 13C NMR (75 MHz, CDCl3): d 12.78,
41.42, 43.54, 50.78, 64.27, 80.00, 122.30, 126.25, 127.75,
128.60, 129.03, 129.31, 129.96, 131.37, 133.65, 147.70,
151.30, 167.19, 173.94, 175.55.