Synthesis and chemistry of pyrazolines derived from diphenyldiazomethane

Article abstract of DOI:10.1515/HC.2011.034

The reaction of diphenyldiazomethane with N-substituted maleimides produces Δ 1-pyrazolines. The photolysis of Δ 1-pyrazolines leads to cyclopropanes. 2011 · Copyright by Walter de Gruyter.

Full text of DOI:10.1515/HC.2011.034

Heterocycl. Commun., Vol. 17(5-6), pp. 215–218, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.034
Synthesis and chemistry of pyrazolines derived
from diphenyldiazomethane
(Amr et al., 2003b). This paper describes the synthesis and
reactivity of pyrazolines derived from diphenyldiazomethane
(Richard et al., 1961a; Jaz and Millet, 1967; Millet, 1969;
Dietrich-Bucheker and Frank-Neumann, 1977; Boukamcha et
al., 1999).
Nesrine Louhichi, Amel Haouas, Naoufel Ben
Hamadi* and Moncef Msaddek
Laboratory of Synthesis Heterocyclic and Natural
Substances, Faculty of Sciences of Monastir, Boulevard of
Environment, 5000 Monastir, Tunisia
*Corresponding author
e-mail: bh_naoufel@yahoo.fr
Results and discussion
The 1,3-dipolar cycloaddition reaction of diphenyldia-
zomethane 1 with N-arylmaleimides 2 led to exclusive for-
mation of pyrazolines 3 (Scheme 1).
Abstract
The reaction of diphenyldiazomethane with N-substituted
maleimides produces ∆1-pyrazolines. The photolysis of ∆1-
pyrazolines leads to cyclopropanes.
O
Keywords: cyclopropanes; 1,3-dipolar cycloaddition;
O
irradiation; pyrazolines.
N
Ph
2
1
5
hν, Et2O
6
N
R
3
N
N
R
4
Ph
Introduction
Ph
O
O
Ph
3a-d
The synthesis of pyrazoles and their derivatives remains
of great interest owing to the wide application of such
heterocycles in the pharmaceutical and agrochemical indus-
try (Elguero, 1984, 1986). In particular, a 1,3-dipolar cyclo-
addition reaction of alkenes with diazoalkanes has been used
to prepare pyrazolines (Huisgen, 1984; Padwa and Pearson,
2002). Many pyrazolines show antibacterial (Bilgin et al.,
1992, 1993, 1994), antidepressant (Gokhan et al., 2003),
anticonvulsant (Amr et al., 2003a), antiparkinsonian (Amr
and Abou-Ghalia, 2004), and anti-inflammatory activities
4a-d
4a: R=CH3
4b: R=C6H5
4c: R=p-CH3OC6H4
4d: R=p-NO2C6H4
Scheme 2 The 1,3-dipolar cycloaddition of diphenyldiazomethane
(1) with maleic anhydride (5), at 40°C, furnished a cyclopropane
derivative 6 (Thomas et al., 1976). The lactone moiety of 6 was
opened by the reaction with an amine yielding the product 7 (Scheme
3) (Richard et al., 1961b; Hibbs et al., 1997).
O
O
H
Ph
N
6
4
1
6a
3a
N
N
N
R
N
N
R
5
2
3
Ph
Ph
H
O
Ph
O
1
3a-d
2a-d
3a: R=CH3
3b: R=C6H5
3c: R=p-CH3OC6H4
3d: R=p-NO2C6H4
Scheme 1 The photolysis of an ethereal solution of the ∆1-pyrazolines 3 at 0–5°C led to exclusive formation of gem-diphenylcyclopropanes
4 (Scheme 2) (Nesrine et al., 2011).
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216 N. Louhichi et al.
O
O
OH
O
O
1
Ph
Ph
3
H
H
Ph
Ph
NH2R, Et2O
AcOEt, 40°C
O
N
N
2
Ph
Ph
NHR
O
5
1
O
O
6
7a-d
7a: R=C6H5
7b: R=p-CH3OC6H4
7c: R=p-CH3C6H4
7d: R=p-NO2C6H4
7e: R=p-ClC6H4
Scheme 3 The suggested cis substitution of the cyclopropane moiety of 7 is consistent with the coupling constant JH1,H3=8.7 Hz for deriva-
tives 7a–d and 9.0 Hz for 7e.
3,3-Diphenyl-5-(4-methoxyphenyl)-3,3a,4,5,6,6a-
Experimental section
hexahydropyrrolo[3,4-c]pyrazole (3c) Yield 1.59 g (80%); white
solid; mp 134°C; IR: ν 1535, 1695, 1705; 1H-NMR (CDCl3): δ 3.72
General
(s, 3H, OCH3), 4.12 and 6.49 (2H, H3a, H6a, J=8.4 Hz), 6.67–7.73
(m, 14H, Harom); 13C-NMR (CDCl3): δ 47.9 (C3a), 55.9 (OCH3), 96.3
Infrared spectra were recorded on a Perkin-Elmer IR-197 spectropho-
(C6a), 105.1 (C3), 114.6–159.6 (Carom), 169.5 (C4), 172.6 (C6). Anal.
calcd. for C24H19N3O3: C, 72.53; H, 4.82; N, 10.57. Found: C, 72.51;
H, 4.85; N, 10.53.
tometer. Mass spectra were determined on a Nierjohnson MS80RF
spectrometer. Melting points were determined on a BuchI-510 capil-
lary melting point apparatus and were not corrected. Thin layer chro-
matography (TLC) was performed on silica gel 254 plates (Merck)
with UV (254 nm) visualisation, and preparative chromatographic
separations were conducted on silica gel Si-60-7734 (Merck). The
1H-NMR and 13C-NMR spectra were recorded at 300 MHz and 75
MHz, respectively. Elemental analyses were performed on a Perkin-
Elmer 240B microanalyser. Diethyl ether was freshly distilled over
sodium wire with a trace of benzophenone. Dichloromethane was
distilled from calcium hydride.
3,3-Diphenyl-5-(4-nitrophenyl)-3,3a,4,5,6,6a-hexa-
hydropyrrolo[3,4-c]pyrazole (3d) Yield 1.03 g (50%); white
1
crystals; mp 142°C; IR: ν 1530, 1675, 1680; H-NMR (CDCl3):
δ 4.15 and 6.20 (2H, H3a, H6a, J=8.4 Hz), 6.26–8.10 (m, 14H,
H
arom); 13C-NMR (CDCl3): δ 47.6 (C3a), 97.0 (C6a), 104.9 (C3),
124.9–136.3 (Carom), 169.4 (C4), 172.6 (C6). Anal. calcd. for
23H16N4O4: C, 66.99; H, 3.91; N, 13.59. Found: C, 66.93; H,
C
3.89; N, 13.35.
Reaction of diphenyldiazomethane (1b) with
N-arylmaleimides (2)
Synthesis of cyclopropane derivatives 4
A solution of substrate 3 (5 mmol) in ether was irradiated using a
mercury lamp emitting at 254 nm at 5°C until the starting material
was consumed (TLC). Then the solvent was removed on a rotary
evaporator without heating to give brown oil that was purified by
chromatography eluting with ethyl acetate/petroleum ether (1:4).
Products 4a–d were crystallised from ethanol.
To a solution of 2 (5 mmol) in ethyl acetate (20 ml), diphenyldia-
zomethane (6 mmol) was added and the resulting solution was
heated under an argon atmosphere at 40°C for 2 h, after which time
the mixture was cooled to ambient temperature and concentrated
under reduced pressure. Products 3a–d were crystallised from
ethanol.
3-Methyl-6,6-diphenyl-3-azabicyclo[3.1.0]hexane-2,4-dione
(4a) Yield 0.69 g (50%); white crystals; mp 150°C; 1H-NMR
(CDCl3): δ 2.28 (s, 3H, CH3), 3.10 (s, 2H, H1,5), 7.13–7.35 (m, 10H,
5-Methyl-3,3-diphenyl-3,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]-
pyrazole (3a) Yield 1.06 g (70%); white solid; mp 120°C; IR: ν
1530, 1670, 1675 cm-1; 1H-NMR (CDCl3; 300 MHz): δ 2.64 (s, 3H,
CH3), 3.88 and 5.99 (2H, H3a, H6a, J=8.4 Hz), 6.71–7.75 (m, 10H,
H
arom); 13C-NMR (CDCl3): δ 24.11 (CH3), 34.3 (C1,5), 50.7 (C6),
127.3–141.5 (Carom), 173.6 (C2,4). Anal. calcd. for C18H15NO2: C,
77.96; H, 5.45; N, 5.05. Found: C, 77.80; H, 5.37; N, 5.09.
H
arom); 13C-NMR (CDCl3): δ 24.9 (CH3), 47.7 (C3a), 94.9 (C6a),
106.1 (C3), 126.9–139.5 (Carom), 169.4 (C4), 172.6 (C6). Anal. calcd.
for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C, 70.89; H,
4.98; N, 13.67.
3,6,6-Triphenyl-3-azabicyclo[3.1.0]hexane-2,4-dione
(4b) Yield 1.27 g (75%); white solid; mp 172°C; IR: ν 1530; 1670,
1
1675; H-NMR (CDCl3): δ 3.16 (s, 2H, H1,5), 6.76–7.78 (m, 15H,
H
arom); 13C-NMR (CDCl3): δ 35.1 (C1,5), 51.3 (C6), 126.9–139.5
3,3-Diphenyl-5-phenyl-3,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]-
pyrazole (3b) Yield 1.10 g (60%); white solid; mp 150°C; IR: ν
1530, 1670, 1675; 1H-NMR (DMSO-d6): δ 4.17 and 6.22 (2H, H3a,
H6a, J=8.4 Hz), 6.46–7.70 (m, 15H, Harom); 13C-NMR (DMSO-d6) δ:
47.7 (C3a), 96.3 (C6a), 105.3 (C3), 126.9–141.6 (Carom), 169.4 (C4),
172.7 (C6). Anal. calcd. for C23H17N3O2: C, 75.19; H, 4.66; N, 11.44.
Found: C, 75.26; H, 4.70; N, 11.45.
(Carom), 173.7 (C2,4). Anal. calcd. for C23H17N3O2: C, 81.40; H, 5.05;
N, 4.13. Found: C, 81.20; H, 5.00; N, 4.25.
3-(4-Methoxyphenyl)-6,6-diphenyl-3-azabicyclo[3.1.0]hexane-
1
2,4-dione (4c) Yield 1.48 g (80%); white solid; mp 129°C; H-
NMR (CDCl3): δ 3.32 (s, 2H, H1,5), 3.73 (s, 3H, OCH3), 6.20 and
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Synthesis and chemistry of pyrazolines 217
6.72 (d, 4H, Harom, J=9 Hz), 7.23–7.56 (m, 10H, Harom); 13C-NMR
(CDCl3) δ: 33.8 (C1,5), 50.1 (C6), 55.4 (OCH3), 114.4–159.5 (Carom),
172.6 (C2,4). Anal. calcd. for C24H19NO3: C, 78.03; H, 5.18; N, 3.79.
Found: C, 78.10; H, 5.12; N, 3.63.
H1, H3, J=9 Hz), 7.15–7.51 (m, 15H, Harom, NH), 11.59 (s, 1H, CO2H);
13C-NMR (DMSO-d6): δ 35.2 and 35.9 (C1,2), 43.4 (C3), 121.9–146.1
(Carom), 169.2 and 170.8 (Ccar). Anal. calcd. for C23H18ClNO3: C,
70.50; H, 4.63; N, 3.57. Found: C, 70.47; H, 4.60; N, 3.53.
3-(4-Nitrophenyl)-6,6-diphenyl-3-azabicyclo[3.1.0]hexane-2,4-
dione (4d) Yield 1.15 g (60%); white solid; mp 131°C; H-NMR
References
1
(CDCl3): δ 3.38 (s, 2H, H1,5), 6.28 and 8.08 (d, 4H, Harom, J=8.7 Hz),
6.96–7.53 (m, 10H, Harom); 13C-NMR (CDCl3): δ 34.1 (C1,5), 50.1
(C6), 124.2–136.7 (Carom), 171.3 (C2,4). Anal. calcd. for C23H16N2O4:
C, 71.87; H, 4.20; N, 7.29. Found: C, 71.67; H, 4.31; N, 7.18.
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and reactions of some fused oxazinone, pyrimidinone, thiopyrimi-
dinone, and triazinone derivatives with a thiophene ring as analge-
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6,6-Diphenyl-3-oxabicyclo[3.1.0]hexane-2,4-dione 6
Amr, A. E.; Mohamed, A. M.; Ibrahim, A. A. Z. Synthesis of some
new chiral tricyclic and macrocyclic pyridine derivatives as anti-
microbial agents. Z. Naturforsch. 2003b, 58b, 861–868.
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cyclo-(Nα-dipicolinoyl)pentapeptide of a breast and CNS cyto-
toxic activity and an ionophoric specifity. Amino Acids 2004, 26,
283–289.
This compound was prepared as described for the synthesis of ad-
ducts 3: Yield 0.44 g (80%); yellow solid; mp 148°C; 1H-NMR
(CDCl3): δ 3.46 (s, 2H, H1,5), 7.16–7.48 (m, 10H, Harom); 13C-NMR
(CDCl3): δ 35.78 (C1,5), 47.7 (C6), 126.8–139.7 (Carom), 166.5 (C2,4).
Anal. calcd. for C17H12O3: C, 77.26; H, 4.58; N, 3.92. Found: C,
77.30; H, 4.55; N, 3.99.
Bilgin, A.; Yesilada, A.; Palaska, E.; Sunal, R. Synthesis and
antidepressant activity of some new 8-thiocarbamoyl-7,8-
diazabicyclo[4.3.0]non-6-ene derivatives. Arzneim.-forsch./Drug
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pressant activity of some 1-thiocarbamoyl-3,5-diphenyl-2-pyra-
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enyl-2- pyrazolines with antidepressant activities. Pharmazie
1994, 49, 67–69.
Synthesis of cyclopropane derivatives 7
A solution of lactone 6 (10 mmol) in dry CH2Cl2 was stirred at -30°C
under an argon atmosphere and treated dropwise with an amine
RNH2 (15 mmol). The resultant solid product 7 was filtered.
cis-3,3-Diphenyl-2-(phenylcarbamoyl)-1-cyclopropanecarbox-
ylic acid (7a) Yield 1.07 g (60%); yellow solid; mp 215°C; IR:
ν 3330 cm-1; 1H-NMR (DMSO): δ 2.83; 2.94 (AX, H1, H3, JAX=8.7
Hz), 7.09–7.51 (m, 16H, Harom, NH), 11.12 (s, 1H, CO2H); 13C-NMR
(DMSO-d6): δ 34.7 and 35.8 (C1,2), 43.6 (C3), 120.7–145.7 (Carom),
169.5 and 170.3 (Ccar). Anal. calcd. for C23H19NO3: C, 77.29; H,
5.36. Found: C, 77.30; H, 5.31.
Boukamcha, N.; Gharbi, R.; Martin, M. T.; Chironi, A.; Mighri, Z.;
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dition reaction of 2-diazopropane with diarylidenacetones.
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Dietrich-Bucheker, C.; Frank-Neumann, M. Cyclopropenes elec-
trophiles – II: synthese par photolyse de dimethyl-3,3 pyrazole-
nines. Tetrahedron Lett. 1977, 33, 751–755.
Elguero, J. Pyrazoles and their benzo derivatives. In Comprenhensive
Heterocyclic Chemistry. Katritzky, A., Ed. Pergamon Press:
Oxford, 1984; Vol. 5, pp. 277–282.
Elguero, J. Pyrazoles and their benzo derivatives. In Comprenhensive
Heterocyclic Chemistry II. Shinkai, I., Ed. Elsevier: Oxford,
1986; Vol. 3, pp. 3–75.
cis-2-[(4-Methoxyphenyl)carbamoyl]-3,3-diphenyl-1-cyclopro-
panecarboxylic acid (7b) Yield 1.23 g (64%); white solid; mp
1
213°C; IR: ν 3330 cm-1; H-NMR (DMSO-d6): δ 2.83 and 2.92 (d,
2H, H1, H3, J=8.7 Hz), 3.72 (s, 3H, OCH3), 6.91–7.43 (m, 15H,
H
arom, NH), 11.13 (s, 1H, CO2H); 13C-NMR (DMSO-d6): δ 34.6 and
36.3 (C1,2), 43.5 (C3), 55.7 (OCH3), 114.5–156.7 (Carom), 169.6 and
170.3 (Ccar). Anal. calcd. for C24H21NO4: C, 74.40; H, 5.46; N, 3.62.
Found: C, 74.40; H, 5.45 N, 3.60.
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do-peptides incorporating a (2S,3R)-2-amino-cyclopropane car-
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cis-2-[(4-Methylphenyl)carbamoyl]-3,3-diphenyl-1-cyclopro-
panecarboxylic acid (7c) Yield 1.39 g (75%); white solid; mp
170°C; IR: ν 3330; 1H-NMR (DMSO-d6): δ 2.32 (s, 3H, CH3), 2.80
and 2.82 (d, 2H, H1, H3, J=8.7 Hz), 6.87–7.45 (m, 15H, Harom, NH),
11.15 (s, 1H, CO2H); 13C-NMR (DMSO-d6): δ 28.3 (CH3), 34.5 and
37.0 (C1,2), 42.9 (C3), 126.5–136.6 (Carom), 168.5 and 171.4 (Ccar).
Anal. calcd. for C24H21NO3: C, 77.61; H, 5.70; N, 3.77. Found: C,
77.57; H, 5.65; N, 3.80.
cis-2-[(4-Nitrophenyl)carbamoyl]-3,3-diphenyl-1-cyclopro-
panecarboxylic acid (7d) Yield 0.80 g (40%); white solid; mp
151°C; IR: ν 3330; 1H-NMR (DMSO-d6) δ: 2.73 and 2.80 (d, 2H, H1,
H3, J=8.7 Hz), 6.29–8.09 (m, 15H, Harom, NH), 11.08 (s, 1H, CO2H);
13C-NMR (DMSO-d6): δ 34.5 and 35.9 (C1,2), 44.1 (C3), 123.6–
137.6 (Carom), 169.6 and 172.0 (Ccar). Anal. calcd. for C23H18N2O5:
C, 68.65; H, 4.51; N, 6.96. Found: C, 68.62; H, 4.55; N, 7.00.
cis-2-[(4-Chlorophenyl)carbamoyl]-3,3-diphenyl-1-cyclopro-
panecarboxylic acid (7e) Yield 1.36 g (70%); white solid; mp
203°C; IR: ν 3330 cm-1; 1H-NMR (DMSO-d6): δ 2.78 and 2.85 (d, 2H,
Richard, B.; Nariman, M.; Peter, R.; Ronald, B.; Eugene, G.;
Anne, S. Cyclopropanes derived from diaryldiazomethanes. II.
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Received July 19, 2011; accepted August 25, 2011; previously
published online September 22, 2011
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