Efficient synthesis of pyrazole fused [6-7-5] tricyclic frameworks via intramolecular Friedel-Crafts reaction of Morita-Baylis-Hillman adducts

Article abstract of DOI:10.3184/174751914X13891972597451

A novel and efficient synthesis of pyrazole fused[6-7-5]tricyclic derivatives via AlCl₃-catalysed intramolecular Friedel-Crafts reaction of the Morita-Baylis-Hillman adducts was described and a plausible mechanism was given.

Full text of DOI:10.3184/174751914X13891972597451

JOURNAL OF CHEMICAL RESEARCH 2014
FEBRUARY, 85–89
RESEARCH PAPER 85
Efficient synthesis of pyrazole fused [6-7-5] tricyclic frameworks via
intramolecular Friedel–Crafts reaction of Morita–Baylis–Hillman adducts
Weihui Zhong*, Aiping Tu, Kai Chen, Yanbin Liu, Weibo Hu and Xiao Chen
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences,
Zhejiang University of Technology, Hangzhou 310014, P.R. China
A novel and efficient synthesis of pyrazole fused[6-7-5]tricyclic derivatives via AlCl3-catalysed intramolecular Friedel–Crafts
reaction of the Morita–Baylis–Hillman adducts was described and a plausible mechanism was given.
Keywords: Morita–Baylis–Hillman adducts, Friedel–Crafts reaction, aluminium chloride, benzo[6,7]cyclohepta[1,2-c]pyrazoles
Pyrazoles derivatives have been, and continue to be, interesting
and structurally challenging heterocyclic compounds. Their
bioactivities and the structural advantages have contributed to
the broadening of their applications in the medicinal arena.1,2
Pyrazole fused [6-7-5] tricyclic compounds occur widely in
various natural products and bioactive molecules. For example,
2,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2c]pyrazole
(Fig. 1, I) showed good inhibitory activities of hepatitis C virus
(HCV) NS3-4A protease, which also significantly inhibited
tyrosine from the reactive nitrogen species peroxynitrite
(ONOO–)-mediated nitration.3 Also, N-(2,6-dichlorobenzyl)-
8,9-dimethoxy-1,4,5,6-tetrahydrobenzo-[6,7]-cyclohepta[1,2-c]
pyrazol-3-amine(II) was the first inhibitor known of heme-
regulated eukaryotic initiation factor 2á (HRI) kinase.4 Due
to the unfavourable entropic factors in synthesising seven-
membered rings, the development of efficient protocols for
the synthesis of pyrazole fused [6-7-5] tricyclic frameworks
continues to be one of the most challenging areas in organic
chemistry.5
The Morita–Baylis–Hillman (MBH) reaction is a useful
carbon–carbon bond formation reaction and provides multi-
functionalised adducts catalysed by a tertiary amine.6–8 These
MBH adducts and their derivatives were widely employed for
the synthesis of varieties of useful heterocyclic compounds
by us9 and other groups.10–13 Our group has reported an
acid-promoted intramolecular Friedel–Crafts reaction for
the synthesis of 12H-thiochromeno-[2,3-b]quinolines and
5H-benzo[7,8]thiocino[2,3-b]quinolines from MBH adducts
derived from 2-arylthioquinolin-3-carbaldehydes.14 To the
best of our knowledge, the preparation of pyrazole fused [6-
7-5] tricyclic frameworks from MBH adducts has not been
reported and we now report a novel construction of benzo[6,7]
cyclohepta[1,2-c]pyrazoles via intramolecular Friedel–Crafts
reaction of MBH adducts (Fig. 2).
The starting 5-chloropyrazole-4-carbaldehydes
1 were
efficiently prepared via Vilsmeier reaction of 1H-pyrazol-
5(4H)-ones with the bis(trichloromethyl)carbonate/DMF
system instead of the traditional POCl3/DMF system.15 Then
we investigated the MBH reaction of 5-chloropyrazole-
4-carbaldehyde 1a and methyl acrylate in the presence of
various catalysts. Initially, we used DABCO to promote this
reaction at room temperature or 40 °C. Unfortunately, the
MBH reaction of 1a with methyl acrylate was very slow and
gave the desired MBH adduct 2a in very low yield (Table 1,
entries 1 and 2). Then DMAP was tested to promote this MBH
reaction in CH2Cl2 at room temperature for 5 days, but only
a 46% yield of 2a could be isolated (Table 1, entry 3). If the
temperature was increased to 40 °C, 61% of 2a accompanied
by the recovery of 1a (24%) was isolated (Table 1, entry 4).
Under ultrasound irradiation, MBH adduct 2a was formed in
moderate yield in a shorter reaction time, but along with some
unknown byproducts (Table 1, entry 5). In order to optimise
the reaction conditions, various factors including the identity of
catalysts (quinine, DBU, TMEDA, imidazole+L-proline (1:1),
DABCO+LiClO4(1:1), DABCO+Yb(OTf)3(1:1)), solvents
(DMF, THF) and reaction temperature were screened and the
results are summarised in Table 1. Although we optimised the
reaction conditions in many cases, the product yields were not
totally satisfactory and some of the starting materials were also
recovered.16
Cl
H
N
HN
N
HN
In order to assess the scope of this method, the reactivity of
several 5-chloropyrazole-4-carbaldehydes 1 towards activated
alkenes were investigated. Under the above optimal conditions,
2a–f were obtained in 60–69% yields for 5–6 days. The Baylis–
Hillman reaction of 1a and but-3-en-2-one gave the desired
N
OMe
l
C
OMe
II
I
Fig. 1 Pyrazole fused [6-7-5] tricyclic compounds I and II.
Fig. 2 Synthetic strategy of [6-7-5] ring frameworks.
* Correspondent. E-mail: weihuizhong@zjut.edu.cn
JCR1302254_FINAL.indd 85
30/01/2014 11:36:42

86 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 The MBH reaction of 1a under different conditionsa
Yields of 2a
Recovery of
Entry
Catalyst
Solvents
Temp./°C
Time/h
/%b
1ª/%b
1
2
3
DABCO
DABCO
DMAP
DMAP
DMAP
Quinine
DBU
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
r.t.
40
r.t.
40
40
40
40
40
40
40
40
50
40
30
5
5
5
2
7
7
7
7
7
7
5
5
trace
15
46
61
52
12
23
25
29
33
32
41
80
70
38
24
Trace
70
57
55
51
45
4
5c
6
7
8
9
10
11
12
13
TMEDA
Imidazole+L-proline (1:1)
DABCO+LiClO4(1:1)
DABCO+Yb(OTf)3 (1:1)
DMAP
43
36
32
DMAP
THF
44
aConditions: 1a (4.0 mmol), methyl acrylate (12 mmol), catalysts (1.6 mmol), r.t., solvents (12 mL).
bIsolated yields based on 1a.
cUltrasound conditions.
product 2g in only 28% yield after 10 days. But in the presence
of imidazole and L-proline (1:1), 2g was obtained in 75% yield
after 6 days. Similarly, 2h–k were prepared in 55–68% yields
(Table 2).
Encouraged by these results, we turned our attention to the
intramolecular Friedel–Crafts reaction of MBH adducts 2.
Initially, we chose 2a as a model in the presence of several
kinds of catalyst. Firstly we used concentrated H2SO4 to
promote this intramolecular Friedel–Crafts reaction,14 but
unfortunately no desired product [6-7-5] ring framework could
be isolated. T,he substrate formed a salt with the H2SO4. Then,
Yb(OTf)3 and Zn(OTf)2 were tested, but only traces of product
could be detected. It was gratifying that AlCl3 could afford the
corresponding cyclisation product 3a in 89% yield.
With the optimal conditions in hand, we wanted to assess
the scope of this method. Various pyrazole-containing MBH
adducts 2 were screened using AlCl3 as a catalyst and the
results are shown in Table 3. All the substrates 2 in Table 3 could
provide the corresponding products 3 with good to excellent
yields. It seems that the substituent of the benzene ring has little
effect upon the reactivity of MBH adducts. Interestingly, when
the reaction time was prolonged, the intramolecular Friedel–
Table 2 Synthesis of MBH adducts 2 from 2-aryl-5-chloropyrazole-4-
carbaldehydes 1a
Table 3 Synthesis of benzo[6,7]cyclohepta[1,2-c]pyrazoles 3 from MBH
adducts 2a
Yields
Recovery
Entry
R
EWG
Time/days
of 2/%b
of 1/%b
Entry
R
4-Me
4-F
EWG
Time/h
2.5
2
Products Yield/%b
1
2
3
4
5
4-Me
4-F
2-Cl
2-OMe
4-F
4-Me
4-Me
4-Me
H
CO2Me
CO2Me
CN
CN
CN
5
6
5
6
5
6
10
6
5
2a/61
2b/66
2c/69
2d/57
2e/60
2f/65
2g/28
2g/75
2h/63
2i/67
2j/55
2k/68
24
20
13
26
23
14
50
Trace
18
13
1
2
CO Me
CO22Me
CO2Me
CN
CN
CN
3a
3b
88
83
81
78
83
80
83
89
80
85
88
90
3c
4
4-F
5
3b+3bʹ
3c
2-Cl
2-OMe
4-F
4-Me
4-Me
H
2-Cl
2-OMe
4-F
2.3
2.1
4
3
2.5
3
3.5
3
6
7
CN
5
6
7
8
3d
3e
COMe
COMe
COMe
COMe
COMe
COMe
8c
9c
10c
11c
12c
CN
3f
3g
COMe
COMe
COMe
COMe
COMe
2-Cl
2-OMe
4-F
6
8
6
9
3h
3i
29
Trace
10
11
12
3j
3k
aCondition: 1 (4 mmol), activated olefins (12 mmol), DMAP (1.6 mmol),
3
40 °C, CH2Cl2 (12 mL).
aConditions: 2 (1 mmol), AlCl3 (0.4 mmol), CH3NO2 (3 mL), reflux.
bIsolated yields based on 1.
bIsolated yields based on 2.
cImidazole and L-proline (1.2 mmol, 1:1) were used.
cThe reaction time was prolonged under reflux conditions.
JCR1302254_FINAL.indd 86
30/01/2014 11:36:42

JOURNAL OF CHEMICAL RESEARCH 2014 87
Synthesis of MBH adducts 2; general procedure
Crafts reaction of MBH adduct 2b gave a mixture of isomers
3b and 3bʹ (according to the spectra of H NMR, the ratio of
1
A mixture of 1 (4.0 mmol), methyl acrylate (12.0 mmol), DMAP
(1.6 mmol) or imidazole and L-proline (1.2 mmol, 1:1) and
dichloromethane (12 mL) was kept at 40°C for the given time. The
reaction was monitored by TLC. After completion, the reaction
was quenched with saturated brine and extracted with ethyl acetate
(3×30 mL) and the combined organic layer was dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash column
chromatography on silica gel (petroleum ether: ethyl acetate=6:1) to
give 2.
3b/3bʹ is 77/23) in 87% yield (Table 3, entry 3). As a result of
this discovery, we considered whether this special phenomenon
could happen in other products. In order to investigate this
assumption, product 3a was heated under the refluxing
CH3NO2 for 8 hours and the desired rearrangement product
3aʹ was isolated with 75%, accompanied by the recovery of 3a
(Scheme 1).
According to the above results, a possible mechanism for the
formation of compound 3a and its rearrangement product 3aʹ
can be illustrated as shown in Scheme 2.
A similar procedure was used for acrylonitrile and a mixture of
imidazole and L-proline (1.2 mmol, 1:1) was chosen to promote the
MBH reaction between substrates 1 and but-3-en-2-one.
In conclusion, we have developed a novel, efficient strategy
for the synthesis of pyrazole fused [6-7-5] tricyclic frameworks
from MBH adducts mediated by AlCl3 under mild conditions.
The merits of the present process are the simple experimental
procedure, especially the workup operation, environmental
friendliness and good to excellent yields.
Methyl 2-((5-chloro-1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)(hydroxy)
methyl)acrylate (2a): Yellow solid, m.p. 120.1–121.4 °C; IR (KBr): 3440,
2950, 2913, 1717, 1628 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.58–7.63(4H,
m, ArH), 7.48–7.52 (2H, m, ArH), 7.40–7.44 (1H, m, ArH), 7.22 (2H, d,
J=7.6 Hz, ArH), 6.36 (1H, s, CHOH), 5.84–5.86 (2H, m, =CH2), 3.74 (3H,
s, OCH3), 2.38 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) δ 166.8, 152.1,
139.2, 138.3, 138.1, 129.6, 129.1 (2C), 129.0 (2C), 128.6 (2C), 128.4, 126.7,
125.3 (2C), 117.4, 115.5, 65.2, 52.1, 21.3; MS (ESI) m/z=385 (M+ +3,
33), 383 (M+ +1, 100); HRMS (ESI) calcd for C21H20ClN2O3: 383.1162
[M+H]; found: 383.1156.
Experimental
All solvents and reagents were purchased from commercial sources
and were used without additional purification. Melting points were
determined by using a Büchi B-540 capillary melting point apparatus
and were uncorrected. IR spectra were recorded on a Nicolet
Methyl 2-((5-chloro-3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)
(hydroxy)methyl) acrylate (2b): Yellow oil; IR (neat): 3520, 1645, 1468,
Avatar-370 instrument. H and 13C NMR spectra were recorded on
1379 cm–1 1H NMR (400 MHz, CDCl3) δ 7.69–7.71 (2H, m, ArH), 7.57–
1
;
a Varian (400 MHz) instrument using TMS as an internal standard.
Mass spectra were measured with a Finnigan Trace DSQ instrument.
High-resolution mass spectral (HRMS) analyses were measured
on an APEX (Bruker) mass III spectrometer using ESI (electrospray
ionisation) or EI (electron impact) techniques. Silica-gel for column
chromatography was purchased from Qingdao Haiyang Chemical Co.,
Ltd (200–300 mesh). All yields described here are the isolated yields
after column chromatography.
7.60 (2H, m, ArH), 7.41–7.50 (3H, m, ArH), 7.06 (2H, t, J=6.8 Hz, ArH),
6.31–6.32 (1H, m, CHOH), 5.80–5.82 (2H, m, =CH2), 3.73 (3H, s, CH3);
13C NMR (100 MHz, CDCl3) δ 166.5, 164.0, 161.5, 150.9, 138.8, 137.8,
130.5, 128.9 (2C), 138.4, 126.5, 126.2 (2C), 123.0, 117.4, 115.4, 115.2,
115.0, 65.0, 52.1; MS (EI) m/z=386 (M+, 54), 385 (100); HRMS (ESI)
calcd for C20H17ClFN2O3: 387.0912 [M+H]; found: 387.0921.
2-((5-Chloro-3-(2-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)(hydroxy)
methyl)acrylonitrile (2c): Yellow solid, m.p. 105.1–106.5°C; IR (KBr):
Scheme 1 The heat rearrangement reaction of 3a.
Scheme 2 A plausible mechanism for the formation of 3 and 3aʹ.
JCR1302254_FINAL.indd 87
30/01/2014 11:36:42

88 JOURNAL OF CHEMICAL RESEARCH 2014
1
3436, 2921, 2222, 1597, 1376 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.55–7.61 (2H, m, ArH), 7.39–7.50 (5H, m, ArH), 7.32 (2H, m, ArH),
6.00 (1H, d, J=2.0 Hz, =CHH), 5.88 (1H, d, J=2.0 Hz, =CHH), 5.21
(1H, s, CHOH), 2.95 (1H, s, OH); 13C NMR (100 MHz, CDCl3) δ 149.2,
137.3, 133.6, 132.4, 130.8, 130.3, 129.6, 129.2, 128.8 (2C), 128.6, 126.8,
126.6, 125.0(2C), 122.9, 116.6, 115.8, 65.3; MS (ESI) m/z=370 (M+ +1,
100); HRMS (ESI) m/z calcd for C19H12Cl2N3: 352.0408 [M+H]; found:
352.0408.
2228, 1500, 1360 cm−1; H NMR (400 MHz, CDCl3) δ 7.56–7.66 (2H,
m, ArH), 7.41–7.49 (2H, m, ArH), 7.37 (2H, m, ArH), 7.22–7.30 (1H,
m, ArH), 7.00(1H, m, ArH), 6.92 (1H, d, J=2.2 Hz, ArH), 5.98 (1H, d,
J=1.7 Hz, =CHH), 5.89 (1H, d, J=1.3 Hz, =CHH), 5.58 (1H, s, CHOH),
3.82 (3H, s, OCH3), 2.07 (3H, s, CO2CH3);13C NMR (100 MHz, CDCl3)
δ 198.6, 156.5, 147.8, 147.6, 137.9, 131.5, 130.2, 128.6 (2C), 128.0, 126.4,
124.9 (2C), 124.5, 122.3, 121.2, 118.4, 110.9, 64.0, 55.8, 26.2; MS (ESI)
m/z=383 (M+ +1, 100); HRMS (ESI) m/z calcd for C21H20ClN2O3:
383.1162 [M+H]; found: 383.1171.
2-((5-Chloro-3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
(hydroxy)methyl)acrylo nitrile (2d): Yellow oil; IR (KBr): 3439, 2924,
3-((5-Chloro-3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)(hydroxy)
methyl)but-3-en-2-one (2k): Yellow solid, m.p. 60.3–61.1 °C; IR (KBr):
3440, 3007, 1676, 1499 cm−1; H NMR (400 MHz, CDCl3) δ 7.71–7.75
1
2238, 1535, 1499 cm−1; H NMR (400 MHz, CDCl3) δ 7.59–7.65 (2H,
1
m, ArH), 7.36–7.52 (5H, m, ArH), 7.04–7.10 (1H, m, ArH), 6.95 (1H, d,
J=8.3 Hz, ArH), 5.99 (1H, d, J=2.2 Hz, =CHH), 5.80 (1H, d, J=2.2 Hz,
=CHH), 5.29 (1H, s, CHOH), 3.85 (3H, s, OCH3);13C NMR (100 MHz,
CDCl3) δ 156.1, 148.2, 137.6, 131.9, 130.6, 129.2, 128.8 (2C), 128.4,
126.9, 125.0 (2C), 123.6, 121.8, 121.6, 116.7, 116.3, 111.2, 65.3, 56.2; MS
(ESI) m/z=366 (M+ +1, 100); HRMS (ESI) m/z calcd for C20H17ClN3O2:
366.1009 [M+H]; found: 366.1051.
2-((5-Chloro-3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)(hydroxy)
methyl)acrylo nitrile (2e): Yellow solid, m.p. 93.9–94.7 °C; IR (KBr):
3431, 2917, 2253, 1525, 1453 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.60–
7.69 (2H, m, ArH), 7.53–7.59 (2H, m, ArH), 7.39–7.51 (3H, m, ArH),
6,99–7.14 (2H, m, ArH), 6.07 1H, d, J=2.2 Hz, =CHH), 5.98 (1H, d,
J=2.2 Hz, =CHH), 5.41(1H, s, CHOH), 3.11 (1H, s, OH); 13C NMR
(100 MHz, CDCl3) δ 162.9 (JC–F =248 Hz), 151.0, 137.3, 130.7, 130.6,
130.3, 128.9 (2C), 128.7, 127.7, 127.4, 125.1(2C), 123.0, 116.7, 115.4, 115.1,
114.3, 65.1; MS (ESI) m/z=354 (M+ +1, 100); HRMS (ESI) m/z calcd for
C19H14ClFN3O: 354.0809 [M+H]; found: 354.0807.
(2H, m, ArH), 7.59 (2H, t, J=6.0 Hz, ArH), 7.41–7.51 (3H, m, ArH),
7.08 (2H, t, J=8.8 Hz, ArH), 6.16 (1H, s, =CHH), 6.02 (1H, d, J=1.2 Hz,
=CHH), 5.84 (1H, s, CHOH), 3.28 (1H, s, OH), 2.30 (3H, s, CH3); 13C
NMR (100 MHz, CDCl3) δ 200.2, 162.9 (JC–F =245 Hz, 1C), 151.0, 146.9,
137.9, 130.8, 130.7, 129.0, 128.7(2C), 128.5, 127.1, 125.2 (2C), 115.3 (2C),
115.0 (2C), 64.5, 26.4; MS (ESI) m/z=373 (M+ +3, 37), 371 (M+ +1, 100);
HRMS (ESI) m/z calcd for C20H17ClFN2O2: 371.0963 [M+H]; found:
371.0975.
Synthesis of 3; general procedure
A mixture of 2 (1.0 mmol), AlCl3 (0.4 mmol), and CH3NO2 (3.0 mL) was
heated at reflux for the given time. The reaction was quenched by ice-
water and the mixture was extracted with ethyl acetate (3×10 mL). The
extracted solution was dried over Na2SO4 and concentrated in vacuo.
The desired products 3 were obtained by flash column chromatography
on silica (n-hexane/EtOAc, 16:1, v/v).
Methyl 3-chloro-8-methyl-2-phenyl-2,6-dihydrobenzo[6,7]cyclohepta
[1,2-c]pyrazole-5-carboxylate (3a): Yellow solid, m.p. 127.5–128.3°C
(n-hexane/EtOAc); Rf =0.66 (n-hexane/EtOAc, 6:1); IR (KBr): 3521,
2901, 1648, 1455, 1362 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.82 (1H, d,
J=8.0 Hz, ArH), 7.67 (2H, d, J=7.6 Hz, ArH), 7.59 (1H, s, C=CH), 7.43–
7.54 (3H, m, ArH), 7.24 (1H, s, ArH), 7.12 (1H, d, J=7.6 Hz, ArH), 3.83
(3H, s, CH3), 3.63 (2H, s, CH2), 2.38 (3H, s, CH3); 13C NMR (100 MHz,
CDCl3) δ 166.9, 151.5, 140.1, 138.2, 137.2, 130.0, 129.3 (2C), 128.9, 128.4,
128.2, 128.0, 127.9, 127.1, 126.8, 125.3 (2C), 116.6, 52.5, 33.6, 21.7; MS
(EI) m/z=365 (M+ +1, 100). HRMS (ESI) m/z calcd for C21H18ClN2O2:
365.1057 [M+H]; found: 365.1032.
Methyl 3-chloro-8-fluoro-2-phenyl-2,6-dihydrobenzo[6,7]cyclohepta
[1,2-c]pyrazole-5-carboxylate (3b): Yellow oil; IR (neat): 3524, 2501,
1643, 1452, 1379 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.65–7.44 (7H, m,
ArH and CH=C), 7.13–7.10 (2H, m, ArH), 4.30 (2H, s, CH2), 3.88 (3H, s,
CH3); 13C NMR (100 MHz, CDCl3) δ 165.2 (JC–F =150 Hz), 162.0, 150.3,
137.9, 132.5, 131.8, 129.4(2C), 129.1 (2C), 128.3 (2C), 127.2, 125.3 (2C),
116.2, 116.0, 112.2, 52.9, 39.5; MS (ESI) m/z=369 (M+ +1, 100); HRMS
(ESI) m/z calcd for C20H15ClFN2O2: 369.0806 [M+H]; found: 369.0807.
2-((5-Chloro-1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)(hydroxy)methyl)
acrylonitrile (2f): Yellow solid, m.p. 61.4–62.5 °C; IR (KBr): 3445,
2239, 1622, 1499 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41–7.58 (7H, m,
ArH), 7.20 (2H, d, J=8.0 Hz, ArH), 6.08 (1H, d, J=1.6 Hz, =CHH), 6.00
(1H, d, J=1.6 Hz, =CHH), 5.43(1H, t, J=1.8 Hz, CHOH), 2.90 (1H, t,
J=6.4 Hz, CH), 2.37 (3H, s, CH3); 13C NMR(100 MHz, CDCl3) δ 152.2,
138.8, 137.7, 130.4, 129.1(2C), 129.0 (2C), 128.7 (4C), 127.2, 123.5, 125.3
(2C), 116.9, 114.4, 65.2, 21.2; MS (ESI) m/z=352 (M+ +3, 31), 350 (M+ +1,
100); HRMS (ESI) m/z calcd for C20H17ClN3O: 350.1016 [M+H]; found:
350.1015.
3-((5-Chloro-1-phenyl-3-p-tolyl-1H-pyrazol-4-yl)(hydroxy)methyl)
but-3-en-2-one (2g): Yellow solid, m.p. 68.5–70.3 °C; IR (KBr):
1
3420, 2247, 1675, 1499 cm−1; H NMR (400 MHz, CDCl3) δ 7.60 (4H,
t, J=8.0 Hz, ArH), 7.49 (2H, t, J=8.0 Hz, ArH), 7.43 (1H, d, J=7.6 Hz,
ArH), 7.20 (2H, d, J=8.0 Hz, ArH), 6.19 (1H, s, =CHH), 6.03 (1H, s,
=CHH), 5.89 (1H, s, CHOH), 2.38 (3H, s, CH3), 2.34 (3H, s, COCH3); 13
C
NMR (100 MHz, CDCl3) δ 200.5, 152.0, 147.0, 138.3, 138.1, 129.6, 129.0
(4C), 128.7 (2C), 128.4, 127.3, 126.9, 125.3 (2C), 115.8, 64.8, 26.5, 21.3;
MS (ESI) m/z=369 (M+ +3, 33), 367 (M+ +1, 100); HRMS (ESI) m/z calcd
for C21H20ClN2O2: 367.1213 [M+H]; found: 367.1225.
A
mixture of 3b and methyl 3-chloro-8-fluoro-2-phenyl-2,4-
dihydrobenzo[6,7]cyclohepta [1,2-c]pyrazole-5-carboxylate (3bʹ): 1H
NMR (400 MHz, CDCl3) δ 7.68–7.44 (9.83H, m, ArH and CH=C), 7.13–
7.10 (2.63H, m, ArH), 6.92 (0.81H, s, ArH), 4.45 (1.81H, s, CH2), 4.31
(0.54H, s, CH2), 3.89 (0.73H, s, CH3), 3.59 (3H, s, CH3).
3-((5-Chloro-1,3-diphenyl-1H-pyrazol-4-yl)(hydroxy)methyl)but-3-
en-2-one (2h): Yellow solid, m.p. 113.5–115.7 °C; IR (KBr): 3410, 2925,
1
2357, 1685 cm−1; H NMR (400 MHz, CDCl3) δ 7.71 (2H, t, J=2.0 Hz,
ArH), 7.62 (2H, d, J=8.0 Hz, ArH), 7.37–7.52 (6H, m, ArH), 6.18 (1H,
s, =CHH), 6.03 (1H, s, =CHH), 5.89 (1H, s, CHOH), 2.32 (3H, s, CH3);
13C NMR (100 MHz, CDCl3) δ=200.4, 152.0, 147.0, 138.0, 132.5, 129.0,
128.9 (2C), 128.4 (2C), 128.3 (3C), 127.3, 127.0, 125.3 (2C), 115.9, 64.8,
26.5; MS (ESI) m/z=355 (M+ +3, 38), 353 (M+ +1, 100); HRMS (ESI) m/z
calcd for C20H18ClN2O2: 353.1057 [M+H]; found: 353.1073.
3,10-Dichloro-2-phenyl-2,6-dihydrobenzo[6,7]cyclohepta[1,2-c]
pyrazole-5-carbonitrile (3c): Yellow oil; Rf =0.64 (n-hexane/EtOAc,
6:1); IR (KBr): 3426, 2931, 2218, 1598, 1386 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.65–7.63 (2H, m, ArH), 7.43–7.53 (4H, m, ArH), 7.36–7.40
(2H, m, ArH), 7.04 (1H, s, C=CH), 4.23 (2H, s, CH2); 13C NMR
(100 MHz, CDCl3) δ 149.8, 137.4, 136.0, 133.0, 132.0, 130.9, 130.5, 129.9,
129.1, 128.9 (2C), 127.2, 127.1, 125.1 (2C), 115.7, 113.3, 112.4, 45.1; MS
(EI) m/z=354 (M+ +3, 39), 352 (M+ +1, 63), 77 (100). HRMS (ESI) m/z
calcd for C19H12Cl2N3: 352.0408 [M+H]; found: 352.0423.
3- Chloro-10 -methoxy-2-phenyl-2,6 -dihydrobenzo[6,7]
cyclohepta[1,2-c]pyrazole-5-carbonitrile (3d): Yellow oil; Rf =0.58
(n-hexane/EtOAc, 6:1); IR (KBr): 3436, 2919, 2225, 1600, 1394 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.39–7.64 (6H, m, ArH and C=CH), 7.04–7.07
(2H, m, ArH), 6.97 (1H, d, J=8.0 Hz, ArH), 4.24 (2H, s, CH2), 3.83 (3H,
s, CH3); 13C NMR (100 MHz, CDCl3) δ 156.5, 149.6, 137.6, 131.0, 130.8,
129.0 (3C), 128.7, 127.3, 125.1 (3C), 121.0, 120.7, 116.0, 113.5, 110.9, 55.4,
3-((5-Chloro-3-(2-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)(hydroxy)
methyl)but-3-en-2-one (2i): Yellow solid, m.p. 106.8–108.3 °C; IR (KBr):
1
3415, 1666, 1441, 1365 cm−1; H NMR (400 MHz, CDCl3) δ 7.64 (2H,
m, ArH), 7.42–7.51 (5H, m, ArH), 7.31–7.36 (2H, m, ArH), 6.04 (2H, d,
J=7.6 Hz, =CH2), 5.61 (1H, t, J=1.6 Hz, CHOH), 2.21(3H, s, CH3); 13
C
NMR (100 MHz, CDCl3) δ 199.4, 149.3, 146.6, 137.9, 134.2, 132.7, 132.0,
130.1, 129.2 (3C), 128.9, 128.4, 126.5, 126.5, 125.1 (2C), 117.9, 64.5, 26.1;
MS(ESI) m/z=389 (M+ +3, 66), 387 (M+ +1, 100); HRMS (ESI) m/z calcd
for C20H17Cl2N2O2: 387.0667 [M+H]; found: 387.0657.
3-((5-Chloro-3-(2-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)
(hydroxy)methyl)but-3-en-2-one (2j): Yellow oil; IR (KBr): 3495, 2927,
JCR1302254_FINAL.indd 88
30/01/2014 11:36:42

JOURNAL OF CHEMICAL RESEARCH 2014 89
45.4; MS (EI) m/z=350 (M+ +3, 36), 348 (M+ +1, 100). HRMS (ESI) m/z
calcd for C20H15ClN3O: 348.0904 [M+H]; found: 348.0936.
1-(3-Chloro-8-f luoro-2-phenyl-2,6-dihydrobenzo-[6,7]
cyclohepta[1,2-c]pyrazol-5-yl)ethanone (3k): Yellow solid, m.p. 159.5–
161.2 °C (n-hexane/EtOAc); Rf =0.58 (n-hexane/EtOAc, 6:1); IR (KBr):
3-Chloro-8-fluoro-2-phenyl-2,6-dihydrobenzo[6,7]cyclohepta[1,2-c]
pyrazole-5-carbonitrile (3e): Yellow solid, m.p. 104–105.7°C (n-hexane/
EtOAc); Rf =0.58 (n-hexane/EtOAc, 6:1); IR (KBr): 3431, 2917, 2235,
1525, 1453 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.57–7.64 (3H, m, ArH),
7.44–7.54 (3H, m, ArH and C=CH), 7.12–7.16 (3H, m, ArH), 4.32(2H,
s, CH2); 13C NMR (100 MHz, CDCl3) δ 163.1 (JC–F =250 Hz, 1C), 150.4,
137.4, 136.2, 129.5, 129.4, 129.1 (2C), 128.9, 127.7, 125.1 (2C), 116.0 (2C),
115.9, 115.8, 113.3, 111.4, 44.8; MS (EI) m/z=337 (M+ +2, 34), 335 (M+,
100). HRMS (ESI) m/z calcd for C19H12ClFN3: 336.0704 [M+H]; found:
336.0719.
1
3440, 3007, 1676, 1499 cm−1; H NMR (400 MHz, CDCl3) δ 7.48–7.67
(7H, m, ArH), 7.36 (1H, s, C=CH), 7.16–7.12 (1H, m, ArH), 4.32 (2H, s,
CH2), 2.50 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) δ 196.8, 163.1 (JC–
F =248 Hz, 1C), 150.1, 140.3, 137.6, 129.2, 129.1(3C), 128.9, 128.0, 126.9,
125.0 (2C), 116.0, 115.8 (2C), 111.9, 37.9, 29.6; MS (EI) m/z=355 (M+ +3,
38), 353 (M+ +1, 100). HRMS (ESI) calcd for C20H15ClFN2O: 353.0857
[M+H]; found: 353.0896.
Preparation of 3aʹ
A mixture of 3a (1.0 mmol), CH2NO2 (10.0 mL) was heated at reflux for
8 hours. The reaction was monitored by TLC. After completion of the
reaction, the mixture was concentrated in vacuo. The rearrangement
product 3aʹ was obtained by flash column chromatography on silica
(n-hexane/EtOAc, 16:1, v/v) with 75% yield.
Methyl 3-chloro-8-methyl-2-phenyl-2,4-dihydrobenzo[6,7]cyclohepta
[1,2-c]pyrazole-5-carboxylate (3aʹ): White solid, m.p. 133.2–134.6°C
(n-hexane/EtOAc); Rf =0.52 (n-hexane/EtOAc, 6:1); IR (KBr): 3527,
2894, 1656, 1458, 1335 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, d,
J=7.6 Hz, ArH), 7.55 (2H, d, J=8.4 Hz, ArH), 7.53 (1H, s, C=CH), 7.52–
7.34 (3H, m, ArH), 7.24 (1H, s, ArH), 7.22 (1H, d, J=8.0 Hz, ArH), 4.29
(2H, s, CH2), 3.88 (3H, s, CH3), 2.38 (3H, s, CH3); 13C NMR (100 MHz,
CDCl3) δ 165.8, 151.0, 138.7, 137.7, 132.0 (2C), 131.4, 129.4 (2C), 129.0
(2C), 128.6 (2C), 127.3 (2C), 125.3 (2C), 111.9, 52.5, 39.4, 21.5; MS
(EI) m/z=365 (M+ +1, 100). HRMS(ESI) m/z calcd for C21H18ClN2O2:
365.1057 [M+H]; found: 365.1038.
3-Chloro-8-methyl-2-phenyl-2,6-dihydrobenzo[6,7]cyclohepta[1,2-c]
pyrazole-5-carbonitrile (3f): Yellow solid, m.p. 117.8–119.5°C
(n-hexane/EtOAc); Rf =0.58 (n-hexane/EtOAc, 6:1); IR (KBr): 3435,
1
2229, 1628, 1499 cm−1; H NMR (400 MHz, CDCl3) δ 7.61–7.64 (2H,
m, ArH), 7.43–7.52 (5H, m, ArH and C=CH), 7.25 (1H, d, J=8 Hz,
ArH), 7.14 (1H, s, ArH), 4.32 (2H, s, CH2), 2.40 (3H, s, CH3); 13C
NMR(100 MHz, CDCl3) δ 151.5, 139.0, 137.6, 136.8, 129.4 (2C), 129.0
(2C), 128.8, 128.7, 127.9, 127.6 (2C), 125.2 (2C), 116.1, 112.8, 111.5, 44.9,
21.5; MS (EI) m/z=334 (M+ +3, 32), 332 (M+ +1, 100). HRMS (ESI) m/z
calcd for C20H15ClN3: 332.0955 [M+H]; found: 332.0976.
1-(3- Chloro- 8-methyl-2-phenyl-2,6 -dihydrobenzo[6,7]
cyclohepta[1,2-c]pyrazol-5-yl)ethanone (3g): Yellow solid, m.p. 155.6–
156.2°C (n-hexane/EtOAc); Rf =0.58 (n-hexane/EtOAc, 6:1); IR (KBr):
3428, 2237, 1655, 1493 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66 (2H, d,
J=8.0 Hz, ArH), 7.45–7.56 (5H, m, ArH), 7.39 (1H, s, C=CH), 7.25 (1H,
s, ArH), 4.32 (2H, s, CH2), 2.50 (3H, s, CH3), 2.40 (3H, s, COCH3); 13
C
NMR (100 MHz, CDCl3) δ 197.1, 151.2, 140.0, 139.0, 137.8, 131.7, 129.6,
129.2, 129.1, 128.8, 127.4, 126.7, 125.1, 112.0, 38.1, 26.4, 21.3; MS (ESI)
m/z=349.5 (M+ +1, 100); HRMS (ESI) calcd for C21H18ClN2O: 349.1108
[M+H]; found: 349.1127.
We thank the National Natural Science Foundation of China
(No. 21076194 and 21276238) for financial support.
1-(3-Chloro-2-phenyl-2,6-dihydrobenzo[6,7]cyclohepta[1,2-c]
pyrazol-5-yl)ethanone (3h): Yellow solid, m.p. 137.5–138.2°C
(n-hexane/EtOAc); Rf =0.58 (n-hexane/EtOAc, 6:1); IR (KBr): 3420,
Received 26 October 2013; accepted 10 December 2013
Paper 1302254 doi: 10.3184/174751914X13891972597451
Published online: 5 February 2014
1
2935, 1665, 1489 cm−1; H NMR (400 MHz, CDCl3) δ 7.40–7.67 (10H,
m, ArH and CH=C), 4.32 (2H, s, CH2), 2.50 (3H, s, CH3); 13C NMR
(100 MHz, CDCl3) δ 197.0, 151.1, 140.1, 137.8, 129.2 (2C), 129.0 (2C),
128.9 (2C), 128.8 (2C), 127.5 (2C), 126.8, 125.1 (2C), 112.2, 38.1, 26.4;
MS (EI) m/z=336 (M+ +2, 100). HRMS (ESI) calcd for C20H16ClN2O:
335.0951 [M+H]; found: 335.0934.
References
1
2
3
4
D.P. Kishore, C. Balakumar, A.R. Rao, P.P. Roy and K. Roy, Bioorg. Med.
Chem. Lett., 2011, 21, 818.
A.M. Farag, K.A.K. Ali, T.M.A. El-Debss, A.S. Mayhoub, A.-G.E. Amr,
N.A. Abdel-Hafez and M.M. Abdulla, Eur. J. Med. Chem., 2010, 45, 5887.
T.A. Farghaly, N.A.A. Hafez, E.A. Ragab, H.M. Awad and M.M. Abdalla,
Eur. J. Med. Chem., 2010, 45, 492.
M.D. Rosen, C.R. Woods, S.D. Goldberg, M.D. Hack, A.D. Bounds, Y.
Yang, P.C. Wagaman, V.K. Phuong, A.P. Ameriks, T.D. Barrett, K.C.
Kanelakis, J. Chang, N.P. Shankley and M.H. Rabinowitz Bioorg. Med.
Chem. Lett., 2009, 19, 6548.
1-(3,10-Dichloro-2-phenyl-2,6-dihydrobenzo-[6,7]cyclohepta[1,2-c]
pyrazol-5-yl)ethanon (3i): Yellow oil; Rf =0.58 (n-hexane/EtOAc, 6:1);
1
IR (KBr): 3423, 1656, 1451, 1369 cm−1; H NMR (400 MHz, CDCl3)
δ 7.68–7.66 (2H, m, ArH), 7.52–7.54 (5H, m, ArH), 7.33–7.47 (3H, m,
ArH), 4.12 (2H, s, CH2), 2.44 (3H, s, CH3); 13C NMR (100 MHz, CDCl3)
δ 197.1, 149.5, 139.7 (2C), 137.6 (2C), 131.7, 130.2 (2C), 129.2 (2C), 128.5,
127.2 (2C), 126.9 (2C), 125.0, 114.1, 37.9, 26.3; MS (EI) m/z=371 (M+ +3,
63), 369 (M+ +1, 100). HRMS (ESI) calcd for C20H15Cl2N2O: 369.0561
[M+H]; found: 369.0578.
1-(3-Chloro-10-methoxy-2-phenyl-2,6-dihydrobenzo[6,7]
cyclohepta[1,2-c]pyrazol-5-yl)ethanone (3j): Yellow oil; Rf =0.58
(n-hexane/EtOAc, 6:1); IR (KBr): 3469, 2937, 2218, 1510, 1364 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.63–7.65 (2H, m, ArH), 7.49–7.54 (3H, m,
ArH), 7.37–7.46 (2H, m, ArH), 7.32 (1H, s, C=CH), 7.04 (1H, t, J=7.6 Hz,
ArH), 6.94 (1H, d, J=8.2 Hz, ArH), 4.20 (2H, s, CH2), 3.78 (3H, s, CH3),
2.43 (3H, s, COCH3);13C NMR (100 MHz, CDCl3) δ 197.1, 156.2, 149.2,
138.2, 137.7, 132.3, 130.8, 130.7, 129.0 (3C), 128.6, 125.0 (3C), 121.0,
114.1, 111.0, 55.0, 38.4, 26.4; MS (EI) m/z=365 (M+ +1, 100). HRMS
(ESI) calcd for C21H18ClN2O2: 365.1057 [M+H]; found: 365.1035.
5
D. Basavaiah, K. Aravindu, K.S. Kumar and K.R. Reddy, Eur. J. Org.
Chem., 2010, 1843.
6
7
8
9
G.-N. Ma, J.-J. Jiang, M. Shi and Y. Wei, Chem. Commun., 2009, 37, 5496.
V. Singh and S. Batra, Tetrahedron, 2008, 64, 4511.
J. Mansilla and J.M. Saa, Molecules, 2010, 15, 709.
W.H. Zhong, F.L. Lin, R.E. Chen and W.K. Su, Synthesis, 2009, 2333.
10 K.N. Clary, M. Parvez and T.G. Back, Org. Biomol. Chem., 2009, 7, 1226.
11 D. Basavaish and K.R. Reddy, Tetrahedron, 2010, 66, 1215.
12 D. Basavaiah, B.S. Reddy and S.S. Badsara, Chem. Rev., 2010, 110, 5447.
13 H. Kurasaki, I. Okamoto, N. Morita and O. Tamura, Org. Lett., 2009, 11,
1179.
14 W.H. Zhong, W. Ma and Y.B. Liu, Tetrahedron, 2011, 67, 3509.
15 W.H. Zhong, X. Chen and Y.Y. Shen, J. Chem. Res., 2010, 35, 370.
16 S. Nag, V. Singh and S. Batra, ARKIVOC, 2007, 14, 185.
JCR1302254_FINAL.indd 89
30/01/2014 11:36:43

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.