Effect of solvent on the regioselective synthesis of spiropyrazoles

Article abstract of DOI:10.1016/j.tet.2012.08.064

1,3-Dipolarcycloaddition reactions of 6-arylmethylene-6,7,8,9-tetrahydro- 5H-benzocyclohepten-5-ones (1) with nitrilimines 3 were investigated in benzene and chloroform. The reaction products were 2′,4′,6,7,8,9-hexahydro- 2′,4′,5′-triaryl spiro[benzocyclo

Full text of DOI:10.1016/j.tet.2012.08.064

Tetrahedron 68 (2012) 9056e9060
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Effect of solvent on the regioselective synthesis of spiropyrazoles
*
Sayed M. Riyadh, Thoraya A. Farghaly
Department of Chemistry, Faculty of Science, University of Cairo, Giza 12613, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
1,3-Dipolarcycloaddition reactions of 6-arylmethylene-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ones
(1) with nitrilimines 3 were investigated in benzene and chloroform. The reaction products were
20,40,6,7,8,9-hexahydro-20,40,50-triaryl spiro[benzocycloheptene-6(5H),30(3H-pyrazol)-5-ones (4) or
20,30,6,7,8,9-hexahydro-20,30,50-triaryl spiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-ones (5). X-ray
crystallographic analysis was carried out for compound 5b. It was found that the regioselectivity of the
produced compounds was altered based on changing solvent type.
Received 26 February 2012
Received in revised form 31 July 2012
Accepted 20 August 2012
Available online 27 August 2012
Keywords:
Benzocyclohepten-5-ones
Nitrilimines
Ó 2012 Elsevier Ltd. All rights reserved.
Regioselectivity
X-ray crystallographic analysis
Hydrazonoyl halides
1. Introduction
O
C
N
Ar
The varied bioactivities of spiroazoles have encouraged scien-
tists to develop efficient methods to synthesize these compounds
and their analogues. Spiroazoles have prodigious pharmacological
activities, such as, anti-tumor,1,2 antihyperglycemic,3,4 anti-
mycobacterial,5 and antifungal6 activities. Also, they have vasodi-
lation activity7 due to their pivotal role in the expansion of blood
vessels by relaxation of smooth muscle cells within their walls,
especially large, and smaller arterioles, and large veins. Moreover,
spiroazoles of natural origin have been used as antipyretic, anti-
hypertensive, and anticonvulsant medications8 for the treatment
of headache, vertigo, and epilepsy.
Numerous elegant methods have been published to demon-
strate the construction of spiroazoles, such as, (a) 1,3-
dipolarcycloaddition of nitrile imines to a thione group (C]S)
to afford spiro[1,3,4]thiadiazoles;9,10 (b) cycloaddition of mer-
captoacetic acid onto an imine group (C]N) to afford spiro-
thiazolidine11 derivatives; (c) 1,3-dipolarcycloaddition of nitrile
N-oxide to an exocyclic double bond (C]C) to give spiro iso-
xazoles;12 (d) 1,3-dipolarcycloaddition of nitrilimines to exocyclic
double bond (C]C) to give spiro pyrazoles.7,13e16 The regiose-
lectivity of latter cycloadditions proceed via two pathways: route
R
+
N
Ph
Nitrile imine
Route 2
Route 1
R
Ph
N
O
N
N
O
N
Ph
R
Ar
Isomer (A)
Ar
Isomer (B)
Scheme 1.
Previous reports7,13e16 established the formation of regio-
isomer (A) as the reaction product, based on spectroscopic data
and X-ray crystallography. It is worth mentioning that all previous
cycloaddition reactions were carried out in benzene or toluene as
solvent. In the present work, we study the effect of two solvents
(benzene and chloroform) on the regioselective cycloaddition of
nitrilimines and an exocyclic double bond (C]C). The structure of
the product was confirmed by X-ray crystallography.
1: the electron rich nitrogen of the dipole adds to the
a-carbon of
the carbonyl to give regio-isomer (A); route 2: the electron rich
nitrogen of the dipole adds to
b-carbon to give another regio-
2. Results and discussion
isomer (B) (Scheme 1).
1,3-Dipolarcycloaddition reactions of 6-arylmethylene-6,7,8,
* Corresponding author. E-mail address: thoraya-f@hotmail.com (T.A. Farghaly).
9-tetrahydro-5H-benzocyclohepten-5-ones17e19 (1)withnitrilimines
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.064

S.M. Riyadh, T.A. Farghaly / Tetrahedron 68 (2012) 9056e9060
9057
X
H
N
3 in dry benzene in the presence of a catalytic amount of triethyl-
amine were reported by Girgis et al.20 The reaction proceeded
regioselectively to provide 20,40,6,7,8,9-hexahydro-20,40,50-triaryl
spiro[benzocycloheptene-6(5H),30(3H-pyrazol)-5-ones (4) (regio-
isomer AdScheme 1) rather than 20,30,6,7,8,9-hexahydro-20,30,50-tri-
1
Ar
2
N
Ar
2
O
CHCl3 / TEA
-HCl
3
Ar
aryl
spiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-ones
(5)
C
N
2
Ar
1
Ar
+
N
(regio-isomer BdScheme 1) based on spectroscopic data and X-ray
crystallographic data (Scheme 2). The same regio-isomer 4a was ob-
tained when the reaction carried out in dry toluene.
3
1
2
1
Ar
Ar
Cl
H
N
N
N
2
1
Ar
N
O
Ar
O
N
N
Ph
Ph
2
-HCl Benzene / TEA
3
Ar
3
Ar
O
X = Cl or Br
Ar
5a-o
4a-o
C
N
Ph
+
N
Ph
3
1a,b
Ph
Ph
O
N
N
N
O
Ph
Ph
N
Ar
Ar
5a,b
4a,b
a; Ar = 4-FC6H4
b; Ar = 4-ClC6H4
Scheme 3.
Scheme 2.
These reactions were creative strategies toward the con-
struction of spiropyrazoles. Consequently, we attempted these
reactions using chloroform as polar solvent, instead of benzene,
to investigate the effect of polarity on the regioselectivity of the
reaction products. Thus, 1,3-Dipolarcycloaddition of
1 with
Nitrilimines 3, generated in situ from the corresponding
hydrazonoyl halides 2, in chloroform in the presence of trie-
thylamine gave the respective regio-isomer
5 instead of 4
(Scheme 3). Both the arylmethylene and nitrilimine moieties
were chosen as they have differing steric and electronic effects
on reaction outcome.
The elucidation for the structure of regio-isomer 5 was based on
spectroscopic data (IR, 1H NMR, 13C NMR, MS), elemental analyses,
and X-ray crystallography. 1H NMR spectroscopy revealed a singlet
at
d
¼5.41e5.58 ppm assignable to the H-30 pyrazole of regio-isomer
5,21,22 while the H-40 pyrazole of regio-isomer 4 would appear at
lower chemical shift.13e15,20,23 Also, the 13C NMR spectrum of
compound 5 revealed a sp3-spiro carbon signal (adjacent to sp2-
carbon atom) at
d
¼79.17e79.19 ppm, while the sp3-spiro carbon
signal (adjacent to sp3-nitrogen atom) of compound 4 would ap-
pear at
d
¼81.03 ppm15,16 The aforementioned spectral data pro-
vides firm support for the regioselective addition of the nitrilimine
3 to the arylidene olefinic moiety of compound 1 to give the spiro
[benzocycloheptene-6(5H),40(4H-pyrazol)]-5-ones (5) and rules
out the other regio-isomer 4 (Scheme 3). Single crystal X-ray dif-
fraction of 5b was measured and illustrated in Fig. 1, and the se-
lected bond lengths and bond angles are depicted in Table 1.
Attempts to elucidate the effect of solvent’s polarity on the
stability of regio-isomeric structures of 4a and 5a were achieved.
Thus, refluxing of product 4a in chloroform, as polar solvent, did
not interchange its regio-isomeric structure. Moreover, heating of
product 5a in non polar solvents, such as benzene, toluene, or
Fig. 1. X-ray crystal structure of compound 5b.
xylene gave the same structure. These results implied that, these
products are stable under these conditions.
In conclusion, we have found that there are two regioselective
routes possible during the synthesis of spiropyrazoles depending
on the type of solvent. This was confirmed by Single crystal X-ray
diffraction. Further investigation for thermodynamic and kinetic
products by molecular calculations will be performed in another
study.

9058
S.M. Riyadh, T.A. Farghaly / Tetrahedron 68 (2012) 9056e9060
oC];20 [Found: C, 80.64; H, 5.65; N, 6.14 C31H25FN2O requires C,
80.85; H, 5.47; N, 6.08%]; vmax (KBr) 1670 (C]O) cmꢁ1
dH
Table 1
Selected bond lengths and bond angles in the ORTEP of compound 5b in the crystal.
The crystallographic numbering does not reflect systematic numbering
;
(300 MHz, DMSO-d6) 1.40e2.88 (m, 6H, 3CH2), 4.80 (s, 1H,
pyrazoleeH-40), 6.97e7.02 and 7.24e7.58 (m, 14H, ArH), 7.14 (d,
J¼8 Hz, 2H, ArH), 7.78 (d, J¼8 Hz, 2H, ArH); dC (100 MHz, DMSO-d6)
21.45, 28.27, 31.45 (3CH2), 57.53 (pyrazoleeCH), 81.13 (spiroeC),
115.89, 119.61, 123.01, 126.39, 126.88, 127.78, 128.51, 128.84, 131.31,
132.29, 132.91, 133.04, 138.51, 143.78, 151.34, 160.62, 162.89 (AreC),
206.23 (C]O); m/z 460 (Mþ, 30), 341 (100), 328 (20), 230 (10), 104
(30), 77 (55%).
ꢀ
ꢀ
ꢀ
Bond length, A
Bond length, A
Bond length, A
C4eC15, 1.476 (3)
C4eN12, 2.168 (4)
C7eC15, 1.570 (3)
C7eN12, 1.533 (3)
C5eC15, 1.549 (4)
C7eC15, 1.570 (3)
15eC1, 1.539 (4)
17eC29, 1.374 (4)
O2eC5, 1.219 (3)
11eN12, 1.482 (4)
19eC23, 1.409 (4)
C
C
C
C
C5eC6, 1.505 (4)
Angle (
u
)
Angle (
12eC4eC14, 146.5 (2)
14eC4eC15, 126.8 (2)
O2eC5eC15, 118.7 (2)
O2eC5eC6, 118.9 (3)
u
)
Angle (
u)
C4eN3eN12, 109.1 (2)
N3eC4eN12, 34.39 (12)
N3eN12eC7, 113.0 (2)
N3eN12eC11, 123.7 (3)
N
C
N3eC4eC15, 112.7 (2)
C8eC7eN12, 109.7 (2)
C4eC15eC7, 100.6 (2)
C4eC15eC16, 109.6 (3)
3.4.2. 40-(4-Chlorophenyl)-20,50-diphenyl-20,40,6,7,8,9-hexahydrospiro
[benzocycloheptene-6(5H),30(3H-pyrazol)-5-one (4b).20 As yellow
crystals (0.38 g, 80%), mp 172e174 ꢀC [literature mp 172e174 ꢀC];20
[Found: C, 78.14; H, 5.32; N, 5.74 C31H25ClN2O requires C, 78.06; H,
3. Experimental
3.1. General
5.28; N, 5.87%]; vmax (KBr) 1678 (C]O) cmꢁ1
; dH (300 MHz, DMSO-
d6) 1.40e2.87 (m, 6H, 3CH2), 4.81 (s, 1H, pyrazoleeH-40), 6.95e7.01
and 7.23e7.58 (m, 14H, ArH), 7.12 (d, J¼8 Hz, 2H, ArH), 7.69 (d,
J¼8 Hz, 2H, ArH); m/z 478 (Mþþ2, 8), 477 (Mþþ1, 12), 476 (Mþ, 22),
357 (100), 344 (13), 77 (78%).
Melting points were measured on an Electrothermal IA 9000
series digital melting point apparatus. IR spectra were recorded in
potassium bromide discs on Pye Unicam SP 3300 and Shimadzu
FTIR 8101 PC infrared spectrophotometers. NMR spectra were
recorded on a Varian Mercury VX-300 NMR spectrometer operating
at 300 or 400 MHz (1H NMR) or 75 or 100 MHz (13C NMR) and run
in deuterated dimethylsulfoxide (DMSO-d6). Chemical shifts were
related to that of the solvent. Mass spectra were recorded on
a Shimadzu GCeMS-QP1000 EX mass spectrometer at 70 eV. Ele-
mental analyzes were measured by using a German made Ele-
mentar vario LIII CHNS analyzer. 6-Arylmethylene-6,7,8,9-
tetrahydro-5H-benzocyclohepten-5-ones17e19 and hydrazonoyl
halides24e26 were prepared as previously reported in the respective
literature.
3.5. Synthesis of 20,30,6,7,8,9-hexahydro-20,30,50-triaryl spiro
[benzocycloheptene-6(5H),40(4H-pyrazol)-5-ones (5aeo)
To a mixture of equimolar amounts of 6-arylmethylene-6,7,8,9-
tetrahydro-5H-benzocyclohepten-5-one (1) and the appropriate
hydrazonoyl halides 2 (1 mmol) in chloroform (20 mL) was added
triethylamine (0.14 mL, 1 mmol). The reaction mixture was
refluxed until all of the starting materials had disappeared (7e10 h,
monitored by TLC). The solvent was evaporated and the residue
was triturated with methanol. The solid that formed was filtered
and crystallized from appropriate solvent to give compounds
5aeo.
3.2. Crystallographic analysis
3.5.1. 20,50-Diphenyl-30-(4-fluorophenyl)-20,30,6,7,8,9-hexahydrospiro
[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one (5a). As yellow
crystals (0.39 g, 84%) (from ethanol), mp 164e166 ꢀC; [Found: C,
80.64; H, 5.65; N, 6.14 C31H25FN2O requires C, 80.85; H, 5.47; N,
The crystals were mounted on a glass fiber. All measurements
were performed on an ENRAF NONIUS FR 590. The data were col-
lected at a temperature of 25 ꢀC using the
u scanning technique to
6.08%]; vmax (KBr) 1660 (C]O) cmꢁ1
; dH (400 MHz, DMSO-d6)
a maximum of a 20 of 22.986ꢀ. The structure was solved by direct
method using SIR 92 and refined by full-matrix least squares. Non-
hydrogen atoms were refined anisotropically. Hydrogen atoms
were located geometrically and were refined isotropically.
1.12e2.78 (m, 6H, 3CH2), 5.50 (s, 1H, pyrazoleeH), 6.97e7.02 and
7.24e7.48 (m, 14H, ArH), 7.16 (d, J¼8 Hz, 2H, ArH), 7.72 (d, J¼8 Hz,
2H, ArH); dC (100 MHz, DMSO-d6) 21.47, 28.17, 31.42 (3CH2), 57.53
(pyrazoleeCH), 79.01 (spiroeC), 115.69, 119.61, 122.11, 126.19,
126.81, 127.88, 128.54, 128.88, 131.29, 132.25, 132.91, 132.94, 138.51,
143.77, 151.30, 160.42, 162.86 (AreC), 206.13 (C]O); m/z 462
(Mþþ2, 4), 460 (Mþ, 30), 341 (100), 328 (20), 230 (10), 104 (30), 77
(55%).
3.3. Crystal data
For compound 5b: C31H25ClN2O, M¼477.007, Monoclinic,
a¼21.1086 (8), b¼9.1011 (3), c¼12.8520 (4) Ǻ, v¼2465.69 (15),
¼90.00ꢀ,
b
¼92.9753 (11)ꢀ,
g
¼90.00ꢀ, space group: P21/c, Z¼4,
3.5.2. 30-(4-Chlorophenyl)-20,50-diphenyl-20,30,6,7,8,9-hexahydrospiro
[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one (5b). As yellow
crystals (0.38 g, 80%) (from dioxane), mp 158e160 ꢀC; [Found: C,
78.14; H, 5.32; N, 5.74 C31H25ClN2O requires C, 78.06; H, 5.28; N,
a
Dx¼1.285 Mg mꢁ3 1737 reflections measured, qmax¼27.49. Fig. 1
illustrates the structure as determined.27
3.4. Synthesis of 20,40,6,7,8,9-hexahydro-20,40,50-triaryl spiro
5.87%]; vmax (KBr) 1670 (C]O) cmꢁ1
; dH (400 MHz, DMSO-d6)
[benzocycloheptene-6(5H),30(3H-pyrazol)-5-ones (4a,b)
1.09e2.77 (m, 6H, 3CH2), 5.49 (s, 1H, pyrazoleeH), 6.95e7.01 and
7.23e7.48 (m, 14H, ArH), 7.12 (d, J¼8 Hz, 2H, ArH), 7.68 (d, J¼8 Hz,
2H, ArH); dC (100 MHz, DMSO-d6) 21.45, 28.13, 31.31 (3CH2), 57.51
(pyrazoleeCH), 79.17 (spiroeC), 119.72, 122.22, 126.15, 126.80,
127.78, 128.45, 128.50, 128.53, 128.77, 128.85, 131.17, 132.25, 132.58,
135.74,138.47, 143.71, 151.47 (AreC), 206.03 (C]O); m/z 478 (Mþþ2,
4), 477 (Mþþ1, 8), 476 (Mþ, 14), 357 (100), 218 (13), 144 (26), 111 (5),
77 (78%).
To a mixture of equimolar amounts of 6-arylmethylene-6,7,8,9-
tetrahydro-5H-benzocyclohepten-5-ones (1) and the appropriate
hydrazonoyl chlorides 2a,b (1 mmol) in dry benzene or dry toluene
(25 mL) was added triethylamine (0.14 mL, 1 mmol). The reaction
mixture was refluxed for 20 h. The solvent was evaporated and the
residue was triturated with methanol. The solid that formed was
filtered and crystallized from dioxane to give compounds 4a,b.
3.5.3. 30-(3,4-Dichlorophenyl)-20,50-diphenyl-20,30,6,7,8,9-hexahydros-
piro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one (5c). As yellow
solid (0.43 g, 84%) (from ethanol), mp 174e176 ꢀC; [Found: C, 72.64;
H, 4.62; N, 5.34 C31H24Cl2N2O requires C, 72.80; H, 4.73; N, 5.48%];
3.4.1. 20,50-Diphenyl-40-(4-fluorophenyl)-20,40,6,7,8,9-hexahydrospiro
[benzocycloheptene-6(5H),30(3H-pyrazol)-5-one (4a).20 As yellow
crystals (0.30 g, 66%), mp 154e156 ꢀC [literature mp 153e155

S.M. Riyadh, T.A. Farghaly / Tetrahedron 68 (2012) 9056e9060
9059
vmax (KBr) 1674 (C]O) cmꢁ1
;
dH (300 MHz, DMSO-d6) 1.12e3.07 (m,
yellow solid (0.41 g, 76%) (from ethanol), mp 110e112 ꢀC; [Found: C,
6H, 3CH2), 5.56 (s, 1H, pyrazoleeH), 6.86e7.71 (m, 17H, ArH); dC
(75 MHz, DMSO-d6) 21.38, 28.11, 31.03 (3CH2), 56.81 (pyrazoleeCH),
79.18 (spiroeC), 120.21, 121.34, 122.67, 123.11, 124.56, 126.18, 126.83,
127.54, 128.60, 128.74, 128.80, 130.72, 130.92, 131.07, 132.27, 137.94,
138.23,138.55,143.67 (AreC), 206.06 (C]O); m/z 514 (Mþþ4, 7), 512
(Mþþ2, 15), 510 (Mþ, 22), 391 (100), 255 (13), 144 (29), 104 (26), 77
(98%).
73.64; H, 4.62; N, 5.11 C33H26Cl2N2O requires C, 73.74; H, 4.88; N,
5.21%]; vmax (KBr) 1678 (C]O), 1593 (C]C) cmꢁ1
; dH (300 MHz,
DMSO-d6) 1.13e2.74 (m, 6H, 3CH2), 5.58 (s, 1H, pyrazoleeH), 6.98 (d,
1H, J¼15.5 Hz, CH]), 7.05 (d, 1H, J¼15.5 Hz, CH]), 7.15e7.48 (m,
17H, ArH); dC (75 MHz, DMSO-d6) 21.52, 24.65, 27.94 (3CH2), 56.63
(pyrazoleeCH), 79.18 (spiroeC), 119.23, 119.54, 119.88, 120.54,
122.19, 126.39, 126.61, 126.89, 128.15, 128.58, 128.91, 132.33, 132.85,
133.18, 136.15, 138.16, 139.11, 139.43, 143.15, 149.53, 151.98 (AreC),
205.88 (C]O); m/z 540 (Mþþ4, 7), 538 (Mþþ2, 24), 536 (Mþ, 45),
417 (58), 77 (100%).
3.5.4. 30-(3,4-Dimethoxyphenyl)-20,50-diphenyl-20,30,6,7,8,9-hexahy-
drospiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one
(5d). As
yellow solid (0.39 g, 77%) (from ethanol/dioxane), mp 98e100 ꢀC;
[Found: C, 78.64; H, 6.14; N, 5.46 C33H30N2O3 requires C, 78.86; H,
3.5.9. 30-(3,4-Dimethoxyphenyl)-20,30,6,7,8,9-hexahydro-20-phenyl-
50-styrylspiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one
(5i). As yellow solid (0.38 g, 72%) (from ethanol), mp 108e110 ꢀC;
[Found: C, 79.64; H, 6.14; N, 5.48 C35H32N2O3 requires C, 79.52; H,
6.02; N, 5.57%]; vmax (KBr) 1681 (C]O) cmꢁ1
; dH (400 MHz, DMSO-
d6) 1.28e3.10 (m, 6H, 3CH2), 3.71 (s, 6H, 2(OCH3)), 5.44 (s, 1H,
pyrazoleeH), 6.89e7.67 (m, 17H, ArH); dC (75 MHz, DMSO-d6) 21.28,
28.18, 31.15 (3CH2), 51.34, 52.08 (OCH3), 56.85 (pyrazoleeCH), 79.14
(spiroeC), 120.25, 121.11, 122.61, 123.17, 124.59, 126.44, 126.93,
127.51, 128.64, 128.74, 128.88, 130.82, 130.98, 131.17, 132.57, 137.94,
138.83, 139.35, 143.69 (AreC), 206.16 (C]O); m/z 503 (Mþþ1, 24),
502 (Mþ, 67), 388 (100), 251 (15), 77 (50%).
6.10; N, 5.30%]; vmax (KBr) 1659 (C]O), 1593 (C]C) cmꢁ1
; dH
(300 MHz, DMSO-d6) 1.19e2.45 (m, 6H, 3CH2), 3.39 (s, 3H, OCH3),
3.72 (s, 3H, OCH3), 5.53 (s, 1H, pyrazoleeH), 6.84 (d, 1H, J¼15.6 Hz,
CH]), 7.05 (d, 1H, J¼15.6 Hz, CH]), 7.09e7.67 (m, 17H, ArH); dC
(100 MHz, DMSO-d6) 23.50, 26.62, 31.14 (3CH2), 51.88, 52.28
(OCH3), 57.23 (pyrazoleeCH), 79.19 (spiroeC), 119.66, 119.84,
120.54, 120.98, 122.87, 126.39, 126.71, 126.89, 128.35, 128.88, 129.11,
132.36, 132.83, 133.27, 136.45, 138.36, 139.42, 139.88, 142.15, 147.53,
152.98 (AreC), 206.08 (C]O); m/z 528 (Mþ, 96), 409 (100), 264
(26), 77 (70%).
3.5.5. 20,50-Diphenyl-20,30,6,7,8,9-hexahydro-30-(3,4,5-trimethoxyph-
enyl)spiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one (5e). As
orange solid (0.40 g, 75%) (from ethanol) mp 70e72 ꢀC; [Found:
C, 76.54; H, 6.16; N, 5.16 C34H32N2O4 requires C, 76.67; H, 6.06; N,
5.26%]; vmax (KBr) 1678 (C]O) cmꢁ1
; dH (300 MHz, DMSO-d6)
1.25e2.47 (m, 6H, 3CH2), 3.63 (s, 3H, OCH3), 3.72 (s, 3H, OCH3),
3.89 (s, 3H, OCH3), 5.54 (s, 1H, pyrazoleeH), 7.24e7.79 (m, 16H,
ArH); dC (75 MHz, DMSO-d6) 21.41, 28.71, 31.23 (3CH2), 51.36,
52.18 (OCH3), 56.61 (pyrazoleeCH), 79.19 (spiroeC), 120.21,
122.57, 123.14, 124.58, 126.21, 126.84, 128.62, 128.74, 128.91,
130.72, 130.92, 131.17, 132.25, 137.64, 138.13, 138.66, 143.65
(AreC), 206.16 (C]O); m/z 532 (Mþ, 28), 338 (44), 149 (76), 91
(100%).
3.5.10. 20,30,6,7,8,9-Hexahydro-20-phenyl-50-styryl-30-(3,4,5-
trimethoxyphenyl)spiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-
one (5j). As dark yellow solid (0.40 g, 72%) (from ethanol), mp
94e96 ꢀC; [Found: C, 77.64; H, 6.02; N, 5.11 C36H34N2O4 requires C,
77.40; H, 6.13; N, 5.01%]; vmax (KBr) 1678 (C]O), 1593 (C]C)
cmꢁ1
; dH (300 MHz, DMSO-d6) 1.23e2.44 (m, 6H, 3CH2), 3.61 (s,
3H, OCH3), 3.69 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 5.55 (s, 1H,
pyrazoleeH), 6.96 (d, 1H, J¼15.6 Hz, CH]), 7.00 (d, 1H, J¼15.6 Hz,
CH]), 7.04e7.49 (m, 16H, ArH); dC (75 MHz, DMSO-d6) 25.50,
28.62, 32.17 (3CH2), 51.94, 52.97 (OCH3), 57.54 (pyrazoleeCH),
79.16 (spiroeC), 119.51, 120.54, 121.87, 126.19, 126.74, 126.84,
128.18, 128.68, 129.11, 132.38, 132.86, 133.17, 136.65, 138.96, 139.47,
139.85, 142.19, 147.53, 152.78 (AreC), 206.05 (C]O); m/z 558 (Mþ,
65), 439 (100), 77 (84%).
3.5.6. 30-(4-Fluorophenyl)-20,30,6,7,8,9-hexahydro-20-phenyl-50-styr-
ylspiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one (5f). As yel-
low solid (0.39 g, 80%) (from ethanol/dioxane), mp 120e122 ꢀC;
[Found: C, 81.64; H, 5.62; N, 6.01 C33H27FN2O requires C, 81.46; H,
5.59; N, 5.76%]; vmax (KBr) 1663 (C]O), 1593 (C]C) cmꢁ1
; dH
(300 MHz, DMSO-d6) 1.03e3.01 (m, 6H, 3CH2), 5.52 (s, 1H,
pyrazoleeH), 6.98 (d, 1H, J¼15.4 Hz, CH]), 7.00 (d, 1H, J¼15.4 Hz,
CH]), 7.05e7.40 (m, 18H, ArH); dC (75 MHz, DMSO-d6) 21.52, 27.99,
31.60 (3CH2), 56.82 (pyrazoleeCH), 79.22 (spiroeC), 112.83, 115.64,
119.18, 120.59, 122.06, 125.31, 126.34, 126.80, 128.11, 128.33, 128.93,
129.06, 133.06, 133.24, 136.15, 138.18, 143.23, 152.51, 159.96 (AreC),
206.30 (C]O); m/z 488 (Mþþ2, 5), 487 (Mþþ1, 22), 486 (Mþ, 71),
367 (100), 77 (65%).
3.5.11. 30-(4-Fluorophenyl)-20,30,6,7,8,9-hexahydro-20-(4-nitrophenyl)-
50-thienyl spiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one
(5k). As orange solid (0.37, 73%) (from ethanol), mp 158e160 ꢀC;
[Found: C, 68.22; H, 4.45; N, 8.11; S, 6.14 C29H22FN3O3S requires C,
68.09; H, 4.33; N, 8.21; S, 6.27%]; vmax (KBr) 1659 (C]O) cmꢁ1
; dH
(300 MHz, DMSO-d6) 1.10e2.28 (m, 6H, 3CH2), 5.42 (s, 1H,
pyrazoleeH), 6.98e8.12 (m, 11H, ArH), 7.47 (d, 2H, J¼6 Hz, ArH),
8.23 (d, 2H, J¼6 Hz, ArH); dC (75 MHz, DMSO-d6) 21.99, 27.95,
32.42 (3CH2), 56.01 (pyrazoleeCH), 79.87 (spiroeC), 115.29,
115.83, 119.23, 120.62, 124.53, 126.88, 127.15, 127.61, 128.47, 129.03,
133.13, 133.63, 136.74, 138.10, 142.81, 145.10, 148.22 (AreC), 202.73
(C]O); m/z 511 (Mþ, 24), 490 (74), 392 (44), 231 (70), 185 (60), 76
(100%).
3.5.7. 30-(4-Chlorophenyl)-20,30,6,7,8,9-hexahydro-20-phenyl-50-styr-
ylspiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one (5g). As yel-
low solid (0.35 g, 70%) (from ethanol), mp 134e136 ꢀC; [Found: C,
78.84; H, 5.32; N, 5.64 C33H27ClN2O requires C, 78.79; H, 5.41; N,
5.57%]; vmax (KBr) 1678 (C]O), 1593 (C]C) cmꢁ1
; dH (400 MHz,
DMSO-d6) 1.12e3.21 (m, 6H, 3CH2), 5.54 (s,1H, pyrazoleeH), 6.94 (d,
1H, J¼15.5 Hz, CH]), 7.15 (d, 1H, J¼15.5 Hz, CH]), 7.19e7.48 (m,
18H, ArH); dC (75 MHz, DMSO-d6) 21.50, 24.67, 27.92 (3CH2), 56.69
(pyrazoleeCH), 79.15 (spiroeC), 119.23, 119.50, 119.81, 120.58,
122.20,126.39, 126.64,126.83, 128.08, 128.51,128.72,132.32, 132.81,
133.16, 136.12, 138.16, 143.18, 149.51, 152.48 (AreC), 205.48 (C]O);
m/z 504 (Mþþ2, 47), 502 (Mþ, 82), 383 (95), 253 (17), 130 (45), 77
(100%).
3.5.12. 30-(4-Chlorophenyl)-20,30,6,7,8,9-hexahydro-20-(4-nitrophenyl)-
50-thienylspiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one(5l). As
red solid (0.43 g, 82%) (from ethanol/dioxane), mp 124e126 ꢀC;
[Found: C, 65.84; H, 4.27; N, 8.03; S, 6.13 C29H22ClN3O3S requires C,
65.97; H, 4.20; N, 7.96; S, 6.07%]; vmax (KBr) 1664 (C]O) cmꢁ1
; dH
(300 MHz, DMSO-d6) 1.14e2.86 (m, 6H, 3CH2), 5.51 (s, 1H,
pyrazoleeH), 7.03e8.21 (m, 15H, ArH); dC (75 MHz, DMSO-d6) 21.95,
28.03, 32.41 (3CH2), 56.11 (pyrazoleeCH), 79.77 (spiroeC), 115.22,
115.88, 120.22, 120.85, 125.80, 126.78, 127.45, 127.90, 128.43, 128.77,
129.05, 133.45, 136.58, 138.14, 142.47, 145.11, 148.32 (AreC), 203.03
3.5.8. 30-(3,4-Dichlorophenyl)-20,30,6,7,8,9-hexahydro-20-phenyl-50-
styrylspiro[benzocycloheptene-6(5H),40(4H-pyrazol)-5-one (5h). As

9060
S.M. Riyadh, T.A. Farghaly / Tetrahedron 68 (2012) 9056e9060
(C]O); m/z 529 (Mþþ2, 10), 527 (Mþ, 25), 388 (30), 375 (75), 328
148.12 (AreC), 205.16 (C]O); m/z 583 (Mþ, 2), 490 (64), 231 (65),
185 (60), 76 (100%).
(50), 282 (20), 104 (30), 76 (80%).
3.5.13. 30-(3,4-Dichlorophenyl)-20,30,6,7,8,9-hexahydro-20-(4-
nitrophenyl)-50-thienylspiro [benzocycloheptene-6(5H),40(4H-pyrazol)-
5-one (5m). As orange solid (0.39 g, 70%) (from ethanol), mp
122e124 ꢀC; [Found: C, 61.72; H, 3.65; N, 7.31; S, 5.84 C29H21Cl2N3O3S
requires C, 61.93; H, 3.76; N, 7.47; S, 5.70%]; vmax (KBr) 1674 (C]O)
References and notes
1. Hong, H.; Huang, L. J.; Teng, D. W. Chin. Chem. Lett. 2011, 22, 1009e1012.
2. Prado, E. G.; Gimenez, M. D. G.; Vazquez, R. D.; Sanchez, J. L. E.; Rodriguez, M. T.
S. Phytomedicine 2007, 14, 280e284.
3. Cheon, H. G.; Kim, S. S.; Kim, K. R.; Rhee, S. D.; Yang, S. D.; Ahn, J. H.; Park, S. D.;
Lee, J. M.; Jung, W. H.; Lee, H. S.; Kim, H. Y. Biochem. Pharmacol. 2005, 70, 22e29.
4. Ahn, J. H.; Kim, J. A.; Kim, H. M.; Kwon, H. M.; Huh, S. C.; Rhee, S. D.; Kim, K. R.;
Yang, S. D.; Park, S. D.; Lee, J. M.; Kim, S. S.; Cheon, H. G. Bioorg. Med. Chem. Lett.
2005, 15, 1337e1340.
cmꢁ1
; dH (300 MHz, DMSO-d6) 1.18e2.38 (m, 6H, 3CH2), 5.58 (s, 1H,
pyrazoleeH), 6.98e8.11 (m, 10H, ArH), 7.49 (d, 2H, J¼6 Hz, ArH), 8.33
(d, 2H, J¼6 Hz, ArH); dC (75 MHz, DMSO-d6) 21.88, 28.11, 31.93 (3CH2),
56.61 (pyrazoleeCH), 79.88 (spiroeC), 115.34, 115.93, 120.21, 120.64,
124.67, 126.11, 127.36, 127.68, 128.53, 129.14, 133.18, 133.72, 136.92,
138.07, 138.68, 139.11, 142.77, 145.32, 148.34 (AreC), 203.06 (C]O);
m/z 565 (Mþþ4, 7), 563 (Mþþ2, 24), 561 (Mþ, 42), 490 (25), 226 (46),
178 (42), 77 (100%).
5. Prasanna, P.; Balamurugan, K.; Perumal, S.; Yogeeswari, P.; Sriram, D. Eur. J. Med.
Chem. 2010, 45, 5653e5661.
6. Raj, A. A.; Raghunathan, R.; Kumari, M. R. S.; Raman, N. Bioorg. Med. Chem. 2003,
11, 407e419.
7. Girgis, A. S.; Ismail, N. S. M.; Farag, H.; El-Eraky, W. I.; Saleh, D. O.; Tala, S. R.;
Katritzky, A. R. Eur. J. Med. Chem. 2010, 45, 4229e4238.
8. Kang, T. H.; Murakami, Y.; Matsumoto, K.; Takayama, H.; Kitajima, M.; Wata-
nabe, N. A. H. Eur. J. Pharmacol. 2002, 455, 27e34.
9. Hafez, H. H.; Hegab, M. I.; Ahmed-Farag, I. S.; El-Gazzar, A. B. A. Bioorg. Med.
Chem. Lett. 2008, 18, 4538e4543.
10. Caleb, A. A.; Ballo, D.; Rachid, B.; Amina, H.; Mostapha, B.; Abdelfettah, Z.; Rajae,
E.; Essassi El Mokhtara, E. Arkivoc 2011, ii, 217e226.
3.5.14. 30-(3,4-Dimethoxyphenyl)-20,30,6,7,8,9-hexahydro-20-(4-
nitrophenyl)-50-thienyl spiro [benzocycloheptene-6(5H),40(4H-pyr-
azol)-5-one (5n). As orange solid (0.45 g, 81%) (from ethanol), mp
120e122 ꢀC; [Found: C, 67.52; H, 4.98; N, 7.41; S, 5.59 C31H27N3O5S
requires C, 67.25; H, 4.92; N, 7.59; S, 5.79%]; vmax (KBr) 1654 (C]O)
11. Sakhuja, R.; Panda, S. S.; Khanna, L.; Khurana, S.; Jain, S. C. Bioorg. Med. Chem.
Lett. 2011, 21, 5465e5469.
12. Mishriky, N.; Asaad, F. M.; Ibrahim, Y. A.; Girgis, A. S. J. Chem. Res., Synop. 1997,
438, 2758e2770 (M).
13. Dawood, K. M. J. Heterocycl. Chem. 2005, 42, 221e225.
14. Girgis, A. S.; Farag, H.; Ismail, N. S. M.; George, R. F. Eur. J. Med. Chem. 2011, 46,
4964e4969.
15. Mishriky, N.; Girgis, A. S.; Hosni, H. M.; Farag, H. J. Heterocycl. Chem. 2006, 43,
1549e1556.
cmꢁ1
; dH (300 MHz, DMSO-d6) 1.19e2.47 (m, 6H, 3CH2), 3.80 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 5.50 (s, 1H, pyrazoleeH), 7.03e8.12 (m,
10H, ArH), 7.48 (d, 2H, J¼6 Hz, ArH), 8.25 (d, 2H, J¼6 Hz, ArH); dC
(75 MHz, DMSO-d6) 21.88, 28.18, 31.95 (3CH2), 51.84, 52.58 (OCH3),
56.19 (pyrazoleeCH), 79.74 (spiroeC), 115.31, 116.04, 120.05, 120.41,
124.61, 126.77, 127.19, 127.64, 128.93, 129.51, 133.18, 133.67, 136.57,
138.14, 138.83, 139.35, 143.09, 145.11, 148.17 (AreC), 203.06 (C]O);
m/z 553 (Mþ, 12), 490 (23), 76 (100%).
16. Girgis, A. S.; Ibrahim, Y. A.; Mishriky, N.; Lisgarten, J. N.; Potterc, B. S.; Palmer, R.
A. Tetrahedron 2001, 57, 2015e2019.
17. El-Rayyes, N. R.; Ramadan, H. M. J. Heterocycl. Chem. 1987, 24, 589e596.
18. Buu-Hoi, N. P.; Xuong, N. D.; Rips, R. J. Org. Chem. 1957, 22, 193e197.
19. Orlov, V. D.; Surov, Y. N.; Mikhedkina, E. I.; Nodel’man, O. A.; Bazavluk, A. D.;
Lavrushin, V. F. Org. React. 1984, 21, 363e368.
20. Girgis, A. S. J. Chem. Res. 2006, 81e83.
21. Hassaneen, H. M.; Shawali, A. S.; Elwan, N. M. Heterocycles 1990, 31, 247e253.
22. Girgis, A. S. Z. Naturforsch 2000, 55b, 222e230.
23. Girgis, A. S.; Ibrahim, Y. A.; Farag, A. I. S.; Mishriky, N. J. Chem. Res., Synop. 2000,
508e509.
24. Wolkoff, P. Can. J. Chem. 1975, 53, 1333e1335.
25. Hassaneen, H. M.; Hilal, R. H.; Elwan, N. M.; Harhash, A.; Shawali, A. S. J.
Heterocycl. Chem. 1984, 21, 1013e1016.
26. Hassaneen, H. M.; Mousa, H. A. H.; Abed, N. M.; Shawali, A. S. Heterocycles 1988,
27, 695e706.
27. All crystallographic data have been deposited at the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC 827297. Copies of
the data can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK.
3.5.15. 20,30,6,7,8,9-Hexahydro-20-(4-nitrophenyl)-50-thienyl-30-
(3,4,5-trimethoxyphenyl)-spiro[benzocycloheptene-6(5H),40(4H-pyr-
azol)-5-one (5o). As red crystals (0.47 g, 80%) (from ethanol/di-
oxane), mp 140e142 ꢀC; [Found: C, 65.62; H, 4.95; N, 7.11; S, 5.54
C
32H29N3O6S requires C, 65.85; H, 5.01; N, 7.20; S, 5.49%.]; vmax
(KBr) 1678 (C]O) cmꢁ1
;
dH (300 MHz, DMSO-d6) 1.17e2.38 (m, 6H,
3CH2), 3.67 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 5.54
(s, 1H, pyrazoleeH), 6.93e8.12 (m, 9H, ArH), 7.48 (d, 2H, J¼6 Hz,
ArH), 8.25 (d, 2H, J¼6 Hz, ArH); dC (100 MHz, DMSO-d6) 21.91, 28.11,
32.23 (3CH2), 51.66, 52.88 (OCH3), 56.51 (pyrazoleeCH), 79.79
(spiroeC), 115.32, 115.93, 120.21, 120.57, 123.94, 125.88, 127.21,
128.12, 129.14, 133.17, 136.25, 138.64, 138.88, 139.26, 143.65, 145.02,