Regio- and stereoselective synthesis of spiro[1-benzothiepine-4(5H), 3′(3H)-pyrazol]-5-ones

Article abstract of DOI:10.1002/jhet.5570430618

Reaction of (4E)-4-arylmethylene-3,4-dihydro-1-benzothiepin-5(2H)-ones 3a-e with nitrilimines (generated in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 4a, b) in refluxing benzene, afforded 2′,4′,5′-triaryl-2,2′,3

Full text of DOI:10.1002/jhet.5570430618

Nov-Dec 2006
1549
Regio- and Stereoselective Synthesis of Spiro[1-benzothiepine-4(5H),
3'(3H)-pyrazol]-5-ones
Nawal Mishriky, Adel S. Girgis,* Hanaa M. Hosni and Hanaa Farag
Pesticide Chemistry Dept., National Research Centre, Dokki, 12622 Cairo, Egypt.
E-mail: girgisas10@yahoo.com
Received January 29, 2006
R'
O
O
N
N
PhCCl=NNHR'
C6H6, TEA
R
Ph
R
H
S
S
Reaction of (4E)-4-arylmethylene-3,4-dihydro-1-benzothiepin-5(2H)-ones 3a-e with nitrilimines (generated
in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 4a, b) in refluxing
benzene, afforded 2',4',5'-triaryl-2,2',3,4'-tetrahydro-spiro[1-benzothiepine-4(5H),3'(3H)-pyrazol]-5-ones 5a-i
and not the isomeric forms spiro[1-benzothiepine-4(5H),4'(4H)-pyrazol]-5-ones 6 in high regioselective
manner. Single crystal X-ray diffraction studies of 5a, f, g indicated that the isolated products are 3'R, 4'S.
J. Heterocyclic Chem., 43, 1549 (2006).
Introduction.
cells, such as psoriasis and hyperkeratosis [21]. Recent
investigations show their tumor selective cytotoxic action
against human oral tumor cell lines (HSC-2, HSC-3,
HSG) [22].
Hydrazonoyl halides have been proved to be versatile
precursors for synthesis of nitrilimines which intensively
used for construction of various heterocyclic systems [1].
1,3-Dipolar cycloaddition reactions of nitrilimines with
alkenes [2-5], alkynes [6,7], azomethines [8], allenes
[9,10] as well as heterocyclic residues [11-13] were the
basic points of interest for many researchers due to their
unique properties, especially regio- and stereoselective
behaviours.
In the present work, it is intended to investigate 1,3-
dipolar cycloaddition reaction of nitrilimines with 1-
benzothiepine bearing exocyclic olefinic linkage. This
investigation could allow isolation of many spiro 1-
Many other studies reported that, 1-benzothiepines
were CC chemokine receptor 5 (CCR5) antagonists.
CCR5 was found to be a co-receptor for the entry of
macrophage-tropic human immunodeficiency virus type 1
(HIV-1) into host cells, indicating the inhibitory
properties of 1-benzothiepine derivatives against HIV-1
infections [23-25]. Other derivatives were found to be
useful as neuroprotective agents to reduce neurotoxic
injury associated with conditions of hypoxia, anoxia or
ischemia which follow stroke, myocardial infarct,
perinatal asphyxia or hypoglycemic events [26].
Moreover, many 1-benzothiepine analogues were found to
be useful for treatment of pollakiuria and urinary
incontinence [27]. Other investigations revealed their
stimulation properties of ꢀ3 adrenaline receptors reflecting
their ability for treatment of obesity, diabetes,
depression…etc. [28].
benzothiepine
containing
pyrazoline
heterocyclic
derivatives. Regioselectivity of the reactions as well as
stereochemical structure of the isolated products will be
also taken into consideration.
The interest for synthesis of spiro-containing 1-
benzothiepine heterocycle is originated from the well
established biological and pharmacological properties
associated with this ring system. For example, 1-
benzothiepine derivatives were found as ileal bile acid
transport and tourocholate uptake inhibitors, which reveal
their useful applications for prophylaxis and treatment of
hyperlipidemic conditions such as those associated with
atherosclerosis or hypercholesterolemia [14-20]. Other
derivatives were reported to be useful as anti-proliferative
drugs (for treatment of diseases associated with hyper-
proliferation of cells). Specific proliferative diseases
against which psychotropic agents were found to be
effective are cancer, including multi-drug resistant cancer
and diseases associated with hyper-proliferation of skin
In addition, the biological and pharmacological
properties of pyrazoline containing compounds also
prompted the present work.
For example, many
substituted pyrazolines were reported to exhibit human
acyl CoA cholesterol acyltransferase [29], low-density
lipoprotein oxidation inhibition [30], antidepressant
properties [31-34] as well as monoamine oxidase
inhibitory activities [35,36].
Results and Discussion.
3,4-Dihydro-4-[(2-thienyl)methylene]-1-benzothiepin-
5(2H)-one (3e) was prepared in a modified synthetic
experimental method related to the previously described

1550
N. Mishriky, A. S. Girgis, H. M. Hosni and H. Farag
Vol 43
derivatives 3a-d [37,38] via condensation of 3,4-dihydro-
1-benzothiepin-5(2H)-one (1) [39] with thiophene-2-
carbaldehyde (2e) in the presence of piperidine as a basic
catalyst at 160-170 °C. The structure of 3e was inferred
from spectroscopic (IR, H-NMR, MS) and elemental
analyses data.
imines (generated in situ via triethylamine dehydrohalo-
genation of the corresponding hydrazonoyl chlorides 4a,
b) in refluxing dry benzene, afforded only one product as
indicated by TLC. The structure of which was established
to be 2',4',5'-triaryl-2,2',3,4'-tetrahydro-spiro[1-benzothie-
pine-4(5H),3'(3H)-pyrazol]-5-ones 5a-i rather than
2',3',5'-triaryl-2,2',3,3'-tetrahydro-spiro[1-benzothiepine-
4(5H),4'(4H)-pyrazol]-5-ones 6a-i based on spectroscopic
(IR, 1H, 13C-NMR, MS) and elemental analyses data
(Scheme 1).
IR spectra of 5a-i exhibit the presence of a strong
carbonyl stretching vibration band at ꢀ = 1690-1669 cm-1
excluding any cycloaddition reaction pathway taking
place with this moiety. 1H-NMR spectra of 5a-i reveal
the appearance of each of the two adjacent benzothiepine
methylene protons as multiplet signals at ꢃ = 2.27-3.10
1
IR spectrum of 3e exhibits a strong absorption band at ꢀ
= 1679 cm-1 assignable for the ꢁ, ꢂ-unsaturated carbonyl
1
stretching vibration. Moreover, H-NMR spectrum of 3e
reveals each of the benzothiepine methylene protons as
triplet signals at ꢃ = 3.08, 3.21 (J = 6.3 Hz). The olefinic
ylidene proton appears as a sharp singlet signal at ꢃ = 8.04
which supports the isolation of E-form geometrically
stereochemical isomer.
1,3-Dipolar cycloaddition reaction of 4-arylmethylene-
3,4-dihydro-1-benzothiepin-5(2H)-ones 3a-e with nitril-
Scheme (1)
O
S
(1)
(2)
RCHO
piperidine
O
R
S
(3)
(4)
PhCCl=NNHR'
C6H6, TEA
R'
Ph
O
O
N
N
N
Ph
N
R'
R
H
S
R
S
(5)
(6)
2a, 3a, R = 4-ClC6H4
2b, 3b, R = 4-BrC6H4
2c, 3c, R = 4-H3CC6H4
2d, 3d, R = 4-H3COC6H4
2e, 3e, R = 2-thienyl
5a, R= 4-ClC6H4, R' = Ph
5b, R= 4-ClC6H4, R' = 3-ClC6H4
5c, R= 4-BrC6H4, R' = Ph
5d, R= 4-BrC6H4, R' = 3-ClC6H4
5e, R= 4-H3CC6H4, R' = Ph
5f, R= 4-H3COC6H4, R' = Ph
4a, R' = Ph
4b, R' = 3-ClC6H4
5g, R= 4-H3COC6H4, R' = 3-ClC6H4
5h, R= 2-thienyl, R' = Ph
5i, R= 2-thienyl, R' = 3-ClC6H4

Nov-Dec 2006
Synthesis of Spiro[1-benzothiepine-4(5H), 3'(3H)-pyrazol]-5-ones
1551
region. The pyrazoline H-4' is recognized as a sharp
singlet signal at ꢀ = 5.04-5.44 region. The appearance of
this signal at the mentioned chemical shift value supports
the isolation of 5 [40,41], where the other presumed regio-
isomeric form 6 used to reveal its characteristic H-3'
signal at a chemical shift value downfield than ꢀ>5.6 [42].
13C-NMR (on-resonance & APT) spectra of 5g "as a
representative example" adds a good support for the
established structure, where it reveals the two
benzothiepine methylene carbons at ꢀ = 28.89, 32.06, in
addition to the methoxy and carbonyl carbons at ꢀ =
55.08, 204.65, respectively. The pyrazoline HC-4' and
spiro-carbon (quaternary C-3') were observed at ꢀ =
59.52, 81.03, respectively. These values are in accord
with many other similar reported heterocyclic system
values [41,43,44].
Fig. (1): Single crystal X-ray diffraction of 5a
Selected intramolecular bond lengths (Å) and bond angles (°) of 5a.
Cl(1)-C(12) = 1.738(3), S(2)-C(21) = 1.815(4), S(2)-C(28) = 1.773(4), O(3)-C(6) = 1.212(3), N(4)-N(5) = 1.414(3), N(4)-C(8) = 1.268(4),
N(5)-C(14) = 1.507(4), N(5)-C(17) = 1.426(4), C(6)-C(14) = 1.555(4), C(6)-C(20) = 1.499(4), C(7)-C(34) = 1.362(6), C(7)-C(35) = 1.378(7),
C(8)-C(13) = 1.523(4), C(8)-C(16) = 1.475(4), C(9)-C(10) = 1.379(4), C(9)-C(11) = 1.387(4), C(9)-C(13) = 1.503(4), C(10)-C(15) = 1.388(4),
C(11)-C(24) = 1.380(4), C(12)-C(15) = 1.380(4), C(12)-C(24) = 1.374(4), C(13)-C(14) = 1.561(4), C(14)-C(22) = 1.517(4), C(16)-C(23) =
1.399(4), C(16)-C(27) = 1.385(4), C(17)-C(18) = 1.394(4), C(17)-C(26) = 1.384(4), C(18)-C(19) = 1.373(5), C(19)-C(25) = 1.379(5), C(20)-
C(28) = 1.393(5), C(20)-C(29) = 1.377(5), C(21)-C(22) = 1.515(4), C(23)-C(32) = 1.374(4), C(25)-C(30) = 1.372(5), C(26)-C(30) = 1.389(5),
C(27)-C(31) = 1.381(4), C(28)-C(34) = 1.398(5), C(29)-C(35) = 1.381(5), C(31)-C(33) = 1.387(5), C(32)-C(33) = 1.372(5), C(21)-S(2)-C(28)
= 102.1(2), N(5)-N(4)-C(8) = 109.2(3), N(4)-N(5)-C(14) = 108.9(2), N(4)-N((5)-C(17) = 113.3(2), C(14)-N(5)-C(17) = 121.0(2), O(3)-C(6)-
C(14) = 120.0(3), O(3)-C(6)-C(20) = 119.6(3), C(14)-C(6)-C(20) = 120.3(3), C(34)-C(7)-C(35) = 120.6(4), N(4)-C(8)-C(13) = 114.1(3), N(4)-
C(8)-C(16) = 121.8(3), C(13)-C(8)-C(16) = 124.1(3), C(10)-C(9)-C(11) = 117.9(3), C(10)-C(9)-C(13) = 120.9(3), C(11)-C(9)-C(13) =
121.2(3), C(9)-C(10)-C(15) = 121.6(3), C(9)-C(11)-C(24) = 121.8(3), Cl(1)-C(12)-C(15) = 119.8(3), Cl(1)-C(12)-C(24) = 118.9(3), C(15)-
C(12)-C(24) = 121.3(3), C(8)-C(13)-C(9) = 111.3(2), C(8)-C(13)-C(14) = 100.2(2), C(9)-C(13)-C(14) = 114.9(2), N(5)-C(14)-C(6) =
106.1(2), N(5)-C(14)-C(13) = 100.3(2), N(5)-C(14)-C(22) = 109.2(2), C(6)-C(14)-C(13) = 109.9(2), C(6)-C(14)-C(22) = 112.6(2), C(13)-
C(14)-C(22) = 117.5(3), C(10)-C(15)-C(12) = 118.6(3), C(8)-C(16)-C(23) = 118.7(3), C(8)-C(16)-C(27) = 123.0(3), C(23)-C(16)-C(27) =
118.3(3), N(5)-C(17)-C(18) = 119.9(3), N(5)-C(17)-C(26) = 121.7(3), C(18)-C(17)-C(26) = 118.4(3), C(17)-C(18)-C(19) = 120.6(3), C(18)-
C(19)-C(25) = 120.9(3), C(6)-C(20)-C(28) = 118.7(3), C(6)-C(20)-C(29) = 121.6(3), C(28)-C(20)-C(29) = 119.8(3), S(2)-C(21)-C(22) =
115.5(2), C(14)-C(22)-C(21) = 116.4(3), C(16)-C(23)-C(32) = 120.6(3), C(11)-C(24)-C(12) = 118.7(3), C(19)-C(25)-C(30) = 118.8(3), C(17)-
C(26)-C(30) = 120.3(3), C(16)-C(27)-C(31) = 121.0(3), S(2)-C(28)-C(20) = 119.8(3), S(2)-C(28)-C(34) = 120.1(3), C(20)-C(28)-C(34) =
119.8(4), C(20)-C(29)-C(35) = 119.8(4), C(25)-C(30)-C(26) = 120.9(4), C(27)-C(31)-C(33) = 119.7(3), C(23)-C(32)-C(33) = 120.5(3), C(31)-
C(33)-C(32) = 119.9(3), C(7)-C(34)-C(28) = 119.6(4), C(7)-C(35)-C(29) = 120.4(4).

1552
N. Mishriky, A. S. Girgis, H. M. Hosni and H. Farag
Vol 43
Fig. (2): Single crystal X-ray diffraction of 5f.
Selected intramolecular bond lengths (Å) and bond angles (°) of 5f.
S(1)-C(21) = 1.8189(12), S(1)-C(24) = 1.7761(12), O(2)-C(17) = 1.3732(13), O(2)-C(28) = 1.420(2), O(3)-C(19) = 1.2101(13), N(4)-N(5) =
1.3976(12), N(4)-C(8) = 1.5136(13), N(4)-C(9) = 1.4371(14), N(5)-C(22) = 1.2836(13), C(6)-C(8) = 1.556(2), C(6)-C(12) = 1.515(2), C(6)-C(22)
= 1.5250(15), C(7)-C(8) = 1.522(2), C(7)-C(21) = 1.5229(15), C(8)-C(19) = 1.5507(14), C(9)-C(10) = 1.377(2), C(9)-C(20) = 1.387(2), C(10)-
C(33) = 1.389(2), C(11)-C(14) = 1.382(2), C(11)-C(17) = 1.377(2), C(12)-C(14) = 1.3923(15), C(12)-C(18) = 1.381(2), C(13)-C(19) = 1.499(2),
C(13)-C(24) = 1.401(2), C(13)-C(25) = 1.388(2), C(15)-C(22) = 1.463(2), C(15)-C(23) = 1.386(2), C(15)-C(26) = 1.392(2), C(16)-C(17) =
1.383(2), C(16)-C(18) = 1.384(2), C(20)-C(31) = 1.379(2), C(23)-C(32) = 1.391(2), C(24)-C(29) = 1.375(2), C(25)-C(36) = 1.383(2), C(26)-C(30)
= 1.369(2), C(27)-C(31) = 1.372(2), C(27)-C(33) = 1.369(2), C(29)-C(35) = 1.379(2), C(30)-C(34) = 1.379(2), C(32)-C(34) = 1.371(2), C(35)-
C(36) = 1.363(2), C(21)-S(1)-C(24) = 101.94(5), C(17)-O(2)-C(28) = 117.39(10), N(5)-N(4)-C(8) = 109.05(8), N(5)-N(4)-C(9) = 113.51(8), C(8)-
N(4)-C(9) = 120.18(8), N(4)-N(5)-C(22) = 109.32(8), C(8)-C(6)-C(12) = 116.59(9), C(8)-C(6)-C(22) = 100.44(8), C(12)-C(6)-C(22) = 110.60(8),
C(8)-C(7)-C(21) = 116.44(9), N(4)-C(8)-C(6) = 99.84(8), N(4)-C(8)-C(7) = 110.03(9), N(4)-C(8)-C(19) = 106.31(7), C(6)-C(8)-C(7) = 116.73(8),
C(6)-C(8)-C(19) = 109.52(9), C(7)-C(8)-C(19) = 113.15(9), N(4)-C(9)-C(10) = 122.06(11), N(4)-C(9)-C(20) = 118.49(9), C(10)-C(9)-C(20) =
119.45(10), C(9)-C(10)-C(33) = 119.83(13), C(14)-C(11)-C(17) = 120.19(10), C(6)-C(12)-C(14) = 120.86(10), C(6)-C(12)-C(18) = 121.61(9),
C(14)-C(12)-C(18) = 117.49(10), C(19)-C(13)-C(24) = 118.95(10), C(19)-C(13)-C(25) = 121.54(10), C(24)-C(13)-C(25) = 119.40(11), C(11)-
C(14)-C(12) = 121.29(11), C(22)-C(15)-C(23) = 120.83(10), C(22)-C(15)-C(26) = 120.67(11), C(23)-C(15)-C(26) = 118.47(12), C(17)-C(16)-
C(18) = 119.75(11), O(2)-C(17)-C(11) = 115.86(9), O(2)-C(17)-C(16) = 124.64(10), C(11)-C(17)-C(16) = 119.49(10), C(12)-C(18)-C(16) =
121.75(10), O(3)-C(19)-C(8) = 120.16(10), O(3)-C(19)-C(13) = 119.68(10), C(8)-C(19)-C(13) = 120.01(10), C(9)-C(20)-C(31) = 119.85(11),
S(1)-C(21)-C(7) = 115.84(7), N(5)-C(22)-C(6) = 113.21(10), N(5)-C(22)-C(15) = 122.39(9), C(6)-C(22)-C(15) = 124.34(9), C(15)-C(23)-C(32) =
120.61(13), S(1)-C(24)-C(13) = 118.54(9), S(1)-C(24)-C(29) = 121.21(9), C(13)-C(24)-C(29) = 119.99(11), C(13)-C(25)-C(36) = 119.52(13),
C(15)-C(26)-C(30) = 120.66(13), C(31)-C(27)-C(33) = 119.46(13), C(24)-C(29)-C(35) = 119.82(13), C(26)-C(30)-C(34) = 120.44(13), C(20)-
C(31)-C(27) = 120.75(13), C(23)-C(32)-C(34) = 119.79(14), C(10)-C(33)-C(27) = 120.63(13), C(30)-C(34)-C(32) = 119.97(14), C(29)-C(35)-
C(36) = 120.63(14), C(25)-C(36)-C(35) = 120.59(14).
Single crystal X-ray diffraction studies of 5a, f, g add
good support for the established structure. It has been
noticed that, the thiepine ring system takes a modified
boat form configuration. It was expected that, the isolated
products are mixture of different stereoisomeric forms.
However, the obtained data indicated that, the isolated
crystalline form products are 3'R, 4'S (Fig. 1-3).
From all the above it could be concluded that, 1,3-
dipolar cycloaddition reaction of nitrilimines to enone
system 3 takes place in high regioselective manner under
the described reaction conditions. Where, the dipole
compound approaches the olefinic linkage of dipolarofile
suprafacially, or in other words from the less hindered
face affording eventually 5.
EXPERIMENTAL
Melting points are uncorrected and were recorded on an
Electrothermal 9100 digital melting point apparatus. IR spectra
(KBr) were recorded on a Nexus 670 FT-IR spectrophotometer.
NMR spectra were recorded on
a Varian MERCURY
spectrometer (1H: 300, 13C: 75 MHz) in CDCl3. Mass spectra

Nov-Dec 2006
Synthesis of Spiro[1-benzothiepine-4(5H), 3'(3H)-pyrazol]-5-ones
1553
Fig. (3): Single crystal X-ray diffraction of 5g.
Selected intramolecular bond lengths (Å) and bond angles (°) of 5g.
S(1)-C(18) = 1.758(2), S(1)-C(29) = 1.798(2), Cl(2)-C(17) = 1.753(2), O(3)-C(16) = 1.206(2), N(4)-N(6) = 1.381(2), N(4)-C(12) = 1.407(2), N(4)-
C(13) = 1.469(2), O(5)-C(24) = 1.377(2), O(5)-C(35) = 1.435(3), N(6)-C(15) = 1.290(2), C(7)-C(10) = 1.391(3), C(7)-C(15) = 1.469(3), C(7)-
C(28) = 1.388(3), C(8)-C(16) = 1.507(3), C(8)-C(18) = 1.386(3), C(8)-C(30) = 1.396(3), C(9)-C(13) = 1.577(3), C(9)-C(15) = 1.523(3), C(9)-
C(23) = 1.523(3), C(10)-C(27) = 1.381(3), C(11)-C(12) = 1.396(3), C(11)-C(17) = 1.380(3), C(12)-C(14) = 1.381(3), C(13)-C(16) = 1.567(3),
C(13)-C(26) = 1.540(2), C(14)-C(20) = 1.377(3), C(17)-C(25) = 1.373(3), C(18)-C(31) = 1.397(3), C(19)-C(21) = 1.387(3), C(19)-C(24) =
1.378(3), C(20)-C(25) = 1.377(3), C(21)-C(23) = 1.391(3), C(22)-C(23) = 1.387(3), C(22)-C(33) = 1.380(3), C(24)-C(33) = 1.377(3), C(26)-C(29)
= 1.510(3), C(27)-C(32) = 1.382(3), C(28)-C(34) = 1.391(3), C(30)-C(36) = 1.366(3), C(31)-C(37) = 1.366(3), C(32)-C(34) = 1.369(3), C(36)-
C(37) = 1.377(4), C(18)-S(1)-C(29) = 103.02(10), N(6)-N(4)-C(12) = 116.51(15), N(6)-N(4)-C(13) = 110.88(13), C(12)-N(4)-C(13) = 129.7(2),
C(24)-O(5)-C(35) = 118.3(2), N(4)-N(6)-C(15) = 108.87(15), C(10)-C(7)-C(15) = 119.7(2), C(10)-C(7)-C(28) = 118.6(2), C(15)-C(7)-C(28) =
121.7(2), C(16)-C(8)-C(18) = 127.8(2), C(16)-C(8)-C(30) = 114.3(2), C(18)-C(8)-C(30) = 117.9(2), C(13)-C(9)-C(15) = 98.77(14), C(13)-C(9)-
C(23) = 117.35(14), C(15)-C(9)-C(23) = 111.46(15), C(7)-C(10)-C(27) = 121.0(2), C(12)-C(11)-C(17) = 118.9(2), N(4)-C(12)-C(11) = 116.9(2),
N(4)-C(12)-C(14) = 124.1(2), C(11)-C(12)-C(14) = 119.0(2), N(4)-C(13)-C(9) = 99.84(14), N(4)-C(13)-C(16) = 108.73(15), N(4)-C(13)-C(26) =
111.06(14), C(9)-C(13)-C(16) = 106.57(14), C(9)-C(13)-C(26) = 117.1(2), C(16)-C(13)-C(26) = 112.60(15), C(12)-C(14)-C(20) = 120.4(2), N(6)-
C(15)-C(7) = 120.3(2), N(6)-C(15)-C(9) = 112.8(2), C(7)-C(15)-C(9) = 127.0(2), O(3)-C(16)-C(8) = 119.2(2), O(3)-C(16)-C(13) = 119.2(2), C(8)-
C(16)-C(13) = 121.2(2), Cl(2)-C(17)-C(11) = 118.4(2), Cl(2)-C(17)-C(25) = 118.9(2), C(11)-C(17)-C(25) = 122.6(2), S(1)-C(18)-C(8) = 126.1(2),
S(1)-C(18)-C(31) = 114.4(2), C(8)-C(18)-C(31) = 119.5(2), C(21)-C(19)-C(24) = 119.4(2), C(14)-C(20)-C(25) = 121.6(2), C(19)-C(21)-C(23) =
121.8(2), C(23)-C(22)-C(33) = 121.2(2), C(9)-C(23)-C(21) = 122.1(2), C(9)-C(23)-C(22) = 120.5(2), C(21)-C(23)-C(22) = 117.4(2), O(5)-C(24)-
C(19) = 124.3(2), O(5)-C(24)-C(33) = 115.9(2), C(19)-C(24)-C(33) = 119.7(2), C(17)-C(25)-C(20) = 117.5(2), C(13)-C(26)-C(29) = 114.89(15),
C(10)-C(27)-C(32) = 119.9(2), C(7)-C(28)-C(34) = 119.9(2), S(1)-C(29)-C(26) = 114.25(15), C(8)-C(30)-C(36) = 122.1(2), C(18)-C(31)-C(37) =
121.2(2), C(27)-C(32)-C(34) = 119.7(2), C(22)-C(33)-C(24) = 120.5(2), C(28)-C(34)-C(32) = 120.9(2), C(30)-C(36)-C(37) = 119.6(2), C(31)-
C(37)-C(36) = 119.7(2).
were recorded on Schimadzu GCMS-QP 1000 EX and Finnigan
SSQ 7000 spectrometers (EI, 70 eV). The starting compounds
4a,b [45,46] were prepared according to the previously reported
procedures.
70%. IR: ꢀmax. 1679, 1654, 1588 cm-1. 1H-NMR: ꢁ 3.08 (t, 2H,
SCH2CH2, J = 6.3 Hz), 3.21 (t, 2H, SCH2, J = 6.3 Hz), 7.12-7.72
(m, 7H, arom. H), 8.04 (s, 1H, olefinic CH). MS m/z (%): 272
(M, 52), 244(100). Anal. for C15H12OS2 (272.37): Calcd. C,
66.14; H, 4.44; Found C, 66.40; H, 4.63%.
Synthesis of 3,4-dihydro-4-[(2-thienyl)methylene]-1-benzothie-
pin-5(2H)-one (3e).
Synthesis of 2,2',3,4'-tetrahydro-2',4',5'-triaryl-spiro[1-benzo-
thiepine-4(5H),3'(3H)-pyrazol]-5-ones 5a-i.
A mixture of 3,4-dihydro-1-benzothiepin-5(2H)-one 1 (10
mmol), thiophene-2-carbaldehyde 2e (11 mmol) and piperidine
(10-12 drops) was heated in an oil bath at 160-170 °C for 4h.
The separated solid upon triturating the reaction mixture with
methanol (5 ml), was collected and crystallized from n-butanol
affording 3e as very pale yellow crystals, m.p. 141-143 °C, yield
General procedure.
A mixture of equimolar amounts of 3a-e (5 mmol) and the
corresponding 4a,b in dry benzene (25 ml) was boiled under
reflux for the appropriate time. The reaction mixture was
filtered off to remove the formed triethylamine hydrochloride

1554
N. Mishriky, A. S. Girgis, H. M. Hosni and H. Farag
Vol 43
and the remaining reaction mixture was evaporated till dryness
under reduced pressure. The separated solid upon triturating the
residual oily material with methanol (5 ml) (except in case of 5i,
diethyl ether "5 ml" was used), was collected and crystallized
from n-butanol affording the corresponding 5a-i.
OCH3), 5.04 (s, 1H, H-4'), 6.51-7.57 (m, 18H, arom. H). MS
m/z (%): 490 (M, 100), 354 (16), 353 (80), 340 (4), 339 (21).
Anal. for C31H26N2O2S (490.604): Calcd. C, 75.89; H, 5.34; N,
5.71; Found C, 75.64; H, 5.15; N, 5.34%.
2'-(3-Chlorophenyl)-4'-(4-methoxyphenyl)-5'-phenyl-2,2',3,4'-tetra-
hydro-spiro[1-benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5g).
4'-(4-Chlorophenyl)-2',5'-diphenyl-2,2',3,4'-tetrahydro-spiro[1-
benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5a).
Reaction time 55 h, pale yellow crystals, m.p. 181-183 °C, yield
76%. IR: ꢀmax. 1684, 1591, 1480 cm-1. 1H-NMR: ꢁ 2.58-2.69 (m,
2H, SCH2CH2), 2.91-3.10 (m, 2H, SCH2), 3.97 (s, 3H, OCH3),
5.23 (s, 1H, H-4'), 7.06-7.82 (m, 17H, arom. H). 13C-NMR "on-
resonance & APT": ꢁ 28.89, 32.06 (2CH2), 55.08 (OCH3), 59.52
(HC-4'), 81.03 (spiro C-3'), 114.34, 117.94, 120.33, 122.30,
126.46, 127.84, 128.20, 128.59, 129.43, 129.50, 131.38, 131.46
(arom. CH), 127.32, 131.30, 132.22, 134.33, 141.47, 145.43,
152.81 (arom. quaternary C), 159.35 (C=N), 204.65 (C=O). MS
m/z (%): 525 [(M + 1), 14], 524 (M, 48), 388 (29), 387 (100), 374
(8), 373 (19). Anal. for C31H25ClN2O2S (525.047): Calcd. C,
70.91; H, 4.80; N, 5.34; Found C, 71.02; H, 4.97; N, 5.28%.
Reaction time 40 h, yellow crystals, m.p. 208-210 °C, yield
81%. IR: ꢀmax. 1687, 1588, 1486 cm-1. 1H-NMR: ꢁ 2.49-2.65
(m, 2H, SCH2CH2), 2.87-3.07 (m, 2H, SCH2), 5.33 (s, 1H, H-4'),
6.79-7.83 (m, 18H, arom. H). MS m/z (%): 495 [(M+1), 8], 494
(M, 11), 358 (27), 357 (100), 344 (7), 343 (10). Anal. for
C30H23ClN2OS (495.017): Calcd. C, 72.79; H, 4.68; N, 5.66;
Found C, 72.96; H, 4.82; N, 5.95%.
2'-(3-Chlorophenyl)-4'-(4-chlorophenyl)-5'-phenyl-2,2',3,4'-tetra-
hydro-spiro[1-benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5b).
Reaction time 42 h, colourless crystals, m.p. 155-158 °C,
yield 83%. IR: ꢀmax. 1686, 1590, 1482 cm-1. 1H-NMR: ꢁ 2.34-
2.50 (m, 2H, SCH2CH2), 2.74-2.94 (m, 2H, SCH2), 5.05 (s, 1H,
H-4'), 6.95-7.60 (m, 17H, arom. H). MS m/z (%): 529 [(M+1),
5], 528 (M, 11), 392 (42), 391 (100), 378 (3), 377 (8). Anal. for
C30H22Cl2N2OS (529.47): Calcd. C, 68.05; H, 4.19; N, 5.29;
Found C, 68.36; H, 4.33; N, 5.20%.
2',5'-Diphenyl-2,2',3,4'-tetrahydro-4'-(2-thienyl)-spiro[1-benzo-
thiepine-4(5H),3'(3H)-pyrazol]-5-one (5h).
Reaction time 50 h, pale yellow crystals, m.p. 201-203 °C,
yield 73%. IR: ꢀmax. 1689, 1592, 1485 cm-1. 1H-NMR: ꢁ 2.54-
2.71 (m, 2H, SCH2CH2), 2.76-2.97 (m, 2H, SCH2), 5.44 (s, 1H,
H-4'), 6.82-7.68 (m, 17H, arom. H). MS m/z (%): 467 [(M + 1),
16], 466 (M, 48), 330 (24), 329 (100), 316 (10), 315 (36). Anal.
for C28H22N2OS2 (466.60): Calcd. C, 72.07; H, 4.75; N, 6.01;
Found C, 72.36; H, 4.97; N, 6.18%.
4'-(4-Bromophenyl)-2',5'-diphenyl-2,2',3,4'-tetrahydro-spiro[1-
benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5c).
Reaction time 45 h, yellow crystals, m.p. 209-211 °C, yield
89%. IR: ꢀmax. 1688, 1592, 1486 cm-1. 1H-NMR: ꢁ 2.30-2.47
(m, 2H, SCH2CH2), 2.68-2.88 (m, 2H, SCH2), 5.13 (s, 1H, H-4'),
6.59-7.64 (m, 18H, arom. H). MS m/z (%): 539 [(M+1), 6], 538
(M, 14), 402 (47), 401 (100), 388 (3), 387 (3). Anal. for
C30H23BrN2OS (539.473): Calcd. C, 66.79; H, 4.30; N, 5.19;
Found C, 66.98; H, 4.33; N, 5.45%.
2'-(3-Chlorophenyl)-5'-phenyl-2,2',3,4'-tetrahydro-4'-(2-thienyl)-
spiro[1-benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5i).
Reaction time 55 h, pale yellow crystals, m.p. 180-182 °C,
yield 70%. IR: ꢀmax. 1669, 1589, 1478 cm-1. 1H-NMR: ꢁ 2.48-
2.78 (m, 2H, SCH2CH2), 2.81-3.01 (m, 2H, SCH2), 5.35 (s, 1H,
H-4'), 6.95-7.63 (m, 16H, arom. H). MS m/z (%): 501 [(M + 1),
19], 500 (M, 54), 364 (42), 363 (100), 350 (10), 349 (20). Anal.
for C28H21ClN2OS2 (501.043): Calcd. C, 67.12; H, 4.23; N, 5.59;
Found C, 67.08; H, 4.10; N, 5.38%.
4'-(4-Bromophenyl)-2'-(3-Chlorophenyl)-5'-phenyl-2,2',3,4'-tetra-
hydro-spiro[1-benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5d).
Reaction time 45 h, pale yellow crystals, m.p. 169-171 °C,
yield 87%. IR: ꢀmax. 1683, 1589, 1479 cm-1. 1H-NMR: ꢁ 2.34-
2.50 (m, 2H, SCH2CH2), 2.75-2.95 (m, 2H, SCH2), 5.05 (s, 1H,
H-4'), 6.96-7.60 (m, 17H, arom. H). MS m/z (%): 573 [(M+1),
6], 572 (M, 8), 437 (100), 436 (39), 435 (86), 422 (2), 421 (3).
Anal. for C30H22BrClN2OS (573.926): Calcd. C, 62.78; H, 3.86;
N, 4.88; Found C, 62.54; H, 3.73; N, 5.21%.
Single crystal X-ray crystallographic data of 5a, f, g [47].
The crystallographic data were collected at T = 298 °K on a
Kappa CCD Enraf Nonius FR 590 diffractometer using a
graphite momochromator with Mo-Kꢀ radiation (ꢁ = 0.71073 Å).
Compound 5a: For X-ray crystallographic studies, compound
5a was recrystallized as yellow prismatic crystals from n-
butanol. The crystal structure was determined by SIR9248 and
refined by maXus49 (Bruker Nonius, Delft and MacScience,
Japan). Chemical formula C30H23ClN2OS, Mr = 495.044,
triclinic, crystallizes in space group P-1, Cell lengths “a =
10.7287(7), b = 11.1582(9), c = 12.1761(12) Å”, Cell angles “ꢀ
= 68.334(4), ꢁ = 78.557(5), ꢂ = 64.544(5)˚”, V = 1221.8(2) Å3,
Z = 2, Dc = 1.346 mg/m3, ꢃ values 2.910-22.986˚, absorption
coefficient μ (Mo-Kꢀ) = 0.27 mm-1, F(000) = 516. The unique
reflections measured 4802 of which 1622 reflections with
threshold expression I>3ꢄ(I) were used in the structural
analysis. Convergence for 316 variable parameters by least-
2',5'-Diphenyl-4'-(4-methylphenyl)-2,2',3,4'-tetrahydro-spiro[1-
benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5e).
Reaction time 50 h, yellow crystals, m.p. 196-198 °C, yield
76%. IR: ꢀmax. 1690, 1593, 1487 cm-1. 1H-NMR: ꢁ 2.51 (s, 3H,
CH3), 2.53-2.70 (m, 2H, SCH2CH2), 2.84-3.02 (m, 2H, SCH2),
5.33 (s, 1H, H-4'), 6.78-7.87 (m, 18H, arom. H). MS m/z (%):
474 (M, 20), 338 (27), 337 (100), 324 (6), 323 (16). Anal. for
C31H26N2OS (474.604): Calcd. C, 78.45; H, 5.52; N, 5.90; Found
C, 78.09; H, 5.33; N, 5.69%.
2',5'-Diphenyl-4'-(4-methoxyphenyl)-2,2',3,4'-tetrahydro-spiro-
[1-benzothiepine-4(5H),3'(3H)-pyrazol]-5-one (5f).
squares refinement on F2 with w = 1/[ꢄ2(Fo )+0.10000 Fo ]. The
final agreement factors were R = 0.051 and wR = 0.105 with a
goodness-of-fit of 1.747.
2
2
Reaction time 50 h, yellow crystals, m.p. 170-172 °C, yield
82%. IR: ꢀmax. 1686, 1594, 1488 cm-1. 1H-NMR: ꢁ 2.27-2.39
(m, 2H, SCH2CH2), 2.61-2.75 (m, 2H, SCH2), 3.69 (s, 3H,

Nov-Dec 2006
Synthesis of Spiro[1-benzothiepine-4(5H), 3'(3H)-pyrazol]-5-ones
1555
[14] K. J. Koeller and S. J. Tremont (G. D. Searle LLC, USA)
PCT Int. Appl. WO 03 40,127 (Cl. C07D337/00), 15 May 2003, Chem.
Abstr., 138, 385315 (2003).
[15] B. T. Keller, S. J. Tremont, K. C. Glenn and R. E. Manning
(Pharmacia Corporation, USA) PCT Int. Appl. WO 01 68,096 (Cl.
A61K31/495), 20 Sep. 2001, Chem. Abstr., 135, 257253 (2001).
[16] B. T. Keller, K. C. Glenn and R. E. Manning (G. D. Searle &
Co., USA) U. S. US 6,268,392 (Cl. 514-431, A61K31/38), 31 Jul. 2001,
Chem. Abstr., 135, 137410 (2001).
[17] L. F. Lee, S. C. Banerjee, H. C. Huang, J. J. Li, R. E. Miller,
D. B. Reitz and S. J. Tremont (G. D. Searle & Co., USA) U. S. US
6,107,494 (Cl. 549-9; C0D337/00), 22 Aug. 2000, Chem. Abstr., 133,
193089 (2000).
[18] D. B. Reitz, L. F. Lee, J. J. Li, H. C. Huang, S. J. Tremont, R.
E. Miller, S. C. Baneriee, R. E. Manning, K. C. Glenn and B. T. Keller
(G. D. Searle & Co.; et al., USA) PCT Int. Appl. WO 98 40,375 (Cl.
C0D337/00), 17 Sep. 1998, Chem. Abstr., 129, 260353 (1998).
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E. Miller and S. C. Banerjee (G. D. Searle & Co.; Reitz, D. B.; Lee, L.
F.; Li, J. J.; Huang, H. C.; Tremont, S. J.; Miller, R. E.; Banerjee, S. C.,
USA) PCT Int. Appl. WO 97 33,882 (Cl. C07D337/08), 18 Sep. 1997,
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USA) PCT Int. Appl. WO 96 08,484 (Cl. C07D337/08), 21 Mar. 1996,
Chem. Abstr., 125, 114515 (1996).
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Applied Research & Industrial Development Ltd., Israel) PCT Int. Appl.
WO 02 43,652 (Cl. A61K), 6 Jun. 2002, Chem. Abstr., 136, 395953
(2002).
[22] Y. Sugita, H. Hosoya, K. Terasawa, I. Yokoe, S. Fujisawa
and H. Sakagami, Anticancer Research, 21, 2629 (2001).
[23] M. Shiraishi, M. Baba, M. Seto, N. Kanzaki and O.
Nishimura (Takeda Chemical Industries, Ltd., Japan) PCT Int. Appl.
WO 00 68,203 (Cl. C07D217/06), 16 Nov. 2000, Chem. Abstr., 133,
362714 (2000).
Compound 5f: For X-ray crystallographic studies, compound
5f was recrystallized as yellow prismatic crystals from n-butanol.
The crystal structure was determined by SIR92 [48] and refined
by maXus [49] (Bruker Nonius, Delft and MacScience, Japan).
Chemical formula C31H26N2O2S, Mr = 490.625, monoclinic,
crystallizes in space group C-2lc, Cell lengths “a = 17.5813(3), b
= 15.9834(4), c = 18.1402(5) Å”, Cell angles “ꢀ = 90.00, ꢁ =
93.4409(8), ꢂ = 90.00˚”, V = 5088.4(2) Å3, Z = 8, Dc = 1.281
mg/m3, ꢃ values 2.910-27.485˚, absorption coefficient μ (Mo-Kꢀ)
= 0.16 mm-1, F(000) = 2063. The unique reflections measured
10142 of which 3130 reflections with threshold expression
I>3ꢄ(I) were used in the structural analysis. Convergence for 373
variable parameters by least-squares refinement on F2 with w =
2
2
1/[ꢄ2(Fo )+0.10000 Fo ]. The final agreement factors were R =
0.043 and wR = 0.072 with a goodness-of-fit of 2.060.
Compound 5g: For X-ray crystallographic studies, compound
5g was recrystallized as pale yellow platlet crystals from n-
butanol. The crystal structure was determined by SIR92 [48]
and refined by maXus [49] (Bruker Nonius, Delft and
MacScience, Japan). Chemical formula C31H25ClN2O2S, Mr =
525.070, monoclinic, crystallizes in space group P-21lc, Cell
lengths “a = 9.7548(2), b = 14.1909(3), c = 18.9092(6) Å”, Cell
angles “ꢀ = 90.00, ꢁ = 90.4986(8), ꢂ = 90.00˚”, V =
2617.49(11) Å3, Z = 4, Dc = 1.332 mg/m3, ꢃ values 2.910-
26.022˚, absorption coefficient μ (Mo-Kꢀ) = 0.26 mm-1, F(000) =
1096. The unique reflections measured 8919 of which 3266
reflections with threshold expression I>3ꢄ(I) were used in the
structural analysis. Convergence for 334 variable parameters by
2
least-squares refinement on F2 with w = 1/[ꢄ2(Fo )+0.10000
2
Fo ]. The final agreement factors were R = 0.045 and wR = 0.073
with a goodness-of-fit of 1.568.
Acknowledgment:
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Shiraishi, Chem. Pharm. Bull., 52, 254 (2004).
This work is sponsored by the U.S.-Egypt Science and
Technology Joint Fund under project No. MAN10-007-002.
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N. Kanzaki, S. I. Niwa, Y. Iizawa, M. Baba and M. Shiraishi, Chem.
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