Synthesis of some novel 2,3,4,8,9-pentahydro-7-(4-haloaryl)-pyrazolo[5,1-e] benzo[1,5]oxazocines and 2,3(erythro), 7,8-tetrahydro-2-aryl-3-(4-fluoro-3- methylbenzoyl)-6-(4-haloaryl)pyrazolo[5,1-d] benzo[1,4]oxazepines via solid-liquid PTC

Article abstract of DOI:10.1080/00397910601163927

In this communication, a simple and straightforward procedure for the heterocyclization of 1H-4,5-dihydro-3-(4-haloaryl)-5-substituted phenylpyrazoles (4) with 1-bromo-3-chloropropane and 2,3-dibromo-1-(4-fluoro-3-methylphenyl)-3- phe- nylpropanone affording 2,3,4,8,9-pentahydro-7-(4-haloaryl)pyrazolo[5,1-e] benzo[1,5] oxazocines 5 and regioselective synthesis of 2,3(erythro),7,8- tetrahydro-2- aryl-3-(4-fluoro-3-methylbenzoyl)-6-(4-halophenyl)pyrazolo[5,1-d] benzo[1,4]oxa- zepines 6, respectively, via solid-liquid PTC is reported. All the synthesized compounds have been characterized on the basis of their spectral studies (IR, PMR, and MS) and analytical data. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601163927

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Synthesis of Some Novel
2,3,4,8,9‐Pentahydro‐7‐(4‐haloaryl)‐pyrazolo[5,1
and 2,3(erythro),
7,8‐Tetrahydro‐2‐aryl‐3‐(4‐fluoro‐3‐methylbenzo
Benzo[1,4]oxazepines via Solid–Liquid PTC
Vijai N. Pathak a , Ragini Gupta b , Ranjana Tiwari a , Rekha Gupta a ,
Vineeta Sareen a & Bindu Varshney a
a Centre for Advanced Studies, Department of Chemistry, University of
Rajasthan, Jaipur, India
b Department of Chemistry, Malaviya National Institute of Technology,
Jaipur, India
Published online: 24 Feb 2007.
To cite this article: Vijai N. Pathak , Ragini Gupta , Ranjana Tiwari , Rekha
Gupta , Vineeta Sareen & Bindu Varshney (2007): Synthesis of Some Novel
2,3,4,8,9‐Pentahydro‐7‐(4‐haloaryl)‐pyrazolo[5,1‐e]benzo[1,5]oxazocines and 2,3(erythro),
7,8‐Tetrahydro‐2‐aryl‐3‐(4‐fluoro‐3‐methylbenzoyl)‐6‐(4‐haloaryl)pyrazolo[5,1‐d] Benzo[1,4]oxazepines via
Solid–Liquid PTC, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:6, 977-984
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Synthetic Communicationsw, 37: 977–984, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601163927
Synthesis of Some Novel
2,3,4,8,9-Pentahydro-7-(4-haloaryl)-
pyrazolo[5,1-e]benzo[1,5]oxazocines and
2,3(erythro), 7,8-Tetrahydro-2-aryl-3-(4-
fluoro-3-methylbenzoyl)-6-(4-
haloaryl)pyrazolo[5,1-d]
Benzo[1,4]oxazepines via Solid–Liquid PTC
Vijai N. Pathak
Centre for Advanced Studies, Department of Chemistry, University
of Rajasthan, Jaipur, India
Ragini Gupta
Department of Chemistry, Malaviya National Institute of Technology,
Jaipur, India
Ranjana Tiwari, Rekha Gupta, Vineeta Sareen, and Bindu Varshney
Centre for Advanced Studies, Department of Chemistry, University
of Rajasthan, Jaipur, India
Abstract: In this communication, a simple and straightforward procedure for the
heterocyclization of 1H-4,5-dihydro-3-(4-haloaryl)-5-substituted phenylpyrazoles
(4) with 1-bromo-3-chloropropane and 2,3-dibromo-1-(4-fluoro-3-methylphenyl)-3-phe-
nylpropanone affording 2,3,4,8,9-pentahydro-7-(4-haloaryl)pyrazolo[5,1-e]benzo[1,5]
oxazocines
aryl-3-(4-fluoro-3-methylbenzoyl)-6-(4-halophenyl)pyrazolo[5,1-d]benzo[1,4]oxa-
5
and regioselective synthesis of 2,3(erythro),7,8-tetrahydro-2-
zepines 6, respectively, via solid–liquid PTC is reported. All the synthesized
Received August 18, 2006
Address correspondence to Vijai N. Pathak, Centre for Advanced Studies, Depart-
ment of Chemistry, University of Rajasthan, Jaipur 302 004, India. E-mail:
pathakvijain@yahoo.com
977

978
V. N. Pathak et al.
compounds have been characterized on the basis of their spectral studies (IR, PMR,
and MS) and analytical data.
Keywords: 1,4-benzoxazepines, 1,5-benzoxazocines, dihaloalkane, heterocyclization,
pyrazoles, regioselective synthesis, solid–liquid phase-transfer catalysis
INTRODUCTION
Benzo-fused seven-membered and eight-membered ring heterocycles have
gained recognition in the therapeutic armanentarium because they serve as
important central nervous system (CNS) and cardiovascular agents. Nefopam,
a 1H-2,5-benzoxazocine is a nonsedative nonnarcotic analgesic.[1] Basil
et al.[2] have reported the synthesis of a series of 1,5-benzoxazocine derivatives
and have found that 3,4-dihydro-3-hydroxy-6-methyl-1,5-benzoxazocine
possessed high sympathetic b–blocker activity. Diazepam, a 2H-1,4-benzodia-
zepin-2-one is a significant erythro-anxiety drug (tranquilizer).[3–5] More
recently, it has shown potential as an erythroepileptic drug.[6] Dilitiazem, a
1,5-benzothiazepinone is a well-known calcium-channel antagonist used for
the treatment of hypertension.[7,8] 1,5-Benzoxazepine derivatives have been
reported to show potent erythroconvulsant activity by Bajaj et al.[9] 4,1-Benzox-
azepine derivatives exhibited squalene synthase inhibitory activity,[10] and JL
13, a pyridobenzoxazepine, possessed atypical erythropsychotic activity.[11,12]
In light of these observations and in continuation to our previous work on
bioactive fluorinated/nonfluorinated heterocycles and phase-transfer catalysis
(PTC),[13] we thought it worthwhile to synthesize derivatives of these biologi-
cally useful heterocycles by using a simple, convenient, and mild phase-
transfer-catalyzed heterocyclization approach leading to the synthesis of
2,3,4,8,9-pentahydro-7-(4-haloaryl)pyrazolo[5,1-e]benzo
[1,5]oxazocines
5(a–d) and regioselective synthesis of 2,3(erythro),7,8-tetrahydro-2-aryl-
3-(4-fluoro-3-methylbenzoyl)-6-(4-haloaryl)pyrazolo[5,1-d]benzo[1,4]oxa-
zepines 6(a–d) via solid–liquid PTC (Scheme 1).
RESULTS AND DISCUSSION
Synthesis
Various 1,3-diarylprop-2-enones 3(a–d) were prepared by condensation of sal-
icylaldehyde and aryl methyl ketones in the presence of 50% NaOH solution
and characterized as trans 1,3-diaryl-2-propenones on the basis of their IR
and proton magnetic resonance (PMR) spectral data, which were consistent
with earlier results.[14,15]
The appropriate 1,3-diarylprop-2-enone (3) was treated with hydrazine
hydrate (80%) in ethanol to afford the desired 1H-4,5-dihydro-3-(4-
haloaryl)-5-(2-hydroxyphenyl)pyrazole 4(a–d). The PMR spectra of these

Solid–Liquid PTC
979
Scheme 1.
compounds 4 exhibited a characteristic ABX pattern for methylene group
(a prochiral -CH2 group, which contains two nonequivalent protons). The
resonance signals at d 2.8–3.2 (double doublet due to a-CH of CH2 group),
3.5–4.0 (double doublet due to b-CH of CH2 group), and 5.5–5.8 ppm
(double doublet due to methine group -CH). These compounds also
exhibited D2O exchangeable resonance signals at d 11.0 and 8.82 ppm due
to NH and OH protons, respectively. The aromatic resonance signal appears
as a multiplet at d 6.94–8.32 ppm.
The reaction of 1H-4,5-dihydro-3-(4-haloaryl)-5-(2-hydroxyphenyl)pyr-
azoles 4(a–d) with 1-bromo-3-chloropropane in the presence of tetra-n-
butylammonium hydrogen sulphate in dry THF and powdered potassium
hydroxide (KOH) gave 5(a–d). In their PMR spectra, two triplets at d
4.25 and 4.50 ppm corresponding to -N-CH2- and -O-CH2- appeared.
Further confirmation for their formation was obtained from mass spectra.

980
V. N. Pathak et al.
Treatmentof2,3-dibromo-1-(4-fluoro-3-methylphenyl)-3-phenylpropanone
with the dianion of appropriate 1H-4,5-dihydro-3-(4-haloaryl)-5-(2-hydro-
xyphenyl)-pyrazoles 4(a–d) (generated by solid–liquid PTC as described
earlier) gave 6(a–d). In the PMR spectra, appearance of two double doublets
at d 4.10 and 4.50 ppm (J ¼ 10 Hz) corresponds to -N-CH and -O-CH
(erythro). Further evidence is obtained by mass spectra where the molecular
ion peaks Mþ at m/z 476 (33.2%) for the compound 6a and at m/z 510
(9.2%) for the compound 6c are observed (Table 1).
EXPERIMENTAL
Melting points were recorded in open glass capillaries and are uncorrected. IR
spectra (nmax in cm21) were recorded using Perkin-Elmer model 557 in KBr
pellets and Nicholet Magna model-750 spectrophotometer in KBr pellets at
Central Drug Research Institute (CDRI), Lucknow, and Department of
Chemistry, University of Rajasthan, Jaipur. PMR spectra were recorded on
Jeol FX-90 Q at 89.55 Hz at Department of Chemistry, University of
Rajasthan, Jaipur, and on Bruker spectrophotometer (200 MHz) at CDRI,
Lucknow, in CDCl3 solution with TMS as an internal standard (chemical shift
in d ppm). Mass spectra were recorded on Kratos-30 and 50 mass spectrometer
at CDRI, Lucknow. 2,3-Dibromo-1-(4-fluoro-3-methylphenyl)-3-phenylpropa-
none was synthesized by the literature method.[16] All compounds are homo-
geneous on thin-layer chromatography (TLC) in various solvent systems.
Synthesis of 1-(4-Fluorophenyl)-3-(2-hydroxyphenyl)-prop-2-enone
(3d)
A mixture of salicyaldehyde (1) (1.22 g, 10 mmol) and 4-fluoroacetophenone
(2) (1.38 g, 10 mmol) in EtOH (50 mL) was heated in a water bath for 15 min,
then 50% aqueous NaOH solution (10 mL) was added. The resulting thick
mass was stirred for 3 h, then left overnight at room temperature and neutral-
ized by pouring into ice-cold 2 N HCl (100 mL). The solid was filtered, dried,
and recrystallized from ethanol to afford (3d).[17] Yield: 2.38 g (98%), mp:
1508C. Compounds 3(a–c) were prepared similarly.
Synthesis of 1H-4,5-Dihydro-3-(4-fluorophenyl)-5-(2-
hydroxyphenyl)pyrazole (4d)
A mixture of 1-(4-fluorophenyl)-3-(2-hydroxyphenyl)-prop-2-enone (3d)
(0.968 g, 4 mmol) and hydrazine hydrate (5 mL, 80%) in ethanol (50 mL)
was refluxed in a water bath for 5 h, concentrated, and poured over crushed
ice. The solid was filtered and recrystallized from ethanol to yield (4d).

Solid–Liquid PTC
981
Table 1. Spectroscopic data of 2,3,4,8,9-pentahydro-7-(4-haloaryl)pyrazolo[5,1-
e]benzo[1,5] oxazocines (5) and 2,3(erythro),7,8-tetrahydro-2-aryl-3-(4-fluoro-3-
methylbenzoyl)-6-(4-haloaryl)pyrazolo[5,1-d]benzo[1,4]oxazepines (6)
Compound.
no.
IR nmax (cm21) (KBr)
1H NMR d (ppm) (CDCl3) MS: (m/z)
5a
3040–3080 m (aromatic
C-C str.), 2870–2990 m
(aliphatic C-C str.),
7.3–7.5 (m, Ar-H, 9H), 5.5–
5.8 (dd, -CH, 1H), 4.50
—
(t, 3J ¼ 7.0 Hz, -O-CH2, 2H),
3
1610–1600vs (-C55N str.), 4.25 (t, J ¼ 6.8 Hz, -N-CH2,
1580–1575 s (aromatic
-C55C str.), 1500 m,
1450 m, 1300 w, 1200–
1000vs (-C-O-C str.)
2H), 3.5–4.0 (dd, -CHa-CHb,
1H), 2.8–3.2 (dd, -CHa-CHb,
1H), 2.0 (m, -CH2, 2H)
5b
5c
5d
6a
3050–3080 m (aromatic
C-C str.), 2860–2990 m
(C-C str.), 1611–1602vs
(C55N str.), 1587–1582 s
(aromatic -C55C str.),
7.3–7.5 (m, Ar-H, 8H), 5.6– 357
5.8 (dd, -CH, 1H), 4.53
(M þ 1,
(t, 3J ¼ 7.1 Hz, -O-CH2, 2H), 100%) 356
4.26 (t, -N-CH2, 2H), 3.6–4.0 (Mþ,
(dd, -CHa-CHb, 1H), 2.9–3.1 23.2%)
1200–1000 s (-C-O-C str.), (dd, -CHa-CHb, 1H), 2.0 (m,
-CH2, 2H)
530 m (-C-Br str.)
3040–3070 m (aromatic
C-C str.), 2860–2990 m
7.3–7.5 (m, Ar-H, 8H), 5.5– 312 (Mþ,
5.7 (dd, -CH, 1H), 4.54
100%)
(aliphatic C-C str.), 1613– (t, 3J ¼ 7.0 Hz, -O-CH2, 2H),
1605vs (-C55N str.), 1594– 4.28 (t, -N-CH2, 2H), 3.8–4.0
1588 s (aromatic -C55C (dd, -CHa-CHb, 1H), 2.8–3.0
str.), 1200–1000vs (-C-O- (dd, -CHa-CHb, 1H), 2.1 (m, -
C str.), 735 w (-C-Cl str.)
CH2, 2H)
7.5–7.7 (m, Ar-H, 8H), 5.5– 296 (Mþ,
5.8 (dd, -CH, 1H), 4.54 100%)
3050–3070 m (aromatic
C-C str.), 2860–2990 m
(aliphatic C-C str.), 1616– (t, 3J ¼ 7.0 Hz, -O-CH2, 2H),
1609vs (-C55N str.), 1601– 4.29 (t, -N-CH2, 2H), 3.9–4.1
1596s (aromatic -C55C str.), (dd, -CHa-CHb, 1H), 2.9–3.2
1200–1000vs (-C-O-C
str.), 859 m (-C-F str.)
(dd,-CHa-CHb, 1H), 2.2 (m,
-CH2, 2H)
3040–3070 m (aromatic
C-C str.), 2850–2990 m
(aliphatic C22C str.),
1660vs (-C55O str.), 1616– 1H), 5.5–5.8 (dd, -CH, 1H), H17N2O
1609vs (-C55N str.), 1601– 3.9–4.1 (dd, -CHa-CHb, 1H), (100%)
7.5–7.8 (m, Ar-H, 17H), 4.50 476 (Mþ,
(dd, J ¼ 10 Hz, -O-CH, 1H), 33.2%),
4.10 (dd, J ¼ 10 Hz, -N-CH, 325 (C22
1596vs (aromatic -C55C 2.9–3.2 (dd, -CHa-CHb, 1H),
str.), 1200-1010vs (-C-O-C 2.2 (m, -CH2, 2H), 2.1 (s, CH3,
str.), 1585–1575 m (aro-
matic str.), 1110 w, 850 m
(-C-F str.), 625 m
3H)
(continued)

982
V. N. Pathak et al.
Table 1. Continued
Compound.
no.
IR nmax (cm21) (KBr)
1H NMR d (ppm) (CDCl3) MS: (m/z)
6b
3045–3070 m (aromatic
C-C str.), 2840–2980 m
(aliphatic C-C str.),
7.2–7.8 (m, Ar-H, 16H), 4.52
(dd, J ¼ 10 Hz, -O-CH, 1H),
4.15 (dd, J ¼ 10 Hz, -N-CH,
—
1665vs (-C55O str.), 1616– 1H), 5.43–5.82 (dd, -CH, 1H),
1609vs (-C55N str.), 1601– 3.94–4.15 (dd, -CHa-CHb,
1596vs (aromatic -C55C
1H), 2.91–3.2 (dd, -CHa
str.), 1200–1000vs (-C-O- -CHb, 1H), 2.2 (m, -CH2, 2H),
C str.), 1580–1575 m (aro- 2.0 (s, CH3, 3H)
matic str.), 1100 w, 810 m,
780 m, 625 m (-C-Br str.)
6c
3040–3070 m (aromatic
C-C str.), 2850–2990 m
(aliphatic C-C str.),
7.5–7.8 (m, Ar-H, 16H), 4.54 510 (Mþ,
(dd, J ¼ 10 Hz, -O-CH, 1H), 9.2%)
4.18 (dd, J ¼ 10 Hz, -N-CH,
1660vs (-C¼O str.), 1616– 1H), 5.45–5.81 (dd, -CH, 1H),
1609vs (-C55N str.), 1601– 3.89–4.1 (dd, -CHa-CHb,
1596vs (aromatic -C55C
1H), 2.9–3.24 (dd, -CHa
str.), 1210–1000vs (-C-O- -CHb, 1H), 2.2 (m, -CH2, 2H),
C str.), 1580–1575 m (aro- 1.94 (s, CH3, 3H)
matic str.), 1105 w, 615 m
(-C-Cl str.)
6d
3040–3070 m (aromatic
C-C str.), 2850–2990 m
7.3–7.8 (m, Ar-H, 16H), 4.51
—
(dd, J ¼ 10.1 Hz, -O-CH, 1H),
(aliphatic C-C str.), 1670vs 4.12 (dd, J ¼ 10.1 Hz, -N-CH,
(-C55O str.), 1616–1600vs 1H), 5.6–5.8 (dd, -CH, 1H),
(-C55N str.), 1600–1595vs 3.9–4.1 (dd, -CHa-CHb, 1H),
(aromatic -C55C str.), 2.9–3.15 (dd, -CHa-CHb,
1200–1010vs (-C-O-C str.), 1H), 2.18 (m, -CH2, 2H), 2.1
1580–1575 m (aromatic
str.), 1145s (-C-F, str.)
(s, CH3, 3H)
Yield: 1.0 g (98%), mp: 748C. Other compounds 4(a–c) were prepared
similarly.
Synthesis of 2,3,4,8,9-Pentahydro-7-(4-fluorophenyl)pyrazolo[5,1-
e]benzo[1,5] oxazocine (5d)
Compound (4d) (0.51 g, 2 mmol) and tetra-n-butylammonium hydrogen
sulphate (0.68 g, 2 mmol) were dissolved in dry THF (20 mL). Then
powdered KOH (20 g) followed by 1-bromo-3-chloropropane (0.30 mL,
2 mmol) in THF (20 mL) were added. The resultant reaction mixture was
stirred for 8 h. THF was removed, and the resultant residue dissolved into

Solid–Liquid PTC
Table 2. Physical data of compounds 3–6
983
Substituent in
aryl moietya
(X)
Compound
no.
Yieldc
(%)
mpb (8C)
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
H
124
136
140
151
173
150
170
76
80
4-Br
4-Cl
4-F
H
96
98
98
82
92
95
97
52
57
58
56
56
59
54
57
4-Br
4-Cl
4-F
H
102
124
144
150
178
150
120
188
4-Br
4-Cl
4-F
H
4-Br
4-Cl
4-F
aSatisfactory C, H and N analyses were obtained.
bAll compounds were recrystallized form ethanol.
cYield refers to purified products obtained after column
chromatography.
chloroform. It was washed with water, dried over anhydrous sodium sulphate,
and concentrated; light pertroleum was added, and the solid was filtered.
Recrystallization from ethanol afforded (5d). Yield: 0.33 g (55.76%), mp:
1508C. Other compounds were prepared by this method (Table 2).
Synthesis of 2,3(Erythro),7,8-tetrahydro-2-aryl-3-(4-fluoro-3-
methylbenzoyl)-6-(4-fluorophenyl)pyrazolo[5,1-d]
benzo[1,4]oxazepine (6d)
Compound 6d was prepared as described earlier. Yield 56.7%; mp 1888C.
ACKNOWLEDGMENTS
Authors are thankful to University Grants Commission (UGC), New Delhi, for
financial assistance. Authors also record their sincere thanks to V. J. Ram,
emeritus scientist, Medicinal Chemistry Division, Central Drug Research
Institute (CDRI), Lucknow, and K. P. Madhusudanan, deputy director and

984
V. N. Pathak et al.
head, sophisticated analytical instrument facility (SAIF), CDRI, Lucknow, for
spectral and analytical analyses.
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