Synthesis of some fused pyrazoles and isoxazoles

Article abstract of DOI:10.3390/51201281

The α-keto methylene group in 3,5-diaryl-2-cyclohexenones 2 and 3,5-diarylcyclohexanones 8 have been used to obtain fused pyrazoles and isoxazoles. The new compounds were characterized by IR and ¹H-NMR spectral data.

Full text of DOI:10.3390/51201281

Molecules 2000, 5, 1281–1286
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Some Fused Pyrazoles and Isoxazoles
Venkatapuram Padmavathi*, Boggu Jagan Mohan Reddy, Akula Balaiah, Katta Venugopal
Reddy and Dandu Bhaskar Reddy
Department of Chemistry, Sri Venkateswara University, Tirupati-517 502, India.
Fax: +91-8574-48499
*Author to whom correspondence should be addressed; E-mail: vkpuram@usa.net
Received: 16 September 2000; in revised form 30 October 2000 / Accepted: 8 November 2000 /
Published: 18 December 2000
Abstract: The α-keto methylene group in 3,5-diaryl-2-cyclohexenones 2 and 3,5-
diarylcyclohexanones 8 have been used to obtain fused pyrazoles and isoxazoles. The new
compounds were characterized by IR and 1H-NMR spectral data.
Keywords: DDQ, ethyl formate, pyrazoles, isoxazoles
Introduction
The exploitation of a simple molecule with different functionalities for the synthesis of heterocycles
is a worthwhile contribution in the chemistry of heterocycles. In fact, the 6-carbethoxy-3,5-
diarylcyclohexenone has been used as an effective synthon in some projected syntheses of
benzoselenadiazoles/thiadiazoles [1], spirocyclohexanones [2], carbazole derivatives [3], fused
isoxazoles and pyrazoles [4]. In the present communication the former has been chosen as a promising
starting material to develop pyrazole and isoxazole rings. Earlier we have reported various fused and
spiro isoxazoles and pyrazoles by 1,3-dipolar cycloaddition of nitrile oxides and nitrile imines to
activated olefins [5]. The formation of isoxazoles from open chain α-hydroxymethylene ketones and
hydroxylamine is well known [6]. The generality of this reaction is extended to cyclohexanone
derivatives also [7]. In this communication preparations of a new class of fused pyrazoles and
isoxazoles from 3,5-diarylcyclohexenones are reported.
© 2000 MDPI. All rights reserved.

Molecules 2000, 5
1282
Results and Discussion
The 3,5-diaryl-2-cyclohexenones 2 were prepared by the decarboxylation of the corresponding 6-
carbethoxy-3,5-diarylcyclohexenones (1). The latter were obtained by Knoevenagel condensation of
ethyl acetoacetate and 1,3-diaryl-2-propen-1-ones in the presence of sodium ethoxide. The Claisen like
condensation of 2 with ethyl formate in the presence of sodium ethoxide gave 6-hydroxymethylene-
1
3,5-diaryl-2-cyclohexenones 3. The formation of these products was confirmed by IR and H-NMR
spectral studies.
The IR spectra of 3 showed bands around 1645-1660 (C=O), 1590-1624 (C=C and C=CHOH) and
3310-3415 (OH). The 1H-NMR spectra showed two singlets, a triplet and a doublet at 5.38-5.42, 5.32-
5.34, 4.37-4.38 and 3.22-3.26 for =CH-OH, H-2, H-5 and H-4, respectively. The cyclocondensation of
3 with hydrazine hydrate/hydroxylamine hydrochloride in AcOH afforded 4,5-dihydrobenzo[3,4-
d]pyrazoles 4 / isoxazoles 5 (Table 1). The IR spectra of these compounds showed a band in the region
1560-1585 (C=N), whereas 4 displayed a band around 3390-3410 (NH). The 1H-NMR spectra of 4 and
5 exhibited a singlet, a triplet and a doublet at 5.30-5.38, 4.50-4.56 and 3.20-3.25 for H-7, H-4 and H-
5, respectively. Aromatization of 4 and 5 with DDQ gave fused benzopyrazoles 6/isoxazoles 7. The
absence of signals corresponding to methine and methylene protons of cyclohexadiene ring indicates
that aromatization has indeed taken place. The compounds 4 -7 exhibited a multiplet in the region

Molecules 2000, 5
1283
7.12- 8.14 for Ar-H and H-3 [8]. However 4 and 6 displayed a broad singlet at 8.84-8.87 for NH which
disappeared upon deuteration (Table 2). The IR spectra of 6 and 7 are replicas of those of 4 and 5.
Compounds 2 on reduction with H2/Pd at 40 psi gave 3,5-diarylcyclohexanones 8. The 2-
hydroxymethylene-3,5-diaryl-2-cyclohexanone 9 was prepared by the reaction of latter with ethyl
formate. Cyclocondensation of 9 with hydrazine hydrate / hydroxylamine hydrochloride resulted 4,6-
diaryl-4,5,6,7-tetrahydrobenzo[3,4-d]pyrazoles 10 / isoxazoles 11 (Table 1). The IR spectra of 9 are
similar to those of 3 except for the C=C whereas their 1H-NMR spectra showed a triplet, two multiplets
and a doublet at 3.64-3.69, 2.08-2.19, 2.98-3.05 and 2.89-2.94. The hydroxymethylene proton
displayed a singlet at 5.32-5.40. However 10 and 11 exhibited a triplet, two multiplets and a doublet at
3.52-3.60, 2.10-2.21, 3.10-3.18 and 2.80-2.87 (Table 2). A multiplet at 7.14-8.01 accounts for Ar-H
and H-3. In fact the δC values observed for C-3 in 4a, 5a, 10a and 11a around 136-138 ppm account for
such an assignment (Table 3).The compounds 10 and 11 could not be oxidized with DDQ. Thus the
YHUVDWDOLW\ꢀRIꢀ.ꢁketo methylene group in 2 and 8 indicates that they are potential intermediates for fused
pyrazoles and isoxazoles.
Conclusions
The α-keto methylene group in substituted cyclohexenones has been utilized to get pyrazoles and
isoxazoles via Claisen like condensation with ethyl formate followed by cyclocondensation with
hydrazine hydrate and hydroxylamine hydrochloride.
Experimental
General
Melting points were determined on a Mel-Temp apparatus and are uncorrected. The purity of
compounds was checked by TLC (silica gel H, BDH, ethyl acetate/hexane, 1:3). The IR spectra (KBr
pellets) were recorded on a Perkin-Elmer grating infrared spectrophotometer model-337. The 1H-NMR
spectra were recorded in CDCl3 on a Bruker Spectrospin Varian EM-360 spectrophotometer (90 MHz)
with TMS as an internal standard. The elemental analyses were performed at Dr. Reddy`s Research
Foundation, Hyderabad, India. The 6-carbethoxy-3,5-diaryl-2-cyclohexenones 1, 3,5-diaryl-2-
cyclohexenones 2 and 3,5-diarylcyclohexanones 8 were prepared according to literature procedures [9].
6-Hydroxymethylene-3,5-diaryl-2-cyclohexenones(3)/2-hydroxymethylene-3,5-diarylcyclo-
hexanones(9)
To a solution of 10% sodium methoxide (10 mL) in benzene (50 mL) at 00C, a solution of ethyl
formate (10 mmol) in dry benzene (25 mL) was added. To this mixture 2 / 8 (10 mmol) in benzene (25
mL) was added. The mixture was stirred for 4 hours at room temperature and allowed to stand

Molecules 2000, 5
1284
overnight. It was then diluted with cold water, acidified with dil. HCl and extracted with ether. The
solvent was evaporated and the resultant compound was recrystallised from ethanol to get pure 3/9.
4,6-Diaryl-4,5-dihydrobenzo[3,4-d] pyrazoles 4/ 4,6-diaryl-4,5,6,7-tetrahydrobenzo[3,4-d] pyrazoles
(10)
A solution of 3/9 (10 mmol) in glacial acetic acid (25 mL) was stirred with hydrazine hydrate (15
mmol) for 6-8 hours at 70-80o C. The solvent was removed under reduced pressure, and the residue
was diluted with water. It was extracted with ether, washed with saturated NaHCO3 solution, water,
brine solution and dried (Na2SO4). The solvent was removed and the crude product was purified by
recrystallization from ethanol.
4,6-Diaryl-4,5-dihydrobenzo[3,4-d]isoxazoles(5)/4,6-diaryl-4,5,6,7-tetrahydrobenzo[3,4-d] isoxazoles
(11)
A solution of 3/9 (10 mmol) in glacial acetic acid (25 mL) was stirred with hydroxylamine
hydrochloride (12 mmol) for 6-8 hours at 70-80oC. The solvent was removed under reduced pressure.
The viscous mass was diluted with water and extracted with ether. The organic layer was washed
successively with saturated NaHCO3 solution, water and brine solution. It was dried (Na2SO4) and the
solvent was removed. Recrystallization of the crude substance from ethanol afforded pure 5/11.
Oxidation of 4 and 5
A 1:1.5 molar mixture of 4/5 and DDQ in dry benzene (20 mL) was heated at reflux temperature for
2 hours under nitrogen atmosphere. The precipitated DDQ-H2 was filtered off and the filtrate was
subjected to column chromatography on silica gel (60-120 mesh), BDH to obtain 6/7.
Table 1. Physical data of compounds 3-7 and 9-11.
Product
3a
Yield (%)
Product
7a
Yield (%)
M. P (° C)
161 - 162
147 - 148
165 – 166
128 - 129
120- 121
135 - 136
149 - 150
142 - 143
153 - 154
154 - 155
143 - 144
162 - 163
M.P.(° C)
174 - 175
183 - 184
179 - 180
183 - 184
166 - 167
172 -173
162 - 163
149 - 150
157 - 158
176 - 177
158 - 159
165 - 166
82
78
76
74
79
70
78
76
75
65
67
68
66
64
65
80
78
77
72
75
76
75
70
72
3b
3c
4a
4b
4c
5a
5b
5c
7b
7c
9a
9b
9c
10a
10b
10c
11a
11b
11c
6a
6b
6c
Satisfactory elemental analyses were obtained for representative examples of each series: C ± 0.24,
H±0.15, N ± 0.18

Molecules 2000, 5
1285
Table 2. 1H-NMR Spectral Data of 3-7 and 9-11.
1H-NMR δ (ppm)
Product
3a
3c
5.38 (s, 1H, = CH-OH), 5.32 (s, 1H, H-2), 4.38 (t, 1H, H-5), 3.22 (d, 2H, H-4).
5.42 (s, 1H, = CH-OH), 5.33 (s, 1H, H-2), 4.37 (t, 1H, H-5), 3.26
(d, 2H, H-4).
4a
4b
4c
5a
5b
5c
8.85 (brs, 1H, NH), 7.18-7.94 (m, 11H, Ar-H & H-3), 5.36 (s, 1H, H-7), 4.54 (t,
1H, H-4), 3.25 (d, 2H, H-5).
8.87 (brs, 1H, NH), 7.21-7.93 (m, 9H, Ar-H & H-3), 5.30 (s, 1H, H-7), 4.50 (t,
1H, H-4), 3.64 (s, 6H, Ar- OCH3), 3.23 (d, 2H, H-5).
8.86 (brs, 1H, NH), 7.14-7.87 (m, 9H, Ar-H & H-3), 5.38 (s, 1H, H-7), 4.56 (t,
1H, H-4), 3.20 (d, 2H, H-5).
7.19-7.84 (m, 11H, Ar-H & H-3), 5.32 (s, 1H, H-7), 4.50 (t, 1H, H-4),
3.21 (d, 2H, H-5).
7.24-7.93 (m, 9H, Ar-H & H-3), 5.31 (s, 1H, H-7), 4.53 (t, 1H, H-4), 3.66 (s,
6H, Ar-OCH3), 3.20 (d, 2H, H-5).
7.17-7.86 (m, 9H, Ar-H & H-3), 5.37 (s, 1H, H-7), 4.54 (t, 1H, H-4), 3.25 (d,
2H, H-5).
6a
6c
7a
7c
9a
8.84 (brs, 1H, NH), 7.14-8.12 (m, 13H, Ar-H & H-3).
8.85 (brs, 1H, NH), 7.19-8.10 (m, 11H, Ar-H & H-3).
7.12-8.04 (m, 13H, Ar-H & H-3).
7.20-8.14 (m, 11H, Ar-H & H-3).
5.32 (s, 1H, = CH-OH), 3.69 (t, 1H, H-3), 2.98 (m, 1H, H-5), 2.94 (d, 2H, H-6),
2.16 (m, 1H, H-4).
9c
5.35 (s,1H, = CH-OH), 3.64 (t, 1H, H-3), 3.05 (m, 1H, H-5), 2.89 (d, 2H, H-6),
2.19 (m, 2H, H-4).
10a
10b
11a
11c
8.38 (brs, 1H, NH), 7.14-7.93 (m, 11H, Ar-H & H-3), 3.58 (t, 1H, H-4), 3.10 (m,
1H, H-6), 2.83 (d, 2H, H-7), 2.15 (m, 2H, H-5).
8.18 (brs,1H, NH), 7.19-7.95 (m, 9H, Ar-H & H-3), 3.62 (s, 6H, Ar-OCH3), 3.54
(t, 1H, H-4), 3.15 (m, 1H, H-6), 2.80 (d, 2H, H-7), 2.10 (m, 2H, H-5).
7.17-7.96 (m, 11H, Ar-H & H-3), 3.52 (t, 1H, H-4), 3.15 (m, 1H, H-6),
2.80 (d, 2H, H-7), 2.14 (m, 2H, H-5).
7.24-8.01 (m, 9H, Ar-H & H-3), 3.60 (t, 1H, H-4), 3.16 (m, 1H, H-6), 2.87 (d,
2H, H-7), 2.21 (m, 2H, H-5).

Molecules 2000, 5
1286
Table 3. 13C-NMR Spectral Data of 4a, 5a, 10a and 11a.
13C NMR δ (ppm)
Product
4a
138.6(C-3), 55.2(C-4), 29.6(C-5), 118.5(C-6), 114.3(C-7), 143.6(C-8),
136.5(C-9).
5a
137.6(C-3), 56.3(C-4), 29.8(C-5), 119.4(C-6), 116.2(C-7), 144.2(C-8),
135.8(C-9).
10a
11a
136.9(C-3), 55.4(C-4), 29.6(C-5), 35.1(C-6), 30.4(C-7), 140.3(C-8),
135.8(C-9).
136.6(C-3), 55.2(C-4), 29.4(C-5), 35.5(C-6), 30.9(C-7), 142.6(C-8),
134.7(C-9).
Acknowledgements
We are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi for financial
support under Major Research Project.
References
1. Bhaskar Reddy, D.; Somasekhar Reddy, A.; Padmavathi, V. J. Chem. Research (S) 1998, 784.
2. Padmavathi, V.; Sharmila, K.; Somasekhar Reddy, A.; Bhaskar Reddy, D. Indian J. Chem. (in
press).
3. Padmavathi, V.; Sharmila, K.; Padmaja, A.; Bhaskar Reddy, D. Heterocycl Commun 1999, 5, 451.
4. Padmavathi, V.; Sharmila, K.; Balaiah, A.; Somasekhar Reddy, A.; Bhaskar Reddy, D. Synth.
Commun. (in press).
5. (a) Padmavathi, V.; Sumathi, R P.; Chandra Sekhar Babu, N.; Bhaskar Reddy, D. J Chem.
Research (S) 1999, 610; and references cited therein; (b) Padmavathi, V.; Sumathi, R.P.;
Venugopal Reddy, K.; Somasekhar Reddy, A.; Bhaskar Reddy, D. Synth. Commun. 2000, 30,
4007; (c) Bhaskar Reddy, D.; Somasekhar Reddy, A.; Padmaja, A. Synth. Commun. 1999, 29,
4433.
6. (a) Claisen. Ber 1903, 36, 3664; (b) Claisen. Ber 1909, 42, 59.
7. Johnson, W S.; Shelberg, W E. J. Am. Chem. Soc. 1945, 67, 1745; and references cited therein.
8. Mohareb, R M.; Shams, H Z.; Aziz, S I. Sulfur Lett. 1991, 13, 101.
9. (a) Balasubramanian, M.; D`souja, A. Tetrahedron 1968, 24, 5399; (b) Meyer, A Y.; Schelesinger,
J. Israel J. Chem. 1970, 8, 671.
Samples Availability: Samples are available from the authors.
© 2000 by MDPI (http://www.mdpi.org).