Regioselective synthesis of polysubstituted pyrazoles and isoxazoles

Article abstract of DOI:10.1021/jo0101407

A regioselective synthesis has been developed for the preparation of unsymmetrical 1,3,5-triaryl-4-alkylpyrazolines and -pyrazoles by treatment of α-benzotriazolyl-α,β-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring. Reaction of α-benzotriazolyl-α,β-unsaturated ketones with hydroxylamine gives 3,5-disubstituted isoxazoles regioselectively.

Full text of DOI:10.1021/jo0101407

J . Org. Chem. 2001, 66, 6787-6791
6787
Regioselective Syn th esis of P olysu bstitu ted P yr a zoles a n d
Isoxa zoles
Alan R. Katritzky,* Mingyi Wang, Suoming Zhang,‡ and Michael V. Voronkov§
Department of Chemistry, Center for Heterocyclic Compounds, University of Florida,
Gainesville, Florida 32611-7200
Peter J . Steel|
Department of Chemistry, University of Canterbury, Christchurch, New Zealand
katritzky@chem.ufl.edu
Received February 5, 2001
A regioselective synthesis has been developed for the preparation of unsymmetrical 1,3,5-triaryl-
4-alkylpyrazolines and -pyrazoles by treatment of R-benzotriazolyl-R,â-unsaturated ketones with
monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring. Reaction
of R-benzotriazolyl-R,â-unsaturated ketones with hydroxylamine gives 3,5-disubstituted isoxazoles
regioselectively.
Sch em e 1
In tr od u ction
The wide range of biological activities of pyrazoles1a-f
and isoxazoles1d,e,g,h has made them popular synthetic
targets. Numerous methods for the synthesis of these
heterocycles involve approaches based on either (i)
intermolecular [2 + 3] cycloadditions of 1,3-dipoles to
alkynes,1h,2a-c or (ii) condensations of hydrazines2a,d-g or
hydroxylamine2a,g,h with â-diketone equivalent three
carbon 1,3-difunctionalized units bearing sp or sp2 car-
bons, such as propargylic ketones. Although very fre-
quently used, both those routes can give mixtures of
regioisomers (Scheme 1).
Sch em e 2
‡ Present address: Neurogen Corporation, 35 Northeast Industrial
Road, Branford, CT 06405.
§ Present address: Coelacanth Corporation, 279 Princeton-Hights-
town Rd, East Windsor, NJ , 08520.
| E-mail: p.steel@chem.canterbury.ac.nz.
(1) (a) Roth, B. D. E. P.00252476, 1994. Chem. Abstr. 117, 111598e;
114, 185784x. (b) Ashton, W. T.; Hutchins, S. M.; Greenlee, W. J .; Doss,
G. A.; Chang, R. S. L.; Lotti, V. J .; Faust, K. A.; Chen, T. B.; Zingaro,
G. J .; Kivlighn, S. D.; Siegl, P. K. S. J . Med. Chem. 1993, 36, 3595. (c)
Murray, W. V. E. P.00293220B1, 1994. Chem. Abstr. 111, 23508w. (d)
Allen, E. E.; Greenlee, W. J .; MacCoss, M.; Ashton, W. T. WO09115479,
1991. Chem. Abstr. 116, 106284z. (e) Flynn, D. L.; Belliotti, T. R.;
Boctor, A. M.; Conor, D. T.; Kostlan, C. R.; Nies, D. E.; Ortwine, D. F.;
Schrier, D. J .; Sircar, J . C. J . Med. Chem. 1991, 34, 518. (f) Huang, Y.
R.; Katzenellenbogen, J . A. Org. Lett. 2000, 2, 2833. (g) Ricciardi, S.;
Bisiani, C.; Camisasca, C.; Fusi, R.; Ornaghi, F.; Pastoris, R.; Scatturin,
M.; Masotto, C. J . Drug Dev. 1994, 6, 159. (h) Lautens, M.; Roy, A.
Org. Lett. 2000, 2, 555.
(2) (a) For pyrazoles: Elguero, J . In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 3, p 1; for isoxazoles: Sutharcha-
nadevi, M.; Murugan, R. Ibid., p 221. (b) Gru¨nanger, R.; Vita-Finzi, P.
In Heterocyclic Compounds, Vol. 49, Isoxazoles, Part one, J ohn Wiley
& Sons: New York, 1991. (c) Torssell, K. B. G. Nitrile Oxides, Nitrones,
and Nitronates in Organic Synthesis, VCH Publishers: New York,
1988. (d) Coispeau, G.; Elguero, J . Bull. Chim. Soc. Fr. 1970, 2717. (e)
Coispeau, G.; Elguero, J .; J acquier, R. Bull. Chim. Soc. Fr. 1970, 689.
(f) Lazaro, R.; Mathieu, D.; Phan Tan Luu, R.; Elguero, J . Bull. Chim.
Soc. Fr., 1977, 1163. (g) Garcia, H.; Iborra, S.; Miranda, M. A.; Morera,
I. M.; Primo, J . Heterocycles 1991, 32, 1746. (h) Barber, G. N.; Olofson,
R. A. J . Org. Chem. 1978, 43, 3015. (i) Braibante, M, E. F.; Clar, G.;
Martins, M. A. P. J . Heterocycl. Chem. 1993, 30, 1159. (j) Bohrisch, J .;
Pa¨tzel, M.; Mu¨gge, C.; Liebscher, J . Synthesis 1991, 1153. (k) Wang,
X.; Tan, J .; Grozinger, K. Tetrahedron Lett. 2000, 41, 4713. (l) Alberola,
A.; Calvo, L.; Ortega, A. G.; Sa´daba, M. L.; San˜udo M. C.; Granda, S.
G.; Rodr´ıguez, E. G. Heterocycles 1999, 51, 2675.
Several regioselective methods exist for the preparation
of pyrazoles;1f,2d,i-l however, the only regioselective syn-
thesis of 1,3,5-triaryl-4-alkylpyrazoles 1 reported is the
alkylation of the corresponding 1,3,5-triarylpyrazolines1f
(Scheme 2). Previous regioselective syntheses of
isoxazoles3a,b employ R-bromo-R,â-unsaturated ketones
and hydroxylamine; the R-bromine atom behaves as a
leaving group and allows for the direct transformation
(3) (a) Borkhade, K. T.; Marathey, M. G. Indian J . Chem., 1970, 8,
796. (b) Kashima, C.; Yoshihara, N.; Shirai, S. I. Heterocycles 1981,
16, 145.
10.1021/jo0101407 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/08/2001

6788 J . Org. Chem., Vol. 66, No. 20, 2001
Katritzky et al.
Sch em e 3
Ta ble 1. r-Ben zotr ia zolyl-r,â-u n sa tu r a ted Keton es 4
Ta ble 2. ∆2-P yr a zolin es 5 a n d P yr a zoles 8
entry
R1
mp (°C)
yield (%)
entry
R1
R
mp (°C)
yield (%)
4a
4b
4c
4d
4e
4f
Ph
p-Tol
3-Py
i-Pr
4-MeOC6H4
4-ClC6H4
96-99
71
66
55
64
64
59
5a
5b
5c
5d
5e
8a
8b
8c
8d
8e
8f
Ph
Ph
p-Tol
p-Tol
3-Py
Ph
Ph
Me
Ph
Me
Ph
Ph
Me
Ph
Me
Ph
Ph
Me
220-221
129-130
200-201
155-157
250-251
139-140
59-61
115-117
138-139
115-117
oil
80
51
78
68
75
84
90
81
86
94
60
50
145-146
114-116
144-145
-
121-122
Ph
of the initially formed isoxazolines into the aromatic
isoxazoles 2 and 3 (Scheme 2). The ratio of the two
products 2 and 3 depends on the substituents at the
â-position of enones and the base used as a catalyst.3b
The methods mentioned above offer variable versatility,
convenience, and yields.
We now report that trisubstituted pyrazoles 8 can be
conveniently prepared from R-benzotriazolyl-R,â-unsatur-
ated ketones 4 and monosubstituted hydrazines via
intermediates 5. Advantageously, in addition to its leav-
ing group ability, the benzotriazolyl moiety renders the
R-hydrogen acidic and thus allows for its replacement
using an electrophilic reagent,4 so that 5 can be further
functionalized to afford tetrasubstituted pyrazoles 7a -f
via intermediates 6a -f (Scheme 3).
p-Tol
p-Tol
3-Py
i-Pr
8g
i-Pr
oil
regio- and stereoselectively with N-phenyl- or N-meth-
ylhydrazine in the presence of a catalytic amount of
NaOEt in ethanol to form the stable intermediates 5a -e
in 51-80% yields (Scheme 3, Table 2). We found that
N-phenylhydrazine consistently gave higher yields than
the more volatile N-methylhydrazine. This reaction yields
a single 1,3,5-trisubstituted pyrazole regioisomer; no
products of the alternative regiochemistry of addition
1
were detected. According to H NMR spectra and NOE
experiments (Figure 1), the stereochemical relation of R1
and Bt in 5 appears to be exclusively syn. Irradiation of
H-4 at δ 6.72 ppm (d, J ) 4.15 Hz, 1H) in 5c (N-phenyl
derivative) displays the correlation between H-4 and H-5
(δ 5.40 ppm, d, J ) 4.15 Hz, 1H). Similar results were
obtained for 5d (N-methyl derivative) although the J 4,5
coupling constant is larger than that in 5c. Thus, NOE
correlation between H-4 (δ 6.65 ppm, d, J ) 9.7 Hz) and
H-5 (4.61 ppm, d, J ) 9.7 Hz) was observed on the
irradiation of H-4 in 5d . The formation of these syn
products may be explained by the cis stereochemistry of
the starting material 4. The observed diastereoselective
protonation rules out an enamine intermediate which
could easily be protonated from either face.
Resu lts a n d Discu ssion
P r ep a r a tion of r-ben zotr ia zolyl-r,â-u n sa tu r a ted
Keton es (Z)-4a -f. The starting R-benzotriazolyl-R,â-
unsaturated ketones Z-4a -f were generated stereose-
lectively in good yields from benzotriazolylacetophenone
9 and the corresponding aldehyde using piperidine as a
base (Table 1, Scheme 3). The Z-configuration of the
double bond was demonstrated by the X-ray crystal
structure determination of 4c (Supporting Information).
In compound 4c, the 3-pyridyl substituent is disordered
over two conformations in the solid state. In the case of
4d , the surprising shift of the double bond was evidenced
1
When 4d (â,γ-unsaturated ketone) was treated with
hydrazines, the reaction proceeded directly to the corre-
sponding pyrazoles 8f and 8g with no intermediate
pyrazolines 5f and 5g observed. Dihydropyrazoles (py-
razolines) 5a -e can be further converted to trisubstituted
pyrazoles 8a -e by treatment with a mild base in 81-
94% yields. The structures of 8a ,5 8b,6 8c,7 8d ,8 and 8e5
by the H NMR spectrum (δ 5.96 ppm, 1H, dt, J ) 8.8,
1.5 Hz, olefinic proton; δ 1.82 and 1.84 ppm, s and d, J )
1.5 Hz, 2 × CH3). This was explained by steric peculiari-
ties of the structure of 4d and also confirmed by X-ray
crystallography (Supporting Information).
P r ep a r a tion of Dih yd r op yr a zoles 5a -e a n d Tr i-
su bstitu ted P yr a zoles 8a -g. Compounds 4a -c react
(4) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem. Rev.
1998, 98, 409.
(5) Foote, R. S.; Beam, C. F.; Hauser, C. R. J . Heterocycl. Chem.
1970, 7, 589.

Synthesis of Polysubstituted Pyrazoles
J . Org. Chem., Vol. 66, No. 20, 2001 6789
Ta ble 4. 3-P h en ylisoxa zoles 11
entry
R1
mp (°C)
yield (%)
11a
11b
11c
11e
11f
Ph
p-Tol
3-Py
4-MeOC6H4
4-ClC6H4
140-141
135-136
143-144
126-127
177-179
61
79
81
71
55
crystal X-ray crystallography. Surprisingly, the isoxazole
11c crystallizes with the molecule lying on a crystal-
lographic 2-fold rotation axis. As the result, the N/O
atoms and the phenyl/pyridyl rings are each superim-
posed in the asymmetric unit. Hence the X-ray determi-
nation does not distinguish between the two isomeric
possibilities for this compound, despite the excellent level
of data refinement. No such problem exists for 11f, which
crystallizes with a whole molecule in the asymmetric
unit, and the structure is unambiguously established as
the 5-(4-chlorophenyl) isomer (Supporting Information).
In contrast to the preparation of pyrazoles, no stable
adduct 10 was isolated and the reaction proceeded
directly to 11. The lower stability of 10 in comparison
with that of 5 may be explained by the ease of BtH
elimination due to the greater acidity of H-5 of the ring.
In conclusion, tri- and tetrasubstituted pyrazolines and
pyrazoles and disubstituted isoxazoles are readily avail-
able from R-benzotriazolyl-R,â-unsaturated ketones in
regio- and stereoselective and efficient fashion.
F igu r e 1. NOE correlations of 5c and 5d .
Ta ble 3. ∆2-P yr a zolin es 6 a n d P yr a zoles 7
entry
R
R1
R2
mp (°C)
yield (%)
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Me
Me
Me
n-Bu
allyl
benzyl
Me
Me
Me
184-185
184-186
138-140
171-172
195-196
155-157
123-124
134-135
98-99
88
73
95
87
84
91
91
85
99
95
93
95
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
Ph
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
n-Bu
allyl
benzyl
-
-
129-130
Sch em e 4
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined on a
MEL-TEMP capillary melting point apparatus equipped with
a Fluke 51 digital thermometer. NMR spectra were recorded
in CDCl3 with tetramethylsilane as the internal standard for
1H (300 MHz) and 13C (75 MHz) NMR. THF was distilled from
sodium/benzophenone under nitrogen immediately prior to
use. All reactions with air-sensitive compounds were carried
out under argon atmosphere. Column chromatography was
conducted with silica gel (230-400 mesh).
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
4a -f. To a solution of an aldehyde (2.55 mmol) and piperidine
(0.11 g, 1.25 mmol) in ethanol (20 mL) was added 2-(benzo-
triazol-1-yl)-1-phenylethanone 9 (0.59 g, 2.5 mmol) to give a
suspension. The reaction was monitored by TLC and completed
in about 40 h. Ethanol was removed under reduced pressure,
and the desired product was purified by column chromatog-
raphy (hexane:ethyl acetate 4:1).
(Z)-2-(Ben zotr ia zol-1-yl)-1,3-d ip h en yl-2-p r op en -1-on e
(4a ). Yellow plates from methanol (71%), mp 96-99 °C; 1H
NMR δ 8.12-8.09 (dd, J ) 8.3, 1.1 Hz, 1H), 7.82-7.79 (m,
3H), 7.58-7.11 (m, 9H), 6.85 (d, J ) 7.6 Hz, 2H); 13C NMR δ
191.4, 146.0, 142.2, 136.9, 133.4, 133.2, 131.6, 131.5, 131.4,
130.5, 129.4, 129.2, 128.9, 128.6, 124.6, 120.4, 110.3. Anal.
Calcd for C21H15N3O: C, 77.52; H, 4.65; N, 12.91. Found: C,
77.51; H, 4.63; N, 12.57.
were assigned by comparison with their literature spec-
troscopic data.
Tetr a su bstitu ted P yr a zoles 7a -f. Compounds 5a -c
were further functionalized by alkylation at the 4-position
with alkyl iodides in the presence of n-BuLi to afford
derivatives 6a -f in 73-95% yields. The structure of 6b
was initially assigned by NOE experiments; the regio-
and stereochemistry were established unambiguously by
X-ray structure determination (Supporting Information).
Apparently, the alkylations take place with retention of
the stereochemistry at C-4. Treatment of 6a -f with
NaOEt or t-BuOK yielded the desired 1,3,4,5-tetrasub-
stituted pyrazoles 7a 9 and 7b-f in 85-99% yields (Table
3).
P r ep a r a tion of Isoxa zoles 11a -c,e-f. In an exten-
sion of this methodology to the synthesis of trisubstituted
isoxazoles, a number of disubstituted isoxazoles 11 were
regioselectively prepared in 55-81% yields by treatment
of 4 with hydroxylamine in THF (Scheme 4, Table 4). The
structures of 11c10 and 11f10a,11 were examined by single-
(Z)-2-(Ben zotr ia zol-1-yl)-3-(4-m eth ylp h en yl)-1-p h en yl-
2-p r op en -1-on e (4b). Yellow microcrystals from ethanol
1
(66%), mp 145-146 °C; H NMR δ 8.09-8.05 (d, J ) 8.1 Hz,
1H), 7.81 (s, 1H), 7.79 (d, J ) 8.0 Hz, 2H), 7.50 (dd, J ) 7.6,
7.3 Hz, 1H), 7.40-7.27 (m, 4H), 7.21 (d, J ) 8.3 Hz, 1H), 6.88
(6) Cross, B.; Arotin, R. L.; Ruopp, C. F. J . Heterocycl. Chem. 1980,
17, 905.
(7) Akasaka, T.; Nakagawa, M.; Nomura, Y.; Sato, R.; Someno, K.;
Ando, W. Tetrahedron 1986, 42, 3807.
(8) Baddar, F. G.; Al-Hajjar, F. H.; El-Rayyes, N. R. J . Heterocycl.
Chem. 1978, 15, 385.
(9) (a) Barluenga, J .; Lopez-Ortiz, J . F.; Tomas, M.; Gotor, V. J .
Chem. Soc., Perkin Trans. 1 1981, 1891. (b) Begtrup, M.; VedsØ, P.;
Cabildo, P.; Claramunt, R. M.; Elguero, J .; Meutermans, W. Magn.
Reson. Chem. 1992, 30, 455.
(d, J ) 8.1 Hz, 2H), 6.67 (d, J ) 8.3 Hz, 2H), 2.17 (s, 3H); 13
C
NMR δ 190.8, 145.4, 142.3, 141.9, 136.5, 132.8, 132.4, 130.0,
129.9, 129.3, 128.7, 128.2, 128.0, 127.9, 123.9, 119.6, 109.7,
21.1. Anal. Calcd for C22H17N3O: C, 77.86; H, 5.05; N, 12.38.
Found: C, 77.47; H, 5.03; N, 12.33.
(Z)-2-(Ben zotr iazol-1-yl)-1-ph en yl-3-(3-pyr idin yl)-2-pr o-
p en -1-on e (4c). Yellow microcrystals from methanol-chloro-
(10) (a) Beam, C. F.; Dyer, M. C. D.; Schwarz, R. A.; Hauser, C. R.
J . Org. Chem. 1970, 35, 1806. (b) Belgodere, E.; Bossio, R.; Sio, F. D.;
Marcacini, S.; Peoino, R. Heterocycles 1983, 20, 501.
(11) Bandiera, T.; Gru¨nanger, P.; Albini, F. M. J . Heterocycl. Chem.
1992, 29, 1423.

6790 J . Org. Chem., Vol. 66, No. 20, 2001
Katritzky et al.
1
form (55%), mp 114-116 °C; H NMR δ 8.41-8.40 (m, 1H),
6.72 (d, J ) 4.2 Hz, 1H), 5.40 (d, J ) 4.2 Hz, 1H), 2.33 (s, 3H);
13C NMR δ 146.9, 142.5, 140.8, 138.5, 134.8, 130.9, 130.4,
130.3, 129.2, 128.9, 128.7, 128.4, 125.6, 125.4, 124.4, 120.4,
120.3, 113.5, 109.8, 72.0, 70.0, 21.1. Anal. Calcd for C28H23N5:
C, 78.30; H, 5.40; N, 16.30. Found: C, 78.29; H, 5.76; N, 16.29.
cis-1-[1-Meth yl-5-(4-m eth ylp h en yl)-3-p h en yl-4,5-d ih y-
dr o-1H-pyr azol-4-yl]ben zotr iazole (5d). White needles from
8.29 (s, 1H), 8.06-8.03 (m, 1H), 7.82-7.79 (m, 3H), 7.53-7.40
(m, 1H), 7.38-7.21 (m, 5H), 6.99-6.90 (m, 2H); 13C NMR δ
189.9, 150.9, 150.7, 145.2, 137.4, 135.6, 135.5, 132.7, 132.4,
132.3, 128.6, 128.5, 128.2, 127.0, 124.0, 123.1, 119.7, 109.4.
Anal. Calcd for C20H14N4O: C, 73.61; H, 4.32; N, 17.17.
Found: C, 73.75; H, 4.34; N, 17.35.
1
Cr ysta l d a ta for 4c: C20H14N4O, MW 326.35, monoclinic,
space group P21/c, a ) 11.063(5), b ) 12.156(6), c ) 12.200(6)
methanol (68%), mp 155-157 °C; H NMR δ 8.06 (d, J ) 8.0
Hz, 1H), 7.52-7.49 (d, J ) 8.0 Hz, 1H), 7.42-7.34 (m, 4H),
7.17-7.08 (m, 7H), 6.65 (d, J ) 9.7 Hz, 1H), 4.61 (d, J ) 9.8
Hz, 1H), 3.08 (s, 3H), 2.35 (s, 3H); 13C NMR δ 146.7, 142.8,
138.5, 134.2, 131.5, 130.7, 129.8, 128.6, 127.8, 126.9, 124.9,
124.2, 120.3, 110.1, 76.5, 72.8, 40.9, 21.1. Anal. Calcd for
Å, â ) 97.391(5) , V ) 1627(1) Å3, F(000) ) 680, Z ) 4, T )
o
-105 °C, µ (Mo KR) ) 0.086 mm-1, Dcalcd ) 1.332 g cm-3, 2θmax
53° (CCD area detector, Mo KR radiation), GOF ) 1.02, wR(F2)
) 0.1079 (all 3351 data), R ) 0.0401 (2873 data with I > 2σI).
(Z)-2-(Ben zotr ia zol-1-yl)-4-m eth yl-1-p h en yl-3-p en ten -
1-on e (4d ). Colorless needles from hexanes-ethyl acetate
C
23H21N5: C, 75.18; H, 5.76; N, 19.06. Found: C, 75.28; H,
5.98; N, 19.18.
1
(64%), mp 144-145 °C; H NMR δ 8.05-8.02 (m, 3H), 7.62-
cis-1-[1,3-Dip h en yl-5-(3-p yr id in yl)-4,5-d ih yd r o-1H-p y-
r azol-4-yl]ben zotr iazole (5e). White needles from methanol-
7.55 (m, 2H), 7.49-7.41 (m, 3H), 7.37-7.30 (m, 2H), 5.98-
5.94 (dt, J ) 8.8, 1.5 Hz, 1H), 1.84 (s, 3H), 1.82 (d, J ) 1.5 Hz,
3H); 13C NMR δ 193.1, 146.3, 143.5, 134.0, 133.9, 132.6, 128.8,
127.3, 123.8, 119.9, 115.9, 111.2, 62.8, 25.8, 18.5. Anal. Calcd
for C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C, 74.25;
H, 6.01; N, 14.54.
1
chloroform (75%), mp 250-251 °C; H NMR δ 8.63 (m, 2H),
8.07-8.04 (m, 1H), 7.68-7.65 (m, 2H), 7.58-7.55 (m, 1H),
7.34-7.16 (m, 11H), 6.93 (t, J ) 7.2 Hz, 1H), 6.76 (d, J ) 3.9
Hz, 1H), 5.5 (d, J ) 3.8 Hz, 1H); 13C NMR δ 150.2, 147.9, 146.9,
142.1, 141.0, 133.5, 130.8, 129.9, 129.4, 129.2, 128.8, 128.6,
125.5, 124.5, 124.2, 120.9, 120.4, 113.5, 109.5, 71.5, 68.0. Anal.
Calcd for C26H20N6: C, 74.98; H, 4.84; N, 20.18. Found: C,
74.87; H, 4.95; N, 20.10.
Cr ysta l d a ta for 4d : C18H17N3O, MW 291.35, monoclinic,
space group P21/c, a ) 17.387(7), b ) 8.447(3), c ) 10.587(4)
Å, â ) 100.016(5)°, V ) 1531(1) Å3, F(000) ) 616, Z ) 4, T )
-105 °C, µ (Mo KR) ) 0.081 mm-1, Dcalcd ) 1.264 g cm-3, 2θmax
53° (CCD area detector, Mo KR radiation), GOF ) 0.999,
wR(F2) ) 0.0997 (all 3097 data), R ) 0.0379 (2189 data with
I > 2σI).
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
8f a n d 8g. To a freshly prepared solution of NaOEt in ethanol
(by dissolving 5 mg of sodium metal in 20 mL of ethanol) was
added the corresponding hydrazine (1.5 mmol) followed by 4d
(1.2 mmol). The reaction mixture was heated under reflux
overnight. Then ethanol was evaporated in vacuo to dryness.
Purification of the residue by column chromatography afforded
8f and 8g in 50-60% yields.
(Z)-2-(Ben zotr ia zol-1-yl)-3-(4-m eth oxyp h en yl)-1-p h en -
yl-2-p r op en -1-on e (4e). Foam (64%); H NMR δ 8.10-8.07
1
(d, J ) 8.2 Hz, 1H), 7.81-7.76 (m, 3H), 7.52-7.47 (t, J ) 6.2
Hz, 1H), 7.41-7.29 (m, 4H), 7.25-7.20 (m, 1H), 6.70 (d, J )
8.8 Hz, 2H), 6.60 (d, J ) 8.9 Hz, 2H), 3.60 (s, 3H); 13C NMR δ
190.9, 161.8, 145.4, 142.6, 136.7, 132.8, 132.3, 132.2, 128.6,
128.5, 128.2, 128.0, 124.0, 123.1, 119.6, 114.1, 109.7, 54.9.
Anal. Calcd for C22H17N3O2: C, 74.35; H, 4.82; N, 11.82.
Found: C, 74.29; H, 5.01; N, 11.53.
5-Isop r op yl-1,3-d ip h en yl-1H-p yr a zole (8f). Oil (60%); 1H
NMR δ 7.28-7.19 (m, 10H), 6.34 (s, 1H), 3.10 (m, 1H), 1.35
(d, J ) 7.0 Hz, 6H); 13C NMR δ 159.7, 143.2, 140.1, 130.8,
128.7, 128.5, 128.2, 127.8, 126.8, 125.0, 104.7, 27.8, 22.8. Anal.
Calcd for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C,
82.20; H, 7.10; N, 10.98.
(Z)-2-(Ben zotr ia zol-1-yl)-3-(4-ch or op h en yl)-1-p h en yl-2-
p r op en -1-on e (4f). Yellow microcrystals from methanol (59%),
mp 121-122 °C; 1H NMR δ 8.14-8.11 (m, 1H), 7.80-7.74 (m,
3H), 7.62-7.53 (m, 1H), 7.45-7.36 (m, 4H), 7.20-7.12 (m, 3H),
6.77 (d, J ) 0.6 Hz, 2H); 13C NMR δ 190.8, 145.7, 140.1, 1347.4,
136.4, 133.0, 132.9, 131.5, 131.3, 129.7, 129.2, 129.0, 128.6,
128.5, 124.5, 120.3, 109.8. Anal. Calcd for C21H14ClN3O: C,
70.10; H, 3.92; N, 11.68. Found: C, 70.04; H, 3.80; N, 11.66.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
5a -e. To a freshly prepared solution of NaOEt in ethanol (by
dissolving 10 mg of sodium metal in 20 mL of ethanol) was
added a hydrazine (3 mmol) followed by the corresponding 4
(2 mmol). The reaction mixture was heated under reflux
overnight. Subsequent workup and purification by column
chromatography afforded 5a -e.
cis-1-(1,3,5-Tr ip h en yl-4,5-d ih yd r o-1H-p yr a zol-4-yl)ben -
zotr ia zole (5a ). Yellow needles from methanol (80%), mp
220-221 °C; 1H NMR δ 8.07-8.04 (m, 1H), 7.68-7.65 (m, 2H),
7.40-7.18 (m, 15H), 6.93-6.88 (m, 1H), 6.75 (d, J ) 3.9 Hz,
1H), 5.45 (d, J ) 3.9 Hz, 1H); 13C NMR δ 147.0, 142.5, 140.9,
137.8, 131.0, 130.4, 129.7, 129.3, 129.0, 128.8, 128.7, 128.5,
125.8, 125.5, 124.5, 120.5, 120.4, 113.5, 109.8, 71.9, 70.2. Anal.
Calcd for C27H21N5: C, 78.05; H, 5.09; N, 16.86. Found: C,
78.16; H, 4.97; N, 16.76.
5-Isop r op yl-1-m eth yl-3-p h en yl-1H-p yr a zole (8g). Oil
(50%); 1H NMR δ 7.60-7.52 (m, 5H), 6.29 (s, 1H), 3.99 (s, 3H),
3.19 (m, 1H), 1.48 (d, J ) 7.0 Hz, 6H); 13C NMR δ 157.9, 143.7,
130.7, 128.3, 128.2, 127.9, 102.4, 36.8, 27.6, 22.7. HRMS (FAB)
Calcd for C13H16N2 [M + 1]+: 201.1391. Found: 201.1382.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
6a -f. To a solution of a compound 5a -c (0.5 mmol) in THF
(20 mL) was added n-BuLi solution (1.5 M, 0.34 mL, 0.5 mmol)
o
dropwise at -78 C. After 10 min, R2I (0.5 mmol) was added.
The reaction mixture was stirred and allowed to warm up to
room-temperature overnight. The reaction mixture was diluted
with ethyl acetate and washed with H2O, and the organic layer
was dried over MgSO4 and evaporated in vacuo to dryness.
The residue was purified by column chromatography affording
the corresponding products 6a -f in 73-95% yields.
cis-1-(4-Meth yl-1,3,5-tr ip h en yl-4,5-d ih yd r o-1H-p yr a zol-
4-yl)ben zotr ia zole (6a ). White needles from methanol (88%),
1
mp 184-185 °C; H NMR δ 7.77-7.74 (m, 1H), 7.43 (d, J )
7.8 Hz, 2H), 7.34-7.31(m, 1H), 7.23-7.09 (m, 10H), 6.92-6.78
(m, 5H), 5.30 (s, 1H), 2.66 (s, 3H); 13C NMR δ 146.3, 143.8,
132.5, 130.5, 128.9, 128.7, 128.3, 127.8, 127.0, 126.5, 125.8,
123.5, 120.8, 119.4, 114.8, 112.4, 75.9, 27.2. Anal. Calcd for
C
28H23N5: C, 78.30; H, 5.40; N, 16.30. Found: C, 78.42; H,
cis-1-(1-Meth yl-3,5-d ip h en yl-4,5-d ih yd r o-1H-p yr a zol-4-
yl)ben zotr ia zole (5b). Colorless needles from methanol
(51%), mp 129-130 °C; H NMR δ 8.07-8.04 (d, J ) 7.8 Hz,
5.81; N, 15.92.
cis-1-[4-Meth yl-5-(4-m eth ylp h en yl)-1,3-d ip h en yl-4,5-d i-
h yd r o-1H-p yr a zol-4-yl]ben zotr ia zole (6b). Yellow needles
from methanol (73%), mp 184-186 °C; 1H NMR δ 8.13 (d, J )
8.3 Hz, 1H), 7.45-7.42 (d, J ) 8.4 Hz, 1H), 7.36-7.29 (m, 4H),
7.26-7.13 (m, 10H), 6.92 (t, J ) 7.1 Hz, 2H), 5.37 (s, 1H), 2.34
(s, 3H), 1.91 (s, 3H); 13C NMR δ 147.2, 146.2, 144.1, 138.4,
131.9, 131.3, 130.1, 129.7, 128.9, 128.9, 128.6, 127.9, 127.2,
125.6, 124.4, 120.9, 120.4, 115.2, 111.2, 76.2, 75.9, 21.3, 21.2.
Anal. Calcd for C29H25N5: C, 78.53; H, 5.68; N, 15.79. Found:
C, 78.17; H, 5.67; N, 15.82.
1
1H), 7.52-7.49 (m, 1H), 7.42-7.31 (m, 7H), 7.22-7.19 (m, 2H),
7.16-7.13 (m, 3H), 6.67 (d, J ) 9.8 Hz, 1H), 4.63 (d, J ) 9.7
Hz, 1H), 3.10 (s, 3H); 13C NMR δ 146.6, 142.8, 137.2, 131.5,
130.6, 129.1, 128.7, 128.6, 127.8, 126.9, 124.9, 124.2, 120.4,
110.0, 77.0, 72.8, 40.5. Anal. Calcd for C29H25N5: C, 74.77; H,
5.42; N, 19.82. Found: C, 74.85; H, 5.12; N, 19.49.
cis-1-[5-(4-Meth ylp h en yl)-1,3-d ip h en yl-4,5-d ih yd r o-1H-
p yr a zol-4-yl]ben zotr ia zole (5c). White needles from metha-
nol (78%), mp 200-201 °C; 1H NMR δ 8.06-8.03 (m, 1H), 7.66
(d, J ) 8.2 Hz, 2H), 7.33-7.15 (m, 14H), 6.92-6.88 (m, 1H),
Cr ysta l d a ta for 6b: C29H25N5, MW 443.54, monoclinic,
space group P21/c, a ) 10.349(3), b ) 12.211(3), c ) 17.921(4)

Synthesis of Polysubstituted Pyrazoles
J . Org. Chem., Vol. 66, No. 20, 2001 6791
o
Å, â ) 97.260(4) , V ) 2247(1) Å3, F(000) ) 936, Z ) 4, T )
compound 6a -f (0.26 mmol). The reaction mixture was re-
fluxed (in the case of EtONa/EtOH) or heated at 70 °C (for
t-BuOK/toluene) overnight and then evaporated in vacuo to
dryness. The residue was purified by column chromatography
affording 7a -f in 85-99% yields.
4-Met h yl-5-(4-m et h ylp h en yl)-1,3-d ip h en yl-1H -p yr a -
zole (7b). Needles from ethanol (85%), mp 134-135 °C; 1H
NMR δ 7.80 (d, J ) 7.0 Hz, 2H), 7.45 (t, J ) 7.6 Hz, 2H), 7.37-
7.10 (m, 10H), 2.36 (s, 3H), 2.23 (s, 3H); 13C NMR δ 151.1,
141.4, 140.2, 137.9, 133.8, 129.8, 129.1, 128.6, 128.3, 127.8,
127.5, 126.6, 125.7, 125.2, 124.7, 113.9, 21.3, 10.2. Anal. Calcd
for C23H20N2: C, 85.15; H, 6.21; N, 8.63. Found: C, 85.35; H,
6.47; N, 8.69.
-110 °C, µ (Mo KR) ) 0.080 mm-1, Dcalcd ) 1.311 g cm-3, 2θmax
50° (CCD area detector, Mo KR radiation), GOF ) 1.06, wR(F2)
) 0.1268 (all 3959 data), R ) 0.0467 (2837 data with I > 2σI).
cis-1-[1,4-Dim eth yl-5-(4-m eth ylp h en yl)-3-p h en yl-4,5-d i-
h yd r o-1H-p yr a zol-4-yl]ben zotr ia zole (6c). Needles from
methanol (95%), mp 138-140 °C; 1H NMR δ 8.13-8.11 (m,
1H), 7.69-7.67 (m, 1H), 7.35-7.10 (m, 9H), 6.80 (m, 2H), 4.65
(s, 1H), 3.07 (s, 3H), 2.33 (s, 3H), 1.85 (s, 3H); 13C NMR δ 148.4,
147.1, 138.4, 132.0, 130.1, 129.8, 129.3, 128.8, 128.5, 127.6,
127.3, 125.0, 124.1, 120.4, 111.9, 81.4, 76.3, 41.1, 21.1, 18.6.
Anal. Calcd for C24H23N5: C, 75.56; H, 6.08; N, 18.36. Found:
C, 75.83; H, 6.38; N, 17.96.
cis-1-[4-Bu tyl-5-(4-m eth ylp h en yl)-1,3-d ip h en yl-4,5-d i-
h yd r o-1H-p yr a zol-4-yl]b en zot r ia zole (6d ). Needles from
methanol (87%), mp 171-172 °C; 1H NMR δ 7.75-7.72 (m,
1H), 7.46 (d, J ) 7.9 Hz, 2H), 7.39-7.37 (m, 1H), 7.24-7.07
(m, 9H), 6.88 (t, J ) 7.0 Hz, 1H), 6.74 (br s, 2H), 6.55 (br s,
2H), 5.35 (s, 1H), 3.30-3.22 (m, 1H), 3.07-2.99 (m, 1H), 1.98
(s, 3H), 1.53-1.26 (m, 4H), 0.86 (t, J ) 7.0 Hz, 3H); 13C NMR
δ 146.2, 143.6, 137.8, 133.4, 131.2, 129.7, 128.9, 128.6, 128.2,
126.8, 126.4, 125.3, 123.3, 120.5, 119.3, 114.7, 112.7, 112.1,
79.6, 73.6, 37.9, 26.5, 22.6, 20.8, 13.7. Anal. Calcd for
1,4-Dim et h yl-5-(4-m et h ylp h en yl)-3-p h en yl-1H -p yr a -
zole (7c). Needles from ethanol (99%), mp 98-99 °C; 1H NMR
δ 7.72 (d, J ) 8.4 Hz, 2H), 7.43 (t, J ) 7.5 Hz, 2H), 7.34-7.23
(m, 5H), 3.79 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H); 13C NMR δ
149.1, 142.4, 138.3, 134.2, 129.7, 129.3, 128.3, 127.5, 127.4,
127.1, 111.9, 37.1, 21.2, 10.0. Anal. Calcd for C18H18N2: C,
82.41; H, 6.92; N, 10.68. Found: C, 82.33; H, 7.30; N, 10.26.
4-Bu t yl-5-(4-m e t h ylp h e n yl)-1,3-d ip h e n yl-1H -p yr a -
zole (7d ). Oil (95%); 1H NMR δ 7.79-7.75 (m, 2H), 7.47-7.41
(m, 2H), 7.38-7.09 (m, 10H), 2.62 (t, J ) 7.8 Hz, 2H), 2.36 (s,
3H), 1.43-1.33 (m, 2H), 1.25-1.15 (m, 2H), 0.75 (t, J ) 7.1
Hz, 3H); 13C NMR δ 150.9, 141.4, 140.1, 137.9, 134.2, 129.9,
129.2, 128.5, 128.3, 127.9, 127.8, 127.5, 126.5, 124.6, 119.4,
32.8, 23.4, 22.5, 21.3, 13.6. Anal. Calcd for C26H26N2: C, 85.20;
H, 7.17; N, 7.65. Found: C, 85.05; H, 6.94; N, 7.72.
C
32H31N5: C, 79.14; H, 6.43; N, 14.42. Found: C, 79.18; H,
6.57; N, 14.55.
cis-1-[4-Allyl-5-(4-m eth ylp h en yl)-1,3-d ip h en yl-4,5-d ih y-
dr o-1H-pyr azol-4-yl]ben zotr iazole (6e). Needles from metha-
nol (84%), mp 195-196 °C; 1H NMR δ 7.78-7.75 (m, 1H),
7.44-7.40 (m, 3H), 7.23-7.08 (m, 9H), 6.87 (t, J ) 7.0 Hz, 1H),
6.72 (br s, 2H), 6.58 (br s, 2H), 5.76-5.66 (m, 1H), 5.46 (s, 1H),
5.36 (d, J ) 6.9 Hz, 1H), 5.23 (d, J ) 9.9 Hz, 1H), 4.07-3.99
(m, 1H), 3.80 (d, J ) 4.6 Hz, 1H), 3.76 (d, J ) 4.9 Hz, 1H),
1.99 (s, 3H); 13C NMR δ 146.2, 143.6, 143.3, 137.8, 133.5, 131.7,
130.9, 129.6, 128.8, 128.7, 128.3, 127.0, 126.4, 125.5, 123.4,
121.7, 120.6, 119.3, 114.8, 78.6, 72.5, 42.1, 20.8. Anal. Calcd
for C31H27N5: C, 79.29; H, 5.80; N, 14.91. Found: C, 79.39; H,
5.72; N, 15.02.
4-Allyl-5-(4-m et h ylp h en yl)-1,3-d ip h en yl-1H -p yr a zole
(7e). Oil (93%); 1H NMR δ 7.75 (dd, J ) 8.5, 1.4 Hz, 2H), 7.38-
7.06 (m, 12H), 5.98-5.89 (m, 1H), 5.06-4.92 (m, 2H), 3.27-
3.24 (m, 2H), 2.28 (s, 3H); 13C NMR δ 151.4, 142.0, 140.2, 138.2,
137.7, 133.6, 129.7, 129.1, 128.6, 128.3, 127.9, 127.6, 127.5,
126.7, 124.7, 115.8, 115.7, 28.2, 21.3. Anal. Calcd for
C
25H22N2: C, 85.66; H, 6.34; N, 7.99. Found: C, 85.33; H, 6.60;
N, 7.93.
4-Be n zyl-5-(4-m e t h ylp h e n yl)-1,3-d ip h e n yl-1H -p yr a -
cis-1-[4-Ben zyl-5-(4-m eth ylp h en yl)-1,3-d ip h en yl-4,5-d i-
h yd r o-1H-p yr a zol-4-yl]ben zotr ia zole (6f). Needles from
methanol-chloroform (91%), mp 155-157 °C; 1H NMR δ 7.76
(d, J ) 7.9 Hz, 1H), 7.47-7.44 (m, 2H), 7.28-7.03 (m, 14H),
6.86 (d, J ) 8.2 Hz, 2H), 6.79-6.72 (m, 3H), 6.55 (d, J ) 7.6
Hz, 2H), 5.56 (s, 1H), 4.67 (d, J ) 14.0 Hz, 1H), 4.39 (d, J )
14.3 Hz, 1H), 1.97 (s, 3H); 13C NMR δ 146.3, 143.0, 142.8,
137.8, 134.3, 133.6, 131.8, 130.9, 129.8, 128.8, 128.6, 128.3,
127.5, 126.7, 126.4, 125.6, 123.4, 120.3, 119.2, 114.3, 113.0,
80.3, 72.3, 42.9, 20.8. Anal. Calcd for C35H29N5: C, 80.90; H,
5.62; N, 13.48. Found: C, 80.76; H, 5.58; N, 13.67.
zole (7f). Needles from hexanes-ethyl acetate (95%), mp 129-
130 °C; 1H NMR δ 7.66 (d, J ) 6.7 Hz, 2H), 7.36-7.11 (m,
13H), 7.07-6.99 (m, 4H), 3.99 (s, 2H), 2.31 (s, 3H); 13C NMR
δ 151.6, 142.4, 141.4, 140.2, 138.2, 133.6, 129.7, 129.2, 128.6,
128.3, 128.1, 127.8, 127.6, 127.5, 126.7, 125.8, 124.7, 116.5,
29.8, 21.2. Anal. Calcd for C29H24N2: C, 86.96; H, 6.05; N, 7.00.
Found: C, 86.75; H, 6.27; N, 7.07.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 8a -e, 7a ,
11a -c, and 11e-f; X-ray data for 4c-d , 6b and 11c, f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
7a -f. To a freshly prepared solution of NaOEt in ethanol (12
mg of sodium metal in 10 mL of ethanol) or t-BuOK (58 mg,
0.52 mmol) in toluene (10 mL) was added the corresponding
J O0101407