Synthesis of pyrazoles from 1-acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofurans

Article abstract of DOI:10.1007/s007060050329

1-Acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofurans were found to be useful precursors for pyrazole synthesis. In the reaction with hydrazine monohydrate they yielded 3-(2-(α-hydroxyisopropyl)-phenyl) substituted NH-pyrazoles, whereas using alkyl-or arylhydrazine gave access to 5-(2-(α-hydroxyisopropyl)-phenyl) substituted NR-pyrazoles with good regioselectivity. Treatment with orthophosphoric acid led to C,N-fused and C,C-fused pyrazoles, respectively.

Full text of DOI:10.1007/s007060050329

Monatshefte fuÈr Chemie 131, 475±486 (2000)
Synthesis of Pyrazoles from 1-Acylmethylene-
3,3-dimethyl-1,3-dihydroisobenzofurans
Â
Jacek G. Sosnicki
Technical University, Institute of Fundamental Chemistry, PL-71065 Szczecin, Poland
Summary. 1-Acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofurans were found to be useful
precursors for pyrazole synthesis. In the reaction with hydrazine monohydrate they yielded 3-(2-
(ꢀ-hydroxyisopropyl)-phenyl) substituted NH-pyrazoles, whereas using alkyl- or arylhydrazine gave
access to 5-(2-(ꢀ-hydroxyisopropyl)-phenyl) substituted NR-pyrazoles with good regioselectivity.
Treatment with orthophosphoric acid led to C,N-fused and C,C-fused pyrazoles, respectively.
Keywords. Heterocycles; Ring chain transformation reactions; Pyrazoles; Regioselectivity; Intra-
molecular alkylation of pyrazoles.
Introduction
Acylenol ethers as 1,3-dicarbonyl heteroanalogs are useful reagents for the
synthesis of different types of heterocycles in the reaction with binucleophiles. If at
least one electrophilic center of the 1,3-dielectrophilic acylenol ethers is a part of a
ring system, e.g. like in 3-acyl-4,5-dihydrofurans or 5-acyl-3,4-dihydro-2H-pyran,
the reaction with binucleophiles has been shown to give access to chain
functionalized heterocycles [1±5]. The synthesis of side chain functionalized
alkylheterocycles, matching to the general concept of the ring chain transformation
reaction of 1,3-dicarbonyl heteroanalogs, has been reviewed recently [5]. One of
the possible mechanisms consists of the condensation of the carbonyl moiety with
one nucleophilic site, ꢁ-addition of the other nucleophilic position, and ®nal
opening of the spiro intermediate formed.
In this context, 1-acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofurans (1a±c)
as bridged acylenol ethers were expected to be promising starting materials for the
synthesis of heterocycles by treatment with binucleophiles. In the course of previous
studies on reactions with hydroxylamine, the synthesis of spiroisoxazolines has been
reported [6]. For further exploring the synthetic potential of 1-acylmethylene-3,3-
dimethyl-1,3-dihydroisobenzofurans (1) we now focused our interest on the synthesis
of N,N-heterocycles achieved by reaction with hydrazine derivatives.
Result and Discussion
First investigations with hydrazine monohydrate revealed that, unlike to the
formation of spiro products obtained with hydroxylamine, 1-formylmethylene-3,3-

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J. G. Sosnicki
476
dimethyl-1,3-dihydroisobenzofuran (1a) gave a ring chain transformation to the
pyrazole 3h with a 3-(2-(ꢀ-hydroxyisopropyl)-phenyl) substituent at the hetero-
cyclic ring (Scheme 1). This result prompted us to extend our study to 1-
acetylmethylene (1b) and 1-benzoylmethylene- (1c) derivatives of 3,3-dimethyl-
1,3-dihydroisobenzofuran on the one hand and methyl and arylhydrazine
derivatives on the other hand.
Since in the preparation of pyrazoles from masked 1,3-dicarbonyl compounds
different electrophilicity at C-1 and C-3 of the carbonyl reagent and different
nucleophilicity of the two nitrogen atoms of hydrazine determine the formation of
different regioisomers [7], the regioselectivity of the investigated reaction had to be
taken into consideration.
As far as regioselectivity is concerned, regioisomers 2 highly dominated when
aryl hydrazines were used (Table 1). Under the same conditions, methylhydrazine
Table 1. Regioselectivities for compounds 2, 3
2,3
R1
R2
Ratio of
regioisomersa
2 : 3
Procedure
Yield (%)b
2
3
a
b
c
Ph
H
100
100
87
0
0
A
76(92)
A
±
Ph
Me
Ph
H
65(94)
A(88)
65
±
Ph
13c
0
14
d
e
4-NO2C6H4
Me
100
74
A
68(90)
±
H
26
40
14
16
54
A (81)
B (95)
A (95)
B (92)
A (69)
B (89)
C
65
65
80
75
28
73
±
11
60
20
f
Me
Me
Me
Ph
86
11
84
14
g
46
36
85
15d
12
e
h
i
H
H
H
H
85(94)
77(92)
75(96)
e
e
Me
Ph
C
±
j
C
±
a
b
The ratio of regioisomers was estimated by GC-MS of the crude reaction mixture; yield after
puri®cation (yield of the crude product is given in parentheses; for details, see Experimental); cthe ratio
of regioisomers was estimated by 1H NMR; dthe reaction was carried out at room temperature; the
e
ratio could not be determined exactly due to exchange process (see text)

New Aspects of Pyrazole Synthesis
477
Scheme 1
afforded N-methyl substituted pyrazoles 2 and 3 with relatively low regioselec-
tivity. As compared to 1a±b, the regioselectivity of the reaction of 1-benzoyl-
methylene derivative (1c) with hydrazine derivatives was lower in all cases. The
extremely low regioselectivity in the reaction of 1c with methylhydrazine (Table 1,
2g:3g ˆ 46:54) could be improved. Hydrazine hydrate gave 3h±j as dominant
regioisomers.
Only regioisomers above 5% were isolated, and their structures were studied
using spectroscopic methods. Pure pyrazoles 2a±j are easily crystallizable
compounds. In order to separate two isomeric pyrazoles 2 and 3, an initial
enrichment of the minor isomer by fractional crystallization of 2 was performed.
In the electrophilic substitution of the pyrazole ring, the attack of an
electrophile usually takes place at C-4. However, in N-phenyl substituted
derivatives the pyrazole ring behaves like a pseudo-halogen ortho-para directing
substituent; thus, the ortho position of the phenyl ring could compete with position
4 of the pyrazole. Moreover, in the NH-pyrazole series the pyridine-like nitrogen
atom can act as a nucleophilic site yielding N-substituted derivatives.
Among the reagents studied in the intramolecular alkylation of 2 and 3,
orthophosphoric acid was found to be the most convenient one. Stirring of

Â
J. G. Sosnicki
478
Scheme 2
pyrazoles 3h±j in orthophosphoric acid at room temperature caused substitution of
the hydroxy group by the nitrogen atom of pyrazole providing 8,8-dimethylpyr-
azolo[5,1-a]isoindoles (5a±c) (Scheme 2), whereas under the same reaction
conditions pyrazoles 2a±g underwent dehydration to the corresponding alkenes as
documented for derivative 6a (Scheme 2). Heating 2a±g (or the corresponding
alkenes) in orthophosphoric acid at 110ꢀC gave smooth intramolecular electro-
philic substitution at C-4 of the pyrazole ring, affording 4,4-dimethyl-1,4-
dihydroindeno[1,2-c]pyrazoles 7a±f after 2±3 hours (Scheme 2). In the case of
7a±c, no substitution in the ortho position of the N-phenyl ring was observed. The
N-substituted pyrazoles 3c,e±g were found to be sensitive to acids and suffer
destruction in the presence of phosphoric acid. Products 5, 6, and 7 were formed in
1
high yields and good purity according to H NMR spectra and GC-MS analysis.
The structures of pyrazoles 2, 3, 6, and 7 were elucidated using 1D NMR
(1H, 13C, 13C-DEPT), 2D NMR (COSY, COLOC), and mass spectrometry.
Additionally, 15N NMR spectra were recorded for 2, 3, 5, and 7. 15N NMR
chemical shifts were comparable with data reported for different pyrazoles [8], thus
corroborating the assignment. N-Methyl (2e±g, 3e±g) and N-phenyl (2c, 3c)
1
regioisomeric pyrazoles were differentiated by means of their H NMR spectra.
The chemical shift of the OH proton served as the main identi®cation criterion in
these cases. In the regioisomer 2 this proton appears at higher ®eld (ꢂ ˆ 1.65±
2.32 ppm), whereas in 3 it is shifted to lower ®eld (ꢂ ˆ 6.50±7.50 ppm) due to an
1
intramolecular OHÁ Á ÁN hydrogen bond. The equivalence of the H and 13C NMR
resonance position of the two CH3 substituents of the ꢀ-hydroxyisopropyl moiety

New Aspects of Pyrazole Synthesis
479
in 3 gives further evidence for the existence of an OHÁ Á ÁN-2 hydrogen bond. The
absence of the OHÁ Á ÁN-2 hydrogen bond in 2 allows free rotation of the ꢀ-
hydroxyisopropyl fragment, but it is slow with respect to the NMR time scale,
causing nonequivalence of the resonance position of the two CH3 groups. The
intensity of the molecular ion in the mass spectra can also be used as a criterion to
differentiate between 3c,e±g (relative intensity 0.5±1%) and 2a±g (relative
intensity > 25%).
The NH-pyrazoles 3h±j exist in solution in a fast proceeding equilibrium of
1
annular tautomers [9] as indicated by broadening of some signals in the H, 13C,
and 15N NMR spectra. Although we were not able to establish the ratio of
regioisomers accurately, the chemical shifts of the OH proton (ꢂOH ˆ 5.81±
8.68 ppm, giving evidence of the week intramolecular hydrogen bond) and the
value of J4,5 ˆ 2.3 Hz for compound 3h, which is more similar to J4,5 of its N-
methyl ®xed analogue 3e (2.2 Hz) than to J4,5 of the isomer 2e (1.8 Hz) [10],
suggested that the regioisomers 3h±j highly dominated.
Concerning the mechanism of the formation of 2 it could be assumed that the
reaction starts with the condensation yielding the corresponding hydrazone (e.g. 4,
Scheme 1, path a). Subsequent attack of the second amino group of the hydrazine
moiety at the second electrophilic site results in a spiro adduct which ®nally is
opened. This proposed mechanism was con®rmed for p-nitrophenyhydrazine,
where the p-nitrophenylhydrazone (4) could be isolated. Re¯ux of 4 in pyridine in
the presence of hydrochloric acid then yielded 2d.
In the case of methylhydrazine, the lower regioselectivity as compared to
aromatic hydrazines can be explained by competition of the stronger nucleophilic
methyl substituted nitrogen atom relative with the NH2 group for the nucleophilic
attack at the carbonyl or the enol ether carbon atom (Scheme 1, path b). Subsequent
elimination of water provides the corresponding pyrazoles 2 (Scheme 1, path c)
and 3 (Scheme 1, path d).
In conclusion, the formation of the fused parazoles 5a±c and 7a±f by
intramolecular alkylation of the pyrazole ring represents a new and suitable route
to these ring systems. A pyrazole similar to 5a±c, but with an 8-unsubstituted 8H-
pyrazolo[5,1-a]isoindole structure, has been obtained from 5-(2-bromomethylphe-
nyl)-3-phenyl-1H-pyrazole by treatment with sodium in boiling ethanol [11] or as
the by-product in the formation of 2-amino-2,3-dihydro-1H-isoindol-1-one [12].
According to our knowledge there is only one incompletely described example of
the synthesis of 4,4-dimethyl-1,4-dihydroindeno[1,2-c]pyrazole derivatives [13],
whereas systems unsubstituted at position C-4 are easily obtained from 2-acyl-1,3-
indandiones [14,15].
Experimental
1
Melting points were determined on a Boetius hot stage apparatus and are uncorrected. H, 13C, and
15N NMR spectroscopic measurements were performed on a Bruker DPX 400 apparatus. TMS was
used as internal reference for 1H and 13C NMR spactra. 15N NMR chemical shifts were referenced to
CH3NO2 at 300 K. Mass spectra (70 eV) were recorded with a HP 6890 (Hewlett-Packard) GCMS
spectrometer equipped with a mass detector HP 5973. All compounds gave satisfactory elemental
analyses (C,H). Silica gel (0.04±0.063 mm, Merck) was used for preparative column chromatog-

Â
J. G. Sosnicki
480
raphy. In some cases, the yield of crude products is given in parentheses. The starting 1-
acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofurans (1a±c) were prepared from diethyl phthalate
as described earlier [16].
5(3)-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-pyrazoles 2a±g, 3c, 3e±g; General procedure
Procedure A. To a solution of 2.15 mmol 1-acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofuran
(1a±c) in 3.5 cm3 dry pyridine, 2.17 mmol of the appropriate hydrazine hydrochloride or a mixture of
2.17 mmol hydrazine derivative and 2.17 mmol pyridine hydrochloride were added rapidly at
ambient temperature. The mixture was re¯uxed for 1.5±2 h, cooled, and poured into 50 cm3 cold
H2O. The resulting solid or oil was separated, washed with H2O and hexane, and dried.
Crystallization from a mixture of H2O:ethanol ˆ 1:1 yielded isomers 2a±g as white crystals in most
cases. In the case of 2c, 3c, 2e±g, and 3e±g the mother liquors contained mixtures of isomers 2 and 3.
The solvent was evaporated, and the residue was dried by distillation with dry benzene in vacuo. The
residue was chromatographed on silica gel using n-hexane:ethyl acetate ˆ 7:3 as eluent.
N-Methyl-3(5)-(2-(ꢀ-hydroxyisopropyl)-phenyl)-pyrazoles 2e±g, 3e±g; General procedure
Procedure B. 2.15 mmol of 1-acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofuran (1a±c) were
dissolved in 1.35 cm3 (25.35 mmol) of methyl hydrazine, and a few drops of concentrated HCl
added. After re¯ux (1.5±2 h), the excess of methyl hydrazine was evaporated in vacuo. The mixture
of 2 and 3 was separated as described in procedure A.
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-pyrazoles 3h±j; General procedure
Procedure C. 2.15 mmol of 1-acylmethylene-3,3-dimethyl-1,3-dihydroisobenzofuran (1a±c) were
dissolved in 1.25 cm3 (25.75 mmol) of hydrazine monohydrate. After re¯ux (1.5±2 h), the excess of
hydrazine monohydrate was evaporated in vacuo, and the residue was crystallized from a mixture of
H2O-ethanol yielding white crystals.
5-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1-phenylpyrazole (2a; C18H18N2O)
1
Procedure A; yield: 76(92)%; m.p.: 112±114ꢀC; H NMR (CDCl3, ꢂ, 400 MHz): 1.37 (br s, 2CH3),
1.90 (s, OH), 6.40 (d, J ˆ 1.7, 4-H), 7.10 (dd, J ˆ 1.4, 7.6, 7-H), 7.12±7.23 (m, C6H5, 8-H, 4H), 7.30
±7.38 (m, C6H5, 9-H, 3-H), 7.53 (dd, J ˆ 0.9, 8.1, 10-H), 7.70 (d, J ˆ 1.7, 3-H) ppm; 13C NMR
(CDCl3, ꢂ, 100 MHz): 31.4 (12-CH3), 32.9 (12-CH3), 73.8 (C-12), 108.8 (C-4), 123.9, 126.6 128.6,
140.3 (C6H5), 126.3 (C-8), 126.8 (C-10), 127.9 (C-6), 129.1 (C-9), 132.9 (C-7), 139.7 (C-3), 143.6
(C-5), 148.1 (C-11) ppm; 15N NMR (DMSO-d6, ꢂ, 40 MHz): 76.6 (N-2), 163.4 (N-1) ppm; MS
‡
(70 eV): m/z ˆ 278 (43, M ), 263 (100), 245 (15), 219 (15).
5-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-3-methyl-1-phenylpyrazole (2b; C19H20N2O)
1
Procedure A; yield: 65(94)%; m.p.: 129±130ꢀC; H NMR (CDCl3, ꢂ, 400 MHz): 1.48 (br s, 2CH3),
2.00 (s, OH), 2.38 (s, CH3), 6.21 (s, 4-H), 7.05±7.22 (m, C6H5, 7-H, 8-H, 5H), 7.26 ± 7.31 (m, C6H5,
2H), 7.33 (ddd, J ˆ 1.6, 7.3, 8.1, 9-H), 7.51 (dd, J ˆ 0.9, 8.1, 10-H) ppm; 13C NMR (CDCl3, ꢂ
100 MHz): 13.6 (3-CH3), 31.4 (12-CH3), 32.9 (12-CH3), 73.8 (C-12), 108.8 (C-4), 123.7, 126.3,
128.6, 140.3 (C6H5), 126.3 (C-8), 126.7 (C-10), 128.1 (C-6), 129.0 (C-9), 132.9 (C-7), 144.2 (C-5),
147.9 (C-3), 148.9 (C-11) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 82.7 (N-2), 168.0 (N-1) ppm;
‡
MS (70 eV): m/z ˆ 292 (75, M ), 277 (100), 273 (22), 259 (24), 233 (17), 217 (12), 182 (6), 165 (6),
115 (7), 91 (10), 77 (10).

New Aspects of Pyrazole Synthesis
481
5-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1,3-diphenylpyrazole (2c; C24H22N2OÃH2O)
Procedure A; yield: 65%; m.p.: 116±117ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.20 (t, J ˆ 7.0,
CH3CH2OH), 1.39 (br s, 12-CH3), 1.42 (br s, 12-CH3), 1.83 (br s, 2OH), 3.67 (q, J ˆ 7.0,
CH3CH2OH), 6.74 (s, 4-H), 7.15±7.45 (m, 2C6H5, 7-H, 8-H, 9-H, 11H), 7.54 (d, J ˆ 8.0, 10-H), 7.94
(d, J ˆ 7.2, C6H5, 2H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 13.4 (CH3), 31.5 (12-CH3), 32.9 (12-
CH3), 58.3 (CH2OH), 73.8 (C-12), 106.2 (C-4), 123.9, 125.8, 126.7 127.8, 128.6, 128.7, 132.9, 140.3
(2C6H5), 126.4 (C-8), 126.8 (C-10), 127.8 (C-6), 129.2 (C-9), 132.9 (C-7), 145.1 (C-5), 148.0 (C-
11), 151.3 (C-3) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 85.2 (N-2), 164.3 (N-1) ppm; MS (70 eV):
‡
m/z ˆ 354 (100, M ), 339 (85), 336 (44), 335 (44), 321 (36), 295 (14), 244 (17), 217 (15), 91 (12),
77 (13).
5-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1-(4-nitrophenyl)pyrazole (2d; C18H17N3O3)
Procedure A; yield 68(90)%; m.p.: 137±139ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.43 (br s, 12-CH3),
1.45 (br s, 12-CH3), 1.65 (s, OH), 6.46 (d, J ˆ 1.7, 4-H), 7.09 (dd, J ˆ 1.3, 7.6, 7-H), 7.25 (td, J ˆ 1.2,
7.5, 8-H), 7.44 (ddd, J ˆ 1.5, 7.4, 8.0, 9-H), 7.51 (d, J ˆ 9.3, 4-NO2C6H4, 2H), 7.55 (dd, J ˆ 0.9, 8.1,
10-H), 7.77 (d, J ˆ 1.7, 3-H), 8.08 (d, J ˆ 9.3, 4-NO2C6H4, 2H) ppm; 13C NMR (CDCl3, ꢂ,
100 MHz): 31.5 (12-CH3), 33.3 (12-CH3), 73.8 (C-12), 110.2 (C-4), 123.1, 124.3, 145.3, 145.3 (4-
NO2C6H4), 126.9 (C-8), 127.0 (C-10), 127.6 (C-6), 129.7 (C-9), 132.5 (C-7), 141.0 (C-3), 144.6 (C-
5), 147.9 (C-11) ppm; 15N NMR (DMSO-d6, ꢂ, 40 MHz): 11.5 (NO2), 77.1 (N-2), 165.6 (N-1)
‡
ppm; MS (70 eV): m/z ˆ 323 (25, M ), 308 (100), 290 (5), 262 (21), 244 (5), 218 (9).
5-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1-methylpyrazole (2e; C13H16N2O)
Procedure A: yield: 65%; procedure B: yield 65%; m.p.: 123±125ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz):
1.38 (br s, CH3), 1.53 (br s, CH3), 2.32 (br s, OH), 3.59 (s, 1-CH3), 6.23 (d, J ˆ 1.8, 4-H), 7.08 (dd,
J ˆ 1.4, 7.5, 7-H), 7.29 (td, J ˆ 1.3, 7.5, 8-H), 7.43 (ddd, J ˆ 1.5, 7.4, 8.1, 9-H), 7.50 (d, J ˆ 1.8, 3-H),
7.70 (dd, J ˆ 1.0, 8.1, 10-H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 31.8 (2CH3), 36.9 (1-CH3), 73.3
(C-12), 106.9 (C-4), 126.2 (C-8), 126.5 (C-10), 127.8 (C-6), 129.3 (C-9), 132.2 (C-7), 138.1 (C-3),
143.5 (C-5), 148.5 (C-11) ppm; 15N NMR (DMSO-d6, ꢂ, 40 MHz): 75.8 (N-2), 178.5 (N-1) ppm;
‡
MS (70 eV): m/z ˆ 216 (39, M ), 201 (100), 183 (21), 168 (12), 157 (12), 128 (7), 115 (10).
5-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1,3-dimethylpyrazole (2f; C14H18N2O)
Procedure A: yield: 80%; procedure B: yield 75%; m.p.: 123±125ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz):
1.43 (br s, 12-CH3), 1.52 (br s, 12-CH3), 2.17 (br s, OH), 2.30 (s, 3-CH3), 3.52 (s, 1-CH3), 6.02 (s, 4-
H), 7.08 (dd, J ˆ 1.3, 7.6, 7-H), 7.28 (td, J ˆ 1.3, 7.4, 8-H), 7.42 (ddd, J ˆ 1.5, 7.4, 8.0, 9-H), 7.66
(dd, J ˆ 1.0, 8.0, 10-H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 13.5 (3-CH3), 31.7 (12-CH3), 31.9
(12-CH3), 36.6 (1-CH3), 73.4 (C-12), 106.5 (C-4), 126.1 (C-8), 126.5 (C-10), 128.0 (C-6), 129.2
(C-9), 132.2 (C-7), 144.2 (C-5), 147.4 (C-3), 148.4 (C-11) ppm; 15N NMR (DMSO-d6, ꢂ, 40 MHz):
‡
79.4 (N-2), 183.9 (N-1) ppm; MS (70 eV): m/z ˆ 230 (70, M ), 215 (100), 211 (15), 197 (32),
182 (10), 171 (12), 128 (10), 115 (9).
5-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1-methyl-3-phenylpyrazole (2g; C19H20N2O)
Procedure A: yield: 28%; procedure B: yield 73%; m.p.: 101±103ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz):
1.44 (br s, 12-CH3), 1.55 (br s, 12-CH3), 2.06 (s, OH), 3.63 (s, 1-CH3), 6.55 (s, 4-H), 7.15 (dd,
J ˆ 1.2, 7.5, 7-H), 7.25 ± 7.50 (m, 8-H, 9-H, C6H5, 5H), 7.69 (d, J ˆ 8.0, 10-H), 7.82 (d, J ˆ 7.3,
C6H5, 2H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 31.8 (12-CH3), 32.0 (12-CH3), 37.5 (1-CH3), 73.5
(C-12), 104.0 (C-4), 125.5, 127.8, 128.6, 133.2 (C6H5), 126.2 (C-10), 126.6 (C-8), 128.6 (C-6), 129.4
(C-9), 132.2 (C-7), 145.0 (C-5), 148.4 (C-3), 150.1 (C-11) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz):

Â
J. G. Sosnicki
482
‡
85.5 (N-2), 180.4 (N-1) ppm; MS (70 eV): m/z ˆ 292 (100, M ), 277 (79), 273 (27), 259 (37),
233 (11), 131 (8), 104 (7), 77 (8).
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1,5-diphenylpyrazole (3c; C24H22N2O)
1
Procedure A; yield: 14%; oil; H NMR (CDCl3, ꢂ, 400 MHz): 1.59 (s, 2CH3), 6.69 (s, 4-H), 7.23±
7.38 (m, 2C6H5, OH, 8-H, 9-H, 13H), 7.59±7.63 (m, 7-H, 10-H) ppm; 13C NMR (CDCl3, ꢂ,
100 MHz): 30.0 (2CH3), 71.8 (C-12), 108.5 (C-4), 124.8, 127.7, 128.4, 128.6, 128.8, 129.0, 131.5,
139.3 (2C6H5), 126.3 (C-10), 127.0 (C-8), 128.7 (C-9), 129.8 (C-6), 132.1 (C-7), 144.3 (C-3), 146.1
(C-11), 154.4 (C-5) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 85.2 (N-2), 170.6 (N-1) ppm; MS
‡
(70 eV): m/z ˆ 354 (0.5, M ), 339 (100), 335 (29), 296 (12), 77 (10).
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1-methylpyrazole (3e; C13H16N2O)
1
Procedure A: yield: 11%; procedure B: yield: 20%; oil; H NMR (CDCl3, ꢂ, 400 MHz): 1.47 (s,
2CH3), 3.93 (s, 1-CH3), 6.40 (d, J ˆ 2.2, 4-H), 6.50 (br s, OH), 7.25±7.34 (m, 9-H, 10-H), 7.42 (d,
J ˆ 2.2, 5-H), 7.43 ± 7.57 (m, 7-H, 8-H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 29.8 (2CH3), 38.9 (1-
CH3), 71.7 (C-12), 106.4 (C-4), 126.0 (C-8), 126.9 (C-10), 128.0 (C-9), 131.4 (C-5), 132.0 (C-7),
132.0 (C-6), 145.9 (C-11), 154.0 (C-3) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 86.4 (N-2), 183.7
‡
(N-1) ppm; MS (70 eV): m/z ˆ 216 (0.2, M ), 202 (14), 201 (100), 197 (6), 183 (19), 168 (9), 159
(10), 158 (10), 157 (5), 115 (7), 93 (5).
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1,5-dimethylpyrazole (3f; C14H18N2O)
1
Procedure A: yield: 11%; procedure B: yield: 14%; oil; H NMR (CDCl3, ꢂ, 400 MHz): 1.48 (s,
2CH3), 2.28 (s, 5-CH3), 3.75 (s, 1-CH3), 6.16 (s, 4-H), 7.22 (br s, OH), 7.23±7.30 (m, 9-H, 10-H),
7.39±7.44 (m, 9-H), 7.51 ± 7.56 (m, 10-H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 10.8 (5-CH3), 29.7
(2CH3), 35.9 (1-CH3), 71.5 (C-12), 105.8 (C-4), 125.8 (C-8), 126.7 (C-10), 127.6 (C-9), 131.7 (C-7),
132.2 (C-6), 139.8 (C-5), 145.7 (C-11), 152.3 (C-3) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 89.1 (N-
‡
2), 185.3 (N-1) ppm; MS (70 eV): m/z ˆ 230 (1, M ), 215 (100), 211 (10), 197 (10), 173 (10), 172
(9), 156 (5), 128 (4), 100 (6), 56 (5).
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-1-methyl-5-phenylpyrazole (3g; C19H20N2O)
Procedure A: yield: 36%; procedure B: yield: 12%; m.p.: 120±122ꢀC; 1H NMR (CDCl3, ꢂ,
400 MHz): 1.54 (s, 2CH3), 3.91 (s, 1-CH3), 6.48 (s, 4-H), 7.29 (td, J ˆ 1.6, 7.3, 8-H), 7.33 (td,
J ˆ 1.9, 7.3, 9-H), 7.41±7.53 (m, C6H5, 7-H, 6H), 7.45 (br s, OH), 7.58 (dd, J ˆ 1.9, 7.3, 10-H) ppm;
13C NMR (CDCl3, ꢂ, 100 MHz): 30.0 (2CH3), 37.6 (1-CH3), 71.8 (C-12), 106.5 (C-4), 126.1 (C-10),
126.9 (C-8), 128.1 (C-9), 128.7, 128.8, 128.9, 131.9 (C6H5), 129.9 (C-6), 132.0 (C-7), 145.1 (C-5),
146.0 (C-11), 153.1 (C-3) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 85.6 (N-2), 187.7 (N-1) ppm;
‡
MS (70 eV): m/z ˆ 292 (0.5, M ), 277 (100), 273 (17), 259 (7), 234 (13), 217 (6), 131 (8), 77 (5).
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)pyrazole (3h; C12H14N2O)
Procedure C; yield: 85(94)%; m.p.: 158±159ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.50 (s, 2CH3), 6.45
(d, J ˆ 2.3, 4-H), 7.28 ± 7.35 (m, 9-H, 10-H), 7.49±7.58 (m, 7-H, 8-H), 7.57 (d, J ˆ 2.3, 5-H), 7.94
(br s, OH), 12.39 (br s, NH) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 29.8 (2CH3), 72.5 (C-12), 105.5
(C-4), 126.1 (C-8), 127.3 (C-10), 128.1 (C-9), 131.2 (br, C-5), 131.8 (C-6), 132.3 (C-7), 145.0 (C-
11), 151.9 (br, C-3) ppm; 15N NMR (DMSO-d6, ꢂ,40 MHz): 91.3 (br, N-2), 175.6 (br, N-1) ppm;
‡
MS (70 eV): m/z ˆ 202 (16, M ), 187 (72), 169 (100), 144 (9), 128 (8), 115 (23).

New Aspects of Pyrazole Synthesis
483
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-5-methylpyrazole (3i; C13H16N2O)
Procedure C; yield: 77(92)%; m.p.: 152±154ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.53 (s, 2CH3), 2.48
(s, 5-CH3), 6.19 (s, 4-H), 7.24±7.34 (m, 9-H, 10-H), 7.47±7.58 (m, 7-H, 8-H), 8.68 (br s, OH), 12,12
(br s, NH) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 11.0 (5-CH3), 29.7 (2CH3), 72.4 (C-12), 104.6 (C-
4), 126.0 (C-8), 127.1 (C-10), 127.8 (C-9), 132.0 (C-7), 132.3 (C-6), 141.0 (C-5), 145.1 (C-11),
153.0 (C-3) ppm; 15N NMR (DMSO-d6, ꢂ; 40 MHz): 96.0 (br, N-2), 175.6 (br, N-1) ppm; MS
‡
(70 eV): m/z ˆ 216 (11, M ), 201 (46), 198 (20), 197 (19), 183 (100), 168 (11), 158 (10), 128 (9),
115 (15).
3-(2-(ꢀ-Hydroxyisopropyl)-phenyl)-5-phenylpyrazole (3j; C18H18N2O)
Procedure C; yield: 75(96)%; m.p.: 154±157ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.59 (s, 2CH3), 5.81
(br s, OH, NH), 6.76 (s, 4-H), 7.35±7.38 (m, 9-H, 10-H, C6H5, 3H), 7.44 (t, J ˆ 7.7, C6H5, 2H), 7.60
± 7.64 (m, 7-H, 8-H), 7.79 (d, J ˆ 7.2, C6H5, 2H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 29.8 (2CH3),
72.9 (C-12), 102.7 (C-4), 125.7, 128.4, 128.9, 131.0 (C6H5), 126.1 (C-8), 127.4 (C-10), 128.1 (C-9),
131.7 (C-6), 132.1 (C-7), 144.8 (C-5), 145.8 (br, C-11), 152.6 (br, C-3) ppm; 15N NMR: no signals
‡
visible due to fast exchange; MS (70 eV): m/z ˆ 278 (11, M ), 263 (43) 260 (31), 259 (16), 245
(100), 220 (9), 115 (8), 77 (7).
8,8-Dimethylpyrazolo[5,1-a]isoindoles 5a±c; 5-(2-(Isopropenyl)-phenyl)pyrazole 6a;
General procedure
1.44 mmol of 3h±j or 2a was stirred in 6 cm3 of orthophosphoric acid at room temperature for 2±3 h.
After pouring into 50 cm3 of cold H2O, the suspension was cooled in a H2O-ice bath, and the acid
was carefully neutralized by treatment with KOH (pellets). The mixture was extracted twice with
50 cm3 ethyl acetate. The combined organic layers were washed with water, separated, dried over
MgSO4, ®ltered through a 2 cm layer of Celite, and evaporated in vacuo. The crude products 5a±c
and 6a were puri®ed by column chromatography on silica gel with a mixture of n-hexane and ethyl
acetate (7:3) as eluent.
8,8-Dimethylpyrazolo[5,1-a]isoindole (5a; C12H12N2)
Yield: 77(89)%; m.p.: 54±56ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.69 (s, 2CH3), 6.35 (d, J ˆ 1.9, 3-
H), 7.28±7.39 (m, 4-H, 5-H, 6-H), 7.52±7.58 (m, 7-H),7.65 (d, J ˆ 1.9, 2-H) ppm; 13C NMR (CDCl3,
ꢂ, 100 MHz): 26.7 (2CH3), 65.1 (C-8), 96.5 (C-3), 120.5 (C-4), 121.7 (C-7), 127.3 (C-5), 128.1 (C-
6), 128.9 (C-11), 142.8 (C-10), 143.2 (C-2), 151.3 (C-12) ppm; 15N NMR (DMSO-d6, ꢂ, 40 MHz):
‡
90.1 (N-1), 139.8 (N-9) ppm; MS (70 eV): m/z ˆ 184 (46, M ), 169 (100), 128 (8), 115 (18).
2,8,8-Trimethylpyrazolo[5,1-a]isoindoles (5b; C13H14N2)
1
Yield: 84(96)%; oil; H NMR (CDCl3, ꢂ, 400 MHz): 1.67 (s, 2CH3), 2.40 (s, 2-CH3), 6.14 (s, 3-H),
7.27±7.37 (m, 4-H, 5-H, 6-H), 7.50±7.52 (m, 7-H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 14.5 (2-
CH3), 26.8 (2CH3), 64.9 (C-8), 96.0 (C-3), 120.3 (C-4), 121.6 (C-7), 127.1 (C-5), 128.0 (C-6), 129.1
(C-11), 143.6 (C-10), 151.2 (C-12), 152.8 (C-2) ppm; 15N NMR (DMSO-d6, ꢂ, 40 MHz): 93.8 (N-
‡
1), 145.3 (N-9) ppm; MS (70 eV): m/z ˆ 198 (44, M ), 183 (100), 168 (13), 115 (14).
8,8-Dimethyl-2-phenylpyrazolo[5,1-a]isoindole (5c; C18H16N2)
1
Yield: 88(96)%; oil; H NMR (CDCl3, ꢂ, 400 MHz): 1.74 (s, 2CH3), 6.66 (s, 3-H), 7.28±7.45 (m,
C6H5, 4-H, 5-H, 6-H, 6H), 7.58±7.62 (m, 7-H), 7.86 ± 7.91 (m, C6H5, 2H) ppm; 13C NMR (CDCl3, ꢂ,

Â
J. G. Sosnicki
484
100 MHz): 26.8 (2CH3), 65.5 (C-8), 93.6 (C-3), 120.5 (C-4), 121.6 (C-7), 127.4 (C-5), 128.1 (C-6),
125.7, 127.5, 128.6, 134.3 (C6H5), 128.9 (C-11), 144.0 (C-10), 151.1 (C-12), 155.7 (C-2) ppm; 15N
‡
NMR (CDCl3, ꢂ, 40 MHz): 99.7 (N-1), 142.2 (N-9) ppm; MS (70 eV): m/z ˆ 260 (54, M ), 245
(100), 169 (5), 115 (7), 77 (7).
5-(2-Isopropenyl)phenyl-1-phenylpyrazole (6a; C18H16N2)
Yield: 57(63)%; oil; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.45 (br s, 12-CH3), 4.46 (br d,
J ˆ 0.8, ˆ CHH), 4.80 (br t, J ˆ 1.4, ˆ CHH), 6.46 (d, J ˆ 1.7, 4-H), 7.13±7.35 (m, C6H5, 7-H, 8-H,
9-H, 10-H, 9H), 7.70 (d, J ˆ 1.7, 3-H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 22.4 (12-CH3), 109.1
(C-4), 116.2 ( ˆ CH2), 124.1, 127.1, 128.6, 140.3 (C6H5), 126.6 (C-8), 128.4 (C-10), 128.6 (C-6),
128.8 (C-9), 130.8 (C-7), 140.0 (C-3), 142.2 (C-12), 143.2 (C-5), 143.9 (C-11) ppm; MS (70 eV): m/
‡
z ˆ 260 (76, M ), 259 (85), 245 (100), 232 (12), 217 (25), 168 (12), 167 (11), 141 (9), 128 (12), 115
(15), 77 (15).
4,4-Dimethyl-1,4-dihydroindeno[1,2-c]pyrazoles 7a±f; General procedure
The procedure is exactly the same as described for the synthesis of 5a±c and 6a except that the reaction
was conducted at 110ꢀC. The crude products 7a,b,d,f were puri®ed by column chromatography on
silica gel with a mixture of n-hexane and ethyl acetate (7:3) as eluent. Compounds 7c,e were puri®ed
by crystallization from a mixture of n-hexane and ethyl acetate.
4,4-Dimethyl-1-phenyl-1,4-dihydroindeno[1,2-c]pyrazole (7a; C18H16N2)
Yield: 75(82)%; oil; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.53 (s, 2CH3), 7.21 (td, J ˆ 1.2, 7.5, 7-H), 7.27
(td, J ˆ 1.2, 7.5, 6-H), 7.38±7.46 (m, 5-H, 8-H, C6H5, 3H), 7.54 (t, J ˆ 8.2, C6H5, 2H), 7.61 (s, 3-H),
7.73 (br d, J ˆ ca. 8.2, C6H5, 2H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 26.7 (2CH3), 41.2 (C-4),
119.4 (C-8), 123.1, 127.5, 129.3, 140.2 (C6H5), 123.4 (C-5), 126.6 (C-7), 126.9 (C-6), 130.0 (C-8a),
133.6 (C-3), 139.6 (C-3a), 144.9 (C-8b), 159.7 (C-4a) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 67.4
‡
(N-2), 178.1 (N-1) ppm; MS (70 eV): m/z ˆ 260 (55, M ), 245 (100), 228 (7), 217 (11), 77 (9).
3,4,4-Trimethyl-1-phenyl-1,4-dihydroindeno[1,2-c]pyrazole (7b; C19H18N2)
1
Yield: 79(99)%; oil; H NMR (CDCl3, ꢂ, 400 MHz): 1.54 (s, 2CH3), 2.43 (s, 3-CH3), 7.20 (td,
J ˆ 1.2, 7.5, 6-H), 7.26 (td, J ˆ 1.2, 7.4, 7-H), 7.33±7.45 (m, 5-H, 8-H, C6H5, 3H), 7.51 (t, J ˆ 8.2,
C6H5, 2H), 7.70 (br d, J ˆ 8.2, C6H5, 2H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 12.4 (3-CH3), 25.5
(2CH3), 41.2 (C-4), 119.4 (C-8), 122.9, 127.1, 129.3, 140.2 (C6H5), 123.3 (C-5), 126.6 (C-6), 126.7
(C-7), 130.2 (C-8a), 136.8 (C-3a), 143.5 (C-3), 145.6 (C-8b), 159.7 (C-4a) ppm; 15N NMR (CDCl3,
‡
ꢂ, 40 MHz); 69.3 (N-2), 183.5 (N-1) ppm; MS (70 eV): m/z ˆ 274 (49, M ), 259 (100), 244 (8),
217 (23), 77 (7).
4,4-Dimethyl-1,3-diphenyl-1,4-dihydroindeno[1,2-c]pyrazole (7c; C24H20N2)
Yield: 45(78)%; m.p.: 151±153ꢀC; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.66 (s, 2CH3), 7.21 (td, J ˆ 0.8,
7.5, 7-H), 7.28 (td, J ˆ 0.9, 7.5, 6-H), 7.36 (t, J ˆ 7.4, C6H5), 7.38 ± 7.50 (m, 5-H, 8-H, C6H5, 5H),
7.55 (t, J ˆ 7.6, C6H5, 2H), 7.79 (d, J ˆ 7.5, C6H5, 2H), 7.97 (d, J ˆ 8.4, C6H5, 2H) ppm; 13C NMR
(CDCl3, ꢂ, 100 MHz): 25.1 (2CH3), 42.2 (C-4), 119.3 (C-8), 123.3 (C-5), 123.5, 127.5, 127.6, 127.8,
128.5, 129.3, 133.5, 140.1, (2C6H5), 126.6 (C-7), 127.0 (C-6), 129.6 (C-8a), 135.7 (C-3a), 146.7 (C-
8b), 147.1 (C-3), 160.0 (C-4a) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 70.55 (N-2), 180.6 (N-1)
‡
ppm; MS (70 eV): m/z ˆ 336 (69, M ), 321 (100), 305 (48), 243 (6), 229 (6), 217 (15), 77 (10).

New Aspects of Pyrazole Synthesis
485
1,4,4-Trimethyl-1,4-dihydroindeno[1,2-c]pyrazole (7d; C13H14N2)
Yield: 85(98)%; oil; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.46 (s, 2CH3), 4.10 (s, 1-CH3), 7.24±7.32 (m,
6-H, 7-H), 7.35 (s, 3-H), 7.39 (dm, J ˆ ca. 7.3, 5-H), 7.46 (dm, J ˆ ca. 7.3, 8-H) ppm; 13C NMR
(CDCl3, ꢂ, 100 MHz): 26.8 (2CH3), 37.5 (1-CH3), 41.4 (C-4), 118.3 (C-8), 123.5 (C-5), 126.6 (C-7),
126.7 (C-6), 130.0 (C-8a), 131.3 (C-3), 137.7 (C-3a), 145.8 (C-8b), 159.5 (C-4a) ppm; 15N NMR
‡
(CDCl3, ꢂ, 40 MHz): 68.1 (N-2), 198.1 (N-1) ppm; MS (70 eV): m/z ˆ 198 (42, M ), 183 (100),
168 (16), 140 (7), 127 (6).
1,3,4,4-Tetramethyl-1,4-dihydroindeno[1,2-c]pyrazole (7e; C14H16N2)
1
Yield: 79(99)%; m.p.: 85±88ꢀC; H NMR (CDCl3, ꢂ, 400 MHz): 1.47 (s, 2CH3), 2.32 (s, 3-CH3),
4.02 (s, 1-CH3), 7.27 (td, J ˆ 1.3, 7.4, 7-H), 7.28 (td, J ˆ 1.4, 7.4, 6-H), 7.37 (dm, J ˆ ca. 7.3, 5-H),
7.43 (dm, J ˆ ca. 7.3, 1H, 8-H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 12.3 (3-CH3), 25.6 (2CH3),
37.1 (1-CH3), 41.3 (C-4), 118.4 (C-8), 123.4 (C-5), 126.4 (C-7), 126.7 (C-6), 130.2 (C-8a), 134.6 (C-
3a), 141.1 (C-3), 146.5 (C-8b), 159.4 (C-4a) ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 71.6 (N-2),
‡
204.3 (N-1) ppm; MS (70 eV): m/z ˆ 212 (30, M ), 197 (100), 182 (9), 140 (4), 128 (5).
1,4,4-Trimethyl-3-phenyl-1,4-dihydroindeno[1,2-c]pyrazole (7f; C19H18N2)
Yield: 77(83)%; oil; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.49 (s, 2CH3), 4.01 (s, 1-CH3), 7.15±7.39 (m,
5-H, 6-H, 7-H, 8-H, C6H5, 7H), 7.77 (d, J ˆ 7.8, C6H5, 2H) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz):
25.1 (2CH3), 36.5 (1-CH3), 41.3 (C-4), 117.2 (C-8), 122.4 (C-5), 125.6, 125.7 (C-6, C-7), 126.0,
126.3, 127.5, 132.7 (C6H5), 128.5 (C-8a), 132.5 (C-3a), 144.0 (C-3), 146.6 (C-8b), 158.6 (C-4a)
ppm; 15N NMR (CDCl3, ꢂ, 40 MHz): 73.4 (N-2), 200.1 (N-1) ppm; MS (70 eV): m/z ˆ 274 (61,
‡
M ), 259 (100), 230 (4), 156 (5), 127 (4), 77 (4).
Acknowledgments
The author thanks Dr. Z. Wichert-Tur for the initiation of this work and Prof. J. Liebscher from
Humboldt University, Berlin, for helpful discussions and assistance with the preparation of the
manuscript.
References
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È
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J. G. Sosnicki: New Aspects of Pyrazole Synthesis
486
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Received November 4, 1999. Accepted (revised) December 3, 1999