Regioselective synthesis of 1,3,5- and 1,3,4,5-substituted pyrazoles via acylation of N-Boc-N-substituted hydrazones

Article abstract of DOI:10.1016/j.tet.2010.11.057

Acylation of N-Boc-N-methylhydrazones followed by TFA treatment affords regioselective access to substituted pyrazoles. Both regioisomers of 1-methyl-3,5-disubstituted-1H-pyrazoles can be selectively obtained. This procedure can also be employed for the r

Full text of DOI:10.1016/j.tet.2010.11.057

Tetrahedron 67 (2011) 612e617
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Tetrahedron
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Regioselective synthesis of 1,3,5- and 1,3,4,5-substituted pyrazoles via acylation of
N-Boc-N-substituted hydrazones
,
a
b
,
b
Alessandro Tinarelli a, Paolo Righi a , Goffredo Rosini , Daniele Andreotti , Roberto Profeta ,
*
*
Simone Spada b
a
ꢀ
Dipartimento di Chimica Organica ‘A. Mangini’, Alma Mater StudiorumdUniversita di Bologna, Viale del Risorgimento, I-40136 Bologna, Italy
b GlaxoSmithKline, Medicine Research Centre, Via A Fleming 4, 37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2010
Received in revised form 22 October 2010
Accepted 16 November 2010
Available online 24 November 2010
Acylation of N-Boc-N-methylhydrazones followed by TFA treatment affords regioselective access to
substituted pyrazoles. Both regioisomers of 1-methyl-3,5-disubstituted-1H-pyrazoles can be selectively
obtained. This procedure can also be employed for the regioselective preparation of fully substituted
1H-pyrazoles.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Regioselective pyrazole synthesis
N-Boc-N-methylhydrazone acylation
1,3,5-Trisubstituted pyrazoles
1,3,4,5-Tetrasubstituted pyrazoles
1. Introduction
N
S
Pyrazoles are an important class of heteroaromatic ring systems
that find extensive use in the pharmaceutical industry. Examples
are Viagra,1 an inhibitor of 5-phosphodiesterase used for the
treatment of erectile dysfunction, Celebrex, an inhibitor of cyclo-
oxygenase-2 (COX-2) used as potent anti-inflammatory,2 and
Acomplia, antagonist of the CB-1 cannabinoid receptor,3 used for
the treatment of obesity. General methods for the preparation of
pyrazoles include the condensation between hydrazines and 1,3-
dicarbonyl compounds4 and 1,3-dipolarcycloadditions.5 These
methods often present problems that range from low selectivities,
multistep sequences, and drastic conditions. Therefore, there are
still many efforts directed toward the selective preparation of
substituted pyrazoles: recent examples include the repeated met-
alation-electrophile trapping of unsubstituted pyrazoles,6 low-
temperature strong-base mediated reaction of hydrazones with
nitroolefins,7 and condensation of hydrazines with yne-ones.8
Recently, researchers at GlaxoSmithKline reported9 a regiose-
lective synthesis of the pyrazole moiety of compound 1 (Fig. 1),
a highly potent and selective dopamine D3 receptor antagonist.10
In that case, the regioselective synthesis of the pyrazole moiety
was achieved via acylation of acetone N-Boc-N-methylhydrazone
N
N
N
N
1
N
N
Fig. 1. A potent and selective dopamine D3 receptor antagonist.
with a methyl benzoate derivative, followed by exposure to tri-
fluoroacetic acid (TFA), as depicted in Scheme 1.
N
N
Boc
base
TFA
Ar
Ar
CH2Cl2
MeO
Ar
N
N
N
O
N
O
single regioisomer
Boc
NBoc
Ar =
Scheme 1. Regioselective preparation of the pyrazole moiety adopted for the synthesis
of compound 1.
The acylation of hydrazones followed by pyrazole ring closure is
known in the literature11 but the reported procedures often show
drawbacks, such as the requirement of strong bases and low tem-
peratures11a,b or that they allow no direct access to 4-substituted
* Corresponding authors. Tel.: þ39 051 20 93625; fax: þ39 051 20 93630; e-mail
addresses: paolo.righi@unibo.it (P. Righi),daniele.andreotti@Aptuit.com (D. Andreotti).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.057

A. Tinarelli et al. / Tetrahedron 67 (2011) 612e617
613
pyrazoles.8,11c In this paper, we wish to report the results of our
work aimed at investigating the scope of the strategy depicted in
Scheme 1, in order to obtain a new and general regioselective
preparation of 1,3,5-trisubstituted and 1,3,4,5-tetrasubstituted
pyrazoles.
only product, and as reaction proceeds, the hydroxypyrazole 5
starts to form and soon becomes the major product. A second
confirmation came when we observed that subjecting isolated
ketoimine 4a to the same reaction conditions depicted in Scheme 2,
leads to its clean conversion into hydroxypyrazole 5a.
In an attempt to minimize hydroxypyrazole formation, we tried
to replace methyl benzoate with (a) stronger acylating agents, such
as anhydrides or acyl chlorides, to make the first step to ketoimine
much faster than the subsequent conversion to the corresponding
hydropyrazole; (b) Weinreb’s amides in order to stabilize the tet-
rahedral intermediate, that is, initially formed through attack of the
hydrazone anion to the acylating agent, thus slowing down its
conversion into 5.16
2. Results and discussion
From the very beginning of our study it was clear that the
methodology depicted in Scheme 1 was not generally applicable. In
fact, when methyl benzoate (3, X¼OMe) was reacted under the same
conditions with a different N-Boc-N-methylhydrazone12,13 anion 2a,
generated by the addition of lithium bis(trimethylsilyl)amide
(LiHDMS) in THF at 0 ꢀC, a mixture of two compounds was obtained,
where the desired ketoimine14 4a was the minor one (Scheme 2).
The major product was identified to be the 5-hydroxy-4-acylpyr-
azole derivative 5a, which can be present in several tautomeric
forms, hampering its NMR spectroscopic characterization.15
In this regard, we tested hydrazones 2a, 2c, and 2f, the ones that
with methyl benzoate gave significant amounts of 5, by reacting
them with different acylating agents. Table 2 reports the results of
this study.
Table 2
Effect of the nature of the acylating agent on product distribution of the reaction in
Scheme 2
R1
N
Acylating agent 3 (X)
[yield of 4 (%)/yield of 5 (%)]a
N
2
Ph
O
Boc
LiHDMS
Hydrazone
OMe
N(Me)OMe
78/0
PhCOO
Clb
R1
R1
N
Ph
2a
2f
2c
12/42
0/66
15/50
15/65
n.a.
69/0
70/0
71/0e
X
OH
,d
8/45c
n.a.
+
N
N
O
THF, 0°C
N
0/60d
O
3
4
5
Boc
Scheme 2. Acylation of N-Boc-N-methylhydrazones (2).
a
Isolated yields.
b
Reactions performed at ꢁ10 ꢀC.
Chromatographic yields.
Reaction performed at rt.
Crude yields.
c
d
e
When we repeated the reaction using a series of hydrazones 2
(Table 1) we observed that in most of the cases large amounts of 5
are obtained. In some cases as with the N-Boc-N-methylhydrazones
2c, 2d, and 2f (Table 1) the reaction afforded only the corre-
sponding hydroxypyrazole 5, with no trace of the desired ketoi-
mine 4.
The use of the Weinreb amide of benzoic acid [Scheme 2, X¼N
(Me)OMe] in the reaction with hydrazone 2a (Table 2, entry a) gave
the desired ketoimine 4a in a 78% isolated yield, while in the same
reaction with hydrazone 2f (Table 2, entry b) we observed only
a slight improvement over the results obtained with methyl ben-
zoate. This is probably due to the fact this latter reaction is very
slow because of steric hindrance: at rt it takes 15 h to complete, and
under such conditions the tetrahedral intermediate may no longer
be stable generating the ketoimine product during the reaction,
well before it is complete, which then can undergo the degradation
process to hydroxypyrazole 5.
Table 1
Acylation of hydrazones 2 with methyl benzoate 3 (Scheme 2, X¼OMe)
Entry
R1
Time (h)
Yield of 4a (%)
Yield of 5a (%)
a
b
c
d
e
f
Ph
1
12
85
0
0
80
0
42
0
60
45
0
2-Tolyl
2-Pyridinylb
4-Pyridinylb
Me
0.25
15
15
1
0.30
The use of benzoic anhydride (3, X¼PhCOO) led to slightly im-
proved results: both hydrazones 2a and 2f afforded higher amounts
of the desired ketoimines 4a and 4f, respectively. However, 5 was
still the major product.
t-Bu
66
a
Isolated yields.
Reaction performed at rt.
b
Finally, the reaction of hydrazones 2a and 2f with benzoyl
chloride gave ketoimines 4a and 4f as the only products, with no
trace of the unwanted hydroxypyrazole by-products. Also hydra-
zone 2c, that was very reluctant to react with methyl benzoate
(Table 1) affording only 5, when reacted with benzoyl chloride
(Table 2) afforded only ketoimine 4c.
We investigated if this regioselective methodology to 1-methyl-
3,5-disubstituted-1H-pyrazoles could be employed to obtain either
of two possible regioisomers of a specific pyrazole ring. From the
general procedure depicted in Scheme 4, it is possible to see that to
obtain either regioisomer would require the exchange of groups R1
The formation of 5 could be explained assuming that the anion
of ketoimine 4 undergoes an intramolecular cyclization by addition
to the Boc group, followed by tert-butoxide elimination (Scheme 3).
Following this hypothesis, formation of hydroxypyrazoles 5
arises from a consecutive reaction of the ketoimine product: before
the reaction is complete, the ketoimine starts to undergo the
intramolecular cyclization to the unwanted 5. In fact, HPLC profiles
obtained by monitoring at regular intervals the reaction depicted in
Scheme 2 clearly shows that at the beginning the ketoimine 4 is the
Ph
R1
Ph
Ph
O
O
R1
N
R1
R1
R1
R1
N
R2
t
(i)
Cl
R2
– BuO
(ii)
O
N
+
R2
OH
O
N
N
O
N
N
N
N
O
N
N
N
O
2
7
4
Ot-Bu
6
Boc
Boc
5
Scheme 4. General regioselective preparation of 1-methyl-3,5-disubstituted-1H-pyr-
Scheme 3. Formation of by-products 5.
azoles: (I) LiHDMS, THF, 0 ꢀC; (ii) TFA/DCM (2:1; 3 vol), rt, 1 h.

614
A. Tinarelli et al. / Tetrahedron 67 (2011) 612e617
and R2. For example, the reaction between the hydrazone derived
from ketone 2f (R1¼t-Bu) and benzoyl chloride (R2¼Ph) affords,
after the TFA treatment, 1-methyl-3-tert-butyl-5-phenyl-1H-pyr-
azole (6f, Table 3). According to Scheme 2, its regioisomer, 5-(tert-
butyl)-1-methyl-3-phenyl-1H-pyrazole (6h), might be obtained by
using the hydrazone derived from benzophenone (2a, R1¼Ph) and
an acylating agent derived from pivalic acid (R2¼t-Bu).
R3
R1
N
N
8
Boc
O
R3
R3
R1
LiHDMS,
THF, 0 °C
Ph
O
R1
N
Ph
MeO
N
O
N
N
Table 3
O
9
11
Conversion of ketoimines 4 into 1-methyl-3,5-disubstituted-1H-pyrazoles 6
Boc
R1
2 : 1 TFA : DCM (3 vol)
rt, 1h
not observed
R1
Ph
TFA : DCM
rt, 1h
Ph
N
N
O
N
R3
N
Boc
R1
4
6
Ph
N
R1
Yield
N
Entry
10
a
b
c
e
f
Ph
98
Scheme 5. Regioselective synthesis of fully substituted pyrazole systems 10.
2-Tolyl
2-Pyridinyl
Me
Quant.
70a
We were glad to find that reacting the anion derived from
hydrazones 812 with methyl benzoate, cleanly afforded the corre-
sponding ketoimines 9.14 In this case, we do not observe the for-
mation of by-products. The corresponding substituted 1H-pyrazol-5
(4H)-ones 11, that would arise from an intermolecular cyclization of
ketoimines 9, similar to that reported in Scheme 3, were never ob-
served. Ketoimines 9 were cleanly converted by treatment with TFA
into the corresponding fully substituted pyrazoles 10 and where
regioisomeric products are possible, only one was obtained.
Table 5 shows the results obtained and the tolerance of this
methodology to different substituents. In fact, it allows the syn-
thesis of pyrazoles with fused rings, with fluorine atoms, alkyl and
aromatic groups.
Quant.
95
t-Bu
a
overall yield over two steps, starting from benzoyl chloride (3; X¼Cl).
See Scheme 4.
We therefore attempted to selectively obtain the other
regioisomer of pyrazoles 6b and 6f using acyl chlorides as acylating
agents. Table 4 reports the results.
Table 4
Results of the synthesis of Scheme 4
Entry
R1
R2
Pyrazole 6a
Overall yieldb (%)
Table 5
Results of the regioselective synthesis of fully substituted pyrazole systems 10
(Scheme 5)
b
2-Tolyl
Ph
79
Ph
N
N
Entry
Hydrazone 8
Pyrazole 10
Overall yielda (%)
f
t-Bu
Ph
69
77
Ph
N
N
a
89
N
N
N
Ph
N
g
Ph
2-Tolyl
Boc
N
N
N
N
Boc
b
c
69
74
N
N
Ph
h
Ph
t-Bu
65
Ph
N
F
N
F
N
a
N
Regioisomer structure confirmation through NOE experiments.
Isolated yield over the two steps depicted in Scheme 4.
N
b
N
Boc
By reacting the anion of hydrazone 2a (R1¼Ph) with 2-methyl-
Ph
benzoyl chloride(7, R2¼2-tolyl) a smooth reaction occurred and the
desired ketoimine 4g was obtained after 30 min at 0 ꢀC, in a 78%
isolated yield. (Table 4, entry g). The reaction between the anion of
hydrazone 2a and pivaloyl chloride (7, R2¼t-Bu) afforded ketoimine
4h, after 20 min at 0 ꢀC, in 68% isolated yield (Table 4, entry h).
By rapid exposure to TFA at rt, both ketoimines 4g and 4h were
readily converted in nearly quantitative yields, into the corre-
sponding 1-methyl-3,5-disubstituted-1H-pyrazoles 6g and 6h,
which are the regioisomers of 6b and 6f, respectively.
d
79
N
N
Boc
N
N
a
Overall isolated yields over the two steps depicted in Scheme 5.
3. Conclusions
In conclusion, we have presented a methodology for the regio-
selective preparation of 1-methyl-3,5-disubstituted-1H-pyrazoles
6. This is achieved by a reaction through the anion of hydrazones 2
with an acylating agent 3, followed by TFA treatment of the
ketoimine 4 obtained. The choice of the appropriate acylating agent
We also investigated the possibility to apply our methodology to
the regioselective synthesis of fully substituted 1-methyl-3,4,5-
trisubstituted-1H-pyrazole systems 10 (Scheme 5). This requires
the use of hydrazones derived from ‘methylene’ ketones 8.

A. Tinarelli et al. / Tetrahedron 67 (2011) 612e617
615
is critical. While methyl benzoate often affords hydroxypyrazoles 5
as the major or only product, Weinreb amides, anhydrides, and acyl
chlorides offer higher ketoimine yields, with acyl chlorides being
the reagents of choice since they gave no by-product in all the cases.
The procedure is also amenable to be controlled and by the
appropriate choice of the reactant substituents either of the two
regioisomers of a given 1-methyl-3,5-disubstituted-1H-pyrazole
could be obtained in good overall yields.
(yield 69%); Hydrazone 2a and benzoic anhydride: 1 h, 0 ꢀC, 53 mg
of 4a (yield 15%) and 139 mg of 5a (yield 50%). Hydrazone 2a and
benzoic acid Weinreb’s amide: 30 min, 0 ꢀC, 275 mg of 4a (yield
78%). The crude was purified by FC with Cyclohexane/ethyl acetate
9:1. The compound was obtained as a yellow oil.
Compound 4a: 1H NMR (400 MHz, CDCl3)
d
: 1.37 (s, 9H), 3.02 (s,
3H), 5.97 (s, 1H), 7.45 (m, 8H), 7.92 (m, 2H), 11.8 (s, 1H). 13C NMR
(100 MHz, CDCl3) : 28.1 (CH3), 38.6 (CH3), 81.4 (C), 95.6 (CH), 127.4
d
Finally, the methodology was also extended to obtain the fully
substituted pyrazole systems 10 incorporating a wide range of
substituents.
(CH), 127.7 (CH), 128.1 (CH), 128.3 (CH), 129.8 (CH), 131.4 (CH), 134.8
(C), 139.4 (C), 155.2 (C), 166.9 (C), 190.1 (C).
Compound 5a: The compound was obtained as a brownish foam.
1H NMR (400 MHz, CDCl3) : 3.50 (br s, 3H), 6.92 (br m, 11H). 13
d C
4. Experimental section
NMR (400 MHz, CDCl3) d: 31.2 (CH3), 103.2 (C), 127.0 (CH), 127.4
(CH), 128.8 (CH), 129.0 (CH), 130.6 (CH), 133.9 (CH), 138.4 (C), 151.5
(C), 165.1 (C), 191.2 (CH).
All hydrazones were prepared from commercially available ke-
tones according to Refs. 11 or 12. The fluoromethyl phenyl ketone
necessary to obtain hydrazone 8c was prepared according to a lit-
erature method.17
4.1.2. tert-Butyl 1-methyl-2-(3-oxo-3-phenyl-1-o-tolylpropylidene)
hydrazinecarboxylate (4b). From hydrazone 2b and methyl benzo-
ate: 10 min, at 0 ꢀC. The crude was purified by FC with cyclohexane/
ethyl acetate 9:1. The compound was obtained as a yellow oil
All moisture-sensitive reactions were performed in an inert, dry
atmosphere of argon or nitrogen in oven-dried glassware. Reagent
grade solvents were used forchromatographies and extractions. THF
was distilled from Na/benzophenone under argon; CH2Cl2, was
distilled from CaH2 under argon. Analytical thin-layer chromatog-
raphy (TLC) was performed using Merck precoated TLC plates (Silica
gel 60 GF254 0.25 mm). Flash chromatography was performed using
Merck Silica gel 60 (230e400 mesh). The solvent compositions
reported for all separations are on a volume/volume basis. Gas
chromatography (GC) was performed using a Hewlett Packard
HP6890 or an Agilent 6850 instruments using an Agilent 19091Z-
(293 mg; yield 80%). 1H NMR (400 MHz, CDCl3)
d
: 1.51 (s, 9H), 2.22
(s, 3H), 3.19 (s, 3H), 5.82 (s, 1H), 7.25 (m, 4H), 7.89 (m, 3H), 7.89 (m,
2H), 11.95 (s, 1H). 13C NMR (100 MHz, CDCl3)
: 20.4 (CH3), 28.8
d
(CH3), 38.5 (CH3), 82.6 (C), 96.7 (CH), 127.6 (CH), 127.7 (CH), 128.2
(CH), 128.4 (CH), 130.0 (CH), 131.4 (CH), 131.9 (CH), 134.8 (C), 139.6
(C), 155.4 (C), 167.0 (C), 190.7 (C).
4.1.3. tert-Butyl 1-methyl-2-(3-oxo-3-phenyl-1-(pyridin-2-yl)propy-
lidene)hydrazinecarboxylate (4c). From hydrazone 2c and methyl
benzoate: 15 h at rt, 168 mg of 5c (yield 60%). From hydrazone 2c
and benzoyl chloride: 30 min, ꢁ10 ꢀC, 246 mg of 4c (yield 70%). The
crude was purified by FC with Cyclohexane/ethyl acetate from 95:5
to 70:30. The compound was obtained as a brown oil.
413E, HP-1 Methyl siloxane column, 30 mꢂ320
m
mꢂ0.25
mm.
High performance liquid chromatography (HPLC) was per-
formed using an Agilent 1100 instrument equipped with a C18
Hypersil column (25ꢂ4.6 cm), eluent 40% channel A (ACN); 60%
channel B (ACN/water 1:1); 1 ml/min; UV 254 nm; T 25 ꢀC.
1H NMR spectra were recorded at 300, 400 or 600 MHz at 25 ꢀC
Compound 4c: 1H NMR (400 MHz, CDCl3)
3H), 6.16 (s, 1H), 7.34 (m, 1H), 7.44 (m, 2H), 7.58 (m, 1H), 7.74 (m,
1H), 7.95 (m, 2H), 8.68 (m, 2H). 13C NMR (100 MHz, CDCl3)
: 28.0
d: 1.33 (s, 9H), 3.14 (s,
with either tetramethylsilane (
internal standard. 13C NMR spectra were recorded at 75, 100 or
150 MHz at 25 ꢀC with CDCl3
77.0) as the internal standard.
d
0.00) or chloroform (
d
7.26) as the
d
(CH3), 37.5 (CH3), 81.4 (C), 96.0 (CH), 123.2 (CH), 124.2 (CH), 127.4
(CH), 128.2 (CH), 131.4 (CH), 136.1 (C), 139.2 (CH), 148.9 (CH), 150.7
(C), 155.0 (C), 164.34 (C), 190.5 (C).
(d
Carbon assignments were based on DEPT and/or HMQC experi-
ments. 19F NMR spectra were recorded at 376 MHz at 25 ꢀC using
Compound 5c: The compound was obtained as brown foam. 1H
hexafluorobenzene as external standard (
d
ꢁ163.5 ppm). Melting
NMR (400 MHz, CDCl3)
7.71 (m, 1H), 7.95 (m, 1H), 8.68 (m, 1H), 9.86 (br s, 1H). 13C NMR
(100 MHz, CDCl3) : 37.2 (CH3), 107.3 (C), 122.5 (CH), 123.8 (CH),
128.4 (CH), 129.8 (CH), 132.2 (CH), 136.2 (CH), 137.8 (C), 145.6 (CH),
148.9 (C), 153.3 (C), 167.1 (C), 190.2 (C).
d: 3.80 (s, 3H), 7.19 (m, 1H), 7.45 (m, 5H),
€
points were determined through a Buchi instrument.
Mass spectra were obtained with positive electron spray ioni-
zation on Waters Micromass ZQ4000 instrument. High resolution
mass spectra for new pyrazoles products were obtained by elec-
tronic impact on a Thermo Finnigan MAT95XP instrument.
d
4.1.4. tert-Butyl 1-methyl-2-(4-oxo-4-phenylbutan-2-ylidene)hydra-
zinecarboxylate (4e). From hydrazone 2e (2 mmol) and methyl
benzoate (1 mmol): 1 h, 0 ꢀC. The crude was purified by FC with
cyclohexane/ethyl acetate from 95:5 to 90:10. The compound was
obtained as a yellow oil (232 mg; yield 80%). 1H NMR (400 MHz,
4.1. General procedure for the synthesis of ketoimines 4 and 9
A solution of LiHDMS (1 M in THF; 2.4 equiv) was added, under
a nitrogen atmosphere, to a stirred solution of the hydrazone
(2 mmol) in dry THF (4 vol with respect to hydrazone weight) and
stirred at 0 ꢀC for 1 h. After this time the resulting solution was
added via syringe to a solution of the acylating agent (1 mmol) in
dry THF (8 vol), under N2, at 0 ꢀC. The reaction progress was
monitored by HPLC analysis and the mixture was stirred at 0 ꢀC for
the indicated time. The reaction was quenched with water (10 vol)
and extracted with ethyl acetate (3ꢂ5 vol). The organic phase was
dried and evaporated. The crude product was purified by FC eluting
with a mixture of cyclohexane/AcOEt to obtain the desired
compound.
CDCl3)
d
: 1.40 (s, 9H), 2.26 (s, 3H), 3.22 (s, 3H), 5.97 (s, 2H), 7.38 (m,
: 14.1 (CH3), 28.1
3H), 7.92 (m, 2H). 13C NMR (100 MHz, CDCl3)
d
(CH3), 34.9 (CH3), 36.6 (CH2) 83.0 (C), 128.6 (CH), 129.1 (CH), 132.6
(CH), 137.1 (C), 150.3 (C), 155.2 (C), 190.1 (C).
4.1.5. tert-Butyl 2-(4,4-dimethyl-1-oxo-1-phenylpentan-3-ylid-ene)-
1-methylhydrazinecarboxylate (4f). From hydrazone 2f and methyl
benzoate: 30 min at 0 ꢀC, 170 mg of 5f (yield 66%). From hydrazone
2f and benzoyl chloride: 10 min at ꢁ10 ꢀC, 233 mg of 4f (yield 70%).
From hydrazone 2f and benzoic anhydride: 30 min, 0 ꢀC, 50 mg of
4f (yield 15%). The crude product was purified by FC with cyclo-
hexane/ethyl acetate from 95:5 to 90:10.
4.1.1. tert-Butyl 1-methyl-2-(3-oxo-1,3-diphenylpropylidene)hydra-
zinecarboxylate (4a). Hydrazone 2a and methyl benzoate: 1 h at
0 ꢀC, 42 mg of 4a (yield 12%) and 125 mg of 5a (yield 45%).
Hydrazone 2a and benzoyl chloride 20 min, at ꢁ10 ꢀC, 243 mg of 4a
Compound 4f: 1H NMR (400 MHz, CDCl3)
9H), 2.78 (s, 3H), 3.94 (s, 2H), 7.46 (m, 2H), 7.57 (m, 1H), 7.89 (m,
1H). 13C NMR (100 MHz, CDCl3)
: 27.2 (CH3), 28.1 (CH3), 35.8 (CH3),
d: 1.26 (s, 9H), 1.31 (s,
d

616
A. Tinarelli et al. / Tetrahedron 67 (2011) 612e617
37.9 (CH2), 38.9 (C), 80.2 (C), 127.6 (CH), 128.5 (CH), 132.9 (CH),
137.0 (C), 156.0 (C), 136.1 (C), 181.6 (C), 194.1 (C).
NMR (400 MHz, CDCl3)
d: 1.35 (s, 9H), 2.01 (s, 3H), 3.15 (s, 3H), 7.55
(m, 8H), 7.91 (m, 2H), 11.95 (s, 1H). 13C NMR (100 MHz, CDCl3)
d
:
Compound 5f: The compound was obtained as a white solid
12.4 (s, CH3), 28.3 (CH3), 38.9 (CH3), 81.5 (C), 108.2 (C), (CH), 127.4
(CH), 127.7 (CH), 128.1 (CH), 128.3 (CH), 129.8 (CH), 131.4 (CH), 134.8
(C), 139.4 (C), 155.2 (C), 165.2 (C), 189.2 (C).
(66%). 1H NMR (400 MHz, CDCl3)
d
: 1.14 (s, 9H), 3.56 (s, 3H), 7.49 (m,
5H), 9.34 (br s, 1H). 13C NMR (100 MHz, CDCl3)
d
: 29.3 (CH3), 32.5
(C), 34.0 (CH3) 102.6 (C),127.7 (CH),128.4 (CH),130.1 (CH),140.6 (C),
158.7 (C), 159.6 (C), 193.6 (C).
4.2. General procedure for the synthesis of substituted
pyrazoles 6 and 10
4.1.6. tert-Butyl 1-methyl-2-(3-oxo-1-phenyl-3-o-tolylprop-1-enyl)
hydrazinecarboxylate (4g). From hydrazone 2a and 2-methyl-
benzoyl chloride: 10 min, at ꢁ10 ꢀC, The crude was purified by FC
with cyclohexane/ethyl acetate 9:1. The compound was obtained as
A solution of the ketoimine intermediate (4 or 9; 0.3 mmol) in
dry DCM (0.4 ml) was added dropwise to TFA (0.8 ml) at rt. The
reaction mixture was stirred at rt for 1 h and then evaporated. The
residue was dissolved in DCM and NaOH 1 N was added until
a basic pH. The organic layer was separated and the aqueous layer
was further extracted with DCM (3ꢂ2 ml). The combined organic
phases were dried over MgSO4 and evaporated under vacuum to
obtain the desired pyrazole as a single regioisomer.
yellow oil (293 mg; yield 80%). 1H NMR (400 MHz, CDCl3)
d
: 1.36 (s,
9H), 2.52 (s, 3H), 3.05 (s, 3H), 5.62 (s, 1H), 7.31 (m, 9H), 11.70 (s, 1H).
13C NMR (100 MHz, CDCl3)
: 20.5 (CH3), 28.1 (CH3), 38.8 (CH3), 81.1
d
(C), 99.2 (CH), 125.4 (CH), 127.5 (CH), 127.7 (CH), 128.1 (CH), 129.6
(CH), 129.8 (CH), 131.1 (CH), 134.5 (C), 136.0 (C), 141.0 (C), 155.1 (C),
166.4 (C), 195.0 (C).
4.2.1. 1-Methyl-3,5-diphenyl-1H-pyrazole (6a)18. The title com-
4.1.7. tert-Butyl
2-(4,4-dimethyl-3-oxo-1-phenylpentylidene)-1-
pound was obtained as an off-white solid (69 mg; 98% yield). 1H
methylhydrazinecarboxylate (4h). From hydrazone 2a and pivaloyl
chloride: 20 min, at ꢁ10 ꢀC. The crude was purified by FC with
cyclohexane/ethyl acetate from 95:5 to 90:10. The compound was
obtained as a yellow oil (226 mg; 68% yield). 1H NMR (400 MHz,
NMR (400 MHz, CDCl3)
d
: 3.94 (s, 3H), 6.62 (s,1H), 7.41 (m, 8H), 7.83
(m, 2H). 13C NMR (100 MHz, CDCl3)
d
: 37.5 (CH3), 103.4 (CH), 125.5
(CH), 127.7 (C), 128.0 (CH), 128.6 (CH), 128.7 (CH), 128.7 (CH), 128.9
(CH), 129.8 (C), 130.5 (C), 133.2 (C), 145.1 (C), 150.4 (C). Mp 54e57 ꢀC
(lit.18 58e60 ꢀC). IR (Nujol): 1590, 689 cmꢁ1. MS: (ESIþ, m/z): 235
(MþH)þ; 257 (MþNa)þ.
CDCl3)
d
: 1.15 (s, 9H), 1.61 (s, 9H), 3.30 (s, 3H), 3.72 (s, 2H), 7.48 (m,
3H), 7.71 (m, 2H). 13C NMR (100 MHz, CDCl3)
d: 25.8 (CH3), 29.3
(CH3), 36.6 (CH3), 41.9 (CH2), 44.2 (C), 84.4 (C), 127.4 (CH), 128.4
(CH), 130.2 (CH), 136.1 (C), 146.2 (C), 154.6 (C), 198.6 (C).
4.2.2. 1-Methyl-5-phenyl-3-o-tolyl-1H-pyrazole
compound was obtained in quantitative yield (74 mg). 1H NMR
(400 MHz, CDCl3) : 2.53 (s, 3H), 3.94 (s, 3H), 6.47 (s, 1H), 7.24 (m,
3H), 7.44 (m, 5H), 7.62 (m, 1H). 13C NMR (100 MHz, CDCl3)
: 21.3
(6b). The
title
4.1.8. tert-Butyl
2-(2-benzoylcyclohexylidene)-1-methylhy-
d
drazinecarboxylate (9a). From Hydrazone 8a and methyl benzoate:
20 min, at ꢁ0 ꢀC. The crude was purified by FC with cyclohexane/
ethyl acetate from 95:5 to 85:15. The compound was obtained as
d
(CH3), 37.5 (CH3), 106.4 (CH), 125.7 (CH), 127.5 (C), 128.3 (CH), 128.6
(CH), 128.7 (CH), 129.1 (CH), 130.6 (CH), 132.2 (C), 135.8 (C), 144.0
(C), 150.7 (C). MS: (ESIþ, m/z): 249 (MþH)þ; 271 (MþNa)þ. HRMS
(EI): calcd for C17H16N2: 248.13135; found: 248.13140 (þ0.2 ppm).
a yellow oil (281 mg; 85% yield). 1H NMR (400 MHz, CDCl3)
d: 1.46
(s, 9H), 1.52 (m, 2H), 1.68 (m, 2H), 2.25 (t, 2H, J¼6.4 Hz), 2.40 (t, 2H,
J¼6.4 Hz), 3.17 (s, 3H), 7.36 (m, 5H), 12.12 (s, 1H). 13C NMR
(100 MHz, CDCl3)
d
: 21.4 (CH2), 23.1 (CH2), 24.7 (CH2), 27.5 (CH2),
4.2.3. 2-(1-Methyl-5-phenyl-1H-pyrazol-3-yl)pyridine (6c). The ti-
28.1 (CH3) 38.5 (CH3), 81.1 (C),101.9 (C),126.4 (CH),127.7 (CH),128.7
(CH), 132.7 (C), 142.3 (C), 155.3 (C), 163.7 (C), 196.7 (C).
tle compound was obtained in 70% overall (49 mg) yield from hy-
drazine 2c. 1H NMR (CDCl3)
d
: 3.95 (s, 3H), 6.94 (s, 1H), 7.19 (m, 1H),
7.45 (m, 5H), 7.71 (m, 1H), 7.95 (m, 1H), 8.68 (m, 1H). 13C NMR
(CDCl3) : 37.4 (CH3), 112.0 (CH), 118.8 (CH), 122.3 (CH), 127.8 (CH),
4.1.9. tert-Butyl 1-methyl-2-(2-methyl-1-oxo-1-phenylpentan-3-yli-
dene)hydrazinecarboxylate (9b). From hydrazone 8b and methyl
benzoate: 20 min, at ꢁ0 ꢀC. The crude was purified by FC with cy-
clohexane/ethyl acetate from 95:5 to 85:15. The compound was
obtained as a yellow oil (255 mg; 80% yield). 1H NMR (400 MHz,
d
128.6 (CH), 131.3 (C), 135.4 (CH), 144.2 (C), 148.2 (CH), 151.0 (C),
153.0 (C). MS: (ESIþ, m/z): 236 (MþH)þ; 258 (MþNa)þ. HRMS (EI):
calcd for C15H13N3: 235.11095; found: 235.11105 (þ0.4 ppm).
CDCl3)
d
: 1.01 (t, 3H, J¼8.08 Hz) 1.46 (s, 9H),1.87 (s, 3H), 3.07 (s, 3H),
4.2.4. 1,3-Dimethyl-5-phenyl-1H-pyrazole (6e). The title compound
7.48 (m, 5H), 12.51 (s, 1H). 13C NMR (100 MHz, CDCl3)
d: 9.4 (CH3)
was obtained in quantitative yield (52 mg). 1H NMR (400 MHz,
11.0 (CH3), 23.3 (CH2), 29.5 (CH3) 38.4 (CH3), 82.3 (C),101.4 (C),127.2
(CH), 128.0 (CH), 128.9 (CH), 132.9 (C), 140.2 (C), 156.1 (C), 163.0 (C),
197.1 (C).
CDCl3)
(100 MHz, CDCl3)
d
: 2.32 (s, 3H), 3.83 (3H), 6.10 (s, 1H), 7.45 (m, 5H). 13C NMR
d
: 13.3 (CH3), 37.1 (CH3), 105.6 (CH), 128.3 (CH),
128.6 (CH), 130.7 (C), 144.6 (C), 147.5 (C). MS: (ESþ, m/z): 173
(MþH)þ; 195 (MþNa)þ.
4.1.10. tert-Butyl
2-(2-fluoro-3-oxo-1,3-diphenylpropylidene)-1-
methylhydrazinecarboxylate (9c). From hydrazone 8c and methyl
benzoate: 40 min, at 0 ꢀC, (282 mg; yield 76%). The crude product
was purified by FC with cyclohexane/ethyl acetate from 95:5 to
4.2.5. 3-tert-Butyl-1-methyl-5-phenyl-1H-pyrazole (6f)8. The title
compound was obtained in 95% yield (61 mg). 1H NMR (400 MHz,
CDCl3)
(100 MHz, CDCl3) d: 30.7 (CH3), 32.0 (C), 37.2 (CH3), 102.4 (CH),
d
: 1.35 (s, 3H), 3.84 (s, 3H), 6.16 (s, 1H), 7.42 (m, 5H). 13C NMR
90:10. 1H NMR (400 MHz, CDCl3)
d: 1.39 (s, 9H), 2.96 (s, 3H), 7.45
(m, 8H), 7.92 (m, 2H), 10.56 (s, 1H). 13C NMR (100 MHz, CDCl3)
d:
126.9 (C),128.1 (CH),128.5 (CH),128.6 (CH),131.1 (C),143.9 (C),161.1
28.0 (CH3), 38.8 (CH3), 81.2 (C), 128.0 (CH), 128.7e128.7 (CH), 128.8
(CH), 129.5 (CH), 129.8 (CH), 131.8 (CH), 137.1e137.2 (C), 138.2 (C),
140.5 (C), 152.7e152.9 (C), 155.3 (C), 186.9e187.2 (C).
(C). MS: (ESIþ, m/z): 215 (MþH)þ; 237 (MþNa)þ. IR (neat): 1591,
1498, 779, 701 cmꢁ1
.
4.2.6. 1-Methyl-3-phenyl-5-o-tolyl-1H-pyrazole
compound was obtained in quantitative yield (75 mg). 1H NMR
(400 MHz, CDCl3) : 2.23 (s, 3H), 3.69 (s, 3H), 6.51 (s, 1H), 7.33 (m,
7H), 7.84 (m, 2H), 7.62 (m, 1H). 13C NMR (100 MHz, CDCl3)
: 19.8
(CH3), 23.6 (CH3), 103.6 (CH), 125.4 (CH), 125.7 (C), 127.5 (CH), 128.5
(CH), 129.1 (CH), 130.2 (CH), 130.2 (CH), 133.4 (C), 137.4 (C), 143.9
(6g). The
title
4.1.11. tert-Butyl 1-methyl-2-(2-methyl-3-oxo-1,3-diphenylpropyli-
dene)hydrazinecarboxylate (9d). From hydrazone 8d (2 mmol) and
methyl benzoate (1 mmol): 10 min, at 0 ꢀC. The crude was purified
by FC with cyclohexane/ethyl acetate from 95:5 to 90:10. The
compound was obtained as a yellow oil (286 mg; yield 78%). 1H
d
d

A. Tinarelli et al. / Tetrahedron 67 (2011) 612e617
617
(C), 150.3 (C). MS: (ESIþ, m/z): 249 (MþH)þ; 271 (MþNa)þ. HRMS
(EI): calcd for C17H16N2: 248.13135; found: 248.13128 (ꢁ0.3 ppm).
in part also by Alma Mater StudiorumdUniversita di Bologna, and
ꢀ
ꢀ
by Ministero dell’Istruzione dell’Universita e della Ricerca, Italy
(‘PRIN project n. 2007FJC4SF_004’).
4.2.7. 5-tert-Butyl-1-methyl-3-phenyl-1H-pyrazole (6h). The title
compound was obtained in quantitative yield (64 mg). 1H NMR
(400 MHz, CDCl3)
d
: 1.41 (s, 9H), 4.00 (s, 1H), 6.33 (s, 1H), 7.35 (m,
: 29.6 (CH3), 31.1 (C),
Supplementary data
4H), 7.94 (m, 1H). 13C NMR (100 MHz, CDCl3)
d
Actual 1H, 13C, and 19F NMR spectra of pyrazoles 6 and 10.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.057. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.
39.4 (CH3), 100.9 (CH), 125.2 (CH), 127.0 (CH), 128.4 (CH), 133.5 (C),
148.9 (C), 152.4 (C). MS: (ESIþ, m/z): 215 (MþH)þ; 237 (MþNa)þ.
HRMS (EI): calcd for C14H18N2: 214.14700; found: 214.14686
(ꢁ0.6 ppm).
4.2.8. 2-Methyl-3-phenyl-4,5,6,7-tetrahydro-2H-indazole
(10a)19. The title compound was obtained in quantitative yield
(64 mg). 1H NMR (400 MHz, CDCl3)
d: 1.78 (m, 4H), 2.48 (t, 2H,
References
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2. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.;
Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C.
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(CH2), 37.1 (CH3), 114.6 (C), 127.9 (CH), 128.5 (CH), 129.0 (CH), 130.7
(C), 139.4 (C), 148.1 (C). IR (neat) 3052, 1669, 1485, 749, 698 cmꢁ1
.
MS: (ESIþ, m/z): 213 (MþH)þ; 235 (MþNa)þ. HRMS (EI): calcd for
C14H16N2: 212.13135; found: 212.13127 (ꢁ0.4 ppm).
ꢁ
3. Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.; Calandra, B.; Congy, C.;
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Martinez, S.; Maruani, J.; Neliat, G.; Caput, D.; Ferrara, P.; Soubrie, P.; Breliere, J.
4.2.9. 3-Ethyl-1,4-dimethyl-5-phenyl-1H-pyrazole (10b). The title
C.; Le Fur, G. FEBS Lett. 1994, 350, 240.
compound was obtained in quantitative yield (60 mg). 1H NMR
4. (a) Knorr, L. Ber. 1883, 16, 2587; (b) Patel, M. V.; Bell, R.; Majest, S.; Henry, R.;
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16, 89.
9. Profeta, R.; Mattioli, M.; Micheli, F.; Piga, E.; Spada, S.; Andreotti, D. Synlett 2008,
2283.
(400 MHz, CDCl3)
d
: 1.28 (t, 3H, J¼7.74 Hz), 1.95 (s, 3H), 2.64 (q, 2H,
J¼7.72e15.34 Hz), 3.71 (s, 3H), 7.30 (m, 2H), 7.42 (m, 3H). 13C NMR
(100 MHz, CDCl3) d: 8.3 (CH3), 13.5 (CH3), 20.0 (CH2), 36.6 (CH3),
111.7 (C),128.0 (CH),128.5 (CH),129.6 (CH),130.8 (C),141.3 (C),151.7
(C). MS: (ESIþ, m/z): 201 (MþH)þ; 223 (MþNa)þ. HRMS (EI): calcd
for C13H16N2: 200.13135; found: 200.13144 (þ0.5 ppm).
10. Micheli, F.; Bonanomi, G.; Blaney, F. E.; Braggio, S.; Capelli, A. M.; Checchia, A.;
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MacDonald, G.; Smith, A.; Pecoraio, M.; Petrone, M.; Perini, O.; Piner, J.; Rossi,
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4.2.10. 4-Fluoro-1-methyl-3,5-diphenyl-1H-pyrazole (10c). The title
compound was obtained in quantitative yield (76 mg). 1H NMR
(400 MHz, CDCl3)
(100 MHz, CDCl3)
d
: 3.88 (s, 3H), 7.48 (m, 8H), 7.90 (d, 2H). 13C NMR
d
: 38.5 (CH3), 125.8 (CH), 127.3 (C), 127.7 (CH),
128.6 (CH), 128.9 (CH), 129.8 (C), 131.1 (C), 134.5 (C), 144.3 (C). 19F
NMR (376 MHz, CDCl3)
d
: ꢁ174.6. MS: (ESIþ, m/z): 253 (MþH)þ;
€
11. (a) Dang, T. T.; Dang, T. T.; Fischer, C.; Gorls, H.; Langer, P. Tetrahedron 2008, 64,
€
2207; (b) Turgut, Z.; Ocal, N. Russ. J. Org. Chem. 2002, 38, 602; (c) Stauffer, S. R.;
275 (MþNa)þ. HRMS (EI): calcd for C16H13FN2: 252.10628; found:
252.10633 (þ0.2 ppm).
Huang, Y.; Coletta, C. J.; Tedesco, R.; Katzenellenbogen, J. A. Bioorg. Med. Chem.
2001, 9, 141.
12. All hydrazones
2 and 8 were obtained by condensation of commercially
available 1-(tert-butyloxycarbonyl)-1-methylhydrazine and the corresponding
ketone.
4.2.11. 1,4-Dimethyl-3,5-diphenyl-1H-pyrazole (10d)20. The title
compound was obtained in quantitative yield as a yellowish solid
13. A general preparation of N-BOC-N-substituted hydrazones is reported: Meyer,
K. G. Synlett 2004, 2355 Some of these hydrazones were tested and gave very
similar results to those obtained with 1-BOC-1-methylhydrazones.
14. Most of the ketoimine products were isolated as the corresponding enami-
nones. See Supporting data for details.
(74 mg).1H NMR (400 MHz, CDCl3)
d
:2.15 (s, 3H), 3.87(s, 3H), 7.41 (m,
8H), 7.72 (m, 2H). 13C NMR (100 MHz, CDCl3)
d: 9.9 (CH3), 37.2 (CH3),
112.0 (C), 127.2 (CH), 127.6 (CH), 128.4 (CH), 128.4 (CH), 128.6 (CH),
129.8 (CH), 130.4 (C), 134.1 (C), 142.5 (C), 149.2 (C). Mp 110e11þ2 ꢀC
(lit.20 112.5e116 ꢀC). MS: (ESIþ, m/z): 249 (MþH)þ; 271 (MþNa) .
15. Holzer, W.; Claramunt, R. M.; Perez-Torralba, M.; Guggi, D.; Brehmer, T. H. J. Org.
Chem 2003, 68, 7943.
16. A variety of acylating agents, such as alkyl and aromatic acyl anhydrides,
chlorides and esters can be used for the acylation of hydrazones. See
Ref. 11.
17. Stavber, S.; Jereb, M.; Zupan, M. Chem. Commun. 2000, 1323.
18. Landge, S. M.; Schmidt, A.; Outerbridge, V.; Toeroek, B. Synlett 2007, 1600.
19. Nakhai, A.; Bergman, J. Tetrahedron 2009, 65, 2298.
Acknowledgements
Financial support for the Ph.D. of Alessandro Tinarelli was
granted by GlaxoSmithKline. This research activity was supported
20. Bramley, R. K.; Grigg, R.; Guilford, G.; Milner, P. Tetrahedron 1973, 29, 4159.