The application of vinylogous iminium salt derivatives to the regiocontrolled preparation of heterocyclic appended pyrazoles

Article abstract of DOI:10.1016/S0040-4020(02)00517-3

A variety of vinylogous iminium salt derivatives have been examined as useful precursors for the regiocontrolled synthesis of heterocyclic appended pyrazoles. The reaction conditions for such processes have been optimized and the regiochemical preferences have been determined. Such reaction sequences represent methodologies which may have useful applications for the preparation of biologically interesting substances.

Full text of DOI:10.1016/S0040-4020(02)00517-3

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 5467±5474
The application of vinylogous iminium salt derivatives to the
regiocontrolled preparation of heterocyclic appended pyrazoles
John T. Gupton,a,p Stuart C. Clough,a Robert B. Miller,a Bradley K. Norwood,a
Charles R. Hickenboth,a Itta Bluhn Chertudi,a Scott R. Cutro,a Scott A. Petrich,b Fred A. Hicks,b
Douglas R. Wilkinsonb and James A. Sikorskic
aDepartment of Chemistry, University of Richmond, Richmond, VA 23173, USA
bDepartment of Chemistry, University of Central Florida, Orlando, FL32816, USA
cAtheroGenics Inc., 8995 Westside Parkway, Alpharetta, GA 30004, USA
Received 18 February 2002; accepted 16 May 2002
AbstractÐA variety of vinylogous iminium salt derivatives have been examined as useful precursors for the regiocontrolled synthesis of
heterocyclic appended pyrazoles. The reaction conditions for such processes have been optimized and the regiochemical preferences have
been determined. Such reaction sequences represent methodologies which may have useful applications for the preparation of biologically
interesting substances. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
arthritis and related in¯ammatory diseases. Another signi®-
cant application of pyrazole chemistry has resulted from the
discovery3 that highly functionalized pyrazoles (such as
DPC 423 (2)) can act as orally, bioavailable inhibitors of
blood coagulation factor Xa. Because of the various side
effects associated with current anticoagulants, the identi®-
cation of orally active substances which require minimal
monitoring during treatment has been a priority for drug
discovery in this area. Other pyrazole containing com-
pounds have been found to be high-af®nity ligands4 for
the estrogen receptor and thereby show promise for meno-
pausal hormone replacement, fertility regulation and the
prevention and treatment of breast cancer.
Compounds which contain the pyrazole functionality
continue to attract great interest due to their varied and
signi®cant pharmacological effects. For example, the
identi®cation of new and selective cox-2 inhibitors,1 such
as celecoxib (1), for the relief of pain and the treatment of
the symptoms of arthritis and related diseases has been an
important advance in modern anti-in¯ammatory therapy
(Fig. 1). In a related area, heterocycle-appended pyrazoles
have been reported2 to be potent and selective inhibitors of
the mitogen-activated protein kinase p38 and consequently
provide a novel approach for the treatment of rheumatoid
Figure 1.
Keywords: pyrazoles; vinamidinium salts; chloropropeniminium salts; chlorovinyl aldehydes.
Corresponding author. Tel.: 11-804-287-6498; fax: 11-804-287-1897; e-mail: jgupton@richmond.edu
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00517-3

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J. T. Gupton et al. / Tetrahedron 58 (2002) 5467±5474
Scheme 1.
The standard approach to the synthesis of pyrazoles has
involved the reaction of hydrazine derivatives with 1,3-di-
carbonyl compounds. A recent example of such a reaction is
described by Nugiel and co-workers5 in their preparation of
indenopyrazoles which were examined as novel inhibitors
of cyclin dependent kinases. An alternative strategy is to
employ masked 1,3-dicarbonyl compounds such as
b-aminoenones as described by Gonzalez-Ortega and
co-workers6 and also by Dominguez et al.7 In fact
b-aminoenones (also known as vinylogous amides) have
been recently used by Spivey and co-workers8 in solid-
phase organic synthesis in order to construct a pyrazole
library. A related procedure, which uses halovinylaldehydes
for the construction of fused pyrazoles has been recently
reviewed.9 A somewhat different approach to pyrazole
synthesis developed by Katritzky and co-workers10 relies
on the reaction of hydrazines with a,b-unsaturated ketones,
which contain an a-benzotriazole group, such that an
addition±elimination sequence results in the desired
pyrazole.
Although b-aminoenones (vinylogous amides, (4)) have
been studied with regard to their conversion to pyrazoles,
chloropropeniminium salts (5) and unsymmetrical vinami-
dinium salts (6) have not been thoroughly studied14 with
regard to their ef®ciency or regiochemical outcome in the
preparation of pyrazoles. We have therefore examined a
variety of vinylogous iminium salt derivatives for their
ability to provide heterocyclic appended pyrazoles in an
ef®cient and regiocontrolled fashion. In order to establish
the feasibility of the methodology, we ®rst explored the
reaction of vinamidinium salt 6a with 4-methoxyphenyl-
hydrazine hydrochloride under conditions that had been
previously utilized13 for pyrrole formation (Scheme 2).
Puri®cation of the reaction mixture by radial chroma-
tography produced both the 1,5- and 1,3-pyrazole isomers,
compounds 7a and 8a, respectively, in a 9:1 ratio and in a
combined yield of 90%. The reaction was subsequently
repeated on the 2-thienyl vinamidinium salt (6b) in which
case an 87% combined yield of pyrazole isomers was
obtained after puri®cation. The ratio of isomers was again
9:1 with the 1,5-isomer predominating. The reaction was
repeated with several different arylhydrazines and the
results are reported in Table 1 (compounds a±d). In all
cases, the reactions produced high yields of the pyrazoles
with strong regiochemical preference (9:1) for the 1,5-iso-
mer versus the 1,3-isomer. The yields reported in Table 1
refer to the total yield for both isomers.
2. Results and discussion
We have previously reported11 the novel, ef®cient and regio-
controlled synthesis of highly functionalized pyrroles which
used vinylogous iminium salt derivatives as the key
synthons. It is also of interest to note that vinamidinium
salts, as a consequence of their synthetic utility, have
received signi®cant recent attention by Davies and co-work-
ers12 of the MerckProcess Group for the large scale prepa-
ration of pyridine-based cox-2 inhibitors. We would now
like to report our efforts in applying our pyrrole strategy
to the regioselective preparation of heterocyclic appended
pyrazoles. The vinylogous iminium salt derivatives that are
currently employed in our research program are prepared
according to the following general strategy13 (Scheme 1).
With puri®ed samples of compounds 7b and 8b in hand,
NMR NOE difference spectra were obtained on each
isomer. The NMR NOE studies on pyrazole 7b revealed
an interaction between the phenyl protons and thienyl
protons which establishes the close proximity of these
groups for the 1,5-isomer. No interactions could be
observed between either pyrazole hydrogen and the ortho
hydrogens of the phenyl group. For pyrazole 8b, NMR NOE
Scheme 2.

J. T. Gupton et al. / Tetrahedron 58 (2002) 5467±5474
Table 1. Reaction of vinamidinium salts with arylhydrazines
5469
Compound
R
Ar
% Yield
Isomer ratio of 7/8
a
b
c
d
e
f
4-MeOPh
2-Thienyl
2-Thienyl
2-Thienyl
3-Thienyl
2-Furyl
N-Methyl-2-pyrroyl
N-Methyl-2-pyrroyl
4-MeOPh
4-MeOPh
Ph
90
87
85
90
83
86
79
70
9/1
9/1
9/1
9/1
9/1
9/1
9/1
9/1
4-BrPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
g
h
interactions were observed between the appropriate
pyrazole hydrogens and the respective phenyl and
thienyl hydrogens thereby establishing the relative
relationships of the phenyl and thienyl groups as being 1,3
to each other. In addition, Habraken and co-workers15
have reported a consistent and useful trend in the chemical
shifts of pyrazole hydrogens as a function of the solvent
polarity.
8 exhibited a larger shift differential. It was also noted by
Habraken that the Hc proton always appears down®eld from
the Ha proton with both protons having consistently dif-
ferent (albeit small) coupling constants. With the regio-
chemical assignments established, various heterocycle
appended vinamidinium salts were prepared in the standard
manner and they were treated with 4-methoxyphenylhydra-
zine to yield the anticipated pyrazoles in good yield with a
9:1 preference for the 1,5 disubstituted system (Table 1,
compounds e±h). These analogs represent structurally
interesting biheterocyclic systems whereby thiophene,
furan and pyrrole rings are appended in a regiocontroled
fashion at either the 3 or 5 position of the pyrazole ring
system. A summary of proton NMR chemical shifts and
accompanying coupling constants of the pyrazole hydro-
gens for the analogs prepared are listed in Table 2. The
proton chemical shifts and coupling constants (pyrazole
hydrogens) for the analogs listed follow the pattern
described by Habraken for 1,5- and 1,3-disubstituted
pyrazoles thereby con®rming the NOE based structure
assignments.
The proton NMR chemical shifts for pyrazoles 7 and 8, as
a function of solvent, behaved similarly to pyrazole 9,
reported by Habraken et al., with the exception that the
chemical shift of the corresponding Hc proton for pyrazole
Table 2. Summary of chemical shifts and coupling constants for pyrazole
hydrogens for the 1,5- and 1,3-isomers
It has already been mentioned that chloropropeniminium
salts (5) also function as useful three carbon synthons for
the preparation of heterocyclic compounds. Such substances
have received attention14 for the preparation of pyrazoles
but have not been examined carefully with regard to regio-
chemical control features and to applications for the
synthesis of biheterocyclic systems. Consequently, chloro-
propeniminium salt 5b was treated with 4-bromophenyl-
hydrazine under a somewhat milder set of reaction
conditions involving triethylamine/acetonitrile at room
temperature. A hydrazone intermediate of the vinamidinium
salt was produced as a single regioisomer and this was
cyclized to the 1,5-disubstituted pyrazole in a second step
with sodium hydride/DMF (Scheme 3). No evidence of any
1,3-pyrazole isomer could be detected in the crude reaction
product.
Compound
Y
Ar
Ha (ppm)a Hb (ppm)a Jab (Hz)
9 (Lit. value)
H
5-Pyrazolyl 7.82
6.46
6.55
6.73
6.73
6.74
6.67
6.72
6.57
6.6
1.7
1.6
1.9
1.8
1.8
1.8
1.9
1.6
1.7
7a
7b
7c
7d
7e
7f
4-MeOPh 4-MeOPh
2-Thienyl 4-MeOPh
2-Thienyl Ph
2-Thienyl 4-BrPh
3-Thienyl 4-MeOPh
2-Furyl
2-Pyrrolyl 4-MeOPh
3-Pyrrolyl 4-MeOPh
7.69
7.68
7.74
7.77
7.67
7.71
7.74
7.54
4-MeOPh
7g
7h
Hc (ppm)a
Jbc (Hz)
9 (Lit. value)
H
5-Pyrazolyl 8.22
6.46
6.91
6.9
6.96
6.99
6.88
6.79
7
2.4
2.2
2.4
2.4
2.4
2.5
2.4
±
8a
8b
8c
8d
8e
8f
4-MeOPh 4-MeOPh
2-Thienyl 4-MeOPh
2-Thienyl Ph
2-Thienyl 4-BrPh
3-Thienyl 4-MeOPh
8.42
8.42
8.57
8.61
8.42
8.46
8.39
A variety of reaction conditions were also studied in order to
optimize the formation of the 1,3-disubstituted pyrazole
isomer versus the 1,5-isomer. As part of this process,
chloropropeniminium salts (such as 5b) were examined as
2-Furyl 4-MeOPh
2-Pyrrolyl 4-MeOPh
8g
a
DMSO-d6 was used as the solvent.

5470
J. T. Gupton et al. / Tetrahedron 58 (2002) 5467±5474
Scheme 3.
possible precursors. The most useful results are represented
in Scheme 4 which suggest that the relative amount of the
1,3-isomer can be increased signi®cantly by running the
reaction in the absence of base.
a somewhat similar fashion, we decided to examine both
substrates in greater detail.
Conditions which were employed utilized acetonitrile as the
solvent and involved varying the amounts of arylhydrazine
and base (DABCO) used in the pyrazole formation. Aceto-
nitrile was chosen for this study since it had been the most
effective solvent for the earlier reactions. These trials are
listed in Table 3 and there are several trends which stand
out.
Interestingly, if the arylhydrazine and the chloropropeni-
minium salt are re¯uxed in glacial acetic acid, the
1,5-isomer is produced as the only product (Scheme 5).
The nature of the controlling mechanistic features of this
set of reaction conditions is not clear.
Since chloropropeniminium salts are easily hydrolyzed to
the corresponding chlorovinylaldehydes (e.g. 11), we have
also examined these substances as precursors to disubsti-
tuted pyrazoles. The initial results (Scheme 6) established
the feasibility for this process and since the chloropropeni-
minium salts and the chlorovinylaldehydes should behave in
Pyrazole formation is relatively clean and ef®cient for
both chloropropeniminium salt and chlorovinylaldehyde
substrates when reactions are conducted in the absence of
base (DABCO). If the stoichiometry of the hydrazine is
increased by 2:1 relative to the substrate, the yield of
pyrazole from the chloropropeniminium salt is improved
Scheme 4.
Scheme 5.

J. T. Gupton et al. / Tetrahedron 58 (2002) 5467±5474
5471
Scheme 6.
but this is not the case for the chlorovinylaldehyde. When
the amount of hydrazine is increased17 relative to the
substrate, the pyrazole isomer ratio does not appear to
change. The amount of the major isomer tends to increase
when the chlorovinylaldehyde is used as the starting
material. In an overall sense, both the chloropropeniminium
salt and the chlorovinylaldehyde serve as useful and
ef®cient precursors to the 1,5-disubstituted pyrazoles.
absence of base. Vinamidinium salts, chloropropeniminium
salts and chlorovinylaldehydes can be conveniently and
ef®ciently prepared from a variety of readily available
ketones and they serve as chemo-differentiated three carbon
building blocks with predictable regiochemical selectivity.
Consequently, this synthetic method should provide ready
access to structurally and biologically interesting bihetero-
cyclic substances and complement the existing, available
procedures for the regioselective preparation of highly
functionalized pyrazoles.
3. Conclusions
In summary, we have demonstrated that vinamidinium salts,
chloropropeniminium salts and chlorovinylaldehydes can
be effectively used for the regioselective preparation of
heterocyclic appended 1,5-disubstituted pyrazoles. The
1,5-isomer has been found to predominate in most cases
and can be exclusively formed by running the reaction in
acetic acid or by using a stepwise process where the inter-
mediate hydrazone is obtained and subsequently cyclized.
The amount of the 1,3-isomer can be increased by carrying
out such reactions in acetonitrile under re¯ux and in the
4. Experimental
4.1. General
The following procedures are typical of the experimental
conditions used for the preparation of pyrazoles. All
chemicals were used as received from the manufacturer
(Aldrich Chemicals and Fisher Scienti®c) and all reactions
were carried out under a nitrogen atmosphere. NMR spectra
were obtained on a Varian Gemini 2000 spectrometer in
Table 3. Reaction of chloropropeniminium salts and chlorovinylaldehydes with 4-methoxyphenylhydrazine
Substratea (equiv.)
Hydrazine (equiv.)
DABCO (equiv.)
% Yield of pyrazoleb
Isomer ratio of 7a/8ac
5a (1)
5a (1)
5a (1)
5a (1)
11a (1)
11a (1)
11a (1)
11a (1)
(1)
(1)
(2)
(2)
(1)
(1)
(2)
(2)
(0)
(1)
(0)
(2)
(0)
(1)
(0)
(2)
69
Trace
95
Trace
68
Trace
53
Trace
2/1
±
2/1
±
12/1
±
12/1
±
a
All reactions were run in re¯uxing acetonitrile for approximately 14 h.
The yield of total pyrazole was determined by gas chromatography.
The ratio of pyrazole regioisomers was determined by 1H NMR integration.
b
c

5472
J. T. Gupton et al. / Tetrahedron 58 (2002) 5467±5474
either CDCl3 or d6-DMSO solutions. IR spectra were
recorded on a Perkin±Elmer 1420 spectrometer as either
nujol mulls or KBr pellets. High resolution mass spectra
were provided by the Midwest Center for Mass Spectro-
metry at the University of Nebraska at Lincoln. Melting
points and boiling points are uncorrected. Radial chromato-
graphic separations were carried out on a Harrison
Chromatotron using silica gel plates of 2 mm thickness
with a ¯uoresecent backing. The vinylogous iminium salt
derivatives were prepared by standard methods.16 All
puri®ed compounds gave a single spot upon tlc analysis
on silica gel 7GF using an ethyl acetate/hexane mixture as
eluent. All chromatographed compounds gave 13C NMR
spectra indicative of compounds greater than 95% pure.
Gas chromatographic analyses were carried out on a
Shimadzu QP5050A GC±MS system equipped with a
Restek30 m, XTI-5 capillary column.
56.9, 57.1, 108.6, 115.8, 115.9, 124.2, 128.5, 131.5, 134.9,
141.4, 144.0, 160.1, and 160.8; FTIR (KBr pellet) 1516,
1252 and 831 cm21
; HRMS calcd for C17H16N2O2
280.1212 found 280.1213. The 1,3-isomer (8a) exhibited
the following properties: mp 190±1918C; 1H NMR
(DMSO-d6) d 3.81 (s, 6H), 6.91 (d, Jˆ2.2 Hz, 1H), 7.01
(d, Jˆ9.0 Hz, 2H), 7.07 (d, Jˆ9.0 Hz, 2H), 7.83 (t, Jˆ
9.0 Hz, 4H), and 8.42 (d, Jˆ2.2 Hz, 1H); 13C NMR
(DMSO-d6) d 56.9, 57.2, 106.2, 115.9, 116.3, 121.5,
127.3, 128.5, 130.7, 135.2, 153.1, 159.2, and 160.9; FTIR
(KBr pellet) 1518 and 1248 cm21; HRMS calcd for
C17H16N2O2 280.1212 found 280.1216.
4.1.3. 1-Phenyl-5-(2-thienyl)pyrazole (7c). This compound
was prepared in 85% yield as a 90:10 mixture of isomers and
the 1,5-isomer (7c) exhibited the following properties: bp
868C at 0.05 torr; 1H NMR (DMSO-d6) d 6.73 (d, Jˆ
1.8 Hz, 1H), 6.90±7.10 (m, 2H), 7.30±7.60 (m, 6H), and
7.74 (d, Jˆ1.8 Hz, 1H); 13C NMR (DMSO-d6) d 109.3, 128.0,
129.3, 129.4, 130.4, 131.0, 132.3, 138.3, 141.2, and 141.9;
4.1.1. 1-(4-Methoxyphenyl)-5-(2-thienyl)pyrazole (7b). A
100 mL three-neckround-bottom ¯askwas equipped with a
stir bar, condenser, and placed under a nitrogen atmosphere.
Into the ¯askwas placed 0.226 g (5.6 mmol) of a 60%
mineral oil dispersion of sodium hydride. The dispersion
was washed twice with hexane, and the hexane was
removed via cannula. Dry DMF (10 mL) was added to the
¯askfollowed by 0.74 g (4.2 mmol) of arylhydrazine. This
solution was allowed to stir for 5 min. Finally, 1.00 g
(2.8 mmol) of vinamidinium salt (6b) was added along
with 30 mL of dry DMF. The reaction was stirred overnight
at 1008C and cooled to room temperature. The solvent was
removed in vacuo and the residue was partitioned several
times between water and chloroform. The combined chloro-
form extracts were dried and concentrated. The crude
product was passed through a short plug of silica gel and
puri®ed by radial chromatography using a gradient elution
with hexane and ethyl acetate. A 90:10 mixture of 1,5-pyra-
zole (7b)/1,3-pyrazole (8b) was obtained in 87% yield
(0.65 g). These isomers were easily separated by a second
treatment of radial chromatography. The major isomer,
1,5-pyrazole (7b), exhibited the following properties: mp
FTIR (CCl4) 1598, 1501, 1390, 927, 764, and 695 cm21
HRMS calcd for C13H10N2S 226.0565 found 226.0563.
;
4.1.4. 1-(4-Bromophenyl)-5-(2-thienyl)pyrazole (7d).
This compound was prepared in 90% yield as a 90:10
mixture of isomers and the 1,5-isomer (7d) exhibited the
1
following properties: mp 85±878C; H NMR (CDCl3) d
6.55 (d, Jˆ1.8 Hz, 1H), 6.83 (d, Jˆ3.6 Hz, 1H), 6.98 (d
of d, Jˆ3.6, 5.0 Hz, 1H), 7.26 (d, Jˆ8.8 Hz, 2H), 7.31 (d,
Jˆ5.0 Hz, 1H), 7.52 (d, Jˆ8.8 Hz, 2H), and 7.69 (d, Jˆ
1.8 Hz, 1H); 13C NMR (CDCl3) d 110.4, 123.9, 128.9,
129.3, 129.5, 132.9, 134.1, 138.7, 140.6, and 142.6; FTIR
(CCl4) 1492, 926, 829 and 704 cm21; HRMS calcd for
C13H9N2SBr 303.9670 found 303.9665.
4.1.5. 1-(4-Methoxyphenyl)-5-(3-thienyl)pyrazole (7e).
This compound was prepared in 83% yield as a 90:10
mixture of isomers and the 1,5-isomer (7e) exhibited the
1
following properties: mp 88±908C; H NMR (DMSO-d6)
d 3.82 (s, 3H), 6.67 (d, Jˆ1.8 Hz, 1H), 6.92 (d of d,
Jˆ1.3, 5.0 Hz, 1H), 7.02 (d, Jˆ8.8 Hz, 2H), 7.26 (d, Jˆ
8.8 Hz, 2H), 7.31 (d of d, Jˆ1.3, 3.0 Hz, 1H), 7.55 (d of
d, Jˆ3.0, 5.0 Hz, 1H), and 7.67 (d, Jˆ1.8 Hz, 1H); 13C
NMR (DMSO-d6) d 57.2, 108.5, 116.0, 125.6, 128.5,
129.0, 129.1, 132.1, 134.8, 140.0, 141.3, and 160.6; FTIR
(KBr pellet) 1515, 1250, 840, 805, and 775 cm21; HRMS
calcd for C14H12N2SO 256.0670 found 256.0673.
1
110±1128C; H NMR (DMSO-d6) d 3.83 (s, 3H), 6.73 (d,
Jˆ1.9 Hz, 1H), 7.00±7.10 (m, 4H), 7.30 (d, Jˆ8.9 Hz, 2H),
7.55 (d of d, Jˆ1.8, 4.6 Hz, 1H), and 7.69 (d, Jˆ1.9 Hz,
1H); 13C NMR (DMSO-d6) d 57.2, 108.5, 116.1, 129.0,
129.2, 129.3, 129.8, 132.5, 134.2, 138.6, 141.5, and 161.1;
FTIR (KBr pellet) 1515, 1251, 834 and 720 cm21; HRMS
calcd for C14H12N2SO 256.0670 found 256.0678. The minor
isomer, 1,3-pyrazole (8b), exhibited the following proper-
ties: mp 73±748C; 1H NMR (DMSO-d6) d 3.82 (s, 3H), 6.90
(d, Jˆ2.4 Hz, 1H), 7.00±7.20 (m, 3H), 7.50±7.53 (m, 2H),
7.77 (d, Jˆ9.0 Hz, 2H), and 8.45 (d, Jˆ2.4 Hz, 1H); 13C
NMR (DMSO-d6) d 57.2, 106.6, 116.4, 121.6, 126.4, 127.2,
129.5, 131.0, 134.9, 137.7, 148.9, and 159.4; FTIR (KBr
pellet) 1520 and 1254 cm21; HRMS calcd for C14H12N2SO
256.0670 found 256.0676.
4.1.6. 1-(4-Methoxyphenyl)-5-(2-furyl)pyrazole (7f). This
compound was prepared in 86% yield as a 90:10 mixture of
isomers and the 1,5-isomer (7f) exhibited the following
1
properties: bp 1018C at 0.05 torr; H NMR (DMSO-d6) d
3.83 (s, 3H), 6.01 (d, Jˆ2.9 Hz, 1H), 6.49 (d of d, Jˆ1.8,
2.9 Hz, 1H), 6.72 (d, Jˆ1.9 Hz, 1H), 7.07 (d, Jˆ9.0 Hz,
2H), 7.33 (d, Jˆ9.0 Hz, 2H), and 7.71 (m, 2H); 13C NMR
(DMSO-d6) d 57.2, 107.4, 110.5, 113.4, 116.0, 129.0, 134.6,
135.7, 141.6, 145.2, 145.6, and 161.0; FTIR (CCl4) 1517,
1251 and 836 cm21; HRMS calcd for C14H12N2O2 240.0899
found 240.0913.
4.1.2. 1,5-Bis(4-methoxyphenyl)pyrazole (7a). This com-
pound was prepared in 90% yield as a 90:10 mixture of
isomers and the 1,5-isomer (7a) exhibited the following
1
properties: mp 104±1068C; H NMR (DMSO-d6) d 3.74
(s, 3H), 3.77 (s, 3H), 6.55 (d, Jˆ1.6 Hz, 1H), 6.90 (d,
Jˆ8.9 Hz, 2H), 6.96 (d, Jˆ8.9 Hz, 2H), 7.17 (t, Jˆ8.9 Hz,
4H), and 7.68 (d, Jˆ1.6 Hz, 1H); 13C NMR (DMSO-d6) d
4.1.7. 1-(4-Methoxyphenyl)-5-(2-N-methylpyrrolyl)pyra-
zole (7g). This compound was prepared in 79% yield as a
90:10 mixture of isomers and the 1,5-isomer (7g) exhibited

J. T. Gupton et al. / Tetrahedron 58 (2002) 5467±5474
5473
the following properties: bp 908C at 0.1 torr; 1H NMR
(DMSO-d6) d 3.31 (s, 3H), 3.77 (s, 3H), 5.92 (m, 1H),
6.02 (m, 1H), 6.57 (d, Jˆ1.6 Hz, 1H), 6.85 (m, 1H), 6.94
(d, Jˆ8.9 Hz, 2H), 7.16 (d, Jˆ8.9 Hz, 2H), and 7.74 (d,
Jˆ1.6 Hz, 1H); 13C NMR (DMSO-d6) d 35.9, 57.1, 109.4,
110.6, 112.8, 115.8, 123.4, 125.8, 127.1, 135.0, 136.1,
141.3, and 159.9; FTIR (CCl4) 1515, 1249, 835 and
722 cm21; HRMS calcd for C15H15N3O 253.1215 found
253.1208.
elution with hexane and ethyl acetate. Pyrazole 6c was the
only isomer obtained in 92% yield (0.39 g). This product
was characterized by tlc and proton NMR spectra and
compared to an authentic sample.
4.3. Preparation of pyrazole (7d) under acidic conditions
A 100 mL one-neckround-bottom ¯askwas equipped with
a condenser and stir bar. Into the ¯askwere placed 1.00 g
(2.8 mmol) of chloropropeniminium salt (5d), 1.25 g (5.6
mmol) of arylhydrazine, and 40 mL of acetic acid. The
reaction was heated at re¯ux overnight. The reaction was
cooled, neutralized with sodium bicarbonate, and par-
titioned several times between water and chloroform. The
combined chloroform extracts were dried and concentrated.
The residue was passed through a short plug of silica gel and
puri®ed by radial chromatography using a gradient elution
with hexane and ethyl acetate. Pyrazole 6c was the only
isomer obtained in 88% yield (0.74 g). This product was
characterized by tlc and proton NMR spectra and compared
to an authentic sample.
4.1.8.
1-(4-Methoxyphenyl)-5-(3-N-methylpyrrolyl)-
pyrazole (7h). This compound was prepared in 70% yield
as a 90:10 mixture of isomers and the 1,5-isomer (7h) exhib-
ited the following properties: mp 94±968C; 1H NMR
(DMSO-d6) d 3.60 (s, 3H), 3.82 (s, 3H), 5.73 (m, 1H),
6.40 (d, Jˆ1.7 Hz, 1H), 6.60 (m, 1H), 6.64 (m, 1H), 7.02
(d, Jˆ9.0 Hz, 2H), 7.28 (d, Jˆ9.0 Hz, 2H), and 7.54 (d,
Jˆ1.7 Hz, 1H); 13C NMR (DMSO-d6) d 37.6, 57.2, 105.8,
109.2, 114.4, 115.8, 122.2, 124.2, 129.3, 135.4, 140.8,
141.1, and 160.5; FTIR (CCl4) 1514, 1260, 830 and
781 cm21; HRMS calcd for C15H15N3O 253.1215 found
253.1212.
4.4. Preparation of pyrazoles (7d) and (8d) under neutral
conditions
4.1.9. 1-(4-Bromophenyl)-5-chloro-5-(2-thienyl)-1,2-di-
azapenta-2,4-diene (10d). To a 100 mL one-neckround-
bottom ¯askwere added 1.00 g (2.8 mmol) of chloropro-
peniminium salt (5b), 0.63 g (2.8 mmol) of arylhydrazine,
0.28 g (2.8 mmol) of triethylamine, 40 mL of dry aceto-
nitrile, and a stir bar. The solution was stirred for 1 h at
room temperature. The solvent was removed in vacuo and
the residue was partitioned several times between water and
chloroform. The combined chloroform extracts were dried
and concentrated. The crude product was passed through a
short plug of silica gel and puri®ed by radial chromato-
graphy using a gradient elution with hexane and ethyl
acetate. An 83% yield (0.79 g) of a yellow solid was
obtained and exhibited the following properties: mp 120±
1228C; 1H NMR (DMSO-d6) d 6.97 (d, Jˆ8.9 Hz, 2H), 7.04
(d, Jˆ8.9 Hz, 1H), 7.13 (d of d, Jˆ5.0, 3.7 Hz, 1H), 7.39 (d,
Jˆ8.9 Hz, 2H), 7.52 (d, Jˆ3.7 Hz, 1H), 7.65 (d, Jˆ5.0 Hz,
1H), 7.94 (d, Jˆ8.9 Hz, 1H), and 10.91 (s, 1H); 13C NMR
(DMSO-d6) d 112.3, 116.0, 123.1, 127.0, 127.8, 129.5,
130.3, 133.6, 137.2, 142.9, and 145.3; FTIR (KBr pellet)
3310, 1474 and 826 cm21; HRMS calcd for C13H10N2SBrCl
339.9437 found 339.9434.
A 100 mL one-neckround-bottom ¯askwas equipped with
a condenser and stir bar. Into the ¯askwere placed 1.00 g
(2.8 mmol) of chloropropeniminium salt (5d), 0.63 g
(2.8 mmol) of arylhydrazine, and 40 mL of dry acetonitrile.
The reaction was stirred at room temperature for 2 h
followed by heating at re¯ux overnight. The reaction was
cooled and partitioned several times between water and
chloroform. The combined chloroform extracts were dried
and concentrated. The residue was passed through a short
plug of silica gel and puri®ed by radial chromatography
using a gradient elution with hexane and ethyl acetate. A
3:2 ratio of pyrazole 7d: pyrazole 8d was obtained in 80%
yield (0.68 g). The isomers were separated by a second
treatment of radial chromatography. These products were
characterized by tlc and proton NMR spectra and compared
to an authentic sample.
4.5. Preparation of 1,5-bis(4-methoxyphenyl)pyrazole
(7a) from the b-chlorovinylaldehyde (11)
b-Chlorovinylaldehyde (11) (0.60 g, 3.0 mmol) was placed
in a round bottom ¯askequipped with a condensor and stir
bar followed by 4-methoxyphenylhydrazine hydrochloride
(1.54 g, 15.2 mmol) and dioxane (100 mL). The mixture
was stirred for 2.5 h at room temperature and then heated
at re¯ux for 15 h. The solvent was removed in vacuo and the
residue was partitioned between chloroform (35 mL) and
water (35 mL). The aqueous phase was extracted with
additional chloroform (3£35 mL) and the combined chloro-
form extracts were dried over anhydrous magnesium
sulfate, ®ltered and concentrated in vacuo to yield a dark,
viscous oil. This oil was placed in a round bottom ¯ask
equipped with a re¯ux condensor and stir bar and 50 mL
of DMF were added. The resulting mixture was re¯uxed for
15 h and concentrated in vacuo. The resulting residue was
subjected to the usual chloroform/water workup and subse-
quent puri®cation by radial chromatography. A 42% yield
(0.35 g) of the bis(4-methoxyphenyl)pyrazole (7a) was
4.2. Preparation of pyrazole (7d) using hydrazone (10d)
as starting material
A 50 mL three-neckround-bottom ¯askwas equipped with
a stir bar, condenser and placed under nitrogen. Into the
¯askwas placed 0.112 g (2.8 mmol) of a 60% mineral oil
dispersion of sodium hydride. The dispersion was washed
twice with dry hexane, and the hexane was removed via
cannula. Dry DMF (10 mL) was added to the ¯askfollowed
by 0.50 g (1.4 mmol) of hydrazone (10d) which had been
dissolved in 10 mL of DMF. The solution was heated at
1008C overnight. The reaction was cooled to room tempera-
ture and the solvent was removed in vacuo. The residue was
partitioned several times between water and chloroform.
The combined chloroform extracts were dried and concen-
trated. The residue was passed through a short plug of silica
gel and puri®ed by radial chromatography using a gradient

5474
J. T. Gupton et al. / Tetrahedron 58 (2002) 5467±5474
K.; Sun, J.; Katzenellenbogen, B.; Katzenellenbogen, J.
J. Med. Chem. 2000, 43, 4934.
obtained which was identical by proton NMR spectra and tlc
analysis to a sample prepared via the vinamidinium salt
method.
5. Nugiel, D.; Etzkorn, A.; Vidwans, A.; Ben®eld, P.; Boisclair,
M.; Burton, C.; Cox, S.; Czerniak, P.; Doleniak, D.; Seitz, S.
J. Med. Chem. 2001, 44, 1334.
6. Alberola, A.; Bleye, L.; Gonzalez-Ortega, A.; Sadaba, L.;
Sanudo, C. Heterocycles 2001, 55, 331.
Acknowledgements
7. Olivera, R.; SanMartin, R.; Dominguez, E. J. Org. Chem.
2000, 65, 7010.
We thankthe National Institutes of Health (grant no.
R15-CA67236-02), the Jeffress Memorial Trust and the
American Chemical Society's Petroleum Research Fund
for support of this research. We gratefully acknowledge
the Camille and Henry Dreyfus Foundation for a Scholar/
Fellow Award to John T. Gupton. In addition, we would also
like to thank the Midwest Center for Mass Spectrometry at
the University of Nebraska-Lincoln for providing high
resolution mass spectral analysis on the compounds reported
in this paper.
8. Spivey, A.; Diaper, C.; Adams, H. J. Org. Chem. 2000, 65,
5253.
9. Sekhar, B.; Ramadas, S.; Ramana, D. Heterocycles 2000, 53,
941.
10. Katritzky, A.; Wang, M.; Zhang, S.; Voronkov, M. J. Org.
Chem. 2001, 66, 6787.
11. Gupton, J.; Krumpe, K.; Burnham, B.; Webb, T.; Shuford, J.;
Sikorski, J. Tetrahedron 1999, 55, 14515 and references
therein.
12. Davies, W.; Marcoux, J.; Corley, E.; Journet, M.; Cai, D.;
Palucki, M.; Wu, J.; Larsen, R.; Rossen, K.; Pye, P.;
DiMichele, L.; Dormer, P.; Reider, P. J. Org. Chem. 2000,
65, 8415. Davies, W.; Marcoux, J.; Wu, J.; Hughes, D.;
Dormer, P.; Reider, P. J. Org. Chem. 2001, 66, 4194.
13. Gupton, J.; Keertikar, K.; Krumpe, K.; Burnham, B.; Dwornik,
K.; Petrich, S.; Du, K.; Bruce, M.; Vu, P.; Vargas, M.; Hosein,
K.; Sikorski, J. Tetrahedron 1998, 54, 5075.
References
1. Penning, T.; Talley, J.; Bertenshaw, S.; Carter, J.; Collins, P.;
Docter, S.; Graneto, M.; Lee, L.; Malecha, J.; Miyashiro, J.;
Rogers, R.; Rogier, D.; Yu, S.; Anderson, G.; Burton, E.;
Cogburn, N.; Gregory, S.; Koboldt, C.; Perkins, S.; Seibert,
K.; Veenhuizen, A.; Zhang, Y.; Isakson, P. J. Med. Chem.
1997, 40, 1347.
14. For review articles see: Liebscher, J.; Hartmann, H. Synthesis
1979, 241; and also Lloyd, D.; McNabb, H. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 459.
2. Dumas, J.; Hatoun-Mokad, H.; Sibley, R.; Riedl, B.; Scott,
W.; Monahan, M.; Lowinger, T.; Brennan, C.; Natero, R.;
Turner, T.; Johnson, J.; Schoenleber, R.; Bhargava, A.;
Wilhelm, S.; Housley, T.; Ranges, G.; Shrikhande, A. Biorg.
Med. Chem. Lett. 2000, 10, 2051.
15. Cohen-Fernandes, P.; Erkelens, C.; van Endenberg, C.;
Verhoeven, J.; Habraken, C. J. Org. Chem. 1979, 44, 4156.
16. Gupton, J.; Petrich, S.; Bruce, M.; Hicks, F.; Wilkinson, D.;
Vargas, M.; Hosein, K.; Sikorski, J. Heterocycles 1998, 47,
689.
3. Pinto, D.; Orwat, M.; Wang, S.; Fevig, J.; Quan, M.; Amparo,
E.; Cacciola, J.; Rossi, K.; Alexander, R.; Smallwood, A.;
Luettgen, J.; Liang, L.; Aungst, B.; Wright, M.; Knabb, R.;
Wong, P.; Wexler, R.; Lam, P. J. Med. Chem. 2001, 44, 566.
4. Stauffer, S.; Coletta, C.; Tedesco, R.; Nishiguichi, G.; Carlson,
17. We thankone of the referees for suggesting some of the
experiments described in Table 3.