Regioselective synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles from N-arylhydrazones and nitroolefins

Article abstract of DOI:10.1021/jo7026195

(Chemical Equation Presented) Two general protocols are developed for the regioselective synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles by the reaction of electron-deficient N-arylhydrazones with nitroolefins. Studies on the stereochemistr

Full text of DOI:10.1021/jo7026195

the Knorr reaction suffers one major drawback, i.e., the lack of
regiospecificity (Scheme 1, path a).8 Modifications of this
method by replacing the 1,3-diketones with acetylenic or olefinic
ketones usually allow better control of the regioselectivity.9
Nevertheless, in the cases that Ar2 and Ar3 are similarly
substituted with only minor differences both electronically and
sterically, the complete control of regioselectivity becomes a
daunting task. Meanwhile, 1,3-dipolar cycloaddition reactions
have long been utilized in the syntheses of heterocyclic
compounds including pyrazoles, usually regioselectively.10
Sporadic examples are found in the literature that describe the
reaction of N-monosubstituted hydrazones and nitroolefins
affording pyrazole or pyrazolidine products (path b), presumably
proceeding through the 1,3-dipolar azomethine imine intermedi-
ates generated in situ from hydrazones.11 Compared to Knorr
pyrazole synthesis where regioselectivity relies on differentiating
the reactivity of the two carbonyl groups, path b is intrinsically
more regiospecific because of the significant electronegativity
difference of the N and the C atoms of the hydrazone.
Regioselective Synthesis of 1,3,5-Tri- and
1,3,4,5-Tetrasubstituted Pyrazoles from
N-Arylhydrazones and Nitroolefins
Xiaohu Deng* and Neelakandha S. Mani
Johnson & Johnson Pharmaceutical Research & DeVelopment,
L.L.C., 3210 Merryfield Row, San Diego, California 92121
xdeng@prdus.jnj.com
ReceiVed December 7, 2007
Recently, we have shown that indeed excellent regioselectivity
can be achieved on the reaction of N-monosubstituted hydra-
zones with various nitroolefins in MeOH at room temperature
under air atmosphere.12 Good yields of pyrazole products were
usually obtained with electron-rich hydrazones such as N-
alkylhydrazones. However, even at reflux temperature, electron-
deficient N-arylhydrazones gave low yields of N-arylpyrazole
products that are of most interest to the pharmaceutical
industry.1-5 Hence, there was a clear need of improved reaction
conditions suitable for electron-deficient hydrazones. Herein,
we report two complementary general protocols, one neutral
and the other acidic, for the syntheses of a wide range of 1,3,5-
tri- and 1,3,4,5-tetrasubstituted pyrazoles. The ready availability
of N-arylhydrazones and nitroolefins makes this method par-
ticularly appealing for the library synthesis of the pharmaceuti-
cally relevant pyrazole compounds for drug discovery efforts.
A revised, stepwise mechanism is also proposed based on the
new stereochemistry evidence of the key pyrazolidine interme-
diates.
Two general protocols are developed for the regioselective
synthesis of 1,3,5-tri- and 1,3,4,5-tetrasubstituted pyrazoles
by the reaction of electron-deficient N-arylhydrazones with
nitroolefins. Studies on the stereochemistry of the key
pyrazolidine intermediate suggest a stepwise cycloaddition
mechanism.
Substituted pyrazoles are an important class of compounds
in the pharmaceutical industry.1 Particularly interesting to
medicinal chemists are the 1,3,5-tri- and 1,3,4,5-tetrasubstituted
pyrazoles, which constitute the core structures of commercial
drugs such as Celebrex, Viagra, and Acomplia, as well as
numerous developmental compounds across a wide spectrum
of therapeutic areas such as anti-inflammatory,2 analgesic,3
antibacterial,4 and anti-cancer.5 1,3,5-Triarylpyrazoles have also
been employed as novel ligands in transition-metal-catalyzed
cross-coupling reactions.6 Accordingly, pyrazole synthesis has
long been the subject of interest, which goes back to the 19th
century when Knorr prepared 1,3,5-trisubstituted pyrazoles via
condensation of hydrazines with 1,3-diketones.7 Since then, the
Knorr pyrazole synthesis has been adapted as the standard
method because of its convenience and versatility. However,
(8) (a) Silva, V. L. M.; Silva, A. M. S.; Pinto, D. C. G. A.; Cavaleiro,
J. A. S.; Elguero, J. Eur. J. Org. Chem. 2004, 4348-4356. (b) Heller, S.
T.; Natarajan, S. R. Org. Lett. 2006, 8, 2675-2678.
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2836. (b) Wang, X.-J.; Tan, J.; Grozinger, K. Tetrahedron Lett. 2000, 41,
4713-4716. (c) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V.;
Steel, P. J. J. Org. Chem. 2001, 66, 6787-6791. (d) Bishop, B. C.; Brands,
K. M. J.; Gibb, A. D.; Kennedy, D. J. Synthesis 2004, 43-52. (e) Singh, S.
K.; Reddy, M. S.; Shivaramakrishna, S.; Kavitha, D.; Vasudev, R.; Babu,
J. M.; Sivalakshmidevi, A.; Rao, Y. K. Tetrahedron Lett. 2004, 45, 7679-
7682. (f) Peruncheralathan, S.; Yadav, A. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2005, 70, 9644-9647. (g) Gosselin, F.; O’Shea, P. D.; Webster, R.
A.; Reamer, R. A.; Tillyer, R. D.; Grabowski, E. J. J. Synlett 2006, 19,
3267-3270.
(1) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Targets
Heterocycl. Syst. 2002, 6, 52-98.
(2) (a) Sui, Z.; Guan, J.; Ferro, M. P.; McCoy, K.; Wachter, M. P.;
Murray, W. V.; Singer, M.; Steber, M.; Ritchie, D. M.; Argentieri, D. C.
Bioorg. Med. Chem. Lett. 2000, 10, 601-604. (b) Bekhit, A. A.; Abdel-
Aziem, T. Bioorg. Med. Chem. 2004, 12, 1935-1945. (c) Selvam, C.;
Jachak, S. M.; Thilagavathi, R.; Chakraborti, A. K. Bioorg. Med. Chem.
Lett. 2005, 15, 1793-1797.
(3) Katoch-Rouse, R.; Pavlova, L. A.; Caulder, T.; Hoffman, A. F.;
Mukhin, A. G.; Horti, A. G. J. Med. Chem. 2003, 46, 642-645.
(4) Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.;
Ueda, T.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.; Yamagishi,
J.-I. Bioorg. Med. Chem. 2004, 12, 5515-5524.
(10) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565-632.
(b) Padwa, A., Pearson, W. H., Eds. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural Products; John
Wiley & Sons: New York, 2002.
(5) (a) Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson,
K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem.
2000, 43, 4934-4947. (b) Stauffer, S. R.; Huang, Y.; Coletta, C. J.; Tedesco,
R.; Katzenellenbogen, J. A. Bioorg. Med. Chem. 2001, 9, 141-150.
(6) (a) Singer, R. A.; Caron, S.; McDermott, R. E.; Arpin, P.; Do, N. M.
Synthesis 2003, 1727-1732. (b) Singer, R. A.; Dore, M.; Sieser, J. E.;
Berliner, M. A. Tetrahedron Lett. 2006, 47, 3727-3731.
(11) (a) Snider, B. B.; Conn, R. S. E.; Sealfon, S. J. Org. Chem. 1979,
44, 218-221. (b) Gomez-Guillen, M.; Conde-Jimenez, J. L. Carbohydr.
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Simon, J. M.; Martin-Zamora, M. E. Carbohydr. Res. 1989, 189, 349-
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10.1021/jo7026195 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/16/2008
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J. Org. Chem. 2008, 73, 2412-2415

TABLE 2. Acid Additive Screening and Optimization
SCHEME 1. Pyrazole Synthesis
entry
solvent
acid
conditions
result
1
2
AcOH
TFA
118 °C, 16 h
72 °C, 16 h
58%
complex
mixtures
0%
complex
mixtures
complex
mixtures
52%
3
4
MeOH
TFA, 10 equiv
MeSO3H, 10 equiv rt, 3 d
rt, 3 d
MeOH
MeOH
MeOH
TABLE 1. Solvent Screening on the Pyrazole Formation Reaction
5
H2SO4, 10 equiv
HCl,a 10 equiv
HO(CH2)2OH AcOH, 2 equiv
HO(CH2)2OH TFA, 2 equiv
HO(CH2)2OH TsOH, 2 equiv
rt, 3 d
6
7
8
9
rt, 3 d
70 °C, 16 h
50 °C, 16 h
70 °C, 16 h
45%
62%
complex
mixtures
complex
mixtures
complex
mixtures
63%
10
11
HO(CH2)2OH MeSO3H, 2 equiv
HO(CH2)2OH HCl/aq, 4 equiv
70 °C, 16 h
50 °C, 16 h
12
13
CF3CH2OH
CF3CH2OH
TFA, 5 equiv
TFA, 10 equiv
rt, 16 h
rt, 16 h
70%
a HCl solution in MeOH (ca. 1.25 mol/L from Aldrich).
equiv of TFA (pKa ) -0.25) as the additive, no formation of
pyrazole 3 was observed at room temperature (entry 3). Whereas
MeSO3H (pKa ) -2.6) and H2SO4 (pKa ) -3.0) gave
complicated reaction mixtures (entries 4-5), HCl solution (pKa
) -8.0) in MeOH15 did facilitate a room-temperature pyrazole
formation reaction in 52% yield (entry 6). At least 2 equiv of
HCl was required for the reaction to go to completion. However,
varying the equivalents of HCl did not improve the yield.
Various acid additives were also screened in ethylene glycol
(pKa ) 14.1) that was the optimal solvent under thermal
conditions as shown previously. Slightly elevated temperature
(50-70 °C) had to be employed due to the poor solubility of
the substrates. In this case, weaker acids such as AcOH (pKa )
4.7) and TFA (pKa ) -0.25) were sufficient to provide pyrazole
3 in 45% and 62% yield, respectively (entries 7, 8). TsOH (pKa
) -2.1), MeSO3OH (pKa ) -2.6), and HCl(aq) (pKa ) -8.0)
all caused decomposition (entries 9-11). The above results
appear to suggest that more acidic alcoholic solvent (pKa )
14.1 for ethylene glycol vs 15.5 for MeOH) would require less
acidic additive (pKa ) -0.24 for TFA vs -8.0 for HCl). This
observation prompted us to choose CF3CH2OH (pKa ) 12.5)
as the solvent. Now the pyrazole-forming reaction could be
performed at room temperature with TFA (pKa ) -0.25) as
the additive (entries 12 and 13). Whereas 5 equiv of TFA was
sufficient, 10 equiv of TFA afforded a slightly better isolated
yield at 70%. It is important to note that Lewis acids such as
BF3‚Et2O, SnCl4, TiCl4, AlCl3, FeCl3, ZnCl2, ZnI2, Zn(OTf)2,
Sc(OTf)3, and Yb(OTf)3‚H2O are not effective promoters for
the pyrazole-forming reaction. These results suggest that Bron-
sted acidity, not Lewis acidity, is a critical factor for this
reaction.
During our previous study on the pyrazole-forming reaction
between hydrazones and nitroolefins, alcoholic solvents (MeOH,
EtOH) proved to be optimal.12 However, when then optimized
conditions were applied to electron-deficient hydrazones such
as N-phenylhydrazone 1, a low yield of pyrazole 3 was isolated
even after refluxing for 4 days (Table 1, entry 1). Changing to
higher boiling point alcohols and increasing reaction tempera-
tures did not show any improvement (entries 2-7). Interestingly,
diols effectively facilitated the reaction at 120 °C affording the
desired pyrazole 3 (entries 8-11), which suggests that perhaps
temperature is not the lone determining factor. Among the diols,
ethylene glycol gave the cleanest reaction in 69% isolated yield
after heating at 120 °C for 16 h (entry 8). Glycerol also provided
the desired pyrazole 3, however in low yield (25%), probably
due to the poor solubility of the substrates even at 120 °C (entry
12). In contrast, polar, aprotic solvents such as DMF and DMSO
were not effective for this reaction (entries 13 and 14).
The above solvent screening results suggested that protona-
tion-deprotonation might play an important role in the reaction
pathway. Literature reports also indicated that acids assisted the
cycloaddition reactions of hydrazones with various dipolaro-
philes.13 Indeed, with AcOH (pKa ) 4.714) as the solvent,
pyrazole 3 was obtained at reflux temperature (118 °C) in 58%
yield (Table 2, entry 1). Using a stronger acid, TFA (pKa )
-0.25) as the solvent, however, caused mostly decomposition
even at a lower temperature (72 °C, entry 2). Encouraged by
these results, we set out to screen various acids as additives
with the aim to perform the reaction at ambient temperature.
MeOH (pKa ) 15.5) was first chosen as the solvent. With 10
(13) (a) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1973, 12, 212-
224. (b) Le Fevre, G.; Sinbandhit, S.; Hamelin, J. Tetrahedron 1978, 35,
1821-1824. (c) Shimizu, T.; Hayashi, Y.; Miki, M.; Terashima, K. J. Org.
Chem. 1987, 52, 2277-2285. (d) Kobayashi, S.; Hirabayashi, R.; Shimizu,
H.; Ishitani, H.; Yamashita, Y. Tetrahedron Lett. 2003, 44, 3351-3354.
(14) pKa values in water were used.
(15) Used as the solvent (1.25 mol/L, Aldrich). Bubbling HCl (g) into
MeOH gave a very messy reaction.
J. Org. Chem, Vol. 73, No. 6, 2008 2413

TABLE 3. Reaction Scope with Respect to Nitroolefin
TABLE 4. Reaction Scope with Respect to Hydrazone
a Key: (A) ethylene glycol, heating; (B) CF3CH2OH, 10 equiv of TFA.
4). The same trend was observed at the R1 position. Whereas
heating at 120 °C in ethylene glycol was sufficient for the
reaction to proceed with electron-rich hydrazone 16 (entry 5),
electron-poor hydrazone 17 demanded even higher temperature
(150 °C) and the yield was very low (19%, entry 6). Similarly,
other electron-withdrawing substituents such as F, CN, and SO2-
Me at the R1 position also called for higher reaction temperatures
(entries 7-9). We find that the two sets of reaction conditions,
one neutral and the other acidic, are complementary to each
other in terms of functional group compatibility. When the
functional groups are insensitive to acid, the CF3CH2OH/TFA
system is preferred. For example, in the reaction shown in entry
3, which involves an acid-stable yet temperature-sensitive
phenolic substrate, the CF3CH2OH/TFA system works well at
room temperature to furnish the desired pyrazole product in
excellent yield. Alternatively, for the acid-sensitive substrates,
heating in ethylene glycol is a viable option (entries 2, 4, and
10). Entry 10 is a particularly interesting example. In our
previous study involving the same substrates with MeOH as
the solvent, a Michael addition product was the exclusive
product in 90% yield, even at room temperature.12 Simply
switching the solvent to ethylene glycol, the pyrazole product
31 was obtained in 58% yield (entry 10). Notably, the isolated
Michael addition product does not cyclize to pyrazole 31 upon
heating in ethylene glycol even at 150 °C. This observation
indicates that the formation of Michael addition product is
irreversible.
With the optimized CF3CH2OH/TFA system, the reaction
scope on nitroolefins was probed with hydrazone 1 (Table 3).
All reactions were performed under the standard conditions
without individual optimization. Substitutions at the R4 position
are well tolerated (entries 2 and 3). At the R3 position, various
electron-donating and electron-withdrawing groups on the aryl
ring are compatible with the reaction conditions (entries 4-8).
An aliphatic nitroolefin also affords good yield of pyrazole
product (entry 3). It is noteworthy that even a sterically
demanding nitroolefin affords reasonably good yield of the
pyrazole product (entry 5). Heterocycles such as a thiophene
are also compatible with the reaction conditions (entry 9).
We next turned our attention to defining the scope of the
reaction with respect to the hydrazones (Table 4). Either the
thermal condition in ethylene glycol (A) or the acidic condition
in CF3CH2OH/TFA (B) was applied, depending on functional
group compatibility. The electronic properties of the hydrazone
substituents appear to be the dominant factor controlling
reactivity. For example, hydrazones with electron-donating
substitution at R2 position afford the pyrazole products in decent
yields under standard conditions (entries 1-3). In contrast, the
yield is much lower with electron-deficient hydrazones (entry
Previously, we had demonstrated that the pyrazole-forming
reaction goes through a pyrazolidine intermediate. Analogous
to the mechanism proposed for the reaction of hydrazones with
2414 J. Org. Chem., Vol. 73, No. 6, 2008

SCHEME 2. NMR Study on the Stereochemistry of the
Pyrazolidine Intermediates
SCHEME 3. A Revised, Stepwise Pathway
of the pyrazolidine formation step. From intermediate 41, two
competing reaction pathways can take place. One is an irrevers-
ible protonation to afford the Michael addition product 42. The
other is an intramolecular cyclization to furnish the pyrazolidine
intermediate 43. The key intermediate 43 then undergoes a slow
oxidation by air, followed by a fast elimination of HNO2 to
furnish the pyrazole product.12
In conclusion, a practical, regioselective synthesis of 1,3,5-
tri- or 1,3,4,5-tetrasubstituted pyrazoles from electron-deficient
N-arylhydrazones and nitroolefins has been demonstrated. Two
general protocols were developed, which are complementary
to each other in terms of functional group compatibility. This
pyrazole formation reaction is quite general with respect to
hydrazones and nitroolefins with a variety of substituents, and
the yields range from moderate to good. A revised stepwise
cycloaddition mechanism was also proposed.
other electron-negative olefins,16 we proposed a concerted
cycloaddition pathway in which the hydrazone tautomerized to
azomethine imine and then underwent a 1,3-dipolar cycload-
dition reaction with nitroolefins (Scheme 2) to generate the
pyrazolidine intermediate.11d,12 However, definitive evidence for
a concerted mechanism was not obtained at that time. To
differentiate a concerted or stepwise mechanism in a cycload-
dition reaction, stereochemistry is arguably the best tool.17 If
the pyrazolidine formation step is concerted, the configuration
of the nitroolefin should be retained in the pyrazolidine
intermediate. Our previous study did show that the trans
configuration of nitroolefin 33 was retained in pyrazolidine 36.12
However, we recently found that under the same reaction
conditions, cis-nitroolefin 34 also afforded the same pyrazolidine
36 exclusively. No pyrazolidine 37 with the retention of the cis
configuration was observed whatsoever. This was further
complicated that cis-nitroolefin 34 isomerized to trans isomer
33 in the reaction mixture, although it remained stable in pure
CD3OD.18 To avoid the confusion, cis-nitroolefin 39 was
prepared, which does not isomerize in the reaction solution
during the time frame of the experiments. Both trans-38 and
cis-39 were then reacted with hydrazone 32 in CD3OD in NMR
tubes under N2. In both experiments, the same pyrazolidine 40
in the trans configuration was again generated exclusively. The
lack of stereospecificity in the pyrazolidine formation step
clearly indicate a stepwise mechanism.
Experimental Section
General Procedures for Pyrazole Synthesis. Method A. A
mixture of 4-methyl-â-nitrostyrene (163 mg, 1 mmol, 1.0 equiv)
and 4-chlorobenzaldehyde phenylhydrazone (276 mg, 1.2 mmol,
1.2 equiv) in ethylene glycol (10 mL) was heated at 120 °C open
to air for 16 h and then cooled to room temperature. The reaction
solution was partitioned between EtOAc and brine. The organic
layer was separated, dried over MgSO4, filtered, and concentrated.
The crude product was purified by flash column chromatography
with EtOAc/hexanes as eluent to afford the pure compound as a
light yellow solid (235 mg, 0.69 mmol, 69%). Method B. A mixture
of 4-methyl-â-nitrostyrene (163 mg, 1 mmol, 1.0 equiv) and
4-chlorobenzaldehyde phenylhydrazone (276 mg, 1.2 mmol, 1.2
equiv) was dissolved in CF3CH2OH (10 mL), and TFA (0.77 mL,
10 mmol, 10 equiv) was added. The reaction mixture was stirred
at room temperature open to air for 2 days. The solvent was
evaporated, and the residue was directly purified by flash column
chromatography with EtOAc/hexanes as eluent to afford the pure
compound as a light yellow solid (239 mg, 0.70 mmol, 70%).
In light of the above results, a revised mechanism of pyrazole
formation may be proposed as outlined in Scheme 3. Nucleo-
philic attack of hydrazone on nitroolefin affords a neutral
intermediate 41. Since the C-C single bond between R3 and
R4 can rotate freely, either trans- or cis-nitroolefin affords the
same intermediate 41, which results in the nonstereospecificity
Acknowledgment. We thank Prof. Scott E. Denmark,
University of Illinios at Urbana-Champaign, for helpful dis-
cussions and Dr. Jiejun Wu and Ms. Heather McAllister for
analytical support.
(16) (a) Grigg, R.; Dowling, M.; Jordan, M. W.; Sridharan, V. Tetra-
hedron 1987, 43, 5873-5886. (b) Padmavathi, V.; Reddy, K. V.; Padmaja,
A.; Reddy, D. B. Synth. Commun. 2002, 32, 1227-1235.
(17) Huisgen, R. AdV. Cycloaddition 1988, 1, 1-31.
(18) Same isomerization of cis-nitroolfin was observed in the following
literature: Burdisso, M.; Gamba, A.; Gandolfi, R.; Pevarello, P. Tetrahedron
1987, 43, 1835-1846.
Supporting Information Available: Experimental details and
characterization of compounds 1, 3-31, and 40. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7026195
J. Org. Chem, Vol. 73, No. 6, 2008 2415