Base-mediated reaction of hydrazones and nitroolefins with a reversed regioselectivity: A novel synthesis of 1,3,4-Trisubstituted pyrazoles

Article abstract of DOI:10.1021/ol800200j

A regioselective synthesis of 1,3,4-tri- or 1,3,4,5-tetrasubstituted pyrazoles by the reaction of hydrazones with nitroolefins is described. Mediated with strong bases such as t-Bu OK, the reaction exhibits a reversed, exclusive 1,3,4-regioselectivity. Su

Full text of DOI:10.1021/ol800200j

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1307-1310
Base-Mediated Reaction of Hydrazones
and Nitroolefins with a Reversed
Regioselectivity: A Novel Synthesis of
1,3,4-Trisubstituted Pyrazoles
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 January 28, 2008
ABSTRACT
A regioselective synthesis of 1,3,4-tri- or 1,3,4,5-tetrasubstituted pyrazoles by the reaction of hydrazones with nitroolefins is described. Mediated
with strong bases such as t-BuOK, the reaction exhibits a reversed, exclusive 1,3,4-regioselectivity. Subsequent quenching with strong acids
such as TFA is essential to achieve good yields. A plausible stepwise cycloaddition reaction mechanism is proposed.
Pyrazoles are an important class of compounds in the
pharmaceutical industry. Compounds containing the pyrazole
motif are being developed in a wide range of therapeutic
areas including CNS, metabolic diseases and endocrine
functions, and oncology.1 A number of pyrazole-containing
compounds have been successfully commercialized, such as
the blockbuster drugs Viagra, Celebrex, and Acomplia.
Substituted pyrazoles have also been applied as ligands for
the transition-metal-catalyzed cross-coupling reactions.2
The synthesis of multi-substituted pyrazoles have been
extensively studied, and two methods have certainly stood
out in terms of generality and convenience.3 One is the
venerable Knorr reaction involving the condensation of
substituted hydrazines with 1,3-dicarbonyl compounds or
their derivatives (Scheme 1, eq a).4 The other method is the
1,3-dipolar cycloaddition of diazoalkanes or nitrile imines
with olefins or alkynes (eq b).5 As successful as these two
methods are in preparing pyrazoles with various substitution
patterns, both are not particularly suitable for the regio-
selective synthesis of 1,3,4-trisubstituted pyrazoles. 1,3,4-
Trisubstituted pyrazoles are pharmaceutically important, yet
less represented in the literature, probably due to synthetic
difficulties.6 In the Knorr reaction, the condensation of
substituted hydrazines with â-ketoaldehydes usually favors
1,4,5-trisubstitituted pyrazoles.7 One solution to this issue
is to prepare 3,4-disubstituted pyrazole with unsubstituted
hydrazine (NH2NH2) and introduce the R1 substituent
subsequently. However, the N-substitution step is usually not
regiospecific, either.8 1,3-Dipolar cycloaddition reactions
have been successfully employed in the synthesis of 1,3,4-
trisubstituted pyrazoles or pyrazolidines, usually regioselec-
tively.9 However, the difficulty in generating and handling
Scheme 1. Two General Methods for the Pyrazole Synthesis
(1) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Targets in
Heterocyclic Systems 2002, 6, 52-98 and references therein.
(2) (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.
(3) (a) Elguero, J. Comp. Heterocycl. Chem. 1984, 5, 167. (b) Elguero,
J. Comp. Heterocycl. Chem. II 1996, 3, 1-75, 817-932. (c) Makino, K.;
Kim, H. S.; Kurasawa, Y. J. Heterocyl. Chem. 1998, 35, 489-497.
10.1021/ol800200j CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/27/2008

reactive 1,3-dipoles often limits their synthetic utility.
Therefore, a general, convenient method for the synthesis
of 1,3,4-substituted pyrazoles is highly desirable. Herein, we
report a regioselective synthesis of 1,3,4-tri- or 1,3,4,5-
tetrasubstituted pyrazoles from readily available hydrazones
and nitroolefins mediated with strong bases. To the best of
our knowledge, this is the first time that this transformation
has ever been documented. The reaction scope is quite broad
on a range of substrates, and the functional group compat-
ibility is excellent. Paired with our previously reported
methodology to prepare 1,3,5-trisubstituted pyrazoles from
the same starting material but under neutral or acidic
conditions,10 the reaction of hydrazones and nitroolefins
should offer a powerful tool for the pyrazole synthesis in
general.
affords 3,4-disubstituted pyrazoles.11 1,3,4-Trisubstituted
pyrazoles have also been obtained as the minor products from
the reaction of hydrazones with nitroolefins under microwave
heating conditions.12 We envisioned that the N and C atoms
of a deprotonated hydrazone might possess reversed nucleo-
philicities toward Michael receptors such as nitroolefins.
Indeed, when t-BuOK was added to hydrazone 1 in THF at
0 °C under N2, followed by the addition of nitroolefin 2,
1,3,4-trisubstituted pyrazole 4 was isolated in 45% yield after
30 min reaction time (Scheme 2, conditons B). No formation
of 1,3,5-trisubstituted pyrazole 3 was observed whatsoever.
Notably, air is not required under base-mediated conditons
B, which is essential for the reaction to proceed under
conditions A. In fact, under conditons B in the presence of
air, oxidative dimerization of the hydrazone itself was the
dominant reaction.13
Encouraged by the initial results, we tried to increase the
yield of reaction B. However, optimization efforts by varying
reaction parameters such as solvent, base and temperatrue
were largely unsuccessful. With CH3CN or CH2Cl2 as the
solvent, little reaction was observed, whereas the reactions
in DMF or DMA afforded similar yields as in THF. The
reaction proceeds at as low as -78 °C, but the yield did not
improve. Changing the counter cation of the base by
employing NaOBut or LiOBut gave essentially the same yield
as well. Using NaHMDS, LiHMDS and iPrMgCl as the base
all provided desired pyrazole 4, but the reactions gave lower
yields. Other bases, such as PhMgCl and LDA, afforded only
trace amounts of desired product 4. Changing the addition
order of the reagents, by adding t-BuOK to the solution of
hydrazone 1 and nitroolefin 2 in THF, did not increase the
yield, either.
Recently, we have reported a regioselective synthesis of
1,3,5-trisubstituted pyrazoles through the reactions of hy-
drazones with nitroolefins under either neutral (heating in
MeOH or ethylene glycol) or acidic conditions (10 equiv of
TFA in CF3CH2OH) (Scheme 2, conditons A).10 Excellent
Scheme 2. Complementary Regioselectivity
A solution to the problem emerged when we made the
breakthrough observation that the outcome of the reaction
depended on the quenching reagents used (Scheme 3). The
reaction was performed by adding t-BuOK to a THF solution
of hydrazone 5 under N2 at -78 °C, followed by the addition
of nitroolefin 6 after 10 min. After stirring at -78 °C for 15
min, both hydrazone 5 and nitroolefin 6 were completely
1,3,5-regioselectivity is achieved, presumably resulting from
the different nucleophilicity of the aniline N atom and the
benzylic C atom of phenyl hydrazone 1. We speculated that
by modulating the relative nucleophilicities of the nitrogen
and the carbon atoms of the hydrazone, 1,3,4-regioselectivity
might instead be accomplished. In the literature, it has been
shown that the reaction of nitroolefins with diazoalkanes, in
which the C atom is more nucleophilic than the N atom,
(8) (a) Meanwell, N. A.; Rosenfeld, M. J.; Wright, J. J. K.; Brassard, C.
L.; Buchanan, J. O.; Federici, M. E.; Fleming, J. S.; Seiler, S. M. J. Med.
Chem. 1992, 35, 389-397. (b) Wang, X.; Tan, J.; Zhang, L. Org. Lett.
2000, 2, 3107-3109.
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S.; Henry, R.; Kolasa, T. J. Org. Chem. 2004, 69, 7058-7065. (c)
Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J. Org. Chem. 2005,
70, 10030-10035.
(9) (a) Fathi, T.; Nguyen, D. A.; Schmitt, G.; Cerutti, E.; Laude, B.
Tetrahedron 1988, 44, 4527-4536. (b) Daou, B.; Soufiaoui, M.; Carrie,
R. J. Heterocycl. Chem. 1989, 26, 1485-1488. (c) Lokanatha Rai, K. M.;
Hassner, A. Synth. Commun. 1989, 19, 2799-2807. (d) Abdallah, M. A.;
Abbas, I. M.; Mosselhi, M. A. N.; Albar, H. A.; Shawali, A. S. J. Chem.
Res. Synth. 1994, 2, 76-77. (e) Del Valle, J. L.; Polo, C.; Torroba, T.;
Marcaccini, S. J. Heterocycl. Chem. 1995, 32, 899. (f) Liu, B.; Wang, M.;
Huang, Z. Tetrahedron Lett. 1999, 40, 7399. (g) Molteni, G.; Ponti, A.
Chem. Eur. J. 2003, 9, 2770. (h) Dawood, K. M.; Fuchigami, T. J. Org.
Chem. 2005, 70, 7537-7541.
(5) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565-632. (b)
Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John Wiley & Sons: New
York, 1984; Vol. I. (c) 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.
(6) (a) Kira, M. A.; Abdel-Raeman, M. O.; Gadalla, K. Z. Tetrahedron
Lett. 1969, 2, 109-110. (b) Stauffer, S. R.; Huang, Y.; Coletta, C. J.;
Tedesco, R.; Katzenellenbogen, J. A. Bioorg. Med. Chem. 2001, 9, 141-
150. (c) Bekhit, A. A.; Abdel-Aziem, T. Bioorg. Med. Chem. 2004, 12,
1935-1945. (d) De Paulis, T.; Hemstapat, K.; Chen, Y.; Zhang, Y.; Saleh,
S.; Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.; Conn, P. J. J. Med.
Chem. 2006, 49, 3332-3344.
(7) (a) Robertson, I. R.; Sharp, J. T. Tetrahedron 1984, 40, 3095-3112.
(b) Subramanian, L. M.; Misra, G. S. Synthesis 1984, 12, 1063-1065. (c)
Press, J. B.; Birnberg, G. H. J. Heterocycl. Chem. 1985, 22, 561-4. (d)
Muthusubramanian, L.; Misra, G. S. Eur. J. Med. Chem. 1986, 21, 163-
166. (e) Singh, K.; Sharma, P. K.; Dhawan, S. N.; Singh, S. P. J. Chem.
Res. 2005, 8, 526-529.
(10) Deng, X.; Mani, N. S. Org. Lett. 2006, 8, 3505-3508. (b) Deng,
X.; Mani, N. S. J. Org. Chem. 2008, 73, 2412-2415.
(11) (a) Parham, W. E.; Bleasdale, J. L. J. Am. Chem. Soc. 1950, 72,
3843-3846. (b) Mancera, M.; Rodriguez, E.; Roffe, I.; Galibis, J. A. J.
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Bonnert, R. V. J. Org. Chem. 2003, 68, 5381-5383.
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(13) For the structure of the dimer 4b, see the Supporting Information.
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2007, 72, 7214-7221.
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Org. Lett., Vol. 10, No. 6, 2008

NMR experiments at -25 °C showed the disappearance of
the starting materials several minutes after the sequential
addition of t-BuOK and nitroolefin 6, but failed to provide
a clean spectrum of the intermediate. Nevertheless, these first
two steps are most likely reversible due to the fact that the
starting materials are recovered when no quenching or water
quenching are employed. The role of the acid quenching is
not entirely clear. One possible explanation is that the strong
acid such as TFA efficiently protonates intermediate 12 to
afford intermediate 13 irreversibly, thus driving the equi-
librium toward the desired pyrazole formation pathway.
Intermediate 13 then undergoes an elimination of HNO2,
followed by an oxidative aromatization to furnish the desired
pyrazole product. Since the reaction is performed under N2
with no external oxidants present, the byproduct HNO2
presumably serves as an internal oxidant.
Scheme 3. Study of Different Quenching Methods
consumed based on HPLC analysis. Two equivalents of
quenching reagents such as H2O, MeOH, AcOH, PhSO3H,
CH3SO3H and TFA were then added. After stirred at -78
°C for further 2 h, the reaction solution was warmed to room-
temperature slowly overnight. The results are depicted in
Scheme 3. When no quenching reagent or water was
employed, starting materials were mostly recovered. Quench-
ing with MeOH (pKa ) 15.5) caused a messy reaction. In
addition to the desired pyrazole 7 isolated in 12% yield, the
major side product was 5-aminopyrazole 8 in 18% yield,
which perhaps came from an internal Redox process. With
AcOH (pKa ) 4.7) as the quenching reagent, the major
product was Michael addition product 9 in 40% isolated
yield. Finally, when TFA (pKa ) -0.25) was employed as
the quenching reagent, the reaction was quite clean to afford
desired pyrazole 7 in 77% isolated yield. Similar yields were
also obtained with PhSO3H (pKa ) 2.1) and CH3SO3H (pKa
) -2.6) as the quenching reagents. It is important to note
that when Michael addition product 9 was subjected to the
t-BuOK/TFA quenching sequence, pyrazole 7 was obtained
almost quantitatively, suggesting the intermediacy of com-
pound 9 in the pyrazole formation process.
With the optimized t-BuOK/TFA quenching conditions in
hand, we set out to explore the reaction scope on nitroolefins
(Table 1). A diverse set of representative nitroolefins were
Table 1. Reaction Scope with Respect to the Nitroolefin
Based on the above information, we proposed a possible
mechanism for the pyrazole formation reaction (Scheme 4).
Scheme 4. A Plausible Reaction Pathway
Michael addition of deprotonated hydrazone 10 to a nitro-
olefin affords intermediate 11.14 An intramolecular cycliza-
tion then furnishes intermediate 12. It is not clear whether
intermediate 11 or 12 be the resting stage. Low-temperature
reacted with hydrazone 1 under the standard t-BuOK/TFA
quenching conditions without individual optimization. At the
R3 position, both electron-donating and electron-withdrawing
substituents on the aromatic rings are compatible with the
reaction conditions (entries 1-5). Notably, even a sterically
(14) (a) Fernandez, R.; Gasch, C.; Lassaletta, J-M.; Llera, J-M. Tetra-
hedron Lett. 1994, 35, 471-472. (b) Enders, D.; Syrig, R.; Raabe, G.;
Fernandez, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M. Synthesis 1996,
48-52.
Org. Lett., Vol. 10, No. 6, 2008
1309

hindered di-ortho-substituted nitroolefin afforded an excellent
yield of pyrazole product 14 (entry 2). Substitutions at the
R4 position were well tolerated (entries 6 and 7). Nitroolefins
with aliphatic group (entry 7) or heterocyclic groups such
as thiophene, furan, and pyridine (entries 8-10) at the R3
position afforded good yields of pyrazoles as well.
aryl ring (entries 1-3). Electron-donating substitutuents on
the aryl ring, on the other hand, led to significant yield loss
(entries 4 and 5). A possible explanation for the preference
of an electron-withdrawing substituent at R2 position is that
it helps stabilize deprotonated hydrazone 10 (Scheme 4), thus
facilitating the Michael addition step. Aromatic substitutions
at the R1 position were then investigated. Interestingly, the
electronic requirement at R1 position is reversed vis-a-vis
the R2 position: At R1 position, an electron-withdrawing
substituent on the aryl ring afforded a very poor yield of
pyrazole product (entry 6), whereas an electron-donating
substituent apparently facilitated the reaction (entry 7). We
reasoned that although an electron-withdrawing group at R1
position might have facilitated the first Michael addition step,
it also significantly increased the electron-density of the
nitrogen atom adjacent to R1 in intermediate 11, thus
impeding the formation of intermediate 12 on the subsequent
addition step (Scheme 4). Compared with electronic proper-
ties, the steric influence of substituents at the R1 position is
less prominent. A bulky naphthyl hydrazone furnished
pyrazole 29 in 67% yield (entry 8). Entry 9 is an interesting
case, which again demonstrated the importance of the
quenching method. When no quenching reagent was em-
ployed, desired pyrazole 31 was isolated in a low 16% yield
(entry 9b). In contrast, with the standard TFA quenching
method, open-chain nitroso compound 30 was obtained in
81% yield (entry 9a), presumably through the dehydration
of protonated intermediate 11. Substituents at the R1 and R2
positions are not limited to aryl rings. Hydrazone with an
electron-withdrawing ester group at the R2 position furnished
an excellent yield of pyrazole 32 (entry 10), which is the
regioisomer of the key precursor for the synthesis of
Acomplia. An electron-donating methyl group at the R1
position is also compatible with the reaction conditions (entry
11).
The reaction scope with respect to the hydrazone was next
examined (Table 2). Aromatic substitution at the R2 position
Table 2. Reaction Scope with Respect to the Hydrazone
In conclusion, we have developed a novel regioselective
synthesis of 1,3,4-tri- or 1,3,4,5-tetrasubstituted pyrazoles
with hydrazones and nitroolefins as the starting materials.
Mediated with strong base, a reversed 1,3,4-regioselectivity
pattern was obtained exclusively. The Michael addition
product was shown to be the key intermediate and a plausible
stepwise cycloaddition reaction mechanism was proposed.
Acknowledgment. We thank Prof. Scott E. Denmark,
University of Illinios at Urbana-Champaign, for helpful
discussions, Dr. Daniel J. Pippel and Dr. Christie Morrill
for proofreading the manuscript, and Dr. Jiejun Wu and Ms.
Heather McAllister for analytical support.
a No quenching. b 1-Chloro-4-(2-nitropropenyl)benzene was used in this
reaction.
Supporting Information Available: Experimental details
and characterization of compounds 4, 4b, 7-9, and 14-33.
This material is available free of charge via the Internet at
http://pubs.acs.org.
was first investigated. Excellent yields were achieved with
hydazones bearing electron-withdrawing substituents on the
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Org. Lett., Vol. 10, No. 6, 2008