Synthesis of pyrazoles from 1,3-diols via hydrogen transfer catalysis

Article abstract of DOI:10.1021/acs.orglett.5b00266

1,3-Diols engage in ruthenium-catalyzed hydrogen transfer in the presence of alkyl hydrazines to provide 1,4-disubstituted pyrazoles. Regioselective synthesis of unsymmetrical pyrazoles from β-hydroxy ketones is also described.

Full text of DOI:10.1021/acs.orglett.5b00266

Letter
pubs.acs.org/OrgLett
Synthesis of Pyrazoles from 1,3-Diols via Hydrogen Transfer Catalysis
Daniel C. Schmitt,* Alexandria P. Taylor, Andrew C. Flick, and Robert E. Kyne, Jr.†
Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: 1,3-Diols engage in ruthenium-catalyzed hydrogen
transfer in the presence of alkyl hydrazines to provide 1,4-
disubstituted pyrazoles. Regioselective synthesis of unsymmetrical
pyrazoles from β-hydroxy ketones is also described.
yrazoles are an important structural subunit found in a
variety of biologically active agents, including major drugs
efficiency. This approach has been utilized for the synthesis of
benzazoles, pyridines, pyrazines, pyrroles, and indoles from
readily available alcohol and amine building blocks.11 To date,
hydrogen transfer catalysis has not been applied to pyrazole
synthesis.12 Given the aforementioned limitations of con-
densative pyrazole synthesis, a method that addresses these
issues would represent a valuable advance.
We proposed that hydrogen transfer could enable the use of
1,3-diols rather than the typical masked dialdehydes for
pyrazole synthesis. Recent reports of 1,3-diols undergoing Ir-
catalyzed double allylation and crotylation indicate their
potential as synthetic equivalents to 1,3-dialdehydes.13 The
compatibility of alkyl hydrazines with the reaction conditions
remained a concern, as few examples exist of alcohol
dehydrogenation in the presence of hydrazines. However,
recent research by Li and Porcheddu demonstrates the stability
of hydrazines to both Ir- and Ru-catalyzed hydrogen trans-
fer.11g,14 As a starting point, we selected commercially available
i-Pr diol 1a and phenylhydrazine to investigate the proposed
reaction (Table 1).
P
such as Viagra, Xalkori, Lexiscan, and Celebrex.1 The
prevalence of the pyrazole motif in medicinally relevant
compounds,2 dyes,3 and ligands for metal catalysts4 has
inspired the development of many novel methods for their
preparation.5 Over the course of recent drug discovery efforts,
the unmet need for an efficient route to 4-alkyl pyrazoles was
identified. Despite an abundance of methodology for their
synthesis, pyrazoles are most commonly constructed by the
condensation of an alkyl hydrazine with a 1,3-dicarbonyl.6
However, the inherent instability of many 1,3-dicarbonyls,
particularly dialdehydes,7 limits access to substituted pyrazoles.
As a workaround, the use of vinylogous formamides or 1,3-
diacetals has made a select number of these structural motifs
accessible (Figure 1). These masked dialdehydes possess
Initial experiments surveyed common hydrogen transfer
catalysts, in both the presence and absence of a hydrogen
acceptor (crotonitrile). No pyrazole formation was observed in
the presence of [Cp*IrCl2]2, Milstein’s catalyst, or
RuCl2(PPh3)3 (Table 1, entries 1−3). [Ru3(CO)12] and
Xantphos in tert-amyl alcohol, which was utilized by Beller
and co-workers for vicinal diol dehydrogenation,11e provided
9% of the desired pyrazole. RuH2(PPh3)3CO and Xantphos in
the presence of piperidinium acetate, a system developed by
Williams for transfer of hydrogen from alcohols to crotoni-
trile,11b,15 successfully yielded 68% of pyrazole 3a (entry 5).
Notably, omission of piperidinium acetate results in no desired
product formation. Substitution of piperidinium acetate with
AcOH boosted the yield to 75% (entry 7). The importance of
acidic additives may be due to acceleration of both aldehyde
condensation steps. Under otherwise identical conditions, but
with a decreased catalyst loading, a 40% yield of pyrazole 3a
was isolated (entry 8). Omission of Xantphos led to unreacted
diol 1a, without any formation of the desired pyrazole (entry
Figure 1. Pyrazoles from masked dialdehydes vs diols.
sensitive functional groups and typically require multistep
preparation.8 An additional challenge of traditional pyrazole
syntheses lies in the preparation of unsymmetrical pyrazoles:
conventional condensation often provides inseparable mixtures
of pyrazole regioisomers.9
Metal-catalyzed alcohol dehydrogenation has recently
emerged as a powerful tool for C−N bond formation in
synthetic chemistry. These transformations permit the direct
coupling of alcohols with amines, usually in the presence of an
iridium or ruthenium catalyst, to provide imines, amides, or
heterocycles.10 Such dehydrogenative condensations circum-
vent the need for potentially unstable carbonyl intermediates
and bypass alcohol oxidation steps, thus increasing synthetic
Received: January 27, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00266
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
evaluated, affording 42% and 57% yields, respectively (3f and
3g). Interestingly, aliphatic hydrazines which possessed a C−H
adjacent to nitrogen were not competent nucleophiles; methyl
and isopropylhydrazine both failed to provide the desired
pyrazoles, whereas α-quaternary aliphatic hydrazine 2h
provided the desired pyrazole (3h). In all cases, flash
chromatography easily separated the pyrazole product from
any unreacted starting materials due to the significant difference
in polarity.
Table 1. Reaction Optimization
a
entry
catalyst
solvent
PhMe
additive
yield
1
2
Milstein’s catalyst
RuCl2(PPh3)3
[Cp*lrCl2]2
−
0%
0%
The scope of the diol component was evaluated with
phenylhydrazine. In addition to i-Pr diol (3a), n-propyl (3i),
and cyclohexyl (3j) diols were well-tolerated (Scheme 2).
PhMe
crotonitrile
3
PhMe
−
−
0%
b
4
Ru3(CO)12/L1
t-amylOH
PhMe
9%
c
5
RuH2(PPh3)3CO/L1
RuH2(PPh3)3CO/L1
RuH2(PPh3)3CO/L1
1 mol % [Ru]/L1
RuH2(PPh3)3CO
crotonitrile/A
68%
0%
ab
,
Scheme 2. Diol Scope
6
PhMe
crotonitrile
7
PhMe
crotonitrile/AcOH
crotonitrile/AcOH
crotonitrile/AcOH
crotonitrile/AcOH
75%
40%
0%
8
PhMe
9
PhMe
10
RuH2(PPh3)3CO/L1
t-amylOH
40%
a
15 mol % of each additive was used, except crotonitrile (2.2 equiv
b
c
used). Ligand L1 is Xantphos (3 mol %). Additive A is piperidinium
acetate (15 mol %).
9). Neat conditions, employed successfully by Porcheddu with
this catalytic system,16 resulted in decomposition in this case.
With suitable conditions in hand, the scope of the reaction
was examined. Diol 1a was evaluated with various mono-
substituted hydrazines. Phenyl hydrazines bearing functional
groups such as iodide and trifluoromethyl were tolerated
(Scheme 1). 2-Toluyl hydrazine provided a slightly lower yield
than phenylhydrazine, likely due to steric hindrance of the
condensation step. Since tertiary amines and N-heterocycles are
common subunits of pharmaceutical agents, dimethylamino-
phenyl hydrazine and 4-hydrazinyl-3-phenylcinnoline were
a
All reactions were conducted in round-bottom flasks fitted with reflux
condensers at 0.50 M concentration with 1b−g (1.00 equiv), 2a (1.00
equiv), crotonitrile (2.20 equiv), RuH2(PPh3)3CO (3 mol %),
b
Xantphos (3 mol %), and AcOH (15 mol %) at 110 °C. Yield of
isolated product.
a b
,
Scheme 1. Hydrazine Scope
Notably, lower yields were obtained from 2-aryl-1,3-diols (3k
and 3l). This result could be due to impeded dehydrogenation
or accelerated enolization of the α-aryl aldehyde intermediates,
which could subsequently dimerize or undergo Michael
addition to crotonitrile. Useful functional groups such as aryl
bromides and ketals were also tolerated on the diol component,
albeit in modest yield (3n). Whereas various primary 1,3-diols
were effective reactants, attempts to generate pyrazoles from
secondary alcohols were unsuccessful, likely due to the
significantly diminished rate of secondary alcohol dehydrogen-
ation relative to primary alcohol dehydrogenation.17
To test the scalability of the reaction, 1 g of diol 1a (8.5
mmol) was subjected to the standard conditions in the
presence of phenylhydrazine (Scheme 3). After 24 h in toluene
at reflux, pyrazole 3a was isolated in 84% yield.
Scheme 3. Gram-Scale Reaction
a
All reactions were conducted in round-bottom flasks fitted with reflux
condensers at 0.50 M concentration with 1a−f (1.00 equiv), 2a−h
(1.00 equiv), crotonitrile (2.20 equiv), RuH2(PPh3)3CO (3 mol %),
b
Xantphos (3 mol %), and AcOH (15 mol %) at 110 °C. Yield of
isolated product.
B
DOI: 10.1021/acs.orglett.5b00266
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Organic Letters
Letter
The postulated mechanism may involve an initial migratory
insertion of the Ru dihydride catalyst with crotonitrile (Scheme
4). The resulting C−Ru bond could undergo protodemetala-
Table 2. Regioselective Pyrazole Synthesis
Scheme 4. Proposed Mechanism
metrical pyrazoles with excellent regioselectivity. The ability to
use diols as dicarbonyl equivalents will likely find further utility
in the synthesis of other heterocycles, which will be the subject
of future studies.
tion with diol 1 to generate Ru alkoxide 4. Dehydrogenation
would provide aldehyde 5, which is believed to dissociate from
Ru prior to condensation with the hydrazine, resulting in β-
hydroxy hydrazone 6.18 Hydrogen transfer to crotonitrile
followed by protodemetalation would produce butyronitrile
and ruthenium alkoxide 7.16 Subsequent dehydrogenation
would regenerate the Ru dihydride species as well as β-
hydrazino aldehyde 8, which could cyclodehydrate to provide
the observed pyrazole product 3.
An alternative mechanism could involve full oxidation of diol
1 to a dialdehyde prior to condensation with the hydrazine.
However, the dehydrogenation of electron-poor alcohols, such
as β-hydroxy aldehyde 5, is usually slow and probably does not
proceed until after formation of hydrazone 6. Furthermore,
monitoring of the reaction by LC-MS revealed a mass indicative
of β-hydroxy hydrazone 6, which is consistent with the depicted
catalytic cycle.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: daniel.schmitt@pfizer.com.
Present Address
†Celgene Avilomics Research, 45 Wiggins Ave., Bedford, MA
01730.
Additional utility of this method lies in the regioselective
preparation of unsymmetrical pyrazoles. A well-documented
problem with conventional pyrazole synthesis is unreliable
regioselectivity in the cyclocondensation of hydrazines with
vinylogous amides or esters.19 In contrast, dehydrogenative
coupling of commercially available β-hydroxy ketone 9 provides
3-alkyl pyrazole 10 exclusively (Table 2). Complete regiose-
lectivity was also observed in the preparation of fused pyrazole
12. The observed regioselectivity may be attributed to
condensation of the unsubstituted hydrazine nitrogen with
the ketone prior to alcohol dehydrogenation. Although
complex β-hydroxy ketones are not commercially available,
they may be prepared reliably via aldol reaction with aqueous
formaldehyde.20
In summary, 4-alkyl-pyrazoles may be prepared directly from
2-alkyl-1,3-diols and hydrazines by means of Ru-catalyzed
hydrogen transfer to crotonitrile. This method enhances the
synthetic accessibility of 4-alkyl pyrazoles, which are difficult to
produce by other means. The reaction tolerates both aromatic
and aliphatic substituents on both the hydrazine and diol
component. Beyond entry into elusive 4-alkyl-pyrazole
chemical space, this method enables the synthesis of unsym-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank David Lin and James Mousseau for reviewing this
manuscript. Kathleen Farley and Martin Berliner are thanked
for helpful discussions. All colleagues acknowledged are
affiliated with Pfizer, Inc., Groton, CT, USA.
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DOI: 10.1021/acs.orglett.5b00266
Org. Lett. XXXX, XXX, XXX−XXX