Regioselective one-step synthesis of pyrazoles from alkynes and N-tosylhydrazones: [3+2] dipolar cycloaddition/[1,5] sigmatropic rearrangement cascade

Article abstract of DOI:10.1002/anie.201301284

Rearrangement under control: A wide variety of 3,4,5- and 1,3,5-trisubstituted pyrazoles can be prepared from tosylhydrazones of ketones and terminal alkynes through the title reaction sequence (see scheme; Ts=4-toluenesulfonyl). The rearrangement, and th

Full text of DOI:10.1002/anie.201301284

Angewandte
Chemie
Communications
Synthetic Methods
Rearrangement under control: A wide
variety of 3,4,5- and 1,3,5-trisubstituted
pyrazoles can be prepared from tosylhy-
drazones of ketones and terminal alkynes
through the title reaction sequence (see
scheme; Ts=4-toluenesulfonyl). The
rearrangement, and therefore, the regio-
selectivity of the reaction is controlled by
the nature of the substituents of the
tosylhydrazone.
M. C. Pꢀrez-Aguilar,
C. Valdꢀs*
&&&& — &&&&
Regioselective One-Step Synthesis of
Pyrazoles from Alkynes and N-
Tosylhydrazones: [3+2] Dipolar
Cycloaddition/[1,5] Sigmatropic
Rearrangement Cascade
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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DOI: 10.1002/anie.201301284
Synthetic Methods
Regioselective One-Step Synthesis of Pyrazoles from Alkynes and
N-Tosylhydrazones: [3+2] Dipolar Cycloaddition/[1,5] Sigmatropic
Rearrangement Cascade**
M. Carmen Pꢀrez-Aguilar and Carlos Valdꢀs*
The pyrazole is a very important heterocycle in pharmaceut-
ical and agrochemical industries.[1] Compounds containing the
pyrazole substructure find application in a wide variety of
therapeutical areas, which includes antimicrobials, analgesics,
anti-inflammatory agents, CNS and oncology drugs.[2] Exam-
ples of leading commercial drugs based on the pyrazole
scaffold include celecoxib,[3] lonazolac,[4] and rimonabant.[5]
Currently, pyrazoles are constantly employed as building
blocks in drug discovery programs,[6] and are also found as key
constituents of ligands for transition metals,[7] receptors in
supramolecular chemistry,[8] liquid crystals,[9] and polymers.[10]
For these reasons, the development of new methodologies for
the regioselective synthesis of polysubstituted pyrazoles
continues to be an active area of research of high impact in
fine chemistry.[11]
number of novel transition metal catalyzed[20] and transition-
metal-free[21] reactions have been reported. In this context, we
report herein a new method for the regioselective preparation
of 3,4,5- and 1,3,5-trisubstituted pyrazoles from readily
available N-tosylhydrazones and terminal acetylenes through
a
[3+2] cycloaddition/[1,5] sigmatropic
rearrangement
sequence.
In an initial experiment, we conducted the reaction
between the tosylhydrazone 1a and phenylacetylene (2a) in
1,4-dioxane and in the presence of K2CO3 at 1108C
(Scheme 1). The reaction afforded the pyrazole 3a as
a single regioisomer. Formation of 3a could be explained
through a process which involves a [3+2] dipolar cyclo-
addition of the diazo compound, generated by decomposition
of the hydrazone,[22] with the terminal alkyne to give a 3H-
pyrazole and subsequent [1,5] sigmatropic rearrangement and
aromatization.
The most popular approaches to the synthesis of trisub-
stituted pyrazoles consist of: 1) condensation of hydrazines
with 1,3-dicarbonyl compounds or synthetic equivalents;[12]
=
2) [3+2] cycloadditions of diazo compounds or other N N-
containing dipoles with alkynes[13–15] or alkenes;[16] 3) transi-
tion-metal-catalyzed cross-coupling reactions.[17] Neverthe-
less, the efficient preparation of 3,4,5-trisubstituted pyrazoles
in a regioselective manner is still a challenging task which
involves several synthetic steps.[18] Methodologies based on
condensation reactions require multistep routes to synthesize
the pyrazole precursors, while routes based on dipolar
cycloaddition reactions usually feature regioselectivity prob-
lems, and are limited to the availability of the diazo
compounds.
In the recent years, we have been interested in the
development of new synthetic applications of tosylhydra-
zones. Indeed, we and others, have shown that tosylhydra-
zones can be employed as a general source of diazo
compounds from carbonyl compounds with almost no restric-
tion regarding the structure of the hydrazone.[19] Taking
advantage of this powerful transformation, a remarkable
Scheme 1. Formation of the pyrazole 3a from the tosylhydrazone 1a
and phenylacetylene (2a) through the [3+2] cycloaddition/[1,5] rear-
rangement sequence. The identity of the regioisomer 3a was deduced
by NOESY experiments. PMP=p-MeOC6H4, Ts=4-toluenesulfonyl.
Notably, the synthesis of pyrazoles from tosylhydrazones
and terminal acetylenes had been previously reported by
Aggarwal et al., but it was restricted to hydrazones derived
from aromatic aldehydes, and therefore, to the preparation of
monosubstituted and 3,5-disubstituted pyrazoles.[13] More-
over, the [3+2] cycloaddition/[1,5] sigmatropic rearrange-
ment sequence has been previously described in reactions of
a-diazocarbonyl compounds with alkynes,[14] but the exam-
ples with nonstabilized diazo compounds are very limited in
scope and synthetic interest.[24] Furthermore, the reactions of
tosylhydrazones with terminal alkynes in the presence of
a CuI catalyst proceed in a completely different manner, thus
giving rise to allenes by formation of a Cu carbene inter-
mediate.[24]
[*] M. C. Pꢀrez-Aguilar, Dr. C. Valdꢀs
Instituto Universitario de Quꢁmica Organometꢂlica
“Enrique Moles”, Universidad de Oviedo
c/Juliꢂn Claverꢁa 8, Oviedo, 33006 (Spain)
E-mail: acvg@uniovi.es
[**] Financial support of this work by the DGI of Spain (CTQ-2010-
16790) and Consejerꢁa de Educaciꢃn y Ciencia of Principado de
Asturias (IB08-088). A FPI predoctoral fellowship to M.C.P.-A. is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301284.
2
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Chemie
This initial result prompted us to investigate the scope of
this transformation, oriented to develop a novel method for
the generation of 3,4,5-trisubstituted pyrazoles which are not
easily available from other methodologies. After some
optimization work in the model reaction, we found that the
best yields were achieved by employing a 1:2 hydrazone/
alkyne ratio and 2 equivalents of K2CO3, in 1,4-dioxane as
solvent at 1108C. These reaction conditions were applied to
a set of hydrazones (1) and terminal alkynes (2), and the
results are summarized in Table 1.
respectively). Remarkably, the reaction with triisopropylsilyl-
acetylene led to the straightforward synthesis of the silylsub-
stituted pyrazole 3k in high yield (entry 11).
Regarding the structure of the tosylhydrazone, the process
takes place efficiently with hydrazones derived from aceto-
phenones featuring all types of substituents in the aromatic
ring (Table 1, entries 15–18). Moreover, the hydrazone of 4,4-
diphenyl-3-buten-2-one provided the trisubstituted pyrazole
3s, with migration of the alkenyl group (entry 19). The
replacement of the methyl group by a longer alkyl chain led to
a decrease in the regioselectivity, thus giving rise to a mixture
of the isomeric NH-pyrazoles 3 and 4 (entries 20 and 21), and
can be understood by considering the higher migration ability
of the n-alkyl groups, relative to the methyl group, in the
[1,5] sigmatropic rearrangement. Finally, the reaction with the
tosylhydrazone of 3-pentanone led to the desired pyrazole 3v
(entry 22).[25,26] These results show that the cascade reaction is
an excellent method for the preparation of 3,4-diarylpyra-
zoles, a scaffold present in several compounds with interesting
biological activity.[27]
The observation of two regioisomers (Table 1, entries 20
and 21) prompted us to investigate of the influence of the
substituents R1 and R2 in the outcome of the reactions.
Indeed, the introduction of substituents different from methyl
and aryl led to a change not only in the selectivity but also in
the sense of the [1,5] rearrangement (Scheme 2). While in the
case of a primary alkyl group (R = Et) both isomers 3 and 4
Table 1: Regioselective synthesis of 3,4,5-trisubstituted pyrazoles.[a]
Entry
R1
R2[c]
R3[c]
Yield [%][b,d]
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
PMP
PMP
PMP
PMP
PMP
PMP
Ph
3a
74(56)
82(55)
63
77(63)
80
p-MeOC6H4
p-tol
p-NCC6H4
p-CF3C6H4
m-MeOC6H4
3b
3c
3d
3e
3 f
82
7
8
Me
Me
PMP
PMP
3g
3h
70
81
2-naphtyl
9
Me
PMP
3i
77(75)
10
11
12
13[c]
14
15
16
17
18
19
20
21
22
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
nPr
Et
PMP
PMP
PMP
PMP
2-pyridyl
SiiPr3
Bn
1-cyclohexenyl
Cy
Ph
Ph
p-tol
p-NCC6H4
p-NCC6H4
Ph
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
63
76(62)
53(27)
53(52)
28
75(63)
58
PMP
p-ClC6H4
p-NCC6H4
p-EtO2CC6H4
p-EtO2CC6H4
63
72(62)
(46)
=
Ph2CH CH
Scheme 2. Influence of the structure of the hydrazone 1 on the
regioselective formation of 1H-pyrazoles. Ratio of products determined
by 1H NMR spectroscopy.
Ph
Ph
Et
77(50)[e]
60[f]
Ph
p-NCC6H4
Et
53(32)
[a] See the Supporting Information for reaction conditions. [b] Yield of
isolated product. [c] Carried out with 4 equiv of alkyne. [d] Yields for one-
pot reactions from the ketone and tosylhydrazide[26] are indicated in
brackets. [e] 2:1 mixture of the regioisomers 3 and 4 (Scheme 2). [f] 1:1
mixture of regioisomers.
are obtained in a similar ratio, formation of the 1,3,5-pyrazole
5 through a clockwise migration is clearly preferred when R =
Bn and R = CH2OMe. Finally, the reaction of the hydrazone
derived
from
a-dimethylaminoacetophenone
(R =
CH2NMe2) exclusively provided the disubstituted pyrazole 6
with loss of the R group.
First, the scope of the reaction was evaluated with regard
to the structure of the alkyne employing the hydrazone 1a as
a substrate (Table 1, entries 1–14). The reaction is general for
all types of aromatic-substituted terminal alkynes, bearing
electron-donating or electron-withdrawing substituents
(Table 1, entries 1–8), as well as p-exceeding (entry 9) and
p-deficient heterocycles (entry 10). The reaction with benzyl
acetylene, as an example of a primary alkyl substituent, also
led to the pyrazole 3l with moderate yield (entry 12).
However, a substantial drop in the yield was observed with
alkenyl and secondary alkyl substituents (entries 13 and 14,
The existing mechanistic studies relative to the regiose-
lectivity of [1,5] shifts on 3H-pyrazoles (van Alphen–Hꢀttel
rearrangement)[23,28–30] suggest that the migration of the R
group to N1 to give the pyrazole 5 occurs through the
transition state TS2 with partial charge separation
(Scheme 3). This pathway must be favored for substituents
which stabilize the partial positive charge developed in the
transition state (X = Ph, OMe). Moreover, the higher elec-
tron density on N1 versus C4, justifies the regioselectivity of
the [1,5] shift. In the absence of this effect (X = H), migration
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At this point, the scope of this reaction as a new way to
synthesize 1,3,5-trisubstituted pyrazoles (5) was evaluated. As
presented in Table 2, the reactions with the benzyl containing
hydrazones (entries 1–8) led to the pyrazoles 5 as the major or
unique isomers in all cases, and could be isolated as pure
regioisomers with synthetically acceptable yields. The incor-
poration of a more electron-rich aromatic ring such as the p-
methoxyphenyl group in the migrating fragment led to the
exclusive formation of the pyrazole 5i (entry 9). Very high
regioselectivities were also achieved for the rearrangement of
alkoxymethyl groups (entries 10 and 11). Then we examined
a-N-azole-substituted tosylhydrazones (entries 12–15), with
the expectation that the N-azole substituent might also exert
a weak stabilization of the incipient carbocation in the
transition state. To our delight, these systems provided the
corresponding 1,3,5-substituted pyrazoles 5 with complete
regioselectivity, in reactions suitable for the high-throughput
generation of druglike molecules. For instance, the results in
entry 13 show the assembly of 5m, containing three different
heterocycles, in one single synthetic operation.
Scheme 3. Proposed transition states for the [1,5] shift.
of the aryl group to C4 through TS1 must be favored. Finally,
excessive stabilization of the carbocation (Scheme 2; R =
CH2NMe2) leads to a different reaction pathway with
dissociation of the R group through a retro-Mannich-type
reaction.
Table 2: Regioselective synthesis of the 1,3,5-trisubstituted pyrazoles 5.[a]
We next explored the reactions with the tosylhydrazones 6
derived from cyclic ketones. We anticipated that the [3+2]
cycloaddition/[1,5] rearrangement sequence would give rise
to the trisubstituted pyrazoles 7–8 with expansion of the
carbocyclic ring (Table 3). Indeed, the reactions with hydra-
zones derived from tetralones and indanones led to the
corresponding pyrazoles fused to a seven-membered ring (7)
and to a six-membered ring (8), respectively. The [1,5] rear-
rangement takes place again in a regioselective manner, thus
giving rise exclusively to the pyrazole in which migration of
the aryl group has occurred. Moreover, variations on the
aromatic rings of both coupling partners and also in the
scaffold are tolerated. This transformation could be also
accomplished with the tosylhydrazone of cyclohexenone
Entry
R1
R2
R3
4/5[b]
Yield [%][c,d]
1
2
3
4
5
6
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
p-NCC6H4
p-CF3C6H4
PMP
1:4
1:2
1:3
1:4
0:1
1:5
5a
44
35
67
56
53
47
5b
5c
5d
5e
5 f
m-MeOC6H4
7
8
Ph
Ph
Ph
0:1
0:1
5g
5h
76(63)
56
Table 3: Synthesis of the benzofused pyrazoles 7 and 8 from cyclic
tosylhydrazones 6.
Me
9[d]
Ph
Ph
Me
PMP
MeO
BnO
p-CF3C6H4
p-NCC6H4
p-NCC6H4
0:1
1:7
0:1
5i
5j
5k
70
42
56
10[e,f]
11[e,f]
12[f,g]
Ph
p-CF3C6H4
0:1
5l
74
Ar
Y
R
Yield [%][a]
Ph
H
H
H
5-F
4-MeO
4-MeO
H
H
H
H
H
H
H
Me
H
7a
7b
7c
7d
7e
7 f
45
80
82
64
(78)
60
13[f]
Ph
0:1
5m
45
p-CF3C6H4
p-NCC6H4
p-CF3C6H4
Ph
p-CF3C6H4
p-CF3C6H4
2-pyridyl
14[f]
Ph
p-CF3C6H4
p-CF3C6H4
0:1
0:1
5n
5o
57(23)
57(51)
7g
7h
65
67
H
15[d,f]
PMP
Ph
–
–
–
–
H
H
H
Me
8a
8b
8c
8d
42
57
51 (43)
45
p-CF3C6H4
2-pyridyl
p-CF3C6H4
[a] See the Supporting Information for reaction conditions. [b] Deter-
mined by 1H NMR analysis of the crude reaction mixture. [c] Yield of the
isolated pure regioisomer 5. [d] Yields for one-pot reactions from the
ketone and tosylhydrazide[26] are indicated in brackets. [e] NaOH was
employed as base. [f] 1,4-Dioxane as solvent. [g] Carried out with 4 equiv
of alkyne.
[a] Yields for the one-pot reactions from the ketone and tosylhydrazide[26]
are given within parentheses.
4
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a
catalyst-free [3+2] cycloaddition/
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Received: February 13, 2013
Revised: March 22, 2013
Published online: && &&, &&&&
Keywords: alkyne · heterocycles · hydrazones · rearrangement ·
.
synthetic methods
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Communications
[26] The reactions can be conducted in a one-pot fashion, thus
preforming the hydrazone from the corresponding ketone
(1 equiv) and tosylhydrazide (1.05 equiv) in the reaction solvent
at 708C for 3 h, although slightly lower yields are generally
obtained.
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[30] The mechanistic proposal is also supported by DFT-based
computational calculations, and will be published in a forth-
coming publication.
[31] No reaction product was detected with cycloalkyl tosylhydra-
zones.
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