Synthesis of Chiral Pyrazoles: A 1,3-Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement with Stereoretentive Migration of a Stereogenic Group

Article abstract of DOI:10.1002/anie.201506881

The reactions between terminal alkynes and α-chiral tosylhydrazones lead to the obtention of chiral pyrazoles with a stereogenic group directly attached at a nitrogen atom. The cascade reaction includes decomposition of the hydrazone into a diazocompound, 1,3-dipolar cycloaddition of the diazo compound with the alkyne, and [1,5] sigmatropic rearrangement with migration of the stereogenic group. This strategy has been successfully applied to the synthesis of structurally diverse chiral pyrazoles through α-chiral tosylhydrazones, obtained from α-phenylpropionic acid, α-amino acids, and 2-methoxycyclohexanone. Notably, the stereoretention of the [1,5] sigmatropic rearrangements represent very rare examples of this stereospecific transformation.

Full text of DOI:10.1002/anie.201506881

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506881
German Edition: DOI: 10.1002/ange.201506881
Diazo Compounds
Synthesis of Chiral Pyrazoles: A 1,3-Dipolar Cycloaddition/[1,5]
Sigmatropic Rearrangement with Stereoretentive Migration of a Ste-
reogenic Group
M. Carmen PØrez-Aguilar and Carlos ValdØs*
Abstract: The reactions between terminal alkynes and a-chiral
tosylhydrazones lead to the obtention of chiral pyrazoles with
a stereogenic group directly attached at a nitrogen atom. The
cascade reaction includes decomposition of the hydrazone into
a diazocompound, 1,3-dipolar cycloaddition of the diazo
compound with the alkyne, and [1,5] sigmatropic rearrange-
ment with migration of the stereogenic group. This strategy has
been successfully applied to the synthesis of structurally diverse
chiral pyrazoles through a-chiral tosylhydrazones, obtained
from a-phenylpropionic acid, a-amino acids, and 2-methox-
ycyclohexanone. Notably, the stereoretention of the [1,5] sig-
matropic rearrangements represent very rare examples of this
stereospecific transformation.
theless, these methods are far from general and have been
mostly employed on unsubstituted pyrazoles.
We have recently reported the regioselective synthesis of
the 1,3,5-trisubstituted pyrazoles B and 3,4,5-trisubstituted
pyrazoles C from the reaction of tosylhydrazones A and
terminal alkynes by a 1,3-dipolar cycloaddition/[1,5] sigma-
tropic rearrangement sequence (Scheme 1).[18] The mecha-
T
he pyrazole ring is a five-membered heterocycle present in
a large number of molecules with biological activity.[1]
Compounds containing substituted pyrazoles find widespread
use as antimicrobials, analgesics, and anti-inflamatory agents,
as well as CNS and oncology drugs.[2–5] Indeed, pyrazoles are
constantly employed as building blocks in drug discovery
programs.[6,7] Moreover, structures built around the pyrazole
scaffold are also found as key constituents of ligands for
transition metals with biological or catalytic activity,[8] recep-
tors in supramolecular chemistry,[9] and functional organic
materials.[10] For these reasons, and in spite of the variety of
existing methods, the development of new methodologies for
the efficient regioselective synthesis of polysubstituted pyr-
azoles is still an area of very active research.[11,12]
Scheme 1. Regioselective synthesis of trisubstituted pyrazoles and
mechanism proposed. Ts =4-toluenesulfonyl.
nism proposed for these cascade processes involves the
following steps: 1) decomposition of the tosylhydrazone to
produce a diazo compound D, 2) 1,3-dipolar cycloaddition of
the diazo compound with the terminal alkyne to form a 3H-
pyrazole E,[19,20] 3) [1,5] sigmatropic rearrangement which
may lead to either the 1,3,5-substituted 1H-pyrazole B or
the new 4H-pyrazole F. The latter will undergo additional
[1,5] sigmatropic shifts to provide C (Scheme 1). The step that
determines the regioselectivity of the reaction is the [1,5] sig-
matropic rearrangement. For tosylhydrazones derived from
acetophenones (X = H, R2 = Ar), the only product obtained is
the result of the migration of the aryl group to C4 C. In
contrast, for 2-substituted acetophenones, in many cases the
major or exclusive product obtained is the pyrazole B, derived
from the migration of the CH2X group to the nitrogen
position. This reaction is indeed an intriguing case of double
selectivity: a) chemoselectivity on the migrating group,
b) regioselectivity on the sense of the migration.
A particularly challenging type of pyrazole is a chiral
pyrazole having a stereogenic carbon center attached at the
N-position. Limited examples of this type of chiral pyrazole
with biological activity have been reported,[13] but their
usefulness has been hampered by the lack of general methods
for their preparation. Chiral pyrazoles with a sterogenic
center attached at the nitrogen atom have been synthesized
from chiral amines,[14] and also by alkylation of the corre-
À
sponding N H pyrazole through Mitsunobu reactions of
chiral alcohols,[13,15] ring-opening of chiral or meso epox-
ides,[16] and organocatalytic aza-Michael reactions.[17] Never-
[*] M. C. PØrez-Aguilar, Dr. C. ValdØs
Departamento de Química Orgµnica e Inorgµnica and Instituto
Universitario de Química Organometµlica “Enrique Moles”
Universidad de Oviedo
According to our experimental results and DFT computa-
tional studies, these [1,5] migrations on the 3H-pyrazoles I
(Scheme 2) proceed through [1s,5s] concerted mecha-
nisms.[21,22] Thus, the migration of stereogenic groups should
c/Juliµn Clavería 8, Oviedo 33006 (Spain)
E-mail: acvg@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506881.
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Scheme 3. Synthesis of the chiral tosylhydrazones 3, and preliminary
studies on the reaction sequence for the synthesis of the chiral
pyrazole 4a. a) NH(OMe)Me·HCl, Et(iPr)2NH, CH2Cl2, À58C;
b) R1MgBr, Et2O, 08C, 1 h; c) TsNHNH2, MeOH, RT, 6 h. 3a: R=Ph;
3b: R=Et; 3c: R=Me. Complete description of the synthesis of
tosylhydrazones 3 from 1 are provided in the Supporting Information.
out on the model system to establish proper experimental
conditions by modifying solvent, temperature, and base.
Nevertheless, the conditions developed in our previous
work (K2CO3, 1,4-dioxane, 1108C) turned out to be appro-
priate. As expected, the 1,3,5-trisubstitued pyrazole 4a was
the major isomer (6:1 4a/5a as determined by 1H NMR
spectroscopy on the crude reaction mixture and GC/MS),[18]
which could be easily obtained in pure form after chroma-
tography.
Scheme 2. Proposed synthesis of chiral pyrazoles through a cascade
process involving a [1,5] sigmatropic rearrangement with retention of
configuration within the migrating group. TS(A-B) and TS(A-C): tran-
sition states predicted for the [1,5] sigmatropic rearrangement of I
leading to the chiral N-substituted and NH-pyrazoles II and III,
respectively (b3lyp/6-311+ +G**(PCM, 1,4-dioxane).[20]
The same reaction was then conducted with the tosylhy-
drazone obtained from the enantiomerically pure carboxylic
acid (R)-(À)-2-phenylpropionic acid. Delightfully, a 99% ee
was obtained, as determined by chiral-phase HPLC analysis.
Remarkably, the complete process from the chiral ketone
(R)-(À)-2a, which involves a) formation of the tosylhydra-
zone 3, b) decomposition of 3 to give a diazo compound,
c) 1,3-dipolar cycloaddition, and d) [1,5] sigmatropic rear-
rangement, had taken place with preservation of the enan-
tiomeric purity (Table 1, entry 1). To determine the absolute
configuration of the chiral pyrazole (À)-4a ([a]2D4 = À149.38),
the same compound was synthesized by Mitsunobu reaction
of the corresponding NH-pyrazole with (R)-1-phenyletha-
nol,[15,27] as determined by the opposite sign of the optical
rotation. This observation establishes the R configuration for
the stereogenic center of (À)-4a and confirms that the
cascade reaction has indeed taken place with retention of
configuration.
The cascade sequence was then extended to various
systems featuring different substituents, R1 and R4 (Table 1).
In all cases, moderate to high regioselectivities and very high
enantiomeric excesses for the major isomer were
obtained.[28,29] The reaction was compatible with an array of
substituents on the terminal position of the alkyne, including
aromatics with different electronic properties, heteroarenes,
a benzyl substituent, and even a trialkylsilyl group. Regarding
the non-migrating substituent on the hydrazine, R1, aryl and
primary alkyl groups were tolerated. Importantly, chiral
pyrazoles with a stereogenic center attached to the nitrogen
atom and different substituents (R1 and R4), such as
compounds 4b–k, would be difficult to prepare in a regiose-
lective manner through alternative methodologies.
take place with retention of configuration in the migrating
group.
Noteworthy, [1,5] sigmatropic rearrangements with reten-
tion of configuration in the migrating group, although
theoretically predicted by the Woodward–Hoffmann rules,
are very rare. To the best of our knowledge, the classic
example of the stereospecific rearrangement of a methyl-
substituted spiro[4.4]nona-1,3-diene stands as the unique
example of a [1,5] rearrangement which proceeds with
retention of configuration of the migrating group.[23–25] Addi-
tionally, no synthetic application oriented towards the prep-
aration of enantiomerically enriched materials has been
developed based on this principle.
We have previously shown that tosylhydrazones can be
employed to achieve transformations of a-chiral ketones with
preservation of the configuration of the a-carbon atom, in
both palladium-catalyzed processes and intramolecular
[3+2] cycloadditions.[26] Taken together, we decided to inves-
tigate the employment of tosylhydrazones derived from a-
chiral ketones in the cycloaddition/rearrangement cascade as
a model to study the [1,5] sigmatropic shift with migration of
a stereogenic center (Scheme 2). Additionally, we also
anticipated that it might represent a novel way to prepare
enantiomerically enriched chiral pyrazoles with appealing
structures for medicinal chemistry.
We initiated our study with a-chiral ketones (2), which can
be obtained in enantiomerically pure form from commercially
available carboxylic acids (1, Scheme 3; see the Supporting
Information for details and experimental procedures). Pre-
liminary experiments with the racemic ketone 2a (R1 = Ph)
showed that the cascade sequence proceeded with good yield
and moderate regioselectivity. Several reactions were carried
À
Approaches involving the alkylation of the N H pyrazole,
such as the Mitsunobu reaction used in the synthesis of (S)-
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Table 1: Synthesis of chiral pyrazoles R-(À)-4 from the a-chiral tosylhy-
drazones 3 and terminal alkynes.
Entry
R1
R4
4/5[a]
ee [%][b]
4, Yield [%][c]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Ph
4-Tol
86:14
85:15
93:7
99
99
93
98
99
98
97
92
99
97
4a 51
4b 54
4c 65
4d 71
4e 57
4 f 57
4g 33
4h 45
4i 58
4j 43
4k 40
4-MeOC6H4
4-NCC6H4
Si(iPr)3
3-thienyl
Bn
82:18
73:27
88:12
85:15
68:32
64:36
70:30
100:0
Scheme 5. Synthesis of the chiral pyrazoles 9 and 11. [a] Synthetic
details for the tosylhydrazones 8 and 10 are provided in the Supporting
Information.
Ph
Et
Me
Me
4-FC6H4
4-NCC6H4
4-MeOC6H4
In our previous communication,[18] we had reported that
tosylhydrazones derived from a-N-azole-substituted ketones
led to the 1,3,5-trisubstituted pyrazoles with high yields and
total regioselectivity. Therefore, we decided to explore the
same reaction with the analogous chiral derivatives. To this
end, the chiral tosylhydrazone 10 was prepared from l-
leucine in enantiomerically pure form (Scheme 5). As
expected, the 1,3-dipolar cycloaddition/[1,5] rearrangement
occurred with total regioselectivity, thus leading to the chiral
1-(1H-1-pyrrolyl)ethyl-1H-pyrazole 11 with complete reten-
tion of configuration (99% ee).
10
11
[d]
–
[a] Determined by 1H NMR analysis of the reaction crude reaction
mixture. [b] Determined by chiral-phase HPLC and comparison with
a sample prepared from the racemic tosylhydrazone. [c] Yield of the
major isolated isomer 4 after column chromatography. [d] The ee value
was not determined because of the decomposition of the material under
the HPLC conditions.
(+)-4a, would give a mixture of the two possible regioisomers
derived from the alkylation of each nitrogen atom.
To expand the scope of the synthesis of N-chiral pyrazoles
to different classes of chiral ketones, we decided to explore
the reaction with the tosylhydrazones of a-aminoketones
derived from a-amino acids. Indeed, the reactions of the l-
proline-derived tosylhydrazone 6[26a] with terminal alkynes
gave rise to the N-substituted pyrazoles 7 with complete
regioselectivity (Scheme 4), as the NH-pyrazole derived from
the migration to C4 was not even detected. Again, the cascade
process proceeded with nearly perfect retention of config-
uration in most cases, thus furnishing 7 with very high
enantiomeric ratios.[29] Similarly, starting from N-Bn-N-Boc-
(L)-phenylalanine, the tosylhydrazone 8 was prepared. The
cycloaddition/rearrangement sequence led to the N-chiral
pyrazole 9 as a unique regioisomer, and importantly with
99% ee (Scheme 5).
Finally, we turned our attention to tosylhydrazones
derived from cyclic ketones and the hydrazone of the 2-
methoxycyclohexanone 12 was chosen for this study
(Scheme 6). After some experimentation, it was found that
the cycloaddition/rearrangement sequence proceeded suc-
cessfully by performing the reaction in CH3CN and employ-
ing Cs2CO3 as a base, thus leading to the pyrazole 13.
Interestingly, treatment of the reaction mixture with
BF3·OEt2 led quantitatively to the new pyrazole 14 by loss
of methanol.
Notably, previous examples of the cycloaddition/rear-
rangement cascade on cyclic tosylhydrazones furnished 3,4,5,-
trisubstitued pyrazoles with counterclockwise migration to
C4.[18,19] Thus, in the examples above, the presence of the
methoxy group is essential to drive the reaction towards the
Scheme 6. Synthesis of chiral fused pyrazoles 13. [a] Yield of the major
isolated isomer 13 after column chromatography. [b] The ee value was
determined by chiral-phase HPLC and comparison with a sample
prepared from the racemic tosylhydrazone. [c] Formed upon addition
of BF3·OEt2 to the reaction mixture.
Scheme 4. Synthesis of the chiral pyrazoles 7 from proline derivatives.
[a] The ee value was not determined because of the decomposition of
the material under the HPLC conditions. Boc=tert-butoxycarbonyl.
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synthesis of unprecedented chiral pyrazoles from terminal
alkynes and a-chiral-N-tosylhydrazones, through a cascade
process which involves a 1,3-dipolar cycloaddition followed
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three different levels: 1) chemoselectivity: one of the two
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availability of the starting materials required for these
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Acknowledgements
We gratefully acknowledge financial support of this work
from Ministerio de Economía y Competitividad of Spain
(Grant: MINECO-CTQ2013-41336-P). A FPI predoctoral
fellowship to M.C.P.-A. is gratefully acknowledged.
Keywords: cycloaddition · diazo compounds · heterocycles ·
rearrangements · tosylhydrazone
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13729–13733
Angew. Chem. 2015, 127, 13933–13937
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[27] The description of the synthesis of (+)-4a through the Mitsu-
nobu reaction is included in the Supporting Information.
[28] The employment of a freshly prepared tosylhydrazone is of
outmost importance to obtain the pyrazole with high and
reproducible enantiomeric ratio. The tosylhydrazones 3, which
had been stored for some time, provided pyrazoles with lower
enantiomeric purity.
[29] Partial epimerization over the time has been observed for some
pyrazoles (4 and 7). To obtain reliable values of the enantiomeric
ratio it is important to conduct the HPLC analysis directly after
the isolation.
[26] a) J. Barluenga, M. Escribano, F. Aznar, C. ValdØs, Angew.
Chem. Int. Ed. 2010, 49, 6856; Angew. Chem. 2010, 122, 7008;
Received: July 24, 2015
Published online: September 22, 2015
Angew. Chem. Int. Ed. 2015, 54, 13729 –13733
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13733