A Michael Equilibration Model to Control Site Selectivity in the Condensation toward Aminopyrazoles

Article abstract of DOI:10.1021/acs.orglett.5b01248

A Michael equilibration model is presented to provide for site-selective pyrazole condensations between alkoxyacrylonitriles and hydrazines. Both pyrazole isomers were accessed with high selectivity by employment of kinetically or thermodynamically controlled conditions. Substrate scope and identification of Michael intermediates, as well as competitive pathways, support the presented mechanistic proposal. Sandmeyer derivatization provided site-selective access to fully substituted pyrazoles.

Full text of DOI:10.1021/acs.orglett.5b01248

Letter
pubs.acs.org/OrgLett
A Michael Equilibration Model To Control Site Selectivity in the
Condensation toward Aminopyrazoles
Daniel R. Fandrick,*,† Sanjit Sanyal,† Joseph Kaloko,† Jason A. Mulder,† Yuwen Wang,† Ling Wu,†
Heewon Lee,† Frank Roschangar,† Matthias Hoffmann,‡ and Chris H. Senanayake†
†Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut
06877-0368, United States
‡Department of Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, Biberach an der Riss
88397, Germany
S
* Supporting Information
ABSTRACT: A Michael equilibration model is presented to
provide for site-selective pyrazole condensations between
alkoxyacrylonitriles and hydrazines. Both pyrazole isomers
were accessed with high selectivity by employment of
kinetically or thermodynamically controlled conditions.
Substrate scope and identification of Michael intermediates,
as well as competitive pathways, support the presented
mechanistic proposal. Sandmeyer derivatization provided
site-selective access to fully substituted pyrazoles.
condensation, are readily available while the opposite isomers
he pyrazole heterocycle has been a ubiquitous motif due to
Tits incorporation into pharmaceuticals, agrochemicals, and have limited availability and can only be procured at high cost.7
materials as well as its natural occurrence.1 Since the Knorr
pyrazole synthesis2 and related hydrazine condensation with
alkoxymethylene malonates by Claisen and Haase,3 numerous
approaches toward the pyrazole core have been developed.1,4
The addition and cyclization between hydrazines and alkox-
yacrylonitriles, developed by Robins and Schmidt, has been a
classical reaction toward aminopyrazoles.5 In general, the 5-
aminopyrazole isomer was favored through direct condensation.5
Reversal of this presumed innate reactivity to access the opposite
3-aminopyrazole isomer required indirect approaches such as
employing Schmidt and co-workers’ multistep approach,
developed in the late 1950s, to direct the initial Michael addition
with a suitably protected hydrazine (Scheme 1).6 Accordingly,
specific isomers of aminopyrazoles, resulting from the direct
Rationalization for the site selectivity led to numerous, and at
times conflicting, models that differ by the hydrazine and
electrophile examined.5,8 The common attribute was based on an
initial nucleophilic attack to either the nitrile or activated olefin
by the more nucleophilic substituted nitrogen of alkyl hydrazines
or the unsubstituted nitrogen of aryl hydrazines.2−6,8,9 Although
the models provide reasonable rationales, they do not lead to
general predictions or provide an avenue toward the uncommon
isomer. Only sparse accounts for influence of reaction conditions
or unusual site selectivity exist.9b,d,10 However, the general
consensus relates selectivity to the structure and electronic
properties of the reactants. In contrast to these precedents, we
report a Michael equilibration model to rationalize site selectivity
in pyrazole condensations and to provide for high selectivity
toward both the 3- and 5-aminopyrazoles.
The model system examined for the aminopyrazole
condensation focused on the reaction between methyl hydrazine
1a and ethyl 2-cyano-3-ethoxyacrylate 2a with established
protocols. Subjecting a solution of the electrophile to methyl
hydrazine followed by the typical aging at elevated temperatures
afforded an isomeric mixture with selectivity favoring the
expected 5-aminopyrazole 5a (Table 1). The selectivity toward
the 5-aminopyrazole was modestly improved by utilizing a slight
excess of the electrophile or by employing an ethereal solvent. A
common mechanistic rationalization for the condensation relates
to a rapid Michael addition followed by a slow intramolecular
Scheme 1. General Approaches toward 3- and 5-
Aminopyrazoles5c,6d,7
Received: April 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
adduct 8a to effectively compete with the Michael equilibration.
Conversely, the 5-aminopyrazole was favored under the neutral
conditions due to cyclization of the Michael adduct 7a that was
generated from, and favored in, a Michael equilibration with the
initially generated kinetic adduct 8a.
Table 1. Identification of Site-Selective Pyrazole
Condensation Conditions
a
The selectivity for the Michael addition between the nitrogen
atoms of a monosubstituted hydrazine would be reasonably
influenced by the steric and electronic properties of the
substituent. Increasing the steric size of the hydrazine substituent
from a methyl 1a to a 2-phenylethyl 1d and cyclohexyl 1b group
decreased the selectivity toward the 3-aminopyrazole from
99.2:0.8 to 97:3 and 72:28, respectively (Table 2). The most
sterically demanding tert-butyl substituent 1c reversed the
selectivity to 5:95. Accordingly, the hydrazine substituent steric
influence on the site selectivity was consistent with a competitive
Michael alkylation between the hydrazine nitrogen atoms. The
corresponding neutral, i.e., thermodynamic, conditions favored
the 5-aminopyrazoles 5a−d with increased selectivity in opposite
order to the basic conditions consistent with the dynamic
Michael intermediates. Aryl hydrazines are known to strongly
favor 5-aminopyrazoles,4−6,8 which was observed under the
neutral conditions. However, employing the basic conditions
with phenyl hydrazine 1e provided an equal mixture of the
pyrazoles 3e and 5e, which could be improved to favor the 3-
aminopyrazole 3f (78:22) by utilizing the more electronically
donating p-methoxyphenyl hydrazine 1f. The methodology to
favor both the 3- and 5-aminopyrazoles under complementary
conditions also tolerated the ethoxy 3-methyl-2-cyanoacrylate 2b
and malononitrile counterparts 2d and 2e for the Michael
acceptor (entries 7, 8, 10, and 11).
b
c
d
entry addition (time)
stoich (2a:1a)
conditions
EtOH
ratio (3a:5a)
1
2
3
4
5
6
7
8
9
T (5 min)
T (60 min)
T (60 min)
T (60 min)
T (5 min)
T (5 min)
K (60 min)
K (15 min)
K (60 min)
1:1
1:1
20:80
e
EtOH
21:79
1.05:1
1:1
EtOH
14:86
f
CPME
15:85
1:1
AcOH, EtOH
NaOEt, EtOH
CPME
37:63
81:19
53:47
94:6
1:1
1:1
1:1
NaOEt, EtOH
NaOEt, EtOH
g
1:1
99.2:0.8
a
2 equiv of base or acid additive relative to electrophile 2a was used.
The base additive was neutralized with HCl before heating to 70 °C.
Addition order and duration. Molar stoichiometry between 2a to 1a.
Site selectivity determined by HPLC. 56% crystallization yield to
1:99 ratio. 63% crystallization yield to 1:99 ratio. 83% crystallization
yield. CPME = cyclopentyl methyl ether.
b
c
d
e
f
g
cyclization between the hydrazine and appended nitrile (Scheme
2).2−5,11 However, the 5-aminopyrazole isomer would be derived
Scheme 2. Mechanistic Rationale for Reversal in Site
Selectivity
The proposed thermodynamic Michael adducts have been
reported and were typically derived from hydrazine5b or an aryl
hydrazine11,14 nucleophile. Accordingly, the thermodynamic
Michael adduct 7e derived from the reaction between phenyl
hydrazine and the electrophile 2a was isolated before cyclization
by concentration and recrystallization of the reaction before
heating to 70 °C (eq 1). The corresponding Michael adduct 7g
from cyclization of adduct 7a resulting from a Michael addition
involving the less nucleophilic nitrogen of the methyl
hydrazine.8,9 A similar selectivity situation has been observed
for the corresponding condensation with alkoxymethylenemal-
onates;12 however, a couple of accounts have reversed this
selectivity by using basic conditions.9b,d,10b,13 Application of the
sodium ethoxide conditions to the parent alkoxy-2-cyanoacrylate
2a (entry 6) provided reasonable selectivity toward the 3-
aminopyrazole, which is consistent with cyclization of adduct 8a
derived from the Michael addition with the more nucleophilic
hydrazine nitrogen. The selectivity toward the 3-aminopyrazole
was further improved to greater than 99:1 by reversing the
addition order and employing a metered addition of the
electrophile to the basic hydrazine solution (entry 9). Therefore,
complementary conditions were established to access both
isomers of the aminopyrazoles. The cyclization was also
dramatically accelerated under basic conditions to be complete
within 3 h at 0 °C in contrast to over 5 h at elevated temperatures
under neutral conditions. This difference in cyclization rates
provided for a reasonable rationalization to favor the 3-
aminopyrazole by allowing the cyclization of the kinetic Michael
derived from methyl hydrazine and electrophile 2b was also
isolated by a similar approach. However, the adduct was less
stable and was only able to be characterized from the crude
reaction concentrate wherein the neat oil cyclized upon storage
at ambient temperature. In both systems, the kinetic Michael
counterparts were not observed, and the subsequent pyrazole
condensation (Table 2, entries 5 and 7) furnished the 5-
aminopyrazoles 5e and 5g in high selectivities. Therefore,
characterization of these Michael adducts further supported a
thermodynamic Michael equilibrium toward the intermediate
wherein the subsequent cyclization favored the 5-aminopyrazole.
The main rationale for the Michael equilibration model to
generate 3-aminopyrazoles was establishing conditions for the
cyclization of the kinetic Michael adducts to effectively compete
with the equilibration. This acceleration in certain systems led to
a cyclization toward the ester functional group competitively
over the nitrile (eqs 2 and 3). Utilization of 2-hydroxyethyl
hydrazine 1g or the isopropyl-substituted electrophile 2c under
the kinetic conditions furnished the amide adducts 9 and 10,
B
DOI: 10.1021/acs.orglett.5b01248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Scope for the Site-Selective Pyrazole Synthesis
toward the ester. The hydroxy substituent within the hydrazine
1g may have participated in the cyclization such as by generating
an 1,4-oxazepine intermediate15 and directed the cyclization
toward the ester. Alternatively, the isopropyl substituent within
electrophile 2c reasonably biased the E/Z geometry of the
Michael intermediate to position the hydrazine and ester
functional groups in a syn relationship to minimize steric strain
involving the larger isopropyl group by positioning the
substituent syn to the smaller nitrile. In both cases, the ester
cyclization observed under the basic conditions occurred from
the kinetic Michael adducts and proceeded with a different
chemoselectivity than observed under the thermodynamic
conditions.
Economical access to the uncommon 3-aminopyrazoles
provided an opportunity for greater diversity of the respective
derivatives and applications. The Sandmeyer reaction for 5-
aminopyrazoles has significant precedence,16 while the corre-
sponding derivatization of 3-aminopyrazoles was less common.17
Conversion of the 3-aminopyrazoles 3a and 3g to the
iodopyrazoles 11a and 11g proceeded in good yield under
standard conditions wherein the iodide Sandmeyer variant was
employed to circumvent the use of copper salts (Scheme 3).
Scheme 3. Application
Saponification followed by conversion to the lithium carbox-
ylates allowed for isolation of crystalline materials as the
tetrahydrofuran hemisolvate for the intermediate 12a and
unsolvated form for adduct 12g. Utilization of these lithium
salts allowed a Suzuki coupling to be conducted in water18 and
provided access to derivatize the 3-position of the 3-amino-
pyrazoles as well as the site-selective preparation of a fully
substituted pyrazole 13g.
a
Reactions conducted under either kinetic or thermodynamic
conditions as indicated. An additional 1 or 2 equiv of sodium ethoxide
employed if necessary to compensate for the equivalency of acid
b
introduced by the hydrazine. Reaction selectivity between the 3-
In conclusion, a detailed study on the site selectivity in the
condensation of hydrazines and alkoxy 2-cyanoacrylates is
presented. The results support a dynamic Michael intermediate
equilibrium which when appropriately addressed can provide
access to both the 3- and 5-aminopyrazoles in high selectivity.
Application of this model to the classical Schmidt multistep
approach toward 3-aminopyrazoles indicated that the resulting
selectivity with use of the protected hydrazine was due to
elimination of the Michael equilibration rather than regiose-
amino- (3) and 5-aminopyrazoles (5) determined by HPLC.
c
Unoptimized isolated yield after crystallization or purification to
d
>99:1 isomeric ratio. CPME employed as the reaction solvent.
e
f
Major adduct was compound 9. Not determined; see eq 3.
respectively, as the predominant products. The corresponding
reactions under thermodynamic conditions strongly favored the
5-aminopyrazoles 5h and 5i (Table 2, entries 8 and 9). The two
adducts 9 and 10 reflect substrates which biased the cyclization
C
DOI: 10.1021/acs.orglett.5b01248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Powers, J. J.; Zhang, C. Tetrahedron Lett. 2010, 51, 6799. (e) Ishimoto,
K.; Sawai, Y.; Fukuda, N.; Nagata, T.; Ikemoto, T. Tetrahedron 2013, 69,
8564. (f) Hwang, J. Y.; Kim, H.-Y.; Park, D.-S.; Choi, J.; Baek, S. M.; Kim,
K.; Kim, S.; Seong, S.; Choi, I.; Lee, H-g.; Windisch, M. P.; Lee, J. Bioorg.
Med. Chem. Lett. 2013, 23, 6467.
lective control of the presumed initial Michael addition. Most
importantly, the site-selective preparation of 3-aminopyrazoles19
from cost-effective materials will enhance their availability and
utility for the chemical community.
(11) (a) Constanzo, A.; Bruni, F.; Guerrini, G.; Selleri, S.; Aiello, P. M.;
Lamberti, C. J. Heterocycl. Chem. 1992, 29, 1499. (b) Organ, M. G.;
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Heterocycles 2003, 60, 2323. (b) Guillou, S.; Janin, Y. L. Chem.Eur. J.
2010, 16, 4669.
(13) (a) Maekawa,T.; Hara, R.; Odaka, H.; Kimura, H.; Fune, H.;
Fukatsu, K. Int. Pat. Appl. WO 2003/099793, 2003. (b) Ohno, R.;
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, NMR spectra, and elucidation of site
isomers. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01248.
■
S
AUTHOR INFORMATION
Corresponding Author
■
(14) For an example, see: Liu, Y.; Liu, S.; Li, Y.; Song, H.; Wang, Q.
Bioorg. Med. Chem. Lett. 2009, 19, 2953.
*E-mail: daniel.fandrick@boehringer-ingelheim.com.
Notes
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Perchec, P.; Le; Garapon, J.; Sillion, B. Tetrehedron 1984, 40, 349.
(16) For examples, see: (a) Malet-Sanz, L.; Madrzak, J.; Holvey, R. S.;
Underwood, T. Tetrahedron Lett. 2009, 50, 7263. (b) Gorja, D. R.;
Batchu, V. R.; Ettam, A.; Pal, M. Beilstein J. Org. Chem. 2009,
DOI: 10.3762/bjoc.5.64.
(17) For examples, see: (a) Toto, P.; Chenault, J.; Hakmaoui, A. E.;
Akssira, M.; Guillaumet, G. Synth. Commun. 2008, 38, 674. (b) Numata,
A.; Tanima, D.; Ando, M.; Saito, F.; Iwawaki, Y. PCT Int. Appl. WO
2012/108511, 2002.
(18) For examples, see: (a) Leadbeater, N. E.; Marco, M. J. Org. Chem.
2003, 68, 888. (b) Lipshutz, B. H.; Abela, A. R. Org. Lett. 2008, 10, 5329.
(c) Zhou, J.; Guo, X.; Tu, C.; Li, X.; Sun, H. J. Organomet. Chem. 2009,
694, 697.
(19) For examples of alternate multistep approaches toward 3-
aminopyrazoles, see refs 10c, 17a, and: (a) Berthel, S. J.; Kester, R. F.;
Murphy, D. E.; Prins, T. J.; Ruebsam, F.; Sarabu, R.; Tran, C. V.;
Vourloumis, D. US Pat. Appl. Publ. US 2008/0021032, 2008.
(b) Deprez-Poulain, R.; Cousaert, N.; Toto, P.; Willand, N.; Deprez,
B. Eur. J. Med. Chem. 2011, 46, 3867.
The authors declare no competing financial interest.
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Org. Lett. XXXX, XXX, XXX−XXX