Organocatalytic Asymmetric Michael/Hemiketalization/Retro-aldol Reaction of α-Nitroketones with Unsaturated Pyrazolones: Synthesis of 3-Acyloxy Pyrazoles

Article abstract of DOI:10.1021/acs.orglett.6b03823

An organocatalytic asymmetric cascade Michael/hemiketalization/retro-aldol reaction between unsaturated pyrazolones and α-nitroketones is described. A bifunctional thiourea catalyst was found to be efficient for this reaction. With 10 mol % of catalyst, high yields as well as excellent enantioselectivities are attained for a variety of 3-acyloxy pyrazoles under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.6b03823

Letter
pubs.acs.org/OrgLett
Organocatalytic Asymmetric Michael/Hemiketalization/Retro-aldol
Reaction of α‑Nitroketones with Unsaturated Pyrazolones: Synthesis
of 3‑Acyloxy Pyrazoles
Rajendra Maity, Chandan Gharui, Arun K. Sil, and Subhas Chandra Pan*
Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati, Assam 781039, India
S
* Supporting Information
ABSTRACT: An organocatalytic asymmetric cascade Michael/hemiketalization/retro-aldol reaction between unsaturated
pyrazolones and α-nitroketones is described. A bifunctional thiourea catalyst was found to be efficient for this reaction. With 10
mol % of catalyst, high yields as well as excellent enantioselectivities are attained for a variety of 3-acyloxy pyrazoles under mild
reaction conditions.
yrazoles and pyrazolones are important nitrogen contain-
ing heterocylic motifs that are prevalent in a wide range of
In recent years, unsaturated pyrazolones have been exploited
as electrophiles in a variety of organocatalytic Michael and
cascade reactions.3 Analogously, pyrazolones have also been
found to be suitable nucleophiles in a range of asymmetric
reactions.4 Zhao and co-workers first reported the organo-
catalytic asymmetric synthesis of 3-hydroxy pyrazole via an aza-
Michael addition reaction of pyrazolones to α,β-unsaturated
ketones.4b Ma and co-workers have shown one example of the
synthesis of 3-hydroxy pyrazole in their development of the
organocatlytic Michael reaction to nitroolefins followed by a
dearomatization reaction.4g In contrast, from unsaturated
pyrazolones, only a single report for the synthesis of 3-hydroxy
pyrazoles has been disclosed by the Wang group (Scheme 1).3d
However, to the best of our knowledge, a direct asymmetric
synthesis of 3-acyloxy pyrazoles is still not known. Herein, we
P
bioactive compounds having pharmaceutical and agricultural
activities.1 In particular, 3-hydroxypyrazole derivatives that are
obtained by aromatization of pyrazolones, have interesting
enzyme inhibition2a−d and activation2e properties, and have
been broadly used in antidiabetic,2a−d anticancer,2f−h anti-
inflammatory,2a antipsychosis,2a insecticidal,2i and herbicidal2j
studies. For instance, some aryl-substituted 3-(3-
(dimethylamino)propyloxy)-1H-pyrazoles display potent acti-
vation of soluble guanylate cyclase and potent inhibition of
platelet aggregation (Figure 1).2e Similarly, O-pyrazole
Scheme 1. Organocatalytic Asymmetric Synthesis of 3-
Hydroxy/Acyloxy Pyrazoles from Unsaturated Pyrazolones
Figure 1. Biologically active 3-hydroxy pyrazole derivatives.
glucopyranoside and galactopyranoside derivatives such as
remogliflozin etabonate (Figure 1),2d are inhibitors of human
sodium-glucose contransporters 1 and 2 (SGLT1 and SGLT2)
and may be used for the treatment of diabetes. Thus, the
development of efficient methods for the enantioselective
construction of 3-hydroxy as well as 3-acyloxy pyrazoles having
stereogenic centers is important for the discovery of new chiral
drugs and other utilities.
Received: December 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03823
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
present a method for the synthesis of 3-acyloxy pyrazoles via a
Michael/hemiketalization/retro-aldol strategy employing unsa-
turated pyrazolones and α-nitroketones.
The investigations were initiated by performing a model
reaction between alkylidene pyrazolone 1a and 2-nitro-1-
phenylethanone (2a) with quininidine derived bifunctional
thiourea catalyst I in dichloromethane solvent at 0 °C (Table 1,
studied, and delightfully promising results were attained. For
example, enhancements in enantioselectivities were observed
using chloroform and 1,2-dichloroethane solvent (Table 1,
entries 8−9). Nonpolar solvent such as toluene was also
efficient and afforded the product 3aa in 90% ee (Table 1, entry
10). Finally the best solvent was found to be α,α,α-
trifluorotoluene, and the product 3aa was isolated in 91%
yield with 99% ee (Table 1, entry 11).
After finding the optimal conditions we examined the scope
of the reaction. Initially a variety of pyrazolones 1 having
different benzylidene substitutents were tested (Table 2). It was
Table 1. Catalyst Screening and Optimization of Reaction
Conditions
Table 2. Scope of Pyrazolones with Varied Benzylidene
Substituents
a
b
c
entry
R1
3
yield (%)
ee (%)
1
Ph
3aa
3ba
3ca
3da
3ea
3fa
91
86
85
89
65
93
93
88
83
57
93
80
94
99
97
97
85
97
98
94
93
88
88
95
89
94
2
4-MeC6H4
4-OMeC6H4
4-tBuC6H4
4-FC6H4
3
4
5
6
4-ClC6H4
4-BrC6H4
3-MeC6H4
3-OMeC6H4
3-BrC6H4
2-MeC6H4
2-FC6H4
7
3ga
3ha
3ia
8
9
10
11
12
13
3ja
a
b
c
3ka
3la
entry
catalyst
solvent
yield (%)
ee (%)
1
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
80
82
84
76
85
80
85
89
87
88
91
−44
30
2,4-Me2C6H3
3ma
2
II
a
Reactions were carried out with 0.1 mmol of 1 and 0.1 mmol of 2a in
3
III
IV
V
−36
36
b
α,α,α-trifluorotoluene at 0 °C for 5 days. Isolated yield after silica gel
column chromatography. Determined by HPLC.
4
c
5
61
6
VI
VII
VII
VII
VII
VII
70
7
70
found that a range of electron-withdrawing and -donating
groups can be embedded in the ortho-, meta-, and para-position
of the aryl group, leading to the synthesis of pyrazoles 3aa−3la
in excellent yields and enantioselectivities. A disubstituted aryl
group was also tolerated in the reaction, and product 3ma was
obtained in excellent enantioselectivity (Table 2, entry 13).
The generality of the reaction was further established by
engaging pyrazolones 1 with varied N-substitutions (Table 3).
Accordingly, a variety pyrazolones 1n−r with different N-
substitutions were prepared and employed in the reaction. To
our delight, the reactions progressed well irrespective of the
electronic nature of the aryl group and the products 3na−ra
were attained in excellent enantioselectivities (Table 3).
The next phase of experiments included screening different
α-nitroketones 1 using this method (Scheme 2). As shown in
Scheme 2, a wide range of aryl group containing α-nitroketones
2 could be employed in the reaction, and excellent results were
achieved. Initially, different ortho-, meta-, and para-substitutions
on the phenyl group were incorporated, and delightfully
excellent enantioselectivities (ee = 86−96%) were obtained
(3ab−ak). A heteroaromatic nitroketone 2l and disubstituted
aryl group containing nitroketone 2m also underwent reactions
with pyrazolone 1a delivering products 3al and 3am in
excellent enantioselectivities. Finally, α-nitroketone 2n having a
8
82
9
(CH2Cl)2
PhCH3
PhCF3
87
10
11
90
99
a
Reaction condition: 0.05 mmol of 1a and 0.05 mmol of 2a in 0.5 mL
b
of solvent using 10 mol % catalyst. Isolated yield after silica gel
column chromatography. Determined by HPLC.
c
entry 1). Pleasingly a product was isolated in 80% yield and was
identified to be 3aa by H and 13C NMR analysis. Previously,
1
only a related kind of Michael-benzoyl transfer reaction was
reported in the reaction of α-nitroketone with α,β-unsaturated-
α-ketoesters.5 The enantioselectivity of 3aa was not improved
using hydroquinine derived thiourea catalyst II (Table 1, entry
2). Similar kinds of enantioselectivities were achieved with
Takemoto catalyst III and squaramide catalyst IV (Table 1,
entries 3−4). A higher enantioselectivity was achieved with
catalyst V having an Indane moiety (Table 1, entry 5). Then
tert-leucine derived bifunctional thiourea catalysts VI and VII
were examined. These catalysts were found to be efficient, and
in particular, catalyst VII having a piperidine motif provided the
product 3aa in 85% yield with 70% ee (Table 1, entry 7). Then
the effect of solvent on the yield and enantioselectivity was
B
DOI: 10.1021/acs.orglett.6b03823
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Organic Letters
Letter
Table 3. Scope of Pyrazolones with Varied N-Substituents
Scheme 4. Proposed Mechanism
a
b
c
entry
R2
3
yield (%)
ee (%)
1
2
3
4
5
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
2-MeC6H4
3na
3oa
3pa
3qa
3ra
82
83
81
82
93
96
96
92
89
99
a
Reactions were carried out with 0.1 mmol of 1 and 0.1 mmol of 2a in
b
α,α,α-trifluorotoluene at 0 °C for 5 days. Isolated yield after silica gel
column chromatography. Determined by HPLC.
c
a b
,
Scheme 2. Scope of α-Nitroketones
that nitroketone 2a is activated by the piperidine moiety of the
catalyst VII whereas a thiourea motif binds with pyrazolone
1a.5a Since the Re face of 1a is blocked by catalyst VII, addition
takes place from the Si face to provide intermediate A. Then A
is converted to B via hemiketalization. Finally a retro-aldol
reaction of B delivers product 3aa.
In conclusion, we have developed a mild and operationally
simple Michael−hemiketalization−retro-aldol reaction between
unsaturated pyrazolones and α-nitroketones. This reaction
furnished diverse 3-acyloxypyrazoles in high yields and with
excellent enantioselectivities. Given the high pharmaceutical
and agricultural importance of 3-alkoxypyrazoles, our method
will be useful for the rapid preparation of these compounds.
a
Reactions were carried out with 0.1 mmol of 1a and 0.1 mmol of 2 in
b
α,α,α-trifluorotoluene at 0 °C for 5 days. Isolated yield after silica gel
column chromatography and ee was determined by HPLC.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03823.
cyclohexyl moiety was screened, and gratifyingly excellent
enantioselectivity was maintained.
To demonstrate the synthetic utility of our method, few
reactions were carried out on 3aa (Scheme 3). Nickel
Experimental procedures, characterization data of all the
products (PDF)
Scheme 3. Synthetic Transformations of 3aa
Crystallograhic data for compound 3af (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: span@iitg.ernet.in.
ORCID
Subhas Chandra Pan: 0000-0002-7581-1831
Notes
chloride−sodium borohydride treatment followed by a reaction
with Boc anhydride resulted in the formation of compound 4 in
moderate yield while preserving the excellent enantioselectivity.
A similar reaction with nickel chloride−sodium borohydride
and benzoyl chloride provided amide 5 in an acceptable yield
although a slight erosion in enantioselectivity was detected.
The absolute configuration of the product 3af was
determined to be (S) by X-ray crystallography.6 The absolute
configuration of other products was expected to be the same by
analogy. Based on the absolute configuration a plausible
mechanism has been depicted in Scheme 4. It is expected
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST, DAE for the funding. We also thank CIF,
Indian Institute of Technology Guwahati for the instrumental
facility.
REFERENCES
■
(1) For selected reviews, see: (a) Sondhi, S. M.; Dinodia, M.; Singh,
J.; Rani, R. Curr. Bioact. Compd. 2007, 3, 91. (b) Varvounis, G. Adv.
C
DOI: 10.1021/acs.orglett.6b03823
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Heterocycl. Chem. 2009, 98, 143. (c) Schmidt, A.; Dreger, A. Curr. Org.
Chem. 2011, 15, 1423. (d) Fustero, S.; San
́ ́
chez-Rosello, M.; Barrio, P.;
Simon-Fuentes, A. Chem. Rev. 2011, 111, 6984.
́
(2) (a) Cuberes-Altisent, R.; Holenz, J. PCT Int. Appl.
WO2007098953, 2007; Chem. Abstr. 2007, 147, 301168. (b) Teranishi,
H.; Fushimi, N.; Yonekubo, S.; Shimizu, K.; Shibazaki, T.; Isaji, M.
PCT Int. Appl. WO2004014932, 2004; Chem. Abstr. 2004, 140,
199632. (c) Washburn, W. N. Pct Int. Appl. WO2003020737, 2003;
Chem. Abstr. 2003, 138, 221784. (d) Shiohara, H.; Fujikura, H.;
Fushimi, N.; Ito, F.; Isaji, M. PCT Int. Appl. WO 2002098893, 2002;
Chem. Abstr. 2003, 138, 24917. (e) Selwood, D. L.; Brummell, D. G.;
Budworth, J.; et al. J. Med. Chem. 2001, 44, 78. (f) Baraldi, P. G.;
Nunez, M. d. C.; Tabrizi, M. A.; De Clercq, E.; Balzarini, J.; Bermejo,
J.; Estevez, F.; Romagnoli, R. J. Med. Chem. 2004, 47, 2877. (g) Brana,
M. F.; Gradillas, A.; Ovalles, A. G.; Lopez, B.; Acero, N.; Llinares, F.;
Mingarro, D. M. Bioorg. Med. Chem. 2006, 14, 9. (h) Alterico, D.;
Jereczek-Fossa, B. A.; Fiore, M. R.; Piperno, G.; Ansarin, M.; Orecchia,
R. Anticancer Res. 2007, 27, 1105. (i) Hughes, K. A.; Lahm, G. P.;
Selby, T. P. PCT Int. Appl. WO2004046129, 2009; Chem. Abstr. 2004,
141, 23526. (j) Ohno, R.; Watanabe, A.; Matsukawa, T.; Ueda, T.;
Sakurai, H.; Hori, M.; Hirai, K. J. Pestic. Sci. 2004, 29, 15. For a review,
see: Washburn, W. N. J. Med. Chem. 2009, 52, 1785.
(3) For selected examples, see: (a) Zea, A.; Alba, A. N. P.; Mazzanti,
A.; Moyano, A.; Rios, R. Org. Biomol. Chem. 2011, 9, 6519. (b) Liu, L.;
Zhong, Y.; Zhang, P.; Jiang, X.; Wang, R. J. Org. Chem. 2012, 77,
10228. (c) Chen, Q.; Liang, J.; Wang, S.; Wang, D.; Wang, R. Chem.
Commun. 2013, 49, 10228. (d) Geng, Z.-C.; Chen, X.; Zhang, J.-X.; Li,
N.; Chen, J.; Huang, X.-F.; Zhang, S.-Y.; Tao, J.-C.; Wang, X.-W. Eur. J.
Org. Chem. 2013, 2013, 4738. (e) Chauhan, P.; Mahajan, S.; Loh, C. C.
J.; Raabe, G.; Enders, D. Org. Lett. 2014, 16, 2954. (f) Li, J.-H.; Du, D.-
M. Chem. - Asian J. 2014, 9, 3278. (g) Han, B.; Huang, W.; Ren, W.;
He, Gu.; Wang, J-h.; Peng, C. Adv. Synth. Catal. 2015, 357, 561. (h) Li,
J.-H.; Feng, T.-F.; Du, D.-M. J. Org. Chem. 2015, 80, 11369. (i) Wang,
H.-X.; Wu, L.-L.; Wang, Y. M.; Zhou, Z.-H. RSC Adv. 2015, 5, 42836.
(j) Li, J.-H.; Wen, H.; Liu, L.; Du, D.-M. Eur. J. Org. Chem. 2016, 2016,
2492. (k) Wang, S.; Rodriguez-Escrich, C.; Pericas, M. A. Org. Lett.
́
2016, 18, 556. For a review, see: (l) Chauhan, P.; Mahajan, S.; Enders,
D. Chem. Commun. 2015, 51, 12890.
(4) For selected reports, see: (a) Gogoi, S.; Zhao, C.-G. Tetrahedron
Lett. 2009, 50, 2252. (b) Gogoi, S.; Zhao, C.-G.; Ding, D. Org. Lett.
2009, 11, 2249. (c) Liao, Y.-H.; Chen, W.-B.; Wu, Z.-J.; Du, X.-L.;
Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Adv. Synth. Catal. 2010, 352,
827. (d) Yang, Z.; Wang, Z.; Bai, S.; Liu, X.; Lin, L.; Feng, X. Org. Lett.
2011, 13, 596. (e) Mazzanti, A.; Calbet, T.; Font-Bardia, M.; Moyano,
A.; Rios, R. Org. Biomol. Chem. 2012, 10, 1645. (f) Enders, D.;
Grossmann, A.; Gieraths, B.; Duzdemir, M.; Merkens, C. Org. Lett.
̈
2012, 14, 4254. (g) Li, F.; Sun, L.; Teng, Y.; Yu, P.; Zhao, J. C.-G.; Ma,
̌
J.-A. Chem. - Eur. J. 2012, 18, 14255. (h) Simek, M.; Remes,
̌
M.;
Vesely, J.; Rios, R. Asian J. Org. Chem. 2013, 2, 64. (i) Yetra, S. R.;
́
Mondal, S.; Suresh, E.; Biju, A. T. Org. Lett. 2015, 17, 1417. (j) Hack,
D.; Chauhan, P.; Deckers, K.; Mizutani, Y.; Raabe, G.; Enders, D.
Chem. Commun. 2015, 51, 2266. (k) Vila, C.; Amr, F. i.; Blay, G.;
̌
Munoz, M. C.; Pedro, J. R. Chem. - Asian J. 2016, 11, 1532.
(l) Kumarswamyreddy, N.; Kesavan, V. Org. Lett. 2016, 18, 1354. For
a review, see ref 3k.
(5) (a) Gao, Y.; Ren, Q.; Siau, W.-Y.; Wang, J. Chem. Commun. 2011,
47, 5819. (b) Lu, R.-J.; Yan, J.-Y.; Wang, J.-J.; Du, Q.-S.; Nie, S.-Z.;
Yan, M. J. Org. Chem. 2011, 76, 6230. (c) Li, P.; Chan, S. H.; Chan, A.
S. C.; Kwong, F. Y. Org. Biomol. Chem. 2011, 9, 7997.
(6) CCDC 1523176 contains the crystallographic data for 3af.
D
DOI: 10.1021/acs.orglett.6b03823
Org. Lett. XXXX, XXX, XXX−XXX