Enantioselective synthesis of β-(3-hydroxypyrazol-1-yl) ketones using an organocatalyzed michael addition reaction

Article abstract of DOI:10.1021/ol900538q

β-(3-Hydroxypyrazol-1-yl) ketones have been prepared in high yields and excellent enantioselectivities (94-98% ee) via a Michael addition reaction between 2-pyrazolin-5-ones and aliphatic acyclic α,β-unsaturated ketones using 9-epi-9-amino-9-deoxyquinine

Full text of DOI:10.1021/ol900538q

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2249-2252
Enantioselective Synthesis of
ꢀ-(3-Hydroxypyrazol-1-yl) Ketones Using
an Organocatalyzed Michael Addition
Reaction
Sanjib Gogoi, Cong-Gui Zhao,* and Derong Ding
Department of Chemistry, UniVersity of Texas at San Antonio, One UTSA Circle,
San Antonio, Texas 78249-0698
cong.zhao@utsa.edu
Received March 14, 2009
ABSTRACT
ꢀ-(3-Hydroxypyrazol-1-yl) ketones have been prepared in high yields and excellent enantioselectivities (94-98% ee) via a Michael addition
reaction between 2-pyrazolin-5-ones and aliphatic acyclic r,ꢀ-unsaturated ketones using 9-epi-9-amino-9-deoxyquinine as the catalyst.
These results account for the first example of an aza-Michael addition of the ambident 2-pyrazolin-5-one anion to a Michael acceptor.
Pyrazole is an important pharmacophore. Compounds con-
taining this moiety frequently exhibit various biological and
pharmacological activities.1 Among the pyrazole derivatives,
1-alkyl-3-hydroxyprazole derivatives are potent enzyme
inhibitors2a-d and activators2e and have been widely used
in antidiabetic,2a-d anticancer,2f-h anti-inflammatory,2a
antipsychosis,2a insecticidal,2i and herbicidal2j studies. For
example, O-pyrazole glucopyranoside and galactopyranoside
derivatives, such as remogliflozin etabonate (Figure 1),2d are
inhibitors of human sodium-glucose cotransporters 1 and
2 (SGLT1 and SGLT2) and may be used as antidiabetic
agents.2a-d,k
Figure 1. Remogliflozin etabonate (GlaxoSmithKline), an inhibitor
of SGLT2 for the treatment of type 2 diabetes.
1-Alkyl-3-hydroxyprazoles may be synthesized by
condensing alkylhydrazines and ꢀ-substituted acetylenic
methods cannot be developed into an enantioselective
synthesis for pyrazoles with chiral substituents.
During our recent study of the organocatalyzed reaction
of benzylidenemalononitriles and 3-methyl-2-pyrazolin-5-
ones,4 we envisaged that the anion of 3-methyl-2-pyrazolin-
5-one should also be a suitable nucleophile for the conjugate
esters3a or ꢀ-ketoesters.3b However, intrinsically these
(1) For reviews, see: (a) Sondhi, S. M.; Dinodia, M.; Singh, J.; Rani,
R. Curr. Bioact. Comp. 2007, 3, 91–108. (b) Elguero, J.; Goya, P.; Jagerovic,
N.; Silva, A. M. S. Targets Heterocycl. Systems 2002, 6, 52–98.
10.1021/ol900538q CCC: $40.75
Published on Web 05/05/2009
 2009 American Chemical Society

addition to R,ꢀ-unsaturated ketones. It should be pointed out
that the anion of 3-methyl-2-pyrazolin-5-one is an ambident
nucleophile. There are ample examples that use it as a carbon
nucleophile in carba-Michael addition reactions.5 Moreover,
the carba-Michael addition of this anion to aryl-substituted
R,ꢀ-unsaturated ketones was also reported.5a,b However, to
our knowledge, there is no report on its use as a nitrogen or
an oxygen nucleophile in a Michael addition reaction. Herein
we report the first example of an aza-Michael addition of
the 3-methyl-2-pyrazolin-5-one anion6 for a highly enanti-
oselective synthesis of 1-alkyl-3-hydroxypyrazoles by using
9-epi-9-amino-9-deoxyquinine as the catalyst.
Table 1. Catalyst Screening and Optimization of the Reaction
Conditions for the Michael Addition of 3-Methyl-2-pyrazolin-5-
one (9a) to the R,ꢀ-Unsaturated Ketone 8aa
entry catalyst solvent acid additive yieldb (%) eec (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
6
6
6
6
6
6
6
6
6
6
6
6
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene benzoic acid
Et2O
CHCl3
THF
CH2Cl2
CH3CN
MeOH
toluene
toluene
toluene
TFA
TFA
TFA
TFA
TFA
TFA
TFA
p-TSA
CH3COOH
benzoic acid
30
60
56
53
52
84
77
44
57
85
79
70
67
76
71
52
7
26d
20d
20d
17d
44
Primary amine-catalyzed conjugate addition to R,ꢀ-
unsaturated ketones is an important strategy in organoca-
talysis.7 Thus, some optically active primary amines (Figure
2) were adopted as the catalysts for the Michael addition of
88
70d
88
9
92
96
96
96
96
90
90
76
37
95
95
96
10
11
12
13
14
15
16
17
18e
19f
20g
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
benzoic acid
34
69
34
a Unless otherwise indicated, reactions were carried out with 8a (0.1
mmol), 9a (0.1 mmol), the catalyst (20 mol %), and the acid additive (40
mol %) in the specified solvent (0.6 mL) at rt. b Yield of isolated product
after column chromatography. c Determined by HPLC using a ChiralCel
OD-H column. d The S enantiomer was obtained as the major product. e 10
mol % of catalyst 6 and 40 mol % of benzoic acid were used. f 20 mol %
of catalyst 6 and 20 mol % of benzoic acid were used. g 10 mol % of catalyst
6 and 20 mol % of benzoic acid were used.
deoxyquinine (6) was used as the catalyst under these
conditions, a good yield of 84% of the product was obtained,
and the ee value was improved to 88% ee (entry 6). Catalyst
7, the pseudoenantiomer of 6, also yields the product in good
yield, and a good ee value of 70% was obtained (entry 7). It
Figure 2. Catalysts screened for the aza-Michael addition of
3-methyl-2-pyrazolin-5-one (9a) to the R,ꢀ-unsaturated ketone 8a.
3-methyl-2-pyrazolin-5-one (9a) to an R,ꢀ-unsaturated ketone
8a. The results are listed in Table 1.
(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, 78–93. (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, 2877–2886. (g) Brana, M. F.; Gradillas, A.; Ovalles, A. G.; Lopez,
B.; Acero, N.; Llinares, F.; Mingarro, D. M. Bioorg. Med. Chem. 2006,
14, 9–16. (h) Alterio, D.; Jereczek-Fossa, B. A.; Fiore, M. R.; Piperno, G.;
Ansarin, M.; Orecchia, R. Anticancer Res. 2007, 27, 1105–1125. (i) Hughes,
K. A.; Lahm, G. P.; Selby, T. P. PCT Int. Appl. WO2004046129,
2004;Chem. Abstr. 2004, 141, 23526. (j) Ohno, R.; Watanabe, A.;
Matsukawa, T.; Ueda, T.; Sakurai, H.; Hori, M.; Hirai, K. J. Pesticide Sci.
2004, 29, 15–26. (k) Fujimori, Y.; Katsuno, K.; Nakashima, I.; Ishikawa-
Takemura, Y.; Fujikura, H.; Isaji, M. J. Pharm. Exp. Therap. 2008, 327,
268–276. For a review, see: Washburn, W. N. J. Med. Chem. 2009, 52,
1785–1794.
When 20 mol % of (S)-1-phenylethylamine (1) was used
as the catalyst and 40 mol % of trifluoroacetic acid (TFA)
was used as the cocatalyst in toluene at rt, the reaction of
8a and 9a produced a product in 30% yield (entry 1). The
structure of this product was determined to be the 3-hydrox-
yprazole derivative 10a. This is the first example of the
addition of the anion of 9a as a nitrogen nucleophile onto a
Michael acceptor. The ee value of this aza-Michael product
was determined to be 26%. Further screening some C2-
symmetric primary amines 2-4 revealed that higher yields
of the product could be obtained; however, the ee values of
the product remained low (entries 2-4). The monotosylated
diamine 5 also leads to a poor enantioselectivity of the
product (entry 5). To our pleasure, when 9-epi-9-amino-9-
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Org. Lett., Vol. 11, No. 11, 2009

should be pointed out that the major enantiomer obtained
with catalysts 5 and 6 is opposite that obtained with catalysts
1-4 and 7. Thus, this screening identified catalyst 6 as the
best catalyst for this reaction. Next, the acid cocatalyst was
screened. p-Toluenesulfonic acid (p-TSA) was found to
generate the same ee value of the product as TFA, but it
diminished the yield of the product (entry 8). Acetic acid
generated a slightly better ee value of 92%; nevertheless,
the yield was much lower than that obtained with TFA (entry
9). Benzoic acid was the best cocatalyst because a good yield
of 85% of product was achieved and the ee value of the
product was increased to 96% (entry 10). Further optimiza-
tion of the solvent revealed this excellent ee value may also
be obtained from benzene, Et2O, and CHCl3 (entries 11-13),
albeit with slightly lower yields of the product; however,
THF, CH2Cl2, CH3CN, and MeOH (entries 14-17) are worse
solvents since the ee values and yields obtained were lower.
Thus, toluene was identified as the best solvent for this
reaction. Reducing the catalyst loading to 10 mol % (entry
18), reducing the benzoic acid loading to 20 mol % (entry
19), or reducing the loadings of both the catalyst and the
cocatalyst (entry 20) all led to reduced yields of the product,
whereas the asymmetric induction was not affected. While
lowering the reaction temperature to 0 °C shows no effect
on the enantioselectivity, elevating the reaction temperature
to 40 °C leads to a drop of the ee value to 90% (data not
shown).
Table 2. Aza-Michael Addition of 2-Pyrazolin-5-ones to
R,ꢀ-Unsaturated Ketones Catalyzed by 6a
entry
R1
R2
R3 10 time (h) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
n-Pent
Me
Et
n-Bu
n-Hex
i-Pr
PhCH2
Ph(CH2)2 Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
a
b
c
d
e
f
g
h
i
22
24
26
25
25
27
23
24
25
25
26
24
85
85
87
84
81
79
84
78
79
81
86
82
96
96
96
96
94
98
94
94d
97
98
96
96
9
Et
10
11
12
n-Pr Me
Me
Me
j
k
l
Et
Et
a Unless otherwise indicated, reactions were carried out with 8 (0.1
mmol), 9 (0.1 mmol), catalyst 6 (20 mol %), and benzoic acid (40 mol %)
in toluene (0.6 mL) at rt. b Yield of isolated product after column
chromatography. c Unless otherwise indicated, the ee values were determined
by HPLC analysis using a ChiralCel OD-H column. d Determined by HPLC
analysis using a Chiralpak AS column.
The scope and limitations of this reaction were then studied
under the optimized conditions (20 mol % loading of catalyst
6 and 40 mol % loading of benzoic acid in toluene at rt).
The results are collected in Table 2. As shown by the results
in Table 2, the chain length of the group connected to the
C-C double bond (R1) of the unsaturated ketone 8 has no
effect on the enantioselectivity and reactivity of this reaction
because similarly good results were obtained from methyl
to n-hexyl derivatives (entries 1-5). In addition, excellent
results were obtained when the size of the R1 was increased
to an isopropyl group (entry 6). However, when R1 is a
phenyl group, a mixture of unidentified products was
obtained (data not shown). Nonetheless, if the phenyl group
is not directly attached to the double bond, such as in the
benzyl or the 2-phenylethyl groups, high yields and excellent
ee values of the desired products were again obtained (entries
7 and 8). Similarly, the group (R2) connected the carbonyl
group of 8 has no influence on the enantioselectivity of this
reaction (entries 2, 9, and 10). Nevertheless, if R2 is a phenyl
group, such as in trans-chalcone and trans-crotonophenone,
the reaction failed to proceed (data not shown), probably
due to the low reactivity of such aromatic ketones. A cyclic
enone, cyclohex-2-enone, produces a complex mixture of
unidentified products (data not shown). Excellent ee values
and good yields were also obtained when the alkyl group
on the 2-pyrazolin-5-one was changed from a methyl group
to an ethyl group (entries 11 and 12).
The absolute configuration of the major enantiomers
formed in this reaction was determined by X-ray crystal-
lographic analysis of the product 10d (Table 2, entry 4).8,9
According to the X-ray data, in the solid state, two molecules
of the same product form two complementary intermolecular
hydrogen bonds between the 3-hydroxy group of one
molecule and the 2-nitrogen atom of the other. The absolute
configuration of the carbon stereogenic center formed during
the reaction is determined to be R.9
(3) (a) Hamper, B. C.; Kurtzweil, M. L.; Beck, J. P. J. Org. Chem. 1992,
57, 5680–5686. (b) Carpino, L. A. J. Am. Chem. Soc. 1958, 80, 599–601.
(4) Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009, 50, 2252–2255.
(5) For the cojugate addition to R,ꢀ-unsaturated aryl ketones, see: (a)
Etman, H. A.; El-Ahl, A. S.; Metwally, M. A. Arch. Pharm. Res. 1994, 17,
278–280. (b) Metwally, S. A. M.; Younes, M. I.; Nour, A. M. Bull. Faculty
Sci., Assiut UniV. 1986, 15, 1–9. (c) For a summary, see ref 4.
(6) For related examples, see: (a) Moran, J.; Dornan, P.; Beauchemin,
A. M. Org. Lett. 2007, 9, 3893–3896. (b) Han, X. Tetrahedron Lett. 2007,
48, 2845–2849.
(7) For some leading examples of primary amine-catalyzed Michael
additions, see: (a) Reisinger, C. M.; Wang, X.; List, B. Angew. Chem., Int.
Ed. 2008, 47, 8112–8115. (b) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.;
Wang, Y.; Liang, X.; Ye, J. Org. Lett. 2009, 11, 753–756. (c) Kang, T.-R.;
Xie, J.-W.; Du, W.; Feng, X.; Chen, Y.-C. Org. Biomol. Chem. 2008, 6,
2673–2675. (d) Lu, X.; Liu, Y.; Sun, B.; Cindric, B.; Deng, L. J. Am. Chem.
Soc. 2008, 130, 8134–8135. (e) Tan, B.; Shi, Z.; Chua, P. J.; Zhong, G.
Org. Lett. 2008, 10, 3425–3428. (f) Wang, X.; Reisinger, C. M.; List, B.
J. Am. Chem. Soc. 2008, 130, 6070–6071. (g) Xie, J.-W.; Chen, W.; Li,
R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G.
Angew. Chem., Int. Ed. 2007, 46, 389–392. (h) Xie, J.-W.; Yue, L.; Chen,
W.; Du, W.; Zhu, J.; Deng, J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413–
415. (i) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7,
1967–1969. (j) McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599–
602.
The reaction may be explained by the proposed transition
state in Scheme 1. The enone 8a reacts with catalyst 6 to
form an iminium intermediate under the action of the acid
(8) For details, see the Supporting Information
.
(9) CCDC 721869 contains the supplementary crystallographic data for
10d. These data can be obtained free of charge from the Cambridge
Crystallographic Data centre via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 11, No. 11, 2009
2251

under our mild acidic conditions, the nitrogen site instead
of the carbon site adds to the activated Michael acceptor
probably because the nitrogen site is more nucleophilic.
Scheme 1
.
Proposed Transition State of the Aza-Michael
Addition Reaction
In summary, we have observed the first example of an
aza-Michael addition of the 2-pyrazolin-5-one anion to R,ꢀ-
unsaturated acyclic aliphatic ketones. By using 9-epi-9-
amino-9-deoxyquinine as the catalyst and benzoic acid as
the cocatalyst, high enantioselectivity (94-98% ee) and good
yields have been achieved for the direct synthesis of ꢀ-(3-
hydroxypyrazol-1-yl) ketones.
Acknowledgment. This research is financially supported
by the Welch Foundation (Grant No. AX-1593) and partly
by the National Institute of General Medical Sciences (Grant
No. 1SC1GM082718-01A1), for which the authors are most
grateful. We also thank Dr. William Haskins and the RCMI
Proteomics Core (NIH G12 RR013646) at UTSA for
assistance with HRMS experiment design, sample prepara-
tion, data collection, and results interpretation and Dr. Hadi
Arman (UTSA) for help with the X-ray analysis.
cocatalyst. Simultaneously, catalyst 6 also deprotonates
3-methyl-2-pyrazolin-5-one (9a) to give the anionic inter-
mediate. Due to ionic interactions, this anion and the
quinuclidine ammonium form a tight complex (Scheme 1).
The attack of the nitrogen site of the 3-methyl-2-pyrazolin-
5-one anion onto the R,ꢀ-unsaturated iminium from below
yields the intermediate 11 after hydrolysis, which tautomer-
izes to yield the product 10a. Although it is known that the
3-methyl-2-pyrazolin-5-one anion adds to R,ꢀ-unsaturated
ketones as a carbon nucleophile under basic conditions,5a,b
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and NMR spectra
for new compounds, HPLC analysis spectra, and HRMS
analysis spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL900538Q
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Org. Lett., Vol. 11, No. 11, 2009