Asymmetric Michael/aromatization reaction of azlactones to α,β-unsaturated pyrazolones with C-4 regioselectivity catalyzed by an isosteviol-derived thiourea organocatalyst

Article abstract of DOI:10.1002/ejoc.201300524

Pyrazoles are an important class of molecular structures with significant biological and pharmaceutical activities. Herein, heterocyclic compounds containing both a pyrazole motif and a masked amino acid structure are synthesized through the asymmetric Michael/aromatization of azlactones to α,β-unsaturated pyrazolones by using isosteviol-derived amine thiourea as the organocatalyst. The products are obtained in good yields (up to 93 %) with good diastereoselectivities and good enantioselectivities (up to >10:1 dr, 97 % ee). Copyright

Full text of DOI:10.1002/ejoc.201300524

Job/Unit: O30524
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SHORT COMMUNICATION
Asymmetric Organocatalysis
Z.-C. Geng, X. Chen, J.-X. Zhang, N. Li,
J. Chen, X.-F. Huang, S.-Y. Zhang,
J.-C. Tao,* X.-W. Wang* .................. 1–7
Asymmetric Michael/Aromatization Reac-
tion of Azlactones to α,β-Unsaturated Pyr-
Compounds containing both a pyrazole
motif and a masked amino acid structure
were obtained through the asymmetric
Michael addition/aromatization of azlact-
ones to α,β-unsaturated pyrazolones. The
reaction proceeds with C-4 regioselectivity
by using an isosteviol-derived thiourea or-
ganocatalyst and provides the products in
good yields with good diastereoselectivities
and good enantioselectivities.
azolones with C-4 Regioselectivity Cata-
lyzed by an Isosteviol-Derived Thiourea
Organocatalyst
Keywords: Organocatalysis / Asymmetric
synthesis / Amino acids / Nitrogen hetero-
cycles / Azlactones
0000, 0–0
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J.-C. Tao, X.-W. Wang et al.
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300524
Asymmetric Michael/Aromatization Reaction of Azlactones to α,β-Unsaturated
Pyrazolones with C-4 Regioselectivity Catalyzed by an Isosteviol-Derived
Thiourea Organocatalyst
Zhi-Cong Geng,[a] Xiang Chen,[a] Jin-Xin Zhang,[a] Ning Li,[a] Jian Chen,[a]
Xiao-Fei Huang,[a] Shao-Yun Zhang,[a] Jing-Chao Tao,*[b] and Xing-Wang Wang*[a]
Keywords: Organocatalysis / Asymmetric synthesis / Amino acids / Nitrogen heterocycles / Azlactones
Pyrazoles are an important class of molecular structures with
significant biological and pharmaceutical activities. Herein,
heterocyclic compounds containing both a pyrazole motif
and a masked amino acid structure are synthesized through
the asymmetric Michael/aromatization of azlactones to α,β-
unsaturated pyrazolones by using isosteviol-derived amine
thiourea as the organocatalyst. The products are obtained in
good yields (up to 93%) with good diastereoselectivities and
good enantioselectivities (up to Ͼ10:1dr, 97%ee).
Introduction
Pyrazoles and pyrazolones, which are five-membered
heterocyclic compounds containing two adjacent nitrogen
atoms, are important motifs found in a number of organic
molecules that possess a wide range of agricultural and
pharmaceutical activities. Particularly, 3-hydroxypyrazole
derivatives, obtained by aromatization of pyrazolones, are
extensively studied as potent biological enzyme inhibitors
and activators. For example, some aryl-substituted 3-(3-di-
methylaminopropyloxy)-1H-pyrazoles demonstrate potent
activation of soluble guanylate cyclase and potent inhibi-
tion of platelet aggregation. Remogliflozin etabonate plays
an important role in renal glucose reabsorption and is a
remarkable transporter as a molecular target for the treat-
ment of diabetes (Figure 1).[1] Therefore, the development
of new methods for the efficient synthesis of optically active
pyrazoles and pyrazolones is highly desirable. From 2011,
Rios, Wang, and our group successively reported organoca-
talytic cascade reactions to synthesize spiropyrazolones by
using α,β-unsaturated pyrazolones or pyrazolones as start-
ing materials.[2]
Figure 1. Some biologically active pyrazole, pyrazolone, and α-
amino acid derivatives.
eered by the groups of Fu and Trost (Figure 1).[4–6] Ten
years later, Jørgensen and co-workers first reported the or-
ganocatalytic enantioselective Michael addition of 4-substi-
tuted azlactones to α,β-unsaturated aldehydes with com-
plete C-4 regioselectivity.[7] Shortly thereafter, Hayashi and
co-workers also reported a similar enantioselective transfor-
mation.[8] Subsequently, Jørgensen, Rios and Ooi individu-
ally reported the organocatalyzed Michael additions of 4-
substituted azlactones to nitrostyrenes,[9] unsaturated acyl
phosphonates,[10] phenylsulfonyl-substituted ethylenes,[11]
maleimides,[12] unsaturated amides,[13] electron-deficient tri-
ple bonds,[14] and di- and trienyl N-acylpyrroles[15] to pro-
vide either masked quaternary α-amino acid derivatives (C-
4 regioselectivity) or chiral oxyaminals (C-2 regioselec-
tivity).
The use of azlactones as precursors for the enantioselec-
tive synthesis of quaternary α-amino acid derivatives[3]
found in many biologically active compounds was pion-
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University,
Suzhou 215123, P. R. China
E-mail: wangxw@suda.edu.cn
[b] Department of Chemistry, Zhengzhou University,
Zhengzhou 450001, P. R. China
E-mail: jctao@zzu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300524.
2
www.eurjoc.org
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Asymmetric Michael/Aromatization Reaction of Azlactones
Generally, the relative nucleophilicities of 2,4-disubsti- thiourea organocatalyst, originally devised by the Tao
tuted azlactones were greatly affected by several factors, in- group for enantioselective catalysis,[16] in excellent yields
cluding substituents on the azlactones, electrophiles, cata- with good to excellent enantioselectivities (Scheme 1).
lysts, and reaction conditions. In the reported literature,
many reactions showing C-4 regioselectivity were per-
formed with the use of azlactones derived from phenyl-
glycines as the donors of the Michael addition reactions.
Results and Discussion
Given that azlactones and pyrazolones are highly practical
synthetic blocks, herein we report the organocatalytic
enantioselective Michael addition/aromatization reactions
between alkyl-substituted azlactones and α,β-unsaturated
pyrazolones to provide enantiomerically enriched hetero-
cyclic products containing both a 3-hydroxypyrazole motif
and a masked amino acid structure. These reactions are ef-
ficiently catalyzed by an isosteviol-derived bifunctional
Initially, the reaction between 4-benzyl-2-phenyl-2-oxaz-
oline-5-one (2a) and α,β-unsaturated pyrazolone 3a was se-
lected as the model reaction to examine a series of bifunc-
tional organic catalysts 1a–l (Figure 2) in dichloromethane
at room temperature (Table 1, entries 1–12). Quinine and
its derivatives 1a–d were firstly tested (Table 1, entries 1–4).
When quinine-derived tertiary amino–thiourea organocata-
lyst 1d (10 mol-%) was employed,[17] the Michael addition
of 2a with 3a provided desired product 4a in 70% yield with
43%ee (Table 1, entry 4). Encouraged by these promising
results, (1R,2R)-cyclohexane-1,2-diamine (DACH) and
(1R,2R)-1,2-diphenylethane-1,2-diamine (DPEN) derived
bifunctional thiourea tertiary amine catalysts 1e–i were in-
vestigated for this transformation (Table 1, entries 5–9). We
found that organocatalysts 1h and li with (R)- and (S)-α-
phenylethylamine motifs increased the enantioselectivity of
product 4a to 71 and 72%ee, respectively, with over 10:1dr
(Table 1, entries 8 and 9). Furthermore, several chiral isos-
teviol-derived bifunctional thiourea organocatalysts 1j–l
were synthesized and examined in this reaction (Table 1, en-
tries 10–12). To our delight, if 1j (10 mol-%) was used in
this transformation, product 4a was obtained in 92% yield
with Ͼ10:1dr and 81%ee (Table 1, entry 10). Notably, a
trace amount up to 9% yield of 6a was detected in all of
the above tentative reactions, which might be produced by
Michael/ring opening or a concerted Diels–Alder process,
Scheme 1. The Michael/aromatization reaction of azlactones 2 to
α,β-unsaturated pyrazolones 3. Path a: C-4 regioselectivity and
Path b: C-2 regioselectivity; Bn = benzyl.
Figure 2. Structures of bifunctional organocatalysts 1a–l.
Eur. J. Org. Chem. 0000, 0–0
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J.-C. Tao, X.-W. Wang et al.
SHORT COMMUNICATION
and 5a resulting from C-2 regioselectivity was not detected. Table 2. Optimization of the reaction conditions.[a]
With 1j as the organocatalyst, less than 5% yield of 6a was
obtained (Table 1, entry 10). So, 1j turned out to be the op-
timal organocatalyst in terms of both enantioselectivity and
reactivity.
Table 1. Optimization of the catalysts.[a]
Entry
Solvent
T
[°C]
Conc.
[m]
t
[h]
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
CH2Cl2
Et2O
PhMe
PhCl
PhMe
PhCl
CH2Cl2 –40
Et2O
PhMe
PhCl
CH2Cl2 –40
PhMe
PhCl
r.t.
r.t.
r.t.
r.t.
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
5[d]
5[d]
0.25
8
8
8
8
8
8
8
1
1
1
8
8
8
8
8
92
90
91
94
91
94
97
87
94
94
95
93
93
88
88
92
93
95
91
87
81
80
80
78
86
88
91
82
95
92
93
93
90
92
91
96
97
96
96
96
–40
–40
–40
–40
–40
9[e]
10[e]
11[e]
12[e]
13[e]
14[e]
15[f]
16[g]
17[h]
18[i]
19[j]
20[k]
Entry
Catalyst
t
Yield[b] 4a/6a[c]
dr[c]
ee[d]
[min]
[%]
[%]
–20
–20
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
5
180
15
45
180
25
15
15
15
30
88
60
81
70
50
78
75
93
91
92
89
46
–
–
–
–
–
–
–
–
–
–
–15
–4
37
–43
45
21
49
71
72
81
CH2Cl2 –20
0.1
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
–40
–40
–40
–40
–40
–40
0.20
0.05
0.025
0.025
0.025
0.025
–
–
–
–
16:1
13:1
17:1
10:1
–
Ͼ10:1
Ͼ10:1
Ͼ10:1
Ͼ10:1
–
8
9
10
11
12
1j
1k
1l
[a] Unless noted, reactions were carried out with 2a (0.13 mmol),
3a (0.1 mmol), and 1j (10 mol-%) in solvent (1.0 mL) at r.t. In all
cases, the products were obtained with Ͼ10:1dr, as determined by
1H NMR spectroscopy. [b] Isolated yield of 4a; isomers 4a and 6a
could be easily separated. [c] Determined by chiral HPLC analysis.
[d] Time is given in minutes. [e] With the addition of 4 Å MS
(100 mg). [f] With toluene (0.5 mL), 4 Å MS (50 mg). [g] With tolu-
ene (2.0 mL), 4 Å MS (200 mg). [h] With toluene (4.0 mL), 4 Å MS
(400 mg). [i] 20 mol-% of the catalyst was used. [j] 5 mol-% of the
catalyst was used. [k] 2.5 mol-% of the catalyst was used.
30
180
–73
–51
[a] Unless noted, reactions were carried out with 2a (0.13 mmol),
3a (0.1 mmol), and 1 (10 mol-%) in CH2Cl2 (1.0 mL) at r.t.; Bz =
benzoyl. [b] Isolated yield of 4a; isomers 4a and 6a could be easily
separated. [c] Determined by 1H NMR spectroscopy. [d] Deter-
mined by chiral HPLC analysis.
Having identified 1j as a potent catalyst for this transfor-
mation, the reaction conditions were further optimized by
examination of the effects of solvent, temperature, additive,
Having established the optimized reaction conditions, the
substrate concentration, as well as the catalyst loading, and scope and limitations of the substrate were then explored
the results are shown in Table 2. The effect of solvent was with isosteviol-derived thiourea 1j (10 mol-%) as the cata-
first examined in the presence of 1j (10 mol-%), and several lyst in toluene at –40 °C with 4 Å molecular sieves as an
common solvents, such as CH2Cl2, Et2O, toluene, and additive, and the results are summarized in Table 3. With
PhCl, all exhibited similar reactivity, enantioselectivity, and the use of 2a as the nucleophilic reagent, α,β-unsaturated
diastereoselectivity at the same substrate concentration at pyrazolones 3 were investigated to study the effects of the
room temperature (Table 2, entries 1–4). If the reaction was electronic properties and the steric hindrance of the R3
carried out at –40 °C in CH2Cl2, 91% enantioselectivity was group on enantioselectivity, diastereoselectivity, and reac-
obtained (Table 2, entry 7). To our delight, the enantio- tivity (Table 3, entries 1–9). For aryl-substituted α,β-unsatu-
selectivity could be further improved to 95% by adding ac- rated pyrazolones 3 bearing electron-donating groups (4-
tivated 4 Å molecular sieves (MS) at –40 °C in toluene Me, 4-MeO, 4-SMe) or electron-withdrawing groups (4-F,
(Table 2, entry 9). If the temperature was increased to 4-Cl, 4-Br) on the phenyl ring, all the reactions proceeded
–20 °C, the enantioselectivity decreased slightly (Table 2, smoothly to provide the desired products in 81–91% yield
entry 12 vs. 9). Thus, –40 °C was selected as the optimal with 91–97%ee (Table 3, entries 2–7). 2-Naphthyl-substi-
reaction temperature. Afterwards, the effects of substrate tuted α,β-unsaturated pyrazolone 3h showed quite good
concentration and catalyst loading for this reaction were performance and desired product 4h in 92% yield with
investigated (Table 2, entries 15–20). The highest enantio- 94%ee, although a prolonged reaction time was required
selectivity was obtained if the substrate concentration was (Table 3, entry 8). A lower enantioselectivity (66%) was ob-
0.025 m (Table 2, entry 17). The enantioselectivity slightly served for 2,4-dichloro-substituted α,β-unsaturated pyraz-
dropped by increasing or decreasing the catalyst loading olone 3i probably as a result of steric hindrance (Table 3,
(Table 2, entry 17 vs. entries 18–20).
entry 9). The Michael addition reactions of α,β-unsaturated
4
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Asymmetric Michael/Aromatization Reaction of Azlactones
Table 3. Substrate scope.[a]
Entry
R1, R2
R3
Product, yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Bn, C6H5 (2a)
C6H5 (3a)
4a, 93
4b, 87
4c, 90
4d, 91
4e, 86
4f, 81
4g, 83
4h, 92
4i, 87
4j, 89
4k, 88
4l, 93
4m, 92
4n, 90
4o, 90
4p, 76
4q, 80
4r, Ͻ5
4r, Ͻ5
97
97
96
91
94
93
91
94
66
84
94
84
95
94
80
84
94
–
Bn, C6H5 (2a)
4-MeC6H4 (3b)
4-MeOC6H4 (3c)
4-MeSC6H4 (3d)
4-FC6H4 (3e)
4-ClC6H4 (3f)
4-BrC6H4 (3g)
2-naphthyl (3h)
2,4-Cl2C6H3 (3i)
C6H5 (3a)
Bn, C6H5 (2a)
Bn, C6H5 (2a)
Bn, C6H5 (2a)
Bn, C6H5 (2a)
Bn, C6H5 (2a)
Bn, C6H5 (2a)
9
Bn, C6H5 (2a)
10
11
12
13
14
15
16
17
18
19[d]
Bn, 4-FC6H4 (2b)
Bn, 4-ClC6H4 (2c)
Bn, 4-ClC6H4 (2c)
Bn, 4-MeC6H4 (2d)
Bn, 4-MeC6H4 (2d)
iBu, 4-MeC6H4 (2e)
iPr, C6H5 (2f)
C6H5 (3a)
4-FC6H4 (3e)
C6H5 (3a)
4-FC6H4 (3e)
C6H5 (3a)
C6H5 (3a)
2-(methylthio)ethyl, C6H5 (2g)
iPr, tBu (2h)
iPr, tBu (2h)
C6H5 (3a)
C6H5 (3a)
C6H5 (3a)
–
[a] Unless noted, reactions were carried out with 2 (0.13 mmol), 3 (0.1 mmol), 1j (10 mol-%), and 4 Å MS (400 mg) in toluene (4.0 mL)
1
at –40 °C for 8–12 h. In all cases, the products were obtained with Ͼ10:1dr, as determined by H NMR spectroscopy. [b] Isolated yield
of 4. [c] Determined by chiral HPLC analysis. [d] The reaction was carried out with 2h (1.0 mmol), 3 (0.1 mmol), 1j (30 mol-%), and 4 Å
MS (100 mg) in toluene (1.0 mL) at r.t. for 36 h.
pyrazolones 3a and 3e with azlactones 2b–h were also ex- entries 10–14). Substrates with bulkier R1 groups provided
amined under otherwise identical conditions. It was ob- decreased enantioselectivities (Table 3, entry 15 vs. 13, en-
served that varying the R2 substituent on the benzene ring try 16 vs. 1). A good result was obtained with a methylthi-
also led to some changes in the enantioselectivities (Table 3, oethyl group at the R1 position (Table 3, entry 17). Azlac-
tone 2h with alkyl groups at the R1 and R2 positions failed
to give the product even at room temperature with 30 mol-
% catalyst loading (Table 3, entries 18 and 19). In all of the
above cases, good yields (76–93%) and diastereoselectivities
(Ͼ10:1dr) were obtained. Fortunately, a single crystal of 4d
was obtained by recrystallization from petroleum ether/n-
hexane/CH2Cl2, and the configuration of the two contigu-
ous stereocenters was unambiguously determined by X-ray
analysis (Figure 3).[18]
Figure 3. X-ray crystal structure of chiral compound 4d.
Figure 4. Proposed transition state and mechanism.
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J.-C. Tao, X.-W. Wang et al.
SHORT COMMUNICATION
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On the basis of the X-ray analysis of compound 4d, a
possible transition state and mechanism are proposed and
shown in Figure 4. The tertiary amine of the catalyst depro-
tonates the azlactone, and the thiourea moiety activates the
α,β-unsaturated pyrazolone through hydrogen bonding,
which provides the intermediate. Subsequently, aromatiza-
tion of the intermediate gives the desired chiral product
with a (1R,2S) configuration.
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Conclusions
In summary, we have developed the asymmetric Michael/
aromatization reactions of azlactones to α,β-unsaturated
pyrazolones with complete C-4 regioselectivity by using iso-
steviol-derived amine thiourea as a catalyst. A series of het-
erocyclic compounds containing both a 3-hydroxypyrazole
motif and a masked amino acid structure were synthesized
in good yields with moderate to excellent enantioselectivi-
ties.[19] The development of new chiral organocatalysts to
obtain cyclic compound 6 as the major product is now in
progress in our laboratory.
Experimental Section
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General Procedure for the Asymmetric Michael Addition/Aromatiza-
tion Reaction of Azlactones to α,β-Unsaturated Pyrazolones: In an
ordinary tube equipped with a magnetic stirring bar, a solution of
azlactone 2 (0.13 mmol), 4 Å MS (400 mg), and catalyst 1j (10 mol-
%) in toluene (4.0 mL) was stirred at –40 °C for 30 min, and then
α,β-unsaturated pyrazolone 3 (0.10 mmol) was added. The reaction
mixture was stirred for 8–12 h at –40 °C. The reaction mixture was
directly loaded onto silica gel and purified by flash chromatography
(petroleum ether/dichloromethane = 1:1–1:2) to give desired prod-
ucts 4a–q.
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
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The authors are grateful for financial support by the National Nat-
ural Science Foundation of China (NSFC) (grant numbers
21072145, 21272166), the Program for New Century Excellent Tal-
ents in University (NCET-12-0743), and the Scientific Research
Foundation for Returned Scholars, Ministry of Education of China
([2010]1174). This project was also funded by the Priority Aca-
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Date: 25-06-13 17:27:42
Pages: 7
Asymmetric Michael/Aromatization Reaction of Azlactones
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Received: April 11, 2013
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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