Enantioselective aza-Michael reaction of hydrazide to chalcones through the nonactivated amine moiety conjugated addition

Article abstract of DOI:10.1039/c0cc05804a

The catalytic asymmetric aza-Michael reaction of benzoyl hydrazine toward chalcones through the nonactivated amine moiety conjugated addition was facilitated by the developed N,N′-dioxide-Sc(OTf)₃ complex under mild conditions, affording the pharmacologically and synthetically useful products in moderate to high yields with up to 97% ee. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc05804a

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COMMUNICATION
Enantioselective aza-Michael reaction of hydrazide to chalcones through
the nonactivated amine moiety conjugated additionw
Jun Jiang, Yunfei Cai, Weiliang Chen, Lili Lin, Xiaohua Liu and Xiaoming Feng*
Received 27th December 2010, Accepted 26th January 2011
DOI: 10.1039/c0cc05804a
The catalytic asymmetric aza-Michael reaction of benzoyl
hydrazine toward chalcones through the nonactivated amine
moiety conjugated addition was facilitated by the developed
N,N0-dioxide-Sc(OTf)3 complex under mild conditions, affording
the pharmacologically and synthetically useful products in
moderate to high yields with up to 97% ee.
Over the last decade, tremendous progress has been achieved
in the catalytic asymmetric aza-Michael reaction,1 since the
resulting chiral b-amino carbonyl compounds, are both
biologically and synthetically of great importance.2 As a
result, numerous attractive nitrogen nucleophiles were
attempted. The interest in hydrazine was not only due to its
derivatives with good pharmacological activities,3 but also to
the challenging issue of regioselectivity between two competitive
amines.4 Given the particular structure of hydrazine 1
(Scheme 1),5 the N1 amine exactly like the activated amine,
is engaged in resonance structures with electron-withdrawing
group, and its nucleophilicity could be markedly enhanced
under basic conditions, whereas, the N2 amine represents less
nucleophilicity as a nonactivated amine. Therefore, these
successful examples of hydrazine conjugated addition toward
unsaturated carbonyl compounds, have been mainly limited to
the activated amine moiety (Pathway I), than further achieved
pyrazolidinones or pyrazolines.6 Herein, we firstly carried out
the catalytic asymmetric aza-Michael reaction through the
Fig. 1 N,N0-dioxide ligands screened in the study.
nonactivated amine moiety of benzoyl hydrazine toward
chalcones and achieved highly enantioselective and regioselective
products 3 (Pathway II).
With regard to the nonactivated amine moiety of benzoyl
hydrazine 1a, the N2 has a free lone pair and represents Lewis
base nature. The nucleophilicity could be improved by adjustment
of basicity or using Lewis acid, theoretically. Aiming at this
working hypothesis, we decided to examine the coactivation of
developed N,N0-dioxide complexed with Lewis acid7 toward it
(Fig. 1). Preliminary investigation was initiated on the N,N0-
dioxide L1 complexed with various Lewis acids to catalyze the
reaction between benzoyl hydrazine 1a and chalcone 2a.
Apparently, the metal sources had a decisive effect on the
enantioselectivity, and the Sc(OTf)3 promoted the reaction
smoothly and furnished product 3a with a promising 78% ee
albeit in 58% yield, in contrast to others with racemic results
(Table 1, entries 3 vs. 1 and 2). Subsequently, we turned our
attention to the structure-effects of N,N0-dioxide ligands in situ
with Sc(OTf)3. The introduction of slightly smaller groups
at the ortho positions of aniline led to less selectivity and
low-yielding reaction (Table 1, entries 4 and 5). So we
envisioned that bulkier substituents would enable the catalyst
to enhance the face discrimination. Compared with the
aromatic amines, the aliphatic ones gave poor results
(Table 1, entry 6). As for the chiral backbone moiety of ligand,
L5 derived from L-pipecolic acid and L6 derived from
L-ramipril acid were attempted, but disappointing results
without any improvement were obtained (Table 1, entries 7
and 8). Further optimization for this system revealed that the
combined use of DCM (2.0 mL) as a solvent and 60 mg 4 A
MS as an additive was the better choice for the asymmetric
addition of 0.1 mmol 1a and 2.0 equiv. 2a with 10 mol%
Scheme 1 Regioselective aza-Michael reaction of hydrazine and
unsaturated carbonyl compounds.
Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China. E-mail: xmfeng@scu.edu.cn;
Fax: +862885418249; Tel: +862885418249
w Electronic supplementary information (ESI) available: Experimental
procedures, analytical data (1H NMR, 13C NMR and HRMS)
for all new compounds. CCDC 801220 (compound 3n). For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0cc05804a
c
4016 Chem. Commun., 2011, 47, 4016–4018
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Table 1 Enantioselective conjugate addition of hydrazide 1a to
chalcone 2a catalyzed by N,N0-dioxide-metal complexes under
indicated conditionsa
Table 2 Substrate scope for catalytic asymmetric conjugate addition
of chalcones 2 with hydrazide 1aa
Entry R1
R2
T (h) Pro. Yield (%)b ee (%)c
Entry
Ligand Metal
Solvent
Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
Ph
20
16
20
18
20
3a
3b
3c
3d
3e
3f
3g
3h
3i
78
81
77
75
82
74
71
70
75
68
65
87
93
95
96
89
91
94
94
94
90
90
87
86
91
84(S)
86
91
91
94
97
94
88
97
91
91
85
4-FC6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
1
2
3
4
5
6
7
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
La(OTf)3 CH2Cl2
Y(OTf)3 CH2Cl2
34
78
58
40
30
55
32
24
48
31
0
3
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CHCl3
78
45
18
54
41
75
88
82
85
91
93
93
4-MeOC6H4 18
4-MeC6H4
3-MeC6H4
2-Thienyl
2-Naphthyl 18
Piperonyl 20
CH=CH2Ph 20
Ph
Ph
Ph
Ph
Ph
Ph
20
18
20
9
8
9d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3j
3k
3l
10d
11d
12d,e
13d,e,f
Sc(OTf)3 CH2ClCH2Cl 40
18
16
16
18
16
16
18
20
20
18
20
20
20
3m 67
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
Sc(OTf)3 CH2Cl2
64
73
78
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w 64
69
72
62
71
67
64
51
42
75
14d,e,f,g L1
a
Unless otherwise noted, reactions were carried out with 0.1 mmol
hydrazide 1a and 1.0 equiv. chalcone 2a in solvent (0.5 mL) at 25 1C
for 12 h; 10 mol% catalyst (L/M = 1.0/1.0) was used in one pot.
4-MeOC6H4 Ph
4-PhC6H4
3-Thienyl
1-Naphthyl Ph
2-Naphthyl Ph
Piperonyl Ph
2,3-Cl2C6H3 Ph
b
c
d
Ph
Ph
Isolated yield. Determined by HPLC analysis. Reactions were
e
carried out in solvent (2.0 mL). 2.0 equiv. chalcone 2a and 10 mol%
f
g
catalyst (L/M = 1.2/1.0). 60 mg 4 A MS was used. Using 5 mol%
catalyst for 20 h.
3x
3y
61
60
a
Unless otherwise noted, reactions were carried out with 5 mol%
1.2/1.0), 0.1 mmol hydrazide 1a, and
2.0 equiv. chalcones 2 in DCM (2.0 mL, DCM = dichloromethane)
catalyst (L1/Sc(OTf)3
=
catalyst (L1/Sc(OTf)3 = 1.2/1.0) in one pot (Table 1, entries
9–13).8 Reducing the catalyst loading to 5 mol%, prolonged
the reaction time suitably and the asymmetric induction was
not affected (Table 1, entry 14).
b
c
at 25 1C for 16–20 h. Isolated yield. Determined by HPLC analysis,
absolute configuration determined to be S by single crystal X-ray
analysis, see Supporting Information.w
With optimal conditions established, we set out to examine
the scope of substrates and obtained the nonactivated amine
conjugated adducts 3.8 The electron-withdrawing as well as
electron-donating substituents at the aromatic ring R2 were
tolerated under these conditions with excellent enantio-
selectivity and good yield (Table 2, entries 1–8). In contrast,
the corresponding R1-analogs furnished the desired products
with moderate yields and unequal enantioselectivities, due to
the electronic effect of functional groups (Table 2, entries
13–20). Pleasingly, fused-ring, styryl or multi-substituted and
heteroaromatic-substituted substrates also proceeded well
with benzoyl hydrazine, and provided adducts in moderate
yield with up to 97% ee (Table 2, entries 9–12 and 21–25).
Besides, the resulting product 3n was crystalline and the
absolute configuration of major enantiomers was determined
to be S, and the asymmetric aza-Michael addition occurred at
N2 nonactivated amine moiety was also confirmed.9
Fig. 2 Proposed transition-state model for aza-Michael reaction of
chalcone and benzoyl hydrazine and the X-ray crystallographic structure
of 3n.
In the light of the X-ray structures of the product 3n and the
N,N-dioxide-Sc(III) complex10 as well as the oxophilic property
of Sc(III),11 the transition-state model for aza-Michael reaction
of chalcone and benzoyl hydrazine was proposed. As shown in
Fig. 2, central metal Sc(III) coordinated with both carbonyl
oxygens, N-oxide oxygens of the ligand and two carbonyl
oxygens of the substrates. The attack of terminal amine of
benzoyl hydrazine onto the a,b- unsaturated chalcone from
Si-face yielded the corresponding S-configured products,
because another face was shielded by the neighboring
2,6-diisopropylphenyl group of the ligand.
In conclusion, we have reported an effcient asymmetric aza-
Michael reaction of chalcone and benzoyl hydrazine catalyzed
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4016–4018 4017

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by our developed chiral N,N’-dioxide L1-Sc(OTf)3 complex.
Under mild conditions, various substrates were examined,
delivering the corresponding products in moderate to high
yields with excellent enantioselectivities. The method provided
the convenient and efficient route for the asymmetric functio-
nalization of nonactivated amine moiety of hydrazide, which
were almost unknown in the literature. Additionally, more
investigations about asymmetric mono-substituted of hydrazides
and the application of these relative products in heterocyclic
chemistry are underway in our group.
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We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 20732003 and 21021001) and the
National Basic Research Program of China (973 Program:
No. 2011CB808600) for financial support. We also appreciate
Sichuan University Analytical & Testing Center for NMR
analysis and X-ray crystal analysis.
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8 For more detailed experimental data for optimum conditions and
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Informationw.
9 CCDC: 801220 (S)-3n: C22H19ClN2O2,Mr = 378.84, T = 294 K,
monoclinic, space group P21, a = 12.6570(9), b = 5.2425(3), c =
=
14.9418(10) A, b = 105.291(7)1, Z = 2, V = 956.36(11) A3, Rint
0.0464, wR2 = 0.1209. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.
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c
4018 Chem. Commun., 2011, 47, 4016–4018
This journal is The Royal Society of Chemistry 2011