Catalyst-free aza-Michael addition of azole to β,γ-unsaturated- α-keto ester: An efficient access to C-N bond formation

Article abstract of DOI:10.1016/j.tetlet.2012.03.132

An efficient aza-Michael addition of azoles to β,γ-unsaturated- α-keto esters under room temperature conditions has been developed. In this conjugate addition, no additional catalyst is employed. Azole reacts with β,γ-unsaturated-α-keto ester smoothly to

Full text of DOI:10.1016/j.tetlet.2012.03.132

Tetrahedron Letters 53 (2012) 2887–2889
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Tetrahedron Letters
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Catalyst-free aza-Michael addition of azole to b,c-unsaturated-a-keto ester:
an efficient access to C–N bond formation
Jun Wang a, Peng-Fei Li b,c, , Sau Hing Chan c, Albert S.C. Chan b, Fuk Yee Kwong c,
⇑
⇑
a School of Chinese Medicine, Hong Kong Baptist University, Hong Kong
b Institute of Creativity, Faculty of Science, Hong Kong Baptist University, Hong Kong
c State Key Laboratory for Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient aza-Michael addition of azoles to b,c-unsaturated-a-keto esters under room temperature
conditions has been developed. In this conjugate addition, no additional catalyst is employed. Azole
Received 15 February 2012
Revised 23 March 2012
Accepted 30 March 2012
Available online 5 April 2012
reacts with b,
c
-unsaturated-
a
-keto ester smoothly to afford new C–N bond adducts in good to excellent
yields (up to 96%).
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Michael addition
Azole
Nitroalkene
Nitroolefin
Amination
The significance of N-heterocyclic scaffolds has been recognized
by their high abundance in nature, as well as broad synthetic appli-
cations in pharmaceutical chemistry, biological, and material sci-
ences.1 In particular, azole moiety is commonly found in drug
candidates, such as Voriconazole (antifungal), Fluconazole (anti-
fungal), Losartan (high blood pressure), and INCB018424 (Janus Ki-
nase Inhibitor).1 The conjugate addition of nitrogen nucleophiles to
tion. The N-heterocyclic compound can act as a dual-role reagent
in certain aza-Michael additions.7 Thus, the appropriate choice of
the nitrogen nucleophile represents a crucial factor in the catalytic
aza-Michael addition.
b,c-Unsaturated a-keto ester is a resourceful moiety in synthet-
ically useful building blocks. These unsaturated keto esters have
been investigated in several type of reactions, such as aldol reac-
tions,8 Diels–Alder reactions9 and Michael–type reactions.10 Yet,
a,b-unsaturated carbonyl compounds, termed the aza-Michael
reaction, is a versatile method for constructing new C–N bonds.2
This convergent protocol constitutes a key route for the synthesis
of diversified bioactive natural products. Over the last several years
tremendous progress has been achieved. Seeking of new category
of nitrogen nucleophiles, suitable acceptors as well as more effi-
cient catalyst systems for this important transformation are of cur-
rent interest.3,4 Nevertheless, most established reports with
impressive results were only focused on the aza-Michael addition
of hydroxylamines and their derivatives.5 The organocatalytic
aza-Michael addition of the nitrogen nucleophile containing azole
groups is rarely reported, either in enantioselective manner6 or
non-enantioselective version.4d–g
The majority of organocatalytic reactions are usually based on
amine catalysts. These reactions often proceed via enamine or
iminium intermediates. Indeed, the amine would also serve as a
base. The potential competition between the catalyst and the
nucleophile could happen in the organocatalytic aza-Michael addi-
the Michael addition of b,c-unsaturated a-keto ester has only been
limited to carbon nucleophiles. To the best of our knowledge, only
one example of the nitrogen nucleophile was reported by Palacios
et al. in 2006.11 It should be noted that this reaction is catalyzed by
a metal complex affording 69–88% product yields. Enlightened by
our previous research works focusing on unsaturated carbonyl
compounds,8,10 we are attracted to explore a new aza-Michael
addition of azole to unsaturated keto ester.
In order to find a suitable N-heterocyclic nucleophile that would
give a self-catalytic conjugate reaction, we embarked the aza-Mi-
chael addition of pyrrolidine and azoles to methyl 2-oxo-4-phenyl-
but-3-enoate (1a). Interestingly, pyrrolidine could react with 1a to
afford a product of (E)-4-phenyl-1-(pyrrolidin-1-yl)but-3-ene-1,2-
dione instead of the Michael adduct. When imidazole was used as
the nucleophile, no reaction was observed. To our delight, pyrazole
could afford the 1,4-adduct with high conversion. With this initial
result in hand, the screening of solvent for aza-Michael addition of
pyrazole and 1a was further carried out and the results are
summarized in Table 1. This aza-Michael addition was found to
be nearly independent of commonly used organic solvents. Most
⇑
Corresponding authors.
E-mail address: bcfyk@inet.polyu.edu.hk (F.Y. Kwong).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.132

2888
J. Wang et al. / Tetrahedron Letters 53 (2012) 2887–2889
Table 1
Optimization of reaction conditionsa
N
O
N
O
N
+
Ph
CO2Me
N
H
RT
Ph
CO2Me
1a
3a
2a
Entry
1a (mmol)
2a (mmol)
Solvent
Time (h)
Conversionb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.20
0.10
0.10
0.10
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.20
0.15
0.10
0.10
0.15
0.15
0.15
CH2Cl2
CHCl3
THF
EtOAc
Toluene
MeOH
Et2O
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
18
18
18
18
18
18
18
18
18
18
18
18
24
24
24
99
98
90
96
98
96
97
97
98
97
91
99
75 (isolated yield)
91 (isolated yield)
94 (isolated yield)
CH2Cl2 (0.2 mL)
CH2Cl2 (0.1 mL)
a
Unless noted, the reaction was carried out as following: the mixture of 1a and 2a was stirred in the solvent
(0.3 mL) at room temperature for the time given.
b
Determined by HPLC.
Table 2
Scope of b,
Table 3
c
-unsaturated-
a
-keto estersa+
Scope of azolesa
R1
O
Y
X
O
O
N
R1
X
N
Y
N
CH2Cl2
N
CH2Cl2
RT, 24 h
N
O
R1
CO2R2
N
H
2a
N
+
Ph
CO2Me
+
N
H
RT, 24 h
R1
CO2R2
Ph
CO2Me
1
3
1a
3
2
b
R1
X
Y
Adduct
Yieldb
Entry
R1
R2
Adduct
Yield (%)
Entry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
2-BrPh
3-BrPh
Me
Et
i-Pr
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
Me
Et
Et
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
94
86
87
85
96
90
91
96
83
90
90
92
92
88
96
91
89
34
1
2c
3c
4d
3,5-Di-Me
CH
N
CH
—
CH
CH
N
3ab
3ac
3ad
3ae
84%
37%
42%
Trace
H
H
—
—
a
Unless noted, the reaction was carried out as follows: 1 (0.10 mmol) reacted
with 2a (0.15 mmol) in CH2Cl2 (0.1 mL) at rt for 24 h.
3-ClPh
3-NO2Ph
3-NO2Ph
3-MePh
3-MeOPh
4-FPh
4-ClPh
4-BrPh
4-NO2Ph
4-NO2Ph
4-MePh
4-MeOPh
b
Isolated yield.
C
Compound 1a (0.2 mmol) and N-nucleophile (0.1 mmol) were used.
1H-indazole was used as the nucleophile.
d
(–F, –Cl, –Br, –NO2, entries 4–8, 11–15) and electron-donating (–Me,
–OMe, entries 9–10, 16–17) substituents on the aromatic ring were
compatible under this system. Good to excellent product yields
were obtained (83–96%). No significant electronic effect on the aro-
Et
Et
matic moiety was observed. The heteroaromatic containing b,
c-
5-Methylthiophen-2-yl
unsaturated -keto ester was also tested (entry 18).
a
a
Unless noted, the reaction was carried out as following: 1 (0.10 mmol) reacted
with 2a (0.15 mmol) in CH2Cl2 (0.1 mL) at rt for 24 h.
Apart from the pyrazole, the aza-Michael addition of other
azoles to methyl 2-oxo-4-phenylbut-3-enoate (1a) was also inves-
tigated and the results are shown in Table 3. 3,5-Dimethylpyrazole
reacted with methyl 2-oxo-4-phenylbut-3-enoate smoothly to af-
ford the adducts in 84% yield (entry 1). 1,2,3-Triazole and 1,2,4-tri-
azole were found to react slowly, and 37–42% of adduct yields
were obtained (entries 2 and 3). When 1H-indazole was used as
the nucleophile, the aza-Michael addition did not proceed and only
a trace amount of adduct was detected by LCMS (entry 4).
b
Isolated yield.
reactions proceeded smoothly with excellent substrate conver-
sions (entries 1–8). The best result was obtained in CH2Cl2 (entry
1). The stoichiometry of the reactants was also examined (entries
9–12). Further optimization on the concentration parameter re-
vealed that a more concentrated medium provided a better yield
(entries 13–15).
We propose the mechanism that the intermediate A is initially
formed via the hydrogen bonding between the carbonyl oxygen of
1a and the NH moiety of 2a (Scheme 1). The enamine nitrogen
Under the optimized reaction conditions, the aza-Michael addi-
tion of pyrazole to b,c-unsaturated a-keto ester was explored and
the results are displayed in Table 2. The reactions between pyrazole
and both ethyl and isopropyl esters proceeded smoothly to give
adducts in high yields (entries 2 and 3). Both electron-withdrawing
atom of 2a then attacks the c-position of 1a to afford intermediate
B in the enolization manner. Finally, the intermediate B undergoes
a retro-enolization to afford the desired product 3aa.

J. Wang et al. / Tetrahedron Letters 53 (2012) 2887–2889
2889
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N
H
N
N
O
2a
1a
N
O
N
H
Ph
CO2Me
A
N
N
OH
CO2Me
Ph
CO2Me
Ph
N
O
B
Ph
CO2Me
3aa
Scheme 1. Proposed reaction mechanism.
In conclusion, we have succeeded a general and efficient cata-
lyst-free aza-Michael addition of azoles to b, -unsaturated -keto
esters. Particularly noteworthy is that a wide spectrum of b,
unsaturated -keto esters reacts smoothly under mild reaction
conditions (room temperature) and gives excellent product yields.
Further application of this methodology toward complex heterocy-
cle synthesis is actively in progress.
c
a
c
-
a
Acknowledgments
We thank the European Commission EP7 (CATAFLU.OR project),
Research Grants Council of Hong Kong (GRF: PolyU 5010/11P),
State Key Laboratory of Chirosciences (4-BBX3) and PolyU Internal
Grant DA (A-PD0X) for financial support. Mr. Shun Man Wong and
Ms. Pui Ying Choy (PolyU) are gratefully acknowledged for sup-
porting the azole substrates.
Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.03.132.
8. (a) Li, P.; Zhao, J.; Li, F.; Chan, A. S. C.; Kwong, F. Y. Org. Lett. 2010, 12, 5616–
5619; (b) Li, P.; Chan, S. H.; Chan, A. S. C.; Kwong, F. Y. Adv. Synth. Catal. 2011,
353, 1179–1184. and references cited therein.
9. (a) Juhl, K.; J¢rgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498–1501; (b)
Samanta, S.; Krause, J.; Mandal, T.; Zhao, C. G. Org. Lett. 2007, 9, 2745–2748; (c)
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L.; Wu, Y.; Ma, C. Org. Lett. 2010, 12, 2422–2425; (e) Xu, D.; Zhang, Y.; Ma, D.
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