Catalyst-free efficient aza-Michael addition of azoles to nitroalkenes

Article abstract of DOI:10.1055/s-0031-1290359

An efficient aza-Michael addition of azole to nitroalkene has been developed. In this conjugate addition, no catalyst was employed and azole reacted with nitroolefin smoothly to afford new C-N bond adducts in good to excellent yields. Georg Thieme Verlag

Full text of DOI:10.1055/s-0031-1290359

788
LETTER
Catalyst-Free Efficient Aza-Michael Addition of Azoles to Nitroalkenes
A
za-Michael Addi
i
tion of
n
A
zole
s
to
N
i
troalkenes o Wu,a Jun Wang,b Pengfei Li,*a,c Fuk Yee Kwong*a
a
State Key Laboratory for Chirosciences and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hong Kong, P. R. of China
Fax +852(2364)9932; E-mail: flyli1980@yahoo.com.cn; E-mail: bcfyk@inet.polyu.edu.hk
School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, P. R. of China
Institute of Creativity, Faculty of Science, Hong Kong Baptist University, Hong Kong, P. R. of China
b
c
Received 19 December 2011
methodology for this C–N bond-formation reaction is of
considerable importance. In this letter, we report our
results concerning an efficient aza-Michael addition of
azole to nitroalkene without catalyst.
Abstract: An efficient aza-Michael addition of azole to nitroalkene
has been developed. In this conjugate addition, no catalyst was em-
ployed and azole reacted with nitroolefin smoothly to afford new
C–N bond adducts in good to excellent yields.
Key words: Michael addition, azole, nitroolefin, nitroalkene, ami- Our initial results showed that the aza-Michael addition of
azole to b,g-unsaturated a-keto ester16 to afford new C–N
bond adducts was feasible (Equation 1 in Scheme 1). On
this basis, we wondered whether this approach could be
nation
applied to other electron-poor alkenes.
The catalytic aza-Michael addition is an important reac-
tion within synthetic organic chemistry, given the signifi-
cance of the biologically and synthetically interesting
products.1 Over the last decade, tremendous progress has
been achieved by employing new nitrogen nucleophiles
and suitable acceptors as well as more efficient catalyst
systems for this important transformation.2,3 Particularly,
the catalytic aza-Michael addition of azole remains more
attractive because azole moiety is commonly found in
drug candidates, such as Losartan (high blood pressure),
Voriconazole (antifungal), Fluconazole (antifungal), and
INCB018424 (Janus Kinase Inhibitor). However, the cat-
alytic aza-Michael addition of nucleophile containing
azole groups has been rare, both in enantioselective
manner4 and in non-enantioselective version.3d–h Al-
though several examples of catalyst-free aza-Michael ad-
ditions of azole have been reported, severe conditions
such as high reaction temperature,5 high pressure6 and
UVA irradiation7 are required to yield the adducts. The
only exception is aza-Michael addition of enone with a
limited scope of substrates.8
Initially we examined the reaction of pyrazole with sever-
al typical Michael acceptors, including chalcone, ben-
zylidene acetone, and b-nitrostyrene. However, reactions
between pyrazole and enone were not successful and the
conjugate adducts could not be obtained in substantial
yields (Equations 2 and 3 in Scheme 1). To our delight,
pyrazole reacted with b-nitrostyrene (1a) to afford 1,4-
adduct in excellent yield (95%, Equation
4
in
Scheme 1).17
O
CH2Cl2
N
(1)
N
O
r.t., 24 h
Ph
Ph
CO2Me
Ph
Ph
CO2Me
O
O
CH2Cl2
(2)
(3)
r.t., 24 h
N
+
N
CH2Cl2
H
Ph
Ph
r.t., 24 h
CH2Cl2
As the nitro group is the most electron-withdrawing group
known, nitroalkenes are very attractive among the
Michael acceptors.9 Moreover, the conjugate adduct of nitro-
alkene retains the nitro function, and therefore, a suitable
transformation of the nitro group very often follows the
main addition process. The Nef reaction,10 the nucleo-
philic displacement,11 the reduction to an amino group,12
the Meyer reaction,13 and the conversion into a nitrile
oxide14 are only some examples of the possible transfor-
mations that nitro groups can undergo. Despite the impor-
tant value of these conjugate adducts, only two examples
on aza-Michael addition of nitroalkene were reported by
Wang4b and Jørgensen.15 Therefore, development of
N
NO2
(4)
N
r.t., 24 h
NO2
Ph
Scheme 1 Aza-Michael additions of pyrazole to Michael acceptors
With this encouraging result, we then optimized the reac-
tion conditions, including screening of solvent and molar
ratios of reactants. And the results are displayed in
Table 1. It was found that the reaction medium had an im-
pact on the reaction. No more than 50% of conversion was
obtained when reaction was carried out in THF, Et2O and
EtOAc (entries 2–4, respectively). The using of MeCN as
solvent afforded 87% of conversion (entry 5). Important-
ly, the reactions in CH2Cl2, toluene, MeOH and CHCl3 all
proceeded with excellent conversion (entries 1 and 6–8)
and the best result, 99% of conversion was obtained in
SYNLETT 2012, 23, 788–790
x
x.
x
x.
2
0
1
1
Advanced online publication: 24.02.2012
DOI: 10.1055/s-0031-1290359; Art ID: W78511ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Aza-Michael Addition of Azoles to Nitroalkenes
789
CH2Cl2 (entry 1). Decreasing amount of pyrazole still af- the exception of 3ea, which was obtained in 82% yield
forded more than 90% of conversion (entries 9 and 10). (entry 5). Moreover, Michael adducts 3fa–ha could also
When the ratio of reactants was 1:1, 78% of conversion be obtained with more than 90% yields from reactions be-
was obtained (entry 11). When b-nitrostyrene was em- tween pyrazole and nitroalkenes with electron-donating
ployed in excess, excellent conversion could also be ob- substituents (entries 6–8). Thus, the Michael addition of
tained (entry 12). Reducing the volume of the reaction more sterically congested 1i also resulted in good yield
medium resulted in high conversion within short time (en- (81%, entry 9). The BnO-substituted nitroalkenes 1j and
tries 13 and 14).
lk were found to react quite slowly and adducts 3ja and
3ka were obtained with lower yields (entries 10 and 11).
Under the optimal reaction conditions, aza-Michael addi-
tions of pyrazole to a variety of nitroalkenes were sur- Apart from pyrazole, the aza-Michael additions of other
veyed, and the results are presented in Table 2.
N-nucleophiles to b-nitrostyrene were also investigated
(Scheme 2). Up to 98% yield was obtained from the aza-
Michael addition of 3,5-dimethylpyrazole (2b) to 1a
(Equation 1 in Scheme 2).18 Particularly noteworthy was
that the aza-Michael addition of indoline (2c) to 1a also
resulted in 87% yield (Equation 2 in Scheme 2).19 Howev-
er, imidazole was found to be incompatible under these re-
action conditions and no adduct was obtained (Equation 3
in Scheme 2).
The reaction between b-nitrostyrene (1a) and pyrazole
(2a) afforded 3aa in 78% yield after 12 hours. To our de-
light, up to 98% yield was obtained when the reaction
time was increased to 24 hours (entry 1). It should be not-
ed that both electron-withdrawing (halogen atom) and
electron-donating substituents (Me, MeO, CF3O, BnO)
could be introduced into the aromatic ring, with only a
small effect on the yield of the reaction. And no signifi-
cant electronic effect on the aromatic moiety was ob- In conclusion, we have succeeded in showing a general
served. Thus, halogen-substituted nitroalkenes reacted and efficient aza-Michael addition between azoles and ni-
with pyrazole efficiently, and Michael adducts 3ba–da troalkenes.20 It should be noted that no additional catalyst
were formed in more than 90% yields (entries 2–4) with was employed in this system. The azole serves as both or-
ganocatalyst and N-nucleophile in the reaction system.
Particularly noteworthy is that a wide spectrum of ni-
troalkenes reacts smoothly and most compounds contain-
Table 1 Optimization of Reaction Conditionsa
ing azole group could be obtained in more than 90% yield
solvent
N
NO2
+
N
N
Ph
r.t.
N
H
1a
NO2
Ph
Table 2 Scope of Nitroalkenesa
2a
3a
Entry 1a
2a
Solvent
Time Conversionb
N
NO2
(mmol) (mmol)
CH2Cl2
N
N
R
+
NO2
N
1
2
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
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.15
0.13
0.10
0.10
0.13
0.13
CH2Cl2
THF
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
99%
35%
44%
50%
87%
94%
96%
98%
98%
93%
78%
99%
95%
98%
r.t., 24 h
H
R
3
Et2O
Entry
R
Adduct
3aa
3ba
3ca
Yieldb
4
EtOAc
MeCN
toluene
MeOH
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
2
H, 1a
98% (78%)c
96%
5
2-F, 1b
4-F, 1c
2-Cl, 1d
4-Br, 1e
6
3
93%
7
4
3da
3ea
97%
8
5
82%
9
6
4-Me, 1f
3fa
98%
10
11
12
13
14
7
4-MeO, 1g
4-CF3O, 1h
3ga
3ha
3ia
91%
8
97%
9
2,3-(MeO)2, 1i
2-BnO, 1j
81%
CH2Cl2 (0.2 mL) 12 h
CH2Cl2 (0.1 mL) 12 h
10
11
3ja
56%
4-BnO, 1k
3ka
58%
a Unless otherwise noted, the reaction was carried out as following:
the mixture of 1a and 2a was stirred in the solvent (0.3 mL) for the
time given.
a Unless otherwise noted, the reaction was carried out as following:
the mixture of 1a and 2a was stirred in CH2Cl2 (0.1 mL) for 24 h.
b Isolated yield.
b Determined by HPLC.
c Reaction time was 12 h.
© Thieme Stuttgart · New York
Synlett 2012, 23, 788–790

790
Y. Wu et al.
LETTER
2006, 47, 7723. (g) Han, X. Tetrahedron Lett. 2007, 48,
2845. (h) Kawatsura, M.; Aburatani, S.; Uenishi, J.
Tetrahedron 2007, 63, 4172.
CH2Cl2
N
(1)
N
N
(4) (a) Dinér, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 2007, 46, 1983. (b) Wang, J.; Li, H.;
Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391. (c) Wang, J.;
Zu, L.; Li, H.; Xie, H.; Wang, W. Synthesis 2007, 2576.
(d) Uria, U.; Vicario, J. L.; Badia, D.; Carrillo, L. Chem.
Commun. 2007, 2509. (e) Luo, G.; Zhang, S.; Duan, W.;
Wang, W. Synthesis 2009, 1564. (f) Gogoi, S.; Zhao, C.-G.;
Ding, D. Org. Lett. 2009, 11, 2249. (g) Zhou, Y.; Li, X.; Li,
W.; Wu, C.; Liang, X.; Ye, J. Synlett 2010, 2357.
(5) Zaderenko, P.; López, M. C.; Ballesteros, P. J. Org. Chem.
1996, 61, 6825.
r.t., 24 h
N
NO2
H
Ph
2b
3ab 98% yield
CH2Cl2
NO2
+
(2)
(3)
Ph
N
r.t., 24 h
1a
N
H
NO2
Ph
2c
3ac 87% yield
N
CH2Cl2
r.t., 24 h
(6) Uddin, M. I.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Synlett
2008, 1402.
N
H
(7) Moran, J.; Dornan, P.; Beauchemin, A. M. Org. Lett. 2007,
9, 3893.
Scheme 2 Aza-Michael additions of other N-nucleophiles
(8) Wu, Y.-J. Tetrahedron Lett. 2006, 47, 8459.
(9) For reviews see: (a) Berner, O. M.; Tedeschi, L.; Enders, D.
Eur. J. Org. Chem. 2002, 1877. (b) Sulzer-Mossé, S.;
Alexakis, A. Chem. Commun. 2007, 3123.
via this methodology. Further applications of these reac-
tions in pharmaceutical synthesis are currently underway.
(10) (a) Nef, J. U. Justus Liebigs Ann. Chem. 1894, 280, 263.
(b) Pinnick, H. W. Org. React. (N. Y.) 1990, 38, 655.
(11) Tamura, R.; Kamimura, A.; Ono, N. Synthesis 1991, 423.
(12) For some selected references, see: (a) Loyd, D. H.; Nichols,
D. E. J. Org. Chem. 1986, 51, 4294. (b) Barrett, A. G. M.;
Spilling, C. D. Tetrahedron Lett. 1988, 29, 5733. (c) Beck,
A. K.; Seebach, D. Chem. Ber. 1991, 124, 2897. (d) Maeri,
R. E.; Heinzer, J.; Seebach, D. Liebigs Ann. 1995, 1193.
(e) Poupart, M. A.; Fazal, G.; Goulet, S.; Mar, L. T. J. Org.
Chem. 1999, 64, 1356.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the Research Grants Council of Hong Kong (GRF:
PolyU5014/10P), European Commission CATAFLU.OR, and the
PolyU Internal Grant (A-PD0X) for financial support. Mr. Shun
Man Wong and Ms. Pui Ying Choy (PolyU) are gratefully acknowl-
edged for the sharing of azole substrates.
(13) (a) Meyer, V.; Wurster, C. Ber. Dtsch. Chem. Ges. 1873, 6,
1168. (b) Kamlet, M. L.; Kaplan, L. A.; Dacons, J. C. J. Org.
Chem. 1961, 26, 4371.
(14) Mukayama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
(15) Nielsen, M.; Zhuang, W.; Jørgensen, K. A. Tetrahedron
References and Notes
(1) For some selected references, see: (a) Cardillo, G.;
Tomasini, C. Chem. Soc. Rev. 1996, 25, 117. (b) Davies, S.
G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005,
16, 2833. (c) Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S.
Tetrahedron 2006, 62, 12098. (d) Dorbec, M.; Florent, J. C.;
Monneret, C.; Rager, M. N.; Bertounesque, E. Tetrahedron
2006, 62, 11766. (e) Prakech, M.; Srivastava, S.; Leek, D.
M.; Arya, P. J. Comb. Chem. 2006, 8, 762. (f) Dorbec, M.;
Florent, J. C.; Monneret, C.; Rager, M. N.; Bertounesque, E.
Synlett 2006, 591. (g) Ihara, M. Chem. Pharm. Bull. 2006,
54, 765.
(2) For reviews on enantioselective aza-Michael addition, see:
(a) Vicario, J. L.; Badía, L.; Carrillo, L.; Etxebarria, J.;
Reyes, E.; Ruiz, N. Org. Prep. Proced. Int. 2005, 37, 513.
(b) Xu, L. W.; Xia, C. G. Eur. J. Org. Chem. 2005, 633.
(c) Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis 2007,
2065. (d) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J.
2009, 15, 11058. (e) Krishna, P. R.; Sreeshailam, A.;
Srinivas, R. Tetrahedron 2009, 65, 9657.
(3) For references on catalytic non-enantioselective aza-
Michael addition, see: (a) Xu, L. W.; Li, L.; Xia, C. G.;
Zhou, S. L.; Li, J. W.; Hu, X. X. Synlett 2003, 2337.
(b) Xu, L. W.; Xia, C. G. Tetrahedron Lett. 2004, 45, 4507.
(c) Chaudhuri, M. K.; Hussain, S.; Kantam, M. L.; Neelima,
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(16) For our previous interest in the reaction of b,g-unsaturated a-
keto ester moiety, see: (a) Li, P.; Zhao, J.; Li, F.; Chan, A. S.
C.; Kwong, F. Y. Org. Lett. 2010, 12, 5616. (b) Li, P.;
Chan, S. H.; Chan, A. S. C.; Kwong, F. Y. Adv. Synth. Catal.
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Kwong, F. Y. Org. Biomol. Chem. 2011, 9, 7997.
(17) 1H NMR data of adduct: 1H NMR (400 MHz, CDCl3): d =
7.59 (s, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.36–7.38 (m, 3 H),
7.28–7.30 (m, 2 H), 6.29 (t, J = 1.8 Hz, 1 H), 6.12 (dd, J =
4.8, 9.6 Hz, 1 H), 5.63 (dd, J = 9.6, 14.0 Hz, 1 H), 4.87 (dd,
J = 4.8, 14.0 Hz, 1 H).
(18) 1H NMR data of adduct: 1H NMR (400 MHz, CDCl3): d =
7.29–7.36 (m, 3 H), 7.22–7.24 (m, 2 H), 5.96 (dd, J = 4.4,
10.0 Hz, 1 H), 5.83 (s, 1 H), 5.67 (dd, J = 9.8, 14.2 Hz, 1 H),
4.81 (dd, J = 4.4, 14.0 Hz, 1 H), 2.23 (m, 3 H), 2.18 (m, 3 H).
(19) 1H NMR data of adduct: 1H NMR (400 MHz, CDCl3): d =
7.28–7.39 (m, 5 H), 7.05–7.12 (m, 2 H), 6.67–6.71 (m, 2 H),
5.63 (dd, J = 6.8, 8.4 Hz, 1 H), 5.03 (dd, J = 8.8, 12.0 Hz, 1
H), 4.92 (dd, J = 10.6, 12.2 Hz, 1 H), 3.42–3.48 (m, 1 H),
3.13–3.20 (m, 1 H), 2.86–3.01 (m, 2 H).
(20) Unless noted otherwise, the reaction was carried out as
following: to a solution of CH2Cl2 (0.1 mL) were added
nitroalkene 1 (0.1 mmol) and azole 2 (0.13 mmol). The
reaction mixture was stirred at r.t. for 24 h and then the
solvent was removed under vacuum. The residue was
purified by column chromatography on silica gel to yield the
desired Michael adducts 3.
Synlett 2012, 23, 788–790
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