Sequential Michael addition/retro-Claisen condensation of 1,3-diarylpropan-1,3-diones with nitrostyrenes: one-step synthesis of 4-nitro-1,3-diarylbutan-1-ones

Article abstract of DOI:10.1007/s12039-019-1603-z

Abstract : The sequential Michael addition/retro-Claisen condensation of 1,3-diarylpropan-1,3-diones with nitrostyrenes is described. 4-Nitro-1,3-diarylbutan-1-ones were efficiently synthesized in good to high yield under mild, transition-metal-free condition. This one-step method involving sequential carbon-carbon bond formation and cleavage provides a good alternative to the synthesis of various γ-nitro ketones. Graphical abstract: The sequential Michael addition/retro-Claisen condensation of 1,3-diarylpropan-1,3-diones with nitrostyrenes is described. 4-Nitro-1,3-diarylbutan-1-ones were efficiently synthesized in good to high yield under mild and transition-metal-free condition. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-019-1603-z

J. Chem. Sci.
(2019) 131:26
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1603-z
REGULAR ARTICLE
Sequential Michael addition/retro-Claisen condensation of
1,3-diarylpropan-1,3-diones with nitrostyrenes: one-step synthesis
of 4-nitro-1,3-diarylbutan-1-ones
ZHENG LI∗ , HAO LU, ZHENRONG LIU and XIAOLONG MA
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, Gansu,
People’s Republic of China
E-mail: lizheng@nwnu.edu.cn
MS received 26 November 2018; revised 24 January 2019; accepted 5 February 2019
Abstract. The sequential Michael addition/retro-Claisen condensation of 1,3-diarylpropan-1,3-diones with
nitrostyrenes is described. 4-Nitro-1,3-diarylbutan-1-ones were efficiently synthesized in good to high yield
under mild, transition-metal-free condition. This one-step method involving sequential carbon-carbon bond
formation and cleavage provides a good alternative to the synthesis of various γ -nitro ketones.
Keywords. Michael addition; retro-Claisen condensation; γ -nitro ketone; carbon-carbon bond formation;
carbon-carbon bond cleavage.
1. Introduction
Here, we report a novel method to 4-nitro-1,
3-diarylbutan-1-ones through the sequential Michael
addition/retro-Claisen condensation reactions of 1,3-
diarylpropan-1,3-diones with nitrostyrenes by using
DBU as a catalyst and ethanol as a reagent and solvent
under mild condition.
The Michael addition is one of the most useful methods
for the mild formation of carbon-carbon bonds.1 Mean-
while, retro-Claisen condensation is an efficient method
for the cleavage of carbon-carbon bonds.2 The combina-
tion of Michael addition and retro-Claisen condensation
will possibly produce a novel synthesis.
As one of the main classes of ketone compounds, γ -
nitro ketones are widely used as intermediates for the
synthesis of various functionalized carbocycles.3–8 The
reported typical synthetically viable procedures for the
construction of γ -nitro ketones include: i) the conjugate
addition of nitromethane to chalcone;9–13 ii) the detri-
fluoroacetylative Michael addition of 1-trifluoromethyl-
1,3-diketones to conjugated nitroalkenes;14 iii) the
amine-catalyzed Michael addition of ketones to
nitrostyrene;15–25 iv) the nickel-catalyzed decarboxyla-
tiveMichaeladditionofβ-ketoacidstonitrostyrenes26,27
(Scheme 1). However, some drawbacks, such as low
yield, limited diversity and expensive substrates, still
remains in the existing methods. Therefore, the devel-
opment of other synthetic methods for their direct prepa-
ration from readily accessible materials is required.
2. Experimental
2.1 General information
1H NMR and 13C NMR spectra were obtained with Mercury-
400 BB or Mercury-600 BB instrument using CDCl3 as
solvent and Me4Si as the internal standard. High-resolution
mass spectra (HRMS) (ESI) were obtained with a Bruker
Daltonics APEX II 47e and Orbitrap Elite mass spectrome-
ter. 1,3-Diarylpropan-1,3-diones28 and nitrostyrenes29 were
synthesized according to the literature procedure.
2.2 General procedure for the synthesis of
4-nitro-1,3-diarylbutan-1-ones (3a–3t)
The mixture of 1,3-diarylpropan-1,3-diones 1 (0.5 mmol),
nitrostyrenes 2 (0.5 mmol) and DBU (0.05 mmol) in EtOH
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1603-z) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

26 Page 2 of 7
J. Chem. Sci.
(2019) 131:26
Previous work
O
KOH, THF
r.t., 92%
+
CH3NO2
O
O
NO2
NaOAc, EtOH
r.t., 85%
CF3
+
NO2
O
O
NO2
Proline, ionic liquid
r.t., 51%
+
O
O
NO2
[Ni]
OH
+
THF, r.t., 95%
This work
NO2
O
O
O
NO2
DBU, EtOH
50 oC, 2 h
R1
R1
R2
R2
+
R1
Scheme 1. Preparation of 4-nitro-1,3-diarylbutan-1-ones.
Table 1. Optimization of the reaction conditionsa.
NO2
O
O
O
NO2
Catalyst
Solvent
+
3a
2a
1a
Entry
Catalyst
Solvent
Yield [%]b
1
2
3
4
5
6
7
8
-
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
n-BuOH
0
20
9
NaOH
KOH
NaHCO3
K2CO3
Cs2CO3
DABCO
DMAP
Et3N
DBU
DBU
DBU
DBU
33
40
50
65
76
55
85
Trace
23
0
9
10
11
12
13
aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (0.05 mmol) in alcohol (3 mL) was stirred at 50◦C for 2 h.
bIsolated yield.
(3 mL) was stirred at 50◦C for 2 h. The reaction was using petroleum ether and ethyl acetate (v/v 8:1) as
monitored by TLC. After the completion of the reaction, eluent to give the pure product. The analytical data
the resulting mixture was concentrated under reduced pres- for products are given in the Supplementary Information
sure. The residue was isolated by column chromatography section.

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Page 3 of 7
26
Table 2. Synthesis of 4-nitro-1,3-diarylbutan-1-ones from symmetrical 1,3-
diarylpropan-1,3-diones and nitrostyrenesa.
NO2
O
O
O
DBU, EtOH
50 oC, 2h
NO2
+
Ar2
Ar1
Ar1
Ar1
Ar2
2
3a-3r
1
NO2
NO2
NO2
O
O
O
CH3
OCH3
3b
88
3a
%
3c
85
85
83
%
%
NO2
NO2
NO2
O
O
O
OCH3
F
OCH3
OCH3
Cl
3f 71
3e 65
%
3d
%
%
%
NO2
NO2
NO2
O
O
O
Br
O
O
69
3g
3h
NO2
3i
59
72
87
%
%
NO2
NO2
NO2
S
O
O
O
O
68
%
3j
3l
3k
%
67
%
NO2
NO2
NO2
O
O
O
O
Cl
Br
S
3m
3o 77
%
89
%
3n
85
%
NO2
NO2
NO2
O
O
O
Br
S
S
OCH3
3r
65
62
%
%
70
O
%
3p
3q
NO2
NO2
N
O2
O
O
0
%
0
0
%
%
aReaction conditions: 1,3-diarylpropan-1,3-diones (0.5 mmol), nitrostyrenes (0.5 mmol)
and DBU (0.05 mmol) in EtOH (3 mL) was stirred at 50◦C for 2 h.
3. Results and Discussion
attempted to synthesize 4-nitro-1,3-diphenylbutan-1-
one (3a) under a variety of conditions. It was found
Initially, the reaction of 1,3-diphenylpropan-1,3-dione that the reaction of 1a with 2a in ethanol could not give
(1a) with nitrostyrene (2a) as a model reaction was any product in the absence of a base (Table 1, entry 1).

26 Page 4 of 7
J. Chem. Sci.
(2019) 131:26
NO2
NO2
O
O
O
O
NO2
DBU, EtOH
50 oC, 2 h
+
+
H
3C
CH3
3a
(30 %)
NO2
3l
(62 %)
NO2
O
O
O
O
NO2
DBU, EtOH
50 oC, 2 h
+
+
Br
Br
3o
(31 %)
3a
(58 %)
NO2
NO2
O
O
O
O
NO2
DBU, EtOH
50 oC, 2 h
+
+
H
3CO
N
O2
OCH3
N
O2
3s
(26 %)
3t
(66 %)
NO2
NO2
O
O
O
O
NO2
DBU, EtOH
50 oC, 2 h
+
+
3a
(71 %)
(0 %)
Scheme 2. Synthesis of 4-nitro-1,3-diarylbutan-1-ones from unsymmetrical 1,3-di-
arylpropan-1,3-diones and nitrostyrene.
NO2
O
O
O
NO2
DBU, EtOH
50 oC, 2 h
+
3a
1a
1.12 g
2a
0.75 g
1.02 g (76%)
Scheme 3. Practical synthesis of 3a on gram scale.
However, thereactioncouldafford3ain20%yieldinthe heteroaromatic rings could afford the corresponding
presence of 0.1 equiv. of NaOH in ethanol at 50◦C (entry products in good to high yield. The substituents on aro-
2). In order to improve the yield of 3a, other bases, such matic rings including electron-donating (CH3, CH3O)
as KOH, NaHCO3, K2CO3, Cs2CO3, DABCO, DMAP, and electron-withdrawing (F, Cl, Br, NO2) groups did
Et3N and DBU, as catalysts were examined (entries 3– not show obvious effect on the yield. In contrast,
10). All bases could catalyze the reaction to produce the attempts for the reaction of pentan-2,4-dione with
3a in low to high yield. The best yield of 3a (85%) was nitrostyrene (2a), the reaction of 1,3-diphenylpropan-
obtained by using DBU as a catalyst (entry 10). Because 1,3-dione (1a) with nitropropene, and 1a with 1-
ethanol in this reaction acted as a reactant and solvent, nitrocyclohexene were not successful.
other alcohols, such as MeOH, i-PrOH and n-BuOH,
In addition, the reactions of unsymmetrical 1,3-diaryl
were also attempted for the synthesis of 3a. However, no propan-1,3-diones with nitrostyrenes under standard
better yield of 3a was observed compared with ethanol condition also proceeded smoothly. However, two kinds
(entries 11–13).
of 4-nitro-1,3-diarylbutan-1-ones were generally pro-
Under the optimized conditions, the synthesis of 4- duced. For example, the reaction of 1-phenyl-3-(p-
nitro-1,3-diarylbutan-1-ones (3a–3r) were examined by tolyl)propan-1,3-dione with nitrostyrene (2a) could
reactions of symmetrical 1,3-diarylpropan-1,3-diones give 3a (30%) and 3l (62%). The reaction of 1-
and various nitrostyrenes catalyzed by DBU in ethanol (3-bromophenyl)-3-phenylpropan-1,3-dione with nitro
at 50◦C. The results are summarized in Table 2. It styrene (2a) could give 3a (58%) and 3o (31%).
was found that various symmetrical 1,3-diarylpropan- The reaction of 1-(4-nitrophenyl)-3-(4-methoxyphenyl)
1,3-diones and nitrostyrenes bearing aromatic rings and propan-1,3-dione with nitrostyrene (2a) could give

J. Chem. Sci.
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Page 5 of 7
26
NO2
O
NO2
Ph
O
O
O
DBU, EtOH
50 oC, 5 min
Ph
Ph
(1)
NO2
+
+
Ph
Ph
Ph
Ph
Ph
Ph
O
2a
3a
4a
(17 %)
(45 %)
1a
4a
NO2
Ph
O
O
NO2
O
O
DBU, EtOH
50 oC, 2 h
+
+
OEt
(2)
(3)
Ph
OEt
Ph
+
Ph
Ph
3a
(82%)
O
O
O
O
DBU, EtOH
50 oC, 2 h
Ph
Ph
Ph
OEt
(0%)
Ph
1a
(0%)
Scheme 4. Control experiments.
O
O
O
O
NO2
NO2
DBU
Michael addition
+
4a
1a
2a
retro-Claisen condensation
EtOH
O
O
NO2
OEt
+
3a
Scheme 5. Possible mechanism for the synthesis of 3a.
3s (26%) and 3t (66%) (Scheme 2). These results further showed the potency of optimized condition for
indicated that for the unsymmetrical 1,3-diarylpropan- the bulk processes (Scheme 3).
1,3-diones, the reactions were more advantageous to
Control experiments were conducted as shown in
the products including an electron-donating group on Scheme 4. Treatment of 1,3-diphenylpropan-1,3-dione
aromatic rings than the ones including an electron- (1a)withnitrostyrene(2a)underthestandardconditions
withdrawing group. In addition, aryl-alkyl ketone, such for only 5 min gave a mixture of the desired product
as 1-phenylbutan-1,3-dione, as a substrate was also 3a (17%) and a Michael addition product 4a (45%),
attempted for the reaction, but only one product 3a which could be isolated and identified by NMR spec-
(71%) was observed.
tra (Scheme 4, Eq. 1). Under the standard conditions,
With the success over generality of the protocol, the isolated 4a could react with a small concentration of
the reaction of 1,3-diphenylpropan-1,3-dione (1a) with ethoxide ion formed by DBU and EtOH in the system to
nitrostyrene (2a) was also performed on a gram scale. produce 3a in high yield through retro-Claisen conden-
The reaction of 1.12 g of 1a with 0.75 g of 2a in the pres- sation (Scheme 4, Eq. 2). This indicated that 4a is the
ence of 76 mg of DBU in EtOH (12 mL) was performed intermediate of the formation of product 3a. In addition,
under the optimized condition to give 1.02 g of 3a in the treatment of 1a in the absence of nitrostyrene (2a)
76% isolated yield. This success of gram scale reaction was also tested under standard conditions. However,

26 Page 6 of 7
J. Chem. Sci.
(2019) 131:26
the possible product, acetophenone, was not observed
(Scheme 4, Eq. 3). This implied that retro-Claisen con-
densation could not take place between substrate 1a and
EtOH.
Based on the above control experiments, a plausi-
ble mechanism is proposed for the synthesis of 3a
(Scheme 5). Firstly, the reaction of 1a with 2a cat-
alyzed by DBU give a Michael addition product 4a as an
intermediate. Then retro-Claisen condensation is taken
place through one carbonyl of 4a attacked by ethanol
and subsequent carbon-carbon bond cleavage to give
the final product 3a.
cyclohexane skeletons bearing five stereocenters Chin.
J. Org. Chem. 36 1572
5. Amireddy M and Chen K 2015 Organocatalytic synthe-
sis of spirocyclohexane indane-1,3-diones via a chiral
squaramide-catalyzed Michael/aldol cascade reaction of
γ -nitro ketones and 2-arylideneindane-1,3-diones Tetra-
hedron 71 8003
6. Yu L, Yang Q J and Li P F 2014 Phase-transfer-catalyst-
mediated domino reaction of γ -nitro ketones with chal-
cones: Approach to functionalized six-membered-ring
carbocycles Eur. J. Org. Chem. 7499
7. Tishkov A A, Lyapkalo I M, Kozincev A V, Ioffe S L,
Strelenko Y A and Tartakovsky V A 2000 Novel Me3Si-
mediated intramolecular cyclisation/[4+2] cyclofrag-
mentation of β-substituted γ -nitro ketones Eur. J. Org.
Chem. 3229
8. Zschiesche R and Reissig H U 1988 An efficient synthe-
sis of 5-membered cyclic nitrones from γ -nitro ketones
Tetrahedron Lett. 1685
9. Zhang G P, Zhu C, Liu D Y, Pan J K, Zhang J, Hu D Y and
Song B A 2017 Solvent-free enantioselective conjugate
addition and bioactivities of nitromethane to chalcone
containing pyridine Tetrahedron 73 129
10. Ballini R, Barboni L, Castrica L, Fringuelli F, Lanari D,
Pizzo F and Vaccaro L 2008 Polystyryl-BEMP as an effi-
cient recyclable catalyst for the nucleophilic addition of
nitroalkanes to α, β-unsaturated carbonyl compounds
under solvent-free conditions Adv. Synth. Catal. 350
1218
11. Li S S, Xie Z Y, Bian X Q and Wang C D 2007 New syn-
thesis of 1,3-diaryl-4-nitro-1-butanones by microwave-
promoted Michael addition of nitromethane to chalcones
without solvent J. Chem. Res. 2007 660
12. Oriyama T, Aoyagi M and Iwanami K 2007 Henry reac-
tion and 1,4-addition of nitroalkanes to α,β-unsaturated
carbonyl compounds under the influence of MS 4A in
DMSO Chem. Lett. 36 612
13. Mancuso R, Palmieri A, Ballini R and Gabriele B 2012
Base-free conjugate addition of aliphatic nitro com-
pounds to enones in BmimNTf2: A recyclable synthesis
of γ -nitro ketones Tetrahedron 68 5852
4. Conclusions
In conclusion, a simple and effective protocol for
the synthesis of 4-nitro-1,3-diarylbutan-1-ones through
tandem reaction of 1,3-diarylpropan-1,3-diones and
nitrostyrenes in the presence of DBU has developed.
Although the loss of one acyl group makes the reac-
tions poorly atom economical, mild reaction conditions,
shorter reaction time, high yield, good functional group
tolerance and simplified procedures are the salient fea-
tures of this method. A gram-scale reaction has been
attempted to illustrate the potency of reported procedure
towards the bulk synthesis.
Supporting Information (SI)
The experimental details, analytical data, H NMR and 13C
NMR spectra for the products are available at www.ias.ac.in/
chemsci.
1
Acknowledgements
The authors thank the National Natural Science Foundation 14. Barkov A Y, Korotaev V Y and Sosnovskikh V Y 2013 A
novel synthesis of γ -nitro ketones via detrifluoroacetyla-
tive Michael addition of 1-trifluoromethyl-1,3-diketones
to conjugated nitroalkenes Tetrahedron Lett. 54
6819
of China (21462038) for the financial support of this work.
References
15. Rasalkar M S, Potdar M K, Mohile S S and Salunkhe
M M 2005 An ionic liquid influenced l-proline catalysed
asymmetric Michael addition of ketones to nitrostyrene
J. Mol. Catal. A Chem. 235 267
16. Tsakos M, Kokotos C G and Kokotos G 2012 Primary
amine-thioureas with improved catalytic properties for
“difficult” Michael reactions: Efficient organocatalytic
synthesesof(S)-baclofen, (R)-baclofenand(S)-phenibut
Adv. Synth. Catal. 354 740
17. Li B L, Wang Y F, Luo S P, Zhong A G, Li Z B, Du X
H and Xu D Q 2010 Enantioselective Michael addition
of aromatic ketones to nitroolefins catalyzed by bifunc-
tional thioureas and mechanistic insight Eur. J. Org.
Chem. 656
18. Wang L, Xu X, Huang J, Peng L, Huang Q and Wang L
2010 Asymmetric Michael addition of aromatic ketones
1. Heravi M M, Hajiabbasi P and Hamidi H 2014 Recent
development in the asymmetric Michael addition for
carbon-carbon bond formation Curr. Org. Chem. 18 489
2. Jukic M, Sterk D and Casar Z 2012 Recent advances in
the retro-Claisen reaction and its synthetic applications
Curr. Org. Synth. 9 488
3. Yu L, Cheng Y Y, Qi F, Li R and Li P F 2017
Organocatalytic regioselective, diastereoselective, and
enantioselective annulation of cyclic 1-azadienes with
γ -nitro ketones via 3,4-cyclization Org. Chem. Front. 4
1336
4. Yu L, Cheng Y Y, Li R, Jiao Y H and Li P F 2016
Tandem cyclization reaction between optically active γ -
nitro ketone and chalcone towards the synthesis of chiral

J. Chem. Sci.
(2019) 131:26
Page 7 of 7
26
to nitroolefins catalyzed by simple chiral bifunctional
primary amine-thioureas Lett. Org. Chem. 7 367
promoted by a chiral primary amine-thiourea catalyst J.
Am. Chem. Soc. 128 7170
19. Jiang X, Zhang Y, Chan A S C and Wang R 2009 24. Sun Z, Peng F, Li Z, Zou L, Zhang S, Li X and
Highly enantioselective synthesis of γ -nitro heteroaro-
matic ketones in a doubly stereocontrolled manner
catalyzed by bifunctional thiourea catalysts based
on dehydroabietic amine: A doubly stereocontrolled
Shao Z 2012 Enantioselective conjugate addition of both
aromatic ketones and acetone to nitroolefins catalyzed
by chiral primary amines bearing multiple hydrogen-
bonding donors J. Org. Chem. 77 4103
approach to pyrrolidine carboxylic acids Org. Lett. 11 25. Liu K, Cui H, Nie J, Dong K, Li X and Ma J 2007 Highly
153
enantioselective Michael addition of aromatic ketones
to nitroolefins promoted by chiral bifunctional primary
amine-thiourea catalysts based on saccharides Org. Lett.
9 923
20. Flores-Ferrándiz J, Stiven A, Sotorríos L, Gómez-
Bengoa E and Chinchilla R 2015 Enantioselective
addition of aryl ketones and acetone to nitroalkenes
organocatalyzed by carbamate-monoprotected cyclo- 26. Evans D A, Mito S and Seidel D 2007 Scope and
hexa-1,2-diamines Tetrahedron Asymm. 26 970
21. Chandrasekhar S, Kumar T P, Haribabu K, Reddy
C R and Kumar C R 2011 A chiral pyrrolidine-
pyrazole catalyst for the enantioselective Michael addi-
mechanism of enantioselective Michael additions of
1,3-dicarbonyl compounds to nitroalkenes catalyzed by
nickel(II)-diamine complexes J. Am. Chem. Soc. 129
11583
tion of carbonyls to nitroolefins Tetrahedron Asymm. 22 27. Moon H W and Kim D Y 2012 Enantioselective
697
decarboxylative Michael addition of β-ketoacids to
nitroalkenes catalyzed by binaphthyl-derived organocat-
alysts Tetrahedron Lett. 53 6569
22. Liu J, Yang Z, Liu X, Wang Z, Liu Y, Bai S, Lin L
and Feng X 2009 Organocatalyzed highly stereoselec-
tive Michael addition of ketones to alkylidene malonates 28. Li Z, Li T P, Li J S, He L L, Jia X G and Yang J Y 2015
and nitroolefins using chiral primary-secondary diamine
catalysts based on bispidine Org. Biomol. Chem. 7
4120
2-Hydroxylation of 1,3-diketones with atmospheric oxy-
gen Synlett 26 2863
29. Li Z, Song G Y, He J J, Du Y and Yang J Y 2017
Catalyst-free sulfa-Michael addition of pyrimidine-2-
thiol to nitroolefins J. Sulfur Chem. 38 686
23. Huang H and Jacobsen E N 2006 Highly enantioselec-
tive direct conjugate addition of ketones to nitroalkenes