Phase-Transfer-Catalyst-Mediated Domino Reaction of γ-Nitro Ketones with Chalcones: Approach to Functionalized Six-Membered-Ring Carbocycles

Article abstract of DOI:10.1002/ejoc.201403075

Domino reactions between γ-nitro ketones and chalcones for the construction of functionalized six-membered-ring carbocycles using a phase-transfer catalyst have been developed. In the presence of tetrabutylammonium iodide and potassium hydroxide, domino r

Full text of DOI:10.1002/ejoc.201403075

FULL PAPER
DOI: 10.1002/ejoc.201403075
Phase-Transfer-Catalyst-Mediated Domino Reaction of γ-Nitro Ketones with
Chalcones: Approach to Functionalized Six-Membered-Ring Carbocycles
Lu Yu,[a] Qingjing Yang,[b] and Pengfei Li*[a]
Keywords: Synthetic methods / Phase-transfer catalysis / Cyclization / Domino reactions / Aldol reactions / Michael
addition / Enones
Domino reactions between γ-nitro ketones and chalcones for
the construction of functionalized six-membered-ring
carbocycles using a phase-transfer catalyst have been devel-
ketones and a series of chalcones proceeded smoothly to give
the cyclic products in moderate to high yields with high dia-
stereoselectivities. Importantly, multiply substituted and
oped. In the presence of tetrabutylammonium iodide and po- functionalized six-membered-ring carbocycles could be ef-
tassium hydroxide, domino reactions between γ-nitro
ficiently prepared in one pot using this domino strategy.
then an intramolecular aldol reaction of the intermediate
diketone would give the functionalized six-membered-ring
carbocycles (Scheme 1).
Introduction
Six-membered-ring carbocycles are widespread in natural
products and other important biologically active com-
pounds.[1] Functionalized six-membered-ring carbocycles
also act as building blocks in synthetic chemistry.[2] Due
to the importance of six-membered-ring carbocycles, much
effort has been devoted to this field.[3]
Domino reactions have a high synthetic efficiency as they
allow the number of laboratory operations required and the
quantities of chemicals and solvents used to be decreased.
As a result, they have attracted great interest, and they are
continually used in organic synthesis.[4] Such domino reac-
tions represent an efficient method for the synthesis of a
wide range of complex molecules, including natural prod-
ucts and biologically active compounds such as agrochem-
icals and pharmaceuticals.[5]
Scheme 1. Domino strategy for the construction of functionalized
six-membered-ring carbocycles.
Phase-transfer catalysis has received much attention and
Very recently, we developed an efficient catalytic domino been recognized as one of the most versatile and powerful
reaction between aldehydes and ketones for the synthesis of methods for organic synthesis in both academia and indus-
cyclohexenone derivatives.[6] Continuing our investigations try.[7,8] The advantages of this approach include operational
in this field, we have used this domino strategy in the reac- simplicity, mild reaction conditions, the use of low-cost and
tion between γ-nitro ketones and α,β-unsaturated ketones environmentally friendly starting materials, and so on. Im-
(enones) for the construction of functionalized six-mem- pressive results have been achieved in the field of cyclization
bered-ring carbocycles. A γ-nitro ketone was expected to under phase-transfer catalysis.[9] To our delight, the domino
react with an enone to give an intermediate diketone, and reaction between chalcones and γ-nitro ketones could also
be accomplished under phase-transfer catalysis to construct
functionalized six-membered-ring carbocycles. Compared
[a] Department of Chemistry, South University of Science and
Technology of China,
with other domino processes involving Michael-type reac-
tions either of nitroalkenes[10] or α,β-unsaturated carbonyl
compounds[11] for the synthesis of these functionalized skel-
etons, this alternative method has several advantages, such
as the availability of the reactants, low catalyst loading,
mild reaction conditions, low cost, and high efficiency.
Furthermore, phase-transfer catalysis could mediate certain
reactions of esters, nitriles, and nitro compounds for which
other organocatalysts do not work. In this paper, we present
1088 Xueyuan Blvd., Nanshan District, Shenzhen, Guangdong,
518055, P. R. China
E-mail: flyli1980@gmail.com
li.pf@sustc.edu.cn
http://www.sustc.edu.cn/en/chemistry/index/
[b] State Key Laboratory of Chirosciences and Department of
Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University,
Hung Hom, Kowloon, Hong Kong, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403075.
Eur. J. Org. Chem. 2014, 7499–7504
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Yu, Q. Yang, P. Li
FULL PAPER
this phase-transfer-catalyst-mediated domino reaction be- efficient tool for this kind of domino reaction. Importantly,
tween chalcones and γ-nitro ketones for the construction of functional groups such as hydroxy groups,[12] nitro
functionalized six-membered-ring carbocycles.
groups,[13] and carbonyl groups[14] on the ring could easily
be transformed into other functional groups, which makes
these six-membered-ring carbocycles more valuable in syn-
thetic chemistry.
Results and Discussion
It should be noted that all the reactions tested gave annu-
lation product 3aa with excellent diastereoselectivities, as
confirmed by 1H NMR spectroscopic analysis. Further-
more, annulation product 3al from the Bu4NI/KOH-medi-
ated domino reaction between 5-nitropentan-2-one (1a) and
(E)-3-(4-bromophenyl)-1-(3-chlorophenyl)prop-2-en-1-one
(2l) was unequivocally identified by X-ray analysis as a pair
of enantiomers of [(1S,2R,5S,6R)-6-(4-bromophenyl)-2-
hydroxy-2-methyl-5-nitrocyclohexyl](3-chlorophenyl)meth-
anone and [(1R,2S,5R,6S)-6-(4-bromophenyl)-2-hydroxy-2-
methyl-5-nitrocyclohexyl](3-chlorophenyl)methanone (3al;
Figure 1).[15] The high stereoselectivity is probably due to
an initial highly diastereoselective Michael addition of γ-
nitro ketone to chalcone. The product of the Michael ad-
dition presumably dictates the stereochemistry of the subse-
quent aldol reaction. The configurations of the hydroxy
group and 3-ClPhCO groups are syn, and there is an intra-
molecular hydrogen bond between the hydroxy group and
the carbonyl of the 3-ClPhCO group. A plausible mecha-
nism for the formation of 3al is shown in Scheme 2. The
initial Michael addition of 1a to 2l gave a pair of enantio-
mers with high diastereoselectivity. This was followed by an
aldol reaction to give (1S,2R,5S,6R)- and (1R,2S,5R,6S)-
3al.
At the outset of our initial investigation, we focused on
the domino reaction between 5-nitropentan-2-one (1a) and
chalcone (2a). Using DBU (1,8-diazabicycloundec-7-ene) as
base without phase-transfer catalyst, annulation product
3aa was obtained in 61% yield with Ͼ95% dr from the
domino reaction between chalcone and 5-nitropentan-2-one
(Table 1, entry 1). DABCO (1,4-diazabicyclo[2.2.2]octane)
did not promote the domino reaction (Table 1, entry 2).
When K2CO3 was used as a base, product 3aa was obtained
in 66% yield with similar diastereoselectivity after a long
reaction time (Table 1, entry 3). A remarkable enhancement
in yield without compromising the diastereoselectivity was
achieved when a phase-transfer catalyst, tetrabutylammo-
nium bromide (Bu4NBr), was introduced into the reaction
mixture (Table 1, entry 4). A screening of bases was then
carried out (Table 1, entries 5–10) and a combination of
Bu4NBr and KOH was found to give the best results, 76%
yield after 1.5 h (Table 1, entry 8). A further screening of
phase-transfer catalysts revealed that up to 86% yield could
be obtained within 5 h from a Bu4NI/KOH-mediated dom-
ino reaction between chalcone and 5-nitropentan-2-one
(Table 1, entry 13). These encouraging results indicated that
a phase-transfer catalyst/base combination might be a very
Table 1. Screening catalysts and bases for the domino reaction.
Entry[a] Catalyst
Base
Time [h][b]
Yield
[%][c]
dr
[%][d]
1
2
3
4
5
6
7
8
–
–
–
DBU
18
72[e]
120[e]
15
61
trace
66
70
70
39
61
76
trace
72
Ͼ95
–
DABCO
K2CO3
K2CO3
Cs2CO3
LiOH
NaOH
KOH
Ba(OH)2
tBuOK
KOH
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
–
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NBr
Bu4NF
Bu4NCl
Bu4NI
1.5
96[e]
24
1.5
9
96[e]
0.33
0.5
10
11
12
13
76
67
86
Figure 1. X-ray crystal structure of annulation product 3al.
KOH
KOH
0.83
5
Having identified the best catalytic system, optimization
of reaction conditions was then investigated and representa-
tive results are listed in Table 2. Commonly used organic
solvents were examined first. It should be noted that all
the solvents tested gave functionalized six-membered-ring
carbocycle 3aa in good yield and with excellent diastereo-
selectivity within an acceptable reaction time (Table 2, en-
tries 1–8). In MeCN, the desired product (i.e., 3aa) was
[a] Unless otherwise noted, the reaction was carried out as follows:
5-Nitropentan-2-one (1a; 0.6 mmol) and chalcone (2a; 0.5 mmol)
were mixed in CH2Cl2 (1 mL). Base (20 mol-%) and phase-transfer
catalyst (20 mol-%) were added, and the reaction mixture was
stirred at room temperature for the time given in the Table. [b] After
this time, 2a was fully consumed, and the reaction mixture was
then worked up. [c] Isolated yield. [d] Diastereomeric ratio based
on 1H NMR analysis. [e] After this time, 2a was not fully con-
sumed, but the reaction mixture was still worked up.
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Domino Reaction of γ-Nitro Ketones with Chalcones
yields of Ͼ90% and excellent diastereoselectivities could be
still obtained when less base was used after an extended
reaction time (Table 2, entries 13–15). For example, the
domino reaction gave functionalized six-membered-ring
carbocycle 3aa in 94% yield with Ͼ95% dr after 6 h when
Bu4NI (5 mol-%) and KOH (5 mol-%) were used (Table 2,
entry 15).
Under the optimal reaction conditions, Bu4NI/KOH-cat-
alyzed domino reactions between γ-nitro ketones 1 and a
series of enones 2 were surveyed. All the domino reactions
tested proceeded smoothly to give the functionalized six-
membered-ring carbocycles 3 in moderate to high yields
with excellent diastereoselectivities. Various substituents,
either electron-withdrawing (-F, -Cl, -Br, -NO2, -CF3) or
electron-donating (-Me, -OMe) groups, could be introduced
into both of the aromatic rings of chalcone. The introduc-
tion of electron-withdrawing groups into either of the aro-
matic rings of chalcone led to high reaction rates (Table 3,
entries 2–6, 9, and 12). On the other hand, extended reac-
tion times were necessary for the formation of cyclic prod-
ucts 3 in acceptable yield when electron-donating groups
were introduced into either of the aromatic rings of chalc-
Scheme 2. Proposed mechanism for the domino reaction.
formed in 90% yield with excellent diastereoselectivity after
1 h (Table 2, entry 6). The best results, 93% yield and
Ͼ95% dr, were obtained when the domino reaction was car-
ried out in EtOAc for 3 h (Table 2, entry 7).
Table 2. Optimization of reaction conditions.
Table 3. Scope of the domino reaction.
Entry[a] Bu4NI
KOH Solvent Time[b] Yield[c] dr[d]
[mol-%] [mol-%]
[h]
[%]
[%]
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
15
10
5
20
20
20
20
20
20
20
20
20
20
20
20
15
10
5
CH2Cl2
THF
MeOH
Et2O
5
2
10
11
8
1
3
1
3
3
3.5
4
86
86
78
84
73
90
93
79
96
87
92
79
92
93
94
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Entry[a] R1 R2
R3
Time[b] Yield[c]
dr[d]
[h]
[%]
[%]
toluene
MeCN
EtOAc
DMF
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
1
2
3
4
5
6
7
8
9
10
Me Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
6
4
3
5
1.5
3
15
36
3
1.5
20[e]
19
2
18
23
2.5
144[f]
5
94, 3aa
86, 3ab
90, 3ac
70, 3ad
71, 3ae
92, 3af
85, 3ag
84, 3ah
80, 3ai
49, 3aj
67, 3aj
61, 3ak Ͼ95
67, 3al Ͼ95
75, 3am Ͼ95
57, 3an
81, 3ao
60, 3ap
86, 3aq
93, 3ba
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Me 4-FC6H4
Me 3-BrC6H4
Me 4-BrC6H4
Me 4-O2NC6H4
Me 4-CF3C6H4
Me 4-MeC6H4
Me 4-MeOC6H4
Me Ph
9
10
11
12
13
14
15
0
5
5
5
3.5
4.5
6
3-ClC6H4
4-O2NC6H4
Me Ph
[a] Unless otherwise noted, the reaction was carried out as follows:
5-Nitropentan-2-one (1a; 0.6 mmol) and chalcone (2a; 0.5 mmol)
were mixed in the solvent (1 mL). KOH and Bu4NI were added,
and the reaction mixture was stirred at room temperature for the
time given in the Table. The configuration of 3aa was derived from
compound 3al. [b] After this time, 2a was fully consumed, and the
reaction mixture was then worked up. [c] Isolated yield. [d] Dia-
11
12
13
14
15
16
17
18
Me Ph
3-MeOC6H4
3-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-MeOC6H4
3-ClC6H4
Ph
Me 4-BrC6H4
Me 3-O2NC6H4
Me 4-O2NC6H4
Me 4-MeC6H4
Me 4-MeC6H4
Me 4-MeOC6H4
Et Ph
Ͼ95
Ͼ95
Ͼ95
Ͼ95
Ͼ95
1
stereomeric ratio based on H NMR analysis.
8
[a] Unless otherwise noted, the reaction was carried out as follows:
γ-Nitro ketone (1, 0.6 mmol) and enone (2a, 0.5 mmol) were mixed
in EtOAc (1 mL). KOH (5 mol-%) and Bu4NI (5 mol-%) were
added, and the reaction mixture was stirred at room temperature
for the time given in the Table. The configurations of products 3
were derived from compound 3al. [b] After this time, 2a was fully
consumed, and the reaction mixture was then worked up. [c] Iso-
lated yield. [d] Diastereomeric ratio based on 1H NMR analysis.
[e] The reaction was carried out at 0 °C. [f] After this time, enone
2 was not fully consumed, but the reaction mixture was still worked
A further study was carried out to test different amounts
of base and catalyst loadings. Lowering the catalyst loading
still gave satisfactory yields and diastereoselectivities
(Table 2, entries 9–11). With a catalyst loading of 5 mol-%,
annulation product 3aa was obtained in 92% yield after
3.5 h (Table 2, entry 11). In the presence of KOH but with-
out a phase-transfer catalyst, the domino reaction gave cy-
clic product 3aa in 79% yield after 4 h (Table 2, entry 12), up.
Eur. J. Org. Chem. 2014, 7499–7504
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L. Yu, Q. Yang, P. Li
FULL PAPER
one (Table 3, entries 7, 8, and 11). (E)-1-(4-Nitrophenyl)-3-
phenylprop-2-en-1-one (2j) was found to react promptly
with 5-nitropentan-2-one, and the desired product (i.e., 3aj)
was formed in 49% yield (Table 3, entry 10). The yield of
3aj could be improved to 67% when the domino reaction
was carried out at 0 °C for 20 h. It was found that (E)-1-(4-
methoxyphenyl)-3-p-tolylprop-2-en-1-one (2p) reacted with
5-nitropentan-2-one quite slowly to give the desired product
(i.e., 3ap) in 60% yield after 144 h (Table 3, entry 16). An-
other γ-nitro ketone was also investigated. When 6-ni-
trohexan-3-one (1b) was used to react with chalcone, six-
membered-ring carbocycle 3ba was isolated in 93% yield
with Ͼ95% dr from the domino reaction after 8 h (Table 3,
entry 18).
We also explored the reactivity of the Bu4NI/KOH sys-
tem with enones other than chalcones. The domino reaction
between 5-nitropentan-2-one and (E)-4-phenylbut-3-en-2-
one (2r) gave a mixture of six-membered-ring carbocycles
3ar and 3Јar in a total yield of 78% and a ca. 1:3 ratio,
according to HPLC analysis [Scheme 3, Equation (1)]. Cy-
clohexenone (2s) reacted with 5-nitropentan-2-one to gener-
ate the Michael adduct in 64% yield, with no further annu-
lation product formed [Scheme 3, Equation (2)]. However,
increasing the loading of both the phase-transfer catalyst
and the base could lead to the formation of an annulation
product after a longer time.
Scheme 4. Enantioselective domino reaction between 1a and 2a.
Transformation of the functional groups on the function-
alized six-membered-ring carbocycles was also investigated.
A nitro group was reduced to an amino group with Zn/HCl
in MeOH to give 4aa as a white solid in 91% yield without
optimization (Scheme 5).[17]
Scheme 5. Reduction of 3aa to 4aa.
Conclusions
We have developed a phase-transfer-catalyst-promoted
domino reaction between γ-nitro ketones and α,β-unsatu-
rated ketones for the construction of functionalized six-
membered-ring carbocycles. Under mild reaction condi-
tions, Bu4NI/KOH-mediated domino reactions give the de-
sired annulation products in good to high yields with excel-
lent diastereoselectivities. This provides a new and efficient
method for the construction of functionalized cyclohexanes.
These functionalized cyclohexanes contain common func-
tional groups such as hydroxy groups, nitro groups, carb-
onyl groups, and others, that could be easily transformed
into other functional groups. The applications of this dom-
ino strategy for the synthesis of complex compounds are
underway. These results also inspire us to continue our in-
vestigations into the enantioselective construction of func-
tionalized six-membered-ring carbocycles. Related research
with chiral organocatalysts is ongoing in our lab, and the
results will be reported in the near future.
Scheme 3. Domino reactions between 1a and other enones 2r and
2s.
Asymmetric phase-transfer catalysis has been used as a
strategy to access complex chiral skeletons for more than
thirty years. However, reports of asymmetric [4+2] cycliza-
tion under chiral phase-transfer catalysis are very rare, and
racemic products were frequently obtained from [4+2] cycli-
zation reactions with chiral phase-transfer catalysts.[16]
Fully aware of the potential benefits but also of the many
difficulties we would be likely to encounter, we went on to
investigate the enantioselective [4+2] cyclization between 5-
nitropentan-2-one (1a) and chalcone (2a). A preliminary ex-
periment using N-benzylcinchoninium chloride as the chiral
phase-transfer catalyst gave annulation product 3aa in 81%
yield with 7% ee. When the reaction was carried out at 0 °C,
the ee of annulation product 3aa increased to 32%, but the
yield dropped to 66% (Scheme 4). Notably, the diastereo-
selectivities still remained at a high level.
Experimental Section
General Procedure for the Domino Reaction of 5-Nitropentan-2-one
with Chalcone: 5-Nitropentan-2-one 1a (0.0787 g, 0.6 mmol) and
chalcone 2a (0.1041 g, 0.5 mmol) were dissolved in EtOAc
(1.0 mL), and Bu4NI (5 mol-%) and KOH (5 mol-%) were added
to the stirred solution at room temperature. Upon completion of
the reaction (monitored by TLC), the reaction mixture was purified
by column chromatography on silica gel to give product 3aa
1
(0.1595 g, 94%). Products were fully characterized by H and 13C
NMR spectroscopy and HRMS analysis.
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Domino Reaction of γ-Nitro Ketones with Chalcones
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Supporting Information (see footnote on the first page of this arti-
cle): Characterization data; copies of the 1H and 13C NMR spectra
for functionalized six-membered-ring carbocycles and derivative
4aa; copies of chiral stationary phase HPLC analysis of 3aa.
[6]
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Acknowledgments
The authors gratefully thank the Startup Fund from South Univer-
sity of Science and Technology of China (SUSTC) and the
National Natural Science Foundation of China (NSFC) (grant
number 21302089) for financial support. Ms. Huaixue Mu and
Prof. Zhaoxiang Bian of the Hong Kong Baptist University are
gratefully acknowledged for the HRMS analysis of annulation
products. Prof. Zhongyuan Zhou of the Hong Kong Polytechnic
University is gratefully acknowledged for the crystallographic data
analysis of annulation product 3al.
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Received: August 13, 2014
Published Online: October 6, 2014
7504
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7499–7504