Asymmetric Direct Michael Reactions of Cyclohexanone with Aromatic Nitroolefins in Water Catalyzed by Novel Axially Unfixed Biaryl-Based Bifunctional Organocatalysts

Article abstract of DOI:10.1055/s-0033-1340289

A new family of axially unfixed biaryl-based water-compatible bifuctional organocatalysts were designed and synthesized for the asymmetric direct Michael reaction of cyclohexanone with various nitroolefins in water. One of the organocatalysts incorporates

Full text of DOI:10.1055/s-0033-1340289

LETTER
▌293
lAettserymmetric Direct Michael Reactions of Cyclohexanone with Aromatic Nitro-
olefins in Water Catalyzed by Novel Axially Unfixed Biaryl-Based Bifunctio-
nal Organocatalysts
Asymmetric Direct Michael Reactions of Cyclohexanone
Hong-Wu Zhao,* Zhao Yang, Yuan-Yuan Yue, Hai-Long Li, Xiu-Qing Song, Zhi-Hui Sheng, Wei Meng,
Xiao-Yu Guo
College of Life Science and Bio-engineering, Beijing University of Technology, 100 Pingleyuan, Chaoyang District, Beijing 100124,
P. R. of China
Fax +86(10)67396200; E-mail: hwzhao@bjut.edu.cn
Received: 11.09.2013; Accepted after revision: 17.10.2013
sequester water from the transition states of the direct
Abstract: A new family of axially unfixed biaryl-based water-com-
Michael reactions in water efficiently through hydropho-
patible bifuctional organocatalysts were designed and synthesized
bic interactions. Evidently, sufficient hydrophobicity of
the water-compatible organocatalysts is necessary to
for the asymmetric direct Michael reaction of cyclohexanone with
various nitroolefins in water. One of the organocatalysts incorpo-
rates pyrrolidine and arylsulfonamide motifs as active organocata- achieve high levels of stereocontrol in direct Michael re-
lytic sites, and axially unfixed biaryl as a skeleton; with this
organocatalyst, the direct Michael reactions proceeded readily, fur-
nishing the desired Michael adducts in high yields (up to 99% yield)
introduction of a bulky hydrophobic group into the archi-
with high levels of stereocontrol (up to >99:1 dr and 94% ee).
actions in water. The appropriate hydrophobicity of the
water-compatible organocatalysts can be afforded by the
tecture of the organocatalysts. To date, through the choice
of different bulky hydrophobic scaffolds,6 several tens of
Key words: biaryl compounds, aqueous chemistry, organocata-
lysts, asymmetric Michael reaction, stereoselectivity
highly efficient water-compatible organocatalysts have
already been developed to perform direct Michael reac-
tions in water. However, so far, there have been no reports
The asymmetric organocatalytic direct Michael reaction
on the development of hydrophobic axially unfixed chiral
represents one of the most efficient and powerful methods
biphenyl- or bipyridyl-based water-compatible organo-
for the formation of C–C or C–heteroatom bonds, and has
catalysts for the direct Michael reactions in water. Ac-
been widely used to generate enantioenriched organic
cordingly, the development of novel water-compatible
compounds in the context of drug discovery and organic
organocatalysts that catalyze such reactions efficiently
synthesis of natural products and heterocycles.1 Since the
through the use of hydrophobic axially unfixed chiral bi-
seminal works of List and Barbas, many efficient and
phenyl or bipyridyl as scaffolds is described herein.
highly stereoselective organocatalysts have been devel-
In this paper we describe the design, synthesis and asym-
oped for the asymmetric direct Michael reactions.2 To the
metric catalysis of novel axially unfixed biaryl-based
best of our knowledge, most of the reports deal with such
organocatalysts 2a–c in direct Michael reactions in water
reactions in organic solvents. In view of the clear advan-
(Scheme 1). The designed organocatalysts involve biaryl,
tages of performing organocatalytic direct Michael reac-
pyrrolidine and arylsulfonamide fragments, and their be-
tions in water, many recent efforts have been devoted to
havior is assumed to stem from their bifunctional nature.
the development of highly efficient water-compatible
It was envisioned that in our organocatalytic systems, the
organocatalysts.3 The main challenges with the develop-
Michael donors would be activated through enamine for-
ment of such catalysts stem from interference in the tran-
mation, and the Michael acceptors would be activated by
sition state by water, which reduces the reactivity and
the formation of double hydrogen bonds. Moreover, the
level of stereocontrol of the organocatalysts.4 Encouraged
biaryl group present in the organocatalysts can function as
by the pioneering findings of Barbas, a number of water-
a fundamental scaffold unit that adjusts the spatial orien-
compatible organocatalysts has been devised for the direct
tation of arylsulfonamide and pyrrolidine catalytic sites
Michael additions of ketones or aldehydes to nitroolefins
more freely. In particular, the presence of the hydrophobic
in water with high yields and levels of stereocontrol.5 It
biaryl moiety of the organocatalysts can ensure the or-
has been demonstrated that the success of these water-
ganocatalysts have sufficient hydrophobicity to aggregate
compatible organocatalysts in the direct Michael reac-
with the hydrophobic reactants and exclude water effi-
tions in water depends significantly on the fact that they
ciently from the transition states by means of the hydro-
can assemble with the Michael donors and acceptors, and
phobic interactions, thus yielding high reactivities and
levels of stereocontrol.
SYNLETT 2014, 25, 0293–0297
Advanced online publication: 04.12.2013
DOI: 10.1055/s-0033-1340289; Art ID: ST-2013-W0873-L
© Georg Thieme Verlag Stuttgart · New York
Starting from organocatalysts 1a–c, which showed excel-
lent reactivities and stereoselectivities in organocatalytic
direct aldol reactions in water in our recently published
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

294
H.-W. Zhao et al.
LETTER
chemical yields (15–21%; Table 1, entries 7–10). In com-
parison to catalysts 3 and 4, catalysts 2a–c exhibited much
superior reactivities and slightly lower enantioselectivi-
ties under the same reaction conditions (Table 1, entries 2,
5 and 6 vs. 7 and 9). In the series of catalysts 2a–c, similar
diastereoselectivities and enantioselectivities in the Mi-
chael additions were found; however, significantly differ-
ent reactivities were identified (Table 1, entries 2, 5 and
6). For instance, organocatalyst 2a enabled the Michael
addition to reach completion in 12 hours; in contrast, the
same reaction went to completion in 17 hours under catal-
ysis by 2b. Noticeably, it was found that in the presence
of 2c as catalyst, the Michael addition proceeded very
sluggishly, and reached completion in 30 hours.
NH
NH
LiAlH4
O
NH
NH
NHSO2R
NHSO2R
THF, reflux
1a–c
2a: R = 4-MeC6H4, 56%
2b: R = 4-F3CC6H4, 18%
2c: R = 1-naphthyl, 21%
Scheme 1 Synthesis of novel organocatalysts 2a–c
work,7 a series of novel organocatalysts 2a–c with
C1-symmetry were prepared in 18–56% yields according
to the strategy shown in Scheme 1. Conversion of 1a–c
into 2a–c, respectively, was easily accomplished upon
treatment with LiAlH4 in anhydrous in tetrahydrofuran
(THF) at reflux. In addition, to investigate the structure–
reactivity relationships of organocatalysts 2a–c, organo-
catalyst 1a, with C1-symmetry, and 3/4, bearing C2-sym-
metry, as shown in Figure 1 were also synthesized in a
straightforward manner according to our developed pro-
cedures.7,8
Table 1 Screening of Biaryl Organocatalystsa
O
O
Ph
NO2
cat. (10 mol%)
NO2
+
Ph
additive (10 mol%)
H2O, r.t.
Entry
Cat.
Time
(h)
Yield (
%)b
dr
ee (%)
(syn/anti)c (syn)c
Me
1
2
1a
2a
2a
2a
2b
2c
3
36
12
14
36
17
30
48
48
48
48
24
30
48
69
85
85
–
96:4
97:3
96:4
–
–11
89
85
–
Me
CF3
3d
4d,e
5
O
O
O
O
O
S
S
S
NH
NH
NH
NH
NH
NH
O
O
81
81
18
15
15
21
88
73
42
97:3
97:7
93:7
95:5
94:6
95:5
96:4
96:4
96:4
89
87
90
91
93
92
87
86
86
6
NH
NH
NH
NH
7
1a
2a
2b
8f
3
NH
NH
9
4
O
S
N
N
10f
11g
12h
13i
4
NH
NH
O
NH
NH
NH
NH
2a
2a
2a
NH
NH
2c
3
4
a Reaction conditions: nitroolefin (0.1 mmol), cyclohexanone
(104 μL, 1.0 mmol), catalyst (10 mol%), PhCO2H (10 mol%), H2O
(0.5 mL), r.t.
Figure 1 Organocatalysts examined in this work
b Isolated yield.
With organocatalysts 1a, 2a–c (Scheme 1), 3 and 4 (Fig-
ure 1) in hand, we started to evaluate their reactivities and
levels of stereocontrol in the Michael reaction (Table 1).
The organocatalytic Michael additions of cyclohexanone
to nitroolefin proceeded smoothly in favor of the syn dia-
stereoisomers, and delivered comparable diastereoselec-
tivities in most cases. The chemical yields and
enantioselectivities of the Michael additions changed sig-
nificantly depending on the chemical structure of the
organocatalyst used. Known catalysts 3 and 4, with
C2-symmetry, tended to furnish the Michael products
with up to 93% ee and up to 95:5 dr, albeit with rather low
c Determined by chiral HPLC analysis.
d Brine was used as solvent.
e NaHCO3 was used as additive.
f C17H35CO2H (20 mol%) was used.
g Molar ratio of cyclohexanone to nitroolefin: 5:1.
h Molar ratio of cyclohexanone to nitroolefin: 2:1.
i Molar ratio of cyclohexanone to nitroolefin: 1:1.
Furthermore, under catalysis of 2a, it was revealed that
the use of brine instead of water as the reaction medium
slightly reduced the enantioselectivity and diastereoselec-
tivity of the Michael reaction; however, the chemical
Synlett 2014, 25, 293–297
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Direct Michael Reactions of Cyclohexanone
295
yield remained at the same level (Table 1, entries 2 vs. 3).
Even worse, when the reaction was catalyzed with 2a, no
Michael addition took place at all when brine was chosen
as reaction solvent and NaHCO3 as additive (Table 1, en-
try 4). Moreover, to our surprise it was noted that catalyst
1a showed much inferior reactivity and levels of enanti-
oselectivity compared with those of catalyst 2a (Table 1,
entries 1 vs. 2). Accordingly, by considering reactivities
and levels of stereocontrol in the organocatalyzed Mi-
chael additions mentioned above, catalyst 2a was identi-
fied as the most efficient organocatalyst examined.
Moreover, when the reaction was catalyzed by 10 mol%
2a, it was noted that the reaction rate of the Michael addi-
tion accelerated significantly with an increased ratio of
cyclohexanone to nitroolefin; however, the stereoselectiv-
ity of the reaction did not change drastically (Table 1, en-
tries 2 and 11–13).
Table 2 Extension of the Scope of Nitroolefins at Room Tempera-
turea
O
O
R
NO2
cat. 2a (10 mol%)
NO2
+
R
benzoic acid
(10 mol%)
H2O, r.t.
Entry
R
Time
(h)
Yield
(%)b
dr
ee (%)
(syn/anti)c (syn)c
1
2
3
4
5
6
7
8
9
Ph
12
6
85
99
96
92
99
95
99
80
98
96
96
90
5
97:3
96:4
96:4
96:4
97:3
95:5
>99:1
94:6
95:5
93:7
95:5
92:8
>99:1
92:8
89
89
89
85
89
88
84
91
88
77
87
86
94
89
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-F3CC6H4
4-MeC6H4
4-MeOC6H4
2-furyl
6
4
5
Subsequently, by using 2a as catalyst (10 mol%), the ef-
fects of various catalytic loadings, acidic additives and or-
ganic solvents on the asymmetric organocatalytic Michael
reactions in water were evaluated (see the Supporting In-
formation), and optimal reaction conditions were estab-
lished as 2a (10 mol%)/PhCO2H (10 mol%)/H2O/r.t. As
summarized in Table 2, under the optimized reaction con-
ditions, the scope of the Michael reaction was extended by 10
using a variety of aromatic nitroolefins. In most cases, the
Michael reactions proceeded smoothly, delivering the de-
sired Michael adducts in excellent yields with excellent
levels of diastereoselectivity and good levels of enantiose-
lectivity (Table 2, entries 2–7, 9, 11 and 12). In general,
aromatic nitroolefins containing an electron-withdrawing
group on the benzene ring tended to give the correspond-
ing products in excellent levels of diastereoselectivity and
good levels of enantioselectivity (Table 2, entries 2–8).
Moreover, heteroaromatic nitroolefins also showed simi-
lar levels of stereocontrol in the Michael reactions (Table
2, entries 11 and 12 vs. 2–8). Meanwhile, it should be not-
ed that a nitroolefin bearing a methyl group at the 4-posi-
tion on the benzene ring also produced the Michael adduct
in 98% yield with 95:5 dr and 87% ee. In contrast, use of
a nitroolefin bearing a methoxy group at the 4-position on
the benzene continued to deliver the desired Michael
adduct in excellent yield and diastereoselectivity, but the
enantiomeric excess decreased to a certain degree (Table
2, entries 9 vs. 10). Generally, compared with the aromat-
ic nitroolefins, aliphatic nitroolefins also delivered the de-
sired Michael adducts with comparable levels of
stereoselectivity, but with rather low chemical yields (Ta-
ble 2, entries 1–12 vs. 13–14).
8
4
7
6
18
5
11
12
13
14
2-thienyl
5
cyclohexyl
isopropyl
92
92
24
a Reaction conditions: nitroolefin (0.1 mmol), cyclohexanone
(104 μL, 1.0 mmol), catalyst 2a (10 mol%), PhCO2H (10 mol%), H2O
(0.5 mL), r.t.
b Isolated yield.
c Determined by chiral HPLC analysis.
of pentan-3-one to nitroolefin, the Michael adducts were
achieved in 26% yield with 96:4 dr (syn/anti) and 89% ee
(Table 3, entry 4). Moreover, aliphatic aldehydes such as
propionaldehyde and isobutyraldehyde were examined as
Michael donors in the Michael additions with the use of
2a as catalyst. When propionaldehyde was tested as a
Michael donor, the addition reaction gave rise to the
Michael adduct in 98% yield with 91:9 dr (syn/anti) and
25% ee (syn). When the branched isobutyraldehyde
served as a Michael donor, the desired adduct was isolated
in 32% yield with 77% ee.
Finally, the catalytic efficiency of 2a was also evaluated
in a series of cascade cyclization reactions initiated by
aza- or oxa-Michael addition as shown in Scheme 2. The
Michael addition of 2-hydroxybenzaldehyde (5a) to ni-
troolefin delivered the Michael adduct 6a in 5% yield with
9% ee; in contrast, use of 2-aminobenzaldehyde (5b) as
Michael donor gave the desired Michael adduct 6b in 24%
yield with 5% ee. When nitroolefin was replaced by α,β-
unsaturated aldehyde as Michael acceptor, use of 5a or 5b
Furthermore, the Michael addition of a variety of Michael
donors involving aliphatic aldehydes and ketones to ni-
troolefin was carried out by using catalyst 2a as shown in
Table 3. Catalyzed by 2a, the Michael addition of acetone
to nitroolefin did not take place at all within 62 hours (Ta-
ble 3, entry 1). Similarly, the choice of cyclopentanone
and butan-2-one as Michael donors did not afford the de-
sired Michael adducts after a reaction time of 62 hours
(Table 3, entries 2 and 3). In the case of Michael addition
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 293–297

296
H.-W. Zhao et al.
LETTER
Table 3 Scope of the Reaction with Michael Donorsa
O
N
N
H
cat. 2a (10 mol %)
H
O
O
Ph
R3
H
O
NO2
R1
+
N
H
NO2
Ph
1
Ar
N
benzoic acid (10 mol%)
H2O, r.t.
R
R2
S
O
R2 R3
O
Entry R1
R2
R3
Time Yield dr (syn/anti)c ee (%)
(h)
(%)b
(syn)c
Me
Figure 2 Proposed transition state for the Michael addition under ca-
talysis of 2a
1
2
3
4
5
6
Me
H
H
–
62
62
62
62
62
62
–
–
–
-(CH2)3-
–
–
–
ganocatalytic direct Michael reactions in water.9 Under
the optimal reaction conditions, organocatalyst 2a
performed with high efficiency and delivered high
enantioselectivities and diastereoselectivities in Michael
reactions performed in water. Further studies on the
mechanisms and the utility of the water-compatible bi-
functional organocatalyst in other asymmetric transfor-
mations in water are in progress in our laboratory, and will
be reported in due course.
Me
Et
H
Me
H
H
H
Me
–
–
–
Me
Me
Me
26
98
32
96:4
91:9
–
89
25
77
H
a Reaction conditions: nitroolefin (0.1 mmol), Michael donor (1.0
mmol), catalyst 2a (10 mol%), benzoic acid (10 mol%).
b Isolated yield.
c Determined by chiral HPLC analysis.
Acknowledgment
cat. 2a
NO2
CHO
XH
NO2
We thank the Beijing Municipal Commission of Education (No.
JC015001200902), Beijing Municipal Natural Science Foundation
(No. 7102010, No. 2122008), Basic Research Foundation of Bei-
jing University of Technology (X4015001201101), Funding Pro-
ject for Academic Human Resources Development in Institutions of
Higher Learning Under the Jurisdiction of Beijing Municipality
(No. PHR201008025), and the Doctoral Scientific Research Start-
up Foundation of Beijing University of Technology (No.
52015001200701) for financial support.
(10 mol%)
+
X
PhCO2H
(10 mol%)
H2O, r.t.
5a,b
6a: X = O, 62 h,
5% yield, 9% ee
6b: X = NH, 60 h,
24% yield, 5% ee
cat. 2a
(10 mol%)
CHO
CHO
CHO
+
PhCO2H
(10 mol%)
H2O, r.t.
X
XH
Supporting Information for this article is available online at
5a,b
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
7a: X = O, 62 h,
51% yield, 29% ee
7b: X = NH, 36 h,
77% yield, 15% ee
References and Notes
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Scheme 2 Cascade cyclization reactions catalyzed by 2a initiated by
aza- or oxa-Michael addition
furnished the desired Michael adducts 7a in 51% yield
(29% ee) and 7b in 77% yield (15% ee), respectively.
To account for the stereochemical outcome observed with
organocatalyst 2a, the organocatalytic transition state de-
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behaves as a bifunctional organocatalyst. The activation
of cyclohexanone as a Michael donor was accomplished
through the formation of an enamine with the aid of the
acidic additive; acting as a Michael acceptor, nitroolefin
was simultaneously activated through double hydrogen
bonding interactions. Subsequent attack of the enamine
generated in situ on the Re face of the well-oriented
nitroolefin led to the formation of the desired Michael
adduct with high stereocontrol.
In conclusion, a class of novel water-compatible organo-
catalysts with an axially unfixed biaryl unit as skeleton
has been designed and synthesized for the asymmetric or-
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Synlett 2014, 25, 293–297
© Georg Thieme Verlag Stuttgart · New York

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Asymmetric Direct Michael Reactions of Cyclohexanone
297
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(S)-2-[(R)-2-Nitro-1-phenylethyl]cyclohexanone (Table
2, entry 1): Reaction time: 12 h. Yield: 85%; dr = 97:3
(syn/anti); ee = 89% (syn).1H NMR (400 MHz, CDCl3): δ =
7.28–7.32 (m, 3 H), 7.16–7.17 (m, 2 H), 4.94 (dd, J = 12.4,
4.0 Hz, 1 H), 4.60–4.66 (m, 1 H), 3.76 (d, J = 4.0 Hz, 1 H),
2.69 (s, 1 H), 2.38–2.49 (m, 2 H), 2.07 (d, J = 3.2 Hz, 1 H),
1.55–1.80 (m, 4 H), 1.19–1.28 (m, 1 H).
(6) (a) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka,
F.; Barbas, C. F. J. Am. Chem. Soc. 2006, 128, 4966. (b) Zu,
L.; Wang, J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077.
(c) Palomo, C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puente,
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Synlett 2014, 25, 293–297

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