A novel organocatalyst for direct asymmetric Michael additions of cyclohexanone to nitroolefins

Article abstract of DOI:10.1016/j.catcom.2012.11.020

A novel catalyst combining pyrrolidinyl and cyclohexanediamine was designed and synthesized. Only 5 mol% of catalyst loading was required for enantioselective Michael additions of cyclohexanone and nitroolefins affording desired γ-nitroketones with > 99%

Full text of DOI:10.1016/j.catcom.2012.11.020

Catalysis Communications 32 (2013) 18–22
Contents lists available at SciVerse ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
A novel organocatalyst for direct asymmetric Michael additions of cyclohexanone
to nitroolefins
⁎
⁎
Jun Zhong, Zhi Guan , Yan-Hong He
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 October 2012
Received in revised form 18 November 2012
Accepted 19 November 2012
Available online 24 November 2012
A novel catalyst combining pyrrolidinyl and cyclohexanediamine was designed and synthesized. Only 5 mol%
of catalyst loading was required for enantioselective Michael additions of cyclohexanone and nitroolefins
affording desired γ-nitroketones with >99% yield, up to 91% ee and up to >99/1 dr under mild conditions.
The enantioselectivity of the product could be further improved to >99% ee after a single recrystallization
in petroleum ether/ethyl acetate.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Organocatalyst
Asymmetric Michael reaction
Chiral cyclohexanediamine derivatives
1. Introduction
2. Experimental
Michael addition is one of the most versatile methods for the
formation of C\C bonds in organic synthesis [1]. Since List et al.
reported the L-proline catalyzed asymmetric Michael addition of
ketones to trans-nitrostyrene in 2001 [2], over the past decade, a
great deal of effort has been dedicated towards the development of
organocatalyzed Michael addition for achieving the products with high
reactivity and selectivity. A lot of organocatalysts for asymmetric Michael
addition have been reported. Among them, the pyrrolidinyl as a func-
tional group was quite common, such as pyrrolidinyl tetrazole [3],
pyrrolidinyl triazole [4], pyrrolidine–pyridine [5], bipyrrolidine [6],
pyrrolidine sulfonamide [7], prolinol silyl ether [8], 2-(aminomethyl)
pyrrolidine [9], pyrrolidine thiourea [10], pyrrolidinyl ionic liquid [11],
peptide [12], and others [13–15]. The five-membered cyclic secondary
amine unit is now regarded as one of the essential backbones in
organocatalysts. Chiral cyclohexanediamine derivatives were also a kind
of successful catalysts for asymmetric organic reaction [16–19]. Xiao et
al. have reported several catalysts, L-proline combined with chiral
cyclohexanediamine derivatives by amide bonding, and successfully ap-
plied them in asymmetric aldol reaction [20]. Inspired by the pioneering
work, we designed and synthesized a set of novel catalysts 3a–d
containing the versatile pyrrolidinyl and a chiral cyclohexanediamine
framework (Fig. 1). These novel catalysts displayed high catalytic
activities towards the asymmetric Michael additions of nitroolefins to
cyclohexanone affording desired γ-nitroketones with moderate to good
stereoselectivities.
2.1. General
The 1H NMR spectra were recorded with TMS as the internal stan-
dard in CDCl3 on a Bruker 300 MHz instrument. Data are reported as
follows: chemical shift, multiplicity (s=singlet, d=doublet, t=
triplet, m=multiplet), coupling constants (Hz) and integration. Chiral
HPLC analysis was performed with Chiralpak AS-H and AD-H columns.
The structures of Michael adducts were confirmed from their 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectral studies. The absolute con-
figurations of the major syn adducts were based on the retention time
reported in the literature.
2.2. General procedure for the organocatalyzed asymmetric Michael
additions of nitroolefins to ketones
To a mixture of catalyst 3b (5.0 mg, 0.015 mmol), trans-nitroolefin
(0.3 mmol) and ketone (1.5 mmol) were added a solution of benzoic
acid (0.37 mg, 0.003 mmol) in acetonitrile (0.10 mL) followed by an-
other portion of acetonitrile (0.90 mL). The reaction mixture was
stirred at r.t. Upon completing of the reaction (monitored by TLC),
the mixture was purified by column chromatography, eluting with pe-
troleum ether/ethyl acetate to afford the desired γ-nitroketone.
3. Results and discussion
The synthetic routes for the preparation of catalysts 3a–d are
shown in Scheme 1. Chiral cyclohexanediamine derivatives 1 were
easily prepared from chiral cyclohexanediamine through four steps.
The Boc protected precursors 2 were prepared from 1 which were
⁎
Corresponding authors. Tel./fax: +86 23 68254091.
E-mail addresses: guanzhi@swu.edu.cn (Z. Guan), heyh@swu.edu.cn (Y.-H. He).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2012.11.020

J. Zhong et al. / Catalysis Communications 32 (2013) 18–22
19
Fig. 1. Structures of the organocatalysts.
coupled to N-Boc-(S)-prolinal to give corresponding imines then
followed a reduction by NaBH4. Cleavage of the Boc group from 2 pro-
duced the catalysts 3. The details for the synthesis of catalysts were
given in the Supplementary data.
pyrrolidinyl displayed high activities towards the Michael addition.
The above results clearly indicated that pyrrolidinyl is necessary for
these catalysts to have the catalytic activity for the model Michael
addition. Moreover, among the catalysts 3a–d, 3b showed the best
enantioselectivity which suggested that the electron-donating
group in the para position of the benzene ring may improve the ste-
reochemical outcome of the reaction. Thus, catalyst 3b was selected
for further investigation.
Encouraged by the results, we subsequently investigated the effect of
organic solvents on the model reaction at r.t. in the presence of 5 mol% of
catalyst 3b. Among the solvents screened, MeCN, THF and EtOAc were
superior to other solvents, and the reaction in them gave products in
good yields with high enantioselectivities and diastereoselectivities
(Table 1, entries 11–13). As can be seen from Table 1, enantioselectivity
of the reaction was sensitive to solvents. Toluene was proved as a poor
solvent for 3b. Although the reaction in toluene afforded product in al-
most quantitative yield, enantio- and diastereoselectivities were low
(74% ee, 88:12 dr) (Table 1, entry 20). In addition, the reaction was
not efficient in water which only gave product in a low yield of
16% with high diastereoselectivity and good enantioselectivity
(93:7 dr, 80% ee) (Table 1, entry 19). In general, acetonitrile
displayed an advantage in terms of enantioselectivity (86% ee)
In order to test the feasibility of the novel catalysts for asymmetric
Michael addition, a model Michael reaction between trans-nitrostyrene
(4a, 1.0 equiv) and cyclohexanone (5a, 5.0 equiv) in the presence of
organocatalysts (10 mol%) at r.t. in dichloromethane was carried out.
The results were summarized in Table 1. The chiral cyclohexanediamine
derivatives 1a–d were not effective for this process, and only trace
amount of product was observed after 48 h (Table 1, entries 1–4).
Moreover, no target product could be detected even after 48 h for the
Boc protected precursor 2b (Table 1, entry 5). However, the conjugate
addition process catalyzed by 3b proceeded efficiently with moderate
enantioselectivity (82% ee for the major syn diastereomer), high
diastereoselectivity (91:9 dr, syn/anti) and excellent yield (>99% yield)
within 23 h (Table 1, entry 7). At the same time, 3a, 3c, and 3d
could also catalyze the reaction with high yields, but lower
enantioselectivities (Table 1, entries 6, 8 and 9). From the view of
structure–activity relationship, 1a–d lacked pyrrolidinyl, and 2b
contained Boc protected pyrrolidinyl. They showed neglectable or
no activity towards the Michael addition. However, 3a–d including
i
i
S
Scheme 1. The preparation of catalysts.

20
J. Zhong et al. / Catalysis Communications 32 (2013) 18–22
Table 1
Table 2
Catalysts and solvents in the organocatalytic asymmetric Michael additions.a
Influence of the additives on the direct asymmetric Michael additions.a
Entry Additive (mol%)
Time (h) Yieldb (%) drc (syn/anti) eed (%) (syn)
Entry Cat. (mol%) Solvent Time (h) Yieldb (%) drc (syn/anti) eed (%) (syn)
1
None
32
32
90
98
Trace
0
94/6
94/6
n.de
–
86
87
n.d
–
1
1a/10
1b/10
1c/10
1d/10
2b/10
3a/10
3b/10
3c/10
3d/10
3b/5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
48
48
48
48
48
48
23
26
26
84
Trace
Trace
Trace
Trace
0
n.de
n.d
n.d
n.d
n.d
n.d
77
82
73
67
82
86
84
84
83
83
82
81
81
80
74
85
83
2
PhCOOH/5
2
n.d
3
p-CH3–PhSO3H/5 60
3
n.d
4
TFA/5
72
30
19
30
48
50
72
50
4
n.d
5
6
7
8
PhCOOH/0.5
PhCOOH/1
PhCOOH/2.5
PhCOOH/10
PhCOOH/1
PhCOOH/1
PhCOOH/1
92
>99
95
70
75
94/6
94/6
94/6
95/5
96/4
98/2
95/5
89
90
90
90
90
90
89
5
n.d
6
7
8
9
95
92/8
91/9
88/12
85/15
93/7
94/6
94/6
93/7
95/5
95/5
94/6
93/7
92/8
93/7
88/12
93/7
92/8
>99
>99
>99
80
9f
10g
11h
11
80
10f
11
12
13
14
15
16
17
18
19
20
21g
22g
3b/5
3b/5
3b/5
3b/5
3b/5
3b/5
3b/5
3b/5
3b/5
3b/5
3b/5
3b/5
CH3CN 32
90
a
Unless otherwise noted, the reaction was carried out with trans-nitrostyrene
(0.3 mmol, 1.0 equiv) and cyclohexanone (1.5 mmol, 5.0 equiv) in the presence of
3b (5 mol%) and additive at r.t. in CH3CN (1 mL).
THF
20
24
45
45
>99
>99
94
93
96
97
95
16
>99
95
EtOAc
EtOH
DMF
b
Isolated yield.
c
Diastereomeric ratio, determined by chiral HPLC analysis.
Enantiomeric excess, determined by chiral HPLC analysis.
Not detected.
The reaction temperature was 0 °C.
The reaction temperature was −40 °C.
Cyclohexanone (0.6 mmol, 2.0 equiv).
i-PrOH 45
CHCl3 22
Hexane 45
H2O 46
Toluene 22
CH3CN 45
d
e
f
g
h
EtOAc
22
>99
a
Unless otherwise noted, the reaction was carried out with trans-nitrostyrene
(0.3 mmol, 1.0 equiv) and cyclohexanone (1.5 mmol, 5.0 equiv) in the presence of
catalyst (5–10 mol%) at r.t. in solvent (1 mL).
almost maintained at the same level (Table 2, entry 11). Therefore,
we chose 1 mol% of benzoic acid as additive, and ratio of cyclohexa-
none (5a) to nitrostyrene (4a) to 5:1 at r.t. as optimal conditions.
Finally, a variety of nitroolefins with different substituents were in-
vestigated under the optimized reaction conditions and the results
were summarized in Table 3. Nitroolefins bearing electron-neutral
(Table 3, entry 1), electron-donating (Table 3, entries 2–5) and
electron-withdrawing (Table 3, entries 6–12) aryl groups, as well as
heterocyclic groups (Table 3, entries 13 and 14) gave desired products
with high selectivities (up to >99/1 dr, up to 91% ee). There seemed
to be no direct correlation between the nature of the substituents of
the phenyl ring and the stereochemical outcome of these reactions
under the present conditions. The reactions with nitroolefins bearing
electron-neutral or electron-donating aryl groups proceeded efficiently
(>99% yield, Table 3, entries 1–5). However, the reactions with
nitroolefins bearing electron-withdrawing groups were inefficient,
and only low to moderate yields were obtained (Table 3, entries
7–12). To our surprise, nitroolefin with o-chlorine group on the ben-
zene ring exhibited excellent reactivity and high selectivity in a short
reaction time (18 h, >99% yield, >99/1 dr, 91% ee, Table 3, entry 6).
Furthermore, when reacting with cyclohexanone both furanyl
nitroolefin and thienyl nitroolefin gave products with good selectiv-
ities, but thienyl nitroolefin was much more reactive than furanyl
nitroolefin (Table 3, entries 13 and 14).
b
Isolated yield.
c
Diastereomeric ratio, determined by chiral HPLC analysis.
Enantiomeric excess, determined by chiral HPLC analysis.
Not detected.
The reaction temperature was 0 °C.
d
e
f
g
4 Å MS (10 mg) was added.
(Table 1, entry 11). Based on these results, acetonitrile was chosen as
the optimal solvent for further study. In addition, molecular sieves
were also proved not effective to improve the stereoselectivity
(Table 1, entries 21 and 22).
Since additives have an important influence on the reactivity and
selectivity of organic reaction, and suitable acids are believed to accel-
erate the reaction rate and improve the stereochemical outcome of the
reaction [21], thus, the effect of additive for catalyst 3b in the model
Michael reaction was examined. The reaction rate varied dramatically
with different acids. The reaction with benzoic acid gave product in
better yield and ee value than the reaction without additive (Table 2,
entries 1 and 2). However, stronger acid such as p-TsOH led to a dra-
matic decline in yield; the reaction with p-TsOH only gave trace
amount of product after 60 h (Table 2, entry 3). Moreover, in the pres-
ence of strong acid TFA, no desired product was detected (Table 2,
entry 4). Therefore, benzoic acid was chosen as the optimal additive
for the reason. Next, we checked the influence of additive loading on
reactivity and selectivity (Table 2, entries 5–8). When 1 mol% benzoic
acid was added, the reaction gave product in excellent yield (>99%
yield) with good enantio- (90% ee) and diastereoselectivities (94:6 dr)
after only 19 h (Table 2, entry 6). Furthermore, the influence of temper-
ature on the reaction was also investigated. When the temperature was
lowered down to 0 °C and −40 °C, respectively, the reaction rate de-
creased dramatically, but the enantioselectivity was not improved
(Table 2, entries 9 and 10). Besides, we attempted to decline the ratio
of cyclohexanone (5a) to nitrostyrene (4a) to 2:1, which caused an ob-
vious drop of the yield although enantio- and diastereoselectivities
Moreover, ketones other than cyclohexanone as Michael donors were
evaluated as well. When acetone was used, the desired adduct was gene-
rated in moderate yield with low enantioselectivity (Table 3, entry 15).
The use of cyclopentanone as a Michael donor only gave trace amount
of product (Table 3, entry 16). In addition, to further improve enan-
tioselectivity, some products were recrystallized in petroleum ether/
ethyl acetate. After a single recrystallization, diastereoselectivities and
enantioselectivities increased dramatically (Table 3, entries 1, 2, 5, 10
and 14).
According to the experimental results described above, chiral
cyclohexanediamine derivatives 1a–d and Boc protected precursor

J. Zhong et al. / Catalysis Communications 32 (2013) 18–22
21
Table 3
Scope of the Michael additions of trans-nitroolefins (4) to ketones (5).a
Entry No
Product
Time (h) Yieldb (%)
drc (syn/anti)
eed (%)
1
6a
19
>99 (70)e 94/6 (>99/1)f 90 (>99)f
2
6b
20
>99 (70)e 93/7 (99/1)f
90 (97)f
Fig. 2. A proposed transition state.
3
4
6c
18
30
>99
>99
96/4
94/6
91
89
6d
2b cannot catalyze the asymmetric Michael reaction, so the chiral
pyrroline moiety was believed to play an important role in the reac-
tion process. Based on the previous reported transition state [22],
we proposed a possible transition state (Fig. 2). We envision that
the organocatalyst 3b acts as a bifunctional catalyst. Nitrostyrene is
activated by the NH group through the hydrogen bonding, and the
enamine formed from the pyrrolidine and cyclohexanone would at-
tack the nitrostyrene, giving the corresponding adduct.
5
6e
36
>99 (72)e 91/9 (>99/1)f 84 (>99)f
6
7
6f
18
66
>99
30
>99/1
93/7
91
89
4. Conclusion
6g
In summary, we have designed and synthesized a novel catalyst,
composed of a chiral pyrrolidinyl and a chiral cyclohexanediamine
framework. This organocatalyst was successfully applied in the asym-
metric Michael additions of cyclohexanone with nitroolefins. We
hope that the highlight in our work will provide a meaningful inspira-
tion for the catalyst design in the field of organocatalysis. The im-
provement of designed catalysts and their application in other types
of reactions is undergoing in our laboratory.
8
9
6h
6i
70
70
40
52
96/4
97/3
90
91
10
6j
50
64 (56)e
95/5 (99/1)f
97/3
89 (91)f
Acknowledgment
Financial support from the 2011 Select Project in Scientific and Tech-
nological Activities for Returned Scholars of Chongqing Personnel Bureau
and the Doctoral Foundation of Southwest University (SWU112019) is
gratefully acknowledged.
11
12
6k
6l
50
50
25
86
86
35
42
95/5
92/8
Appendix A. Supplementary data
13
14
15
6m
6n
6o
70
20
72
85
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.11.020.
>99 (75)e 91/9 (99/1)f
87 (98)f
20
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