Asymmetric organocatalytic Michael/α-alkylation reaction of α,β-unsaturated aldehyde with chloroacetophenone

Article abstract of DOI:10.1016/j.tetlet.2011.03.079

Asymmetric organocatalytic Michael/α-alkylation reactions of α,β-unsaturated aldehydes with chloroacetophenones have been developed. The biologically useful cyclopropane motifs were synthesized with high yields and up to >99% ee, >30:1 dr through J?rgense

Full text of DOI:10.1016/j.tetlet.2011.03.079

Tetrahedron Letters 52 (2011) 2715–2718
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric organocatalytic Michael/
a-alkylation reaction
of ,b-unsaturated aldehyde with chloroacetophenone
a
⇑
Wenjun Li, Xin Li, Tingting Ye, Wenbin Wu, Xinmiao Liang, Jinxing Ye
Engineering Research Centre of Pharmaceutical Process Chemistry Ministry of Education, School of Pharmacy, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric organocatalytic Michael/a-alkylation reactions of a,b-unsaturated aldehydes with chloro-
Received 22 December 2010
Revised 9 March 2011
Accepted 17 March 2011
Available online 11 April 2011
acetophenones have been developed. The biologically useful cyclopropane motifs were synthesized with
high yields and up to >99% ee, >30:1 dr through Jørgensen–Hayashi catalyst under mild conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
a,b-Unsaturated aldehyde
Tandem reaction
Organocatalysis
Enantioselective
The cyclopropane motif has been recognized as an interesting
building block in organic chemistry.1 Importantly, the cyclopro-
pane motif exists in more than 4000 natural isolates and holds a
potential to serve as the drug lead.2 In recent years, chemists have
focused their efforts on the enantioselective synthesis of cyclopro-
pane motif.3 The metal-catalyzed cyclopropanation reactions of
electron-rich alkenes have been well established.4 Moreover, the
development of organocatalytic enantio- and diastereoselective
one-pot domino reaction has been become a powerful tool to build
complex molecular scaffolds.5 Up to date, there have been a few
examples of asymmetric cyclopropanation using organocatalysts
until now. For instance, Córdova and Wang pioneered the enantio-
In this communication, we succeed in devising organocatalytic
domino Michael/ -alkylation reactions between ,b-unsaturated
aldehydes and chloroacetophenones to construct the cyclopropane
motif with high yields and up to >99% ee and >30:1 dr under mild
conditions (Scheme 1 (C)).
a
a
To probe the feasibility of the organocatalytic domino Michael/
a-alkylation reaction, we initially combined cinnamaldehyde 1a
and 2-chloro-1-phenyl-ethanone 2a with Jørgensen–Hayashi cata-
lyst I in the solvents.10 The results were summarized in Table 1.
However, the reactions proceeded to low conversions in methanol,
THF, and dichloromethane (Table 1, entries 1–3). Based on these
preliminary results, we supposed that hydrogen chloride generated
selective cyclopropanation reactions between
a,b-unsaturated
from the reaction process hindered the domino Michael/a-alkyl-
aldehydes with bromomalonates catalyzed by Jørgensen–Hayashi
catalyst.6 Aggarwal and Gaunt realized the enantioselective cata-
lytic cyclopropanation process via ylides.7 Besides, Gaunt also
developed the intramolecular cyclopropanation using modified
cinchona alkaloid organocatalysts.8 Notably, MacMillan and
Arvidsson, respectively, disclosed an efficient method to construct
ation reaction. We chose to introduce basic additive to neutralize
hydrogen chloride in order to promote the reaction process. To
our delight, up to 94% of conversion with 93% ee value was
obtained when 1.0 equiv of triethylamine was used in the dichloro-
methane (Table 1, entry 4). Moreover, similar results were ob-
served in EtOAc, THF, and toluene (Table 1, entries 5–7).
However, low conversions were obtained in CH3CN, DMF, and
methanol (Table 1, entries 8–10). These results indicated that the
reaction would become sluggish in protic solvent. A screen of basic
additives showed that triethylamine was the best choice for this
process. For example, lower conversions would be obtained when
DIPEA, DBU, and LiOH were used (Table 1, entries 11–13).
However, dramatic decreases of conversions were observed in
the precence of DABCO and lithium acetate (Table 1, entries
14–15). It should be noted that under the optimized reaction
the cyclopropane motif using a,b-unsaturated aldehydes and stabi-
lized sulfur ylides with secondary amine organocatalysts (Scheme
1 (A–B)).9 However, highly diastereo- and enantioselective one-pot
cyclopropanation reaction of a,b-unsaturated aldehyde under mild
conditions is more desirable and remains a challenge.
⇑
Corresponding author. Tel./fax: +86 21 64251830.
E-mail address: yejx@ecust.edu.cn (J. Ye).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.079

2716
W. Li et al. / Tetrahedron Letters 52 (2011) 2715–2718
Table 2
O
MacMillan's work
R1
COOH
Organocatalytic asymmetric domino Michael/
rated aldehydes and chloroacetophenones
a
-alkylation reactions of
a
,b-unsatu-
O
R1
N
H
R2
S
O
A
R2
CHCl3, -10oC
CHO
CHO
O
I
(20 mol%)
Cl
9 examples, 63-85% yield
6:1-72:1 dr, 89-96% ee
+
R1
O
O
R2
CH2Cl2, Et3N, RT
R1
1
2
3
R2
N
O
N
N
Arvidsson's work
b
c
Entrya
R1
R2
Yield (%)
ee (%)
O
R1
N
H
N
H
R2
S
R1
O
B
R2
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
78, 3a
82, 3b
80, 3c
77, 3d
85, 3e
75, 3f
76, 3g
78, 3h
80, 3i
81, 3j
77, 3k
76, 3l
80, 3m
81, 3n
84, 3o
82, 3p
80, 3q
79, 3r
75, 3s
77, 3t
62, 3u
64, 3v
93
>99
91
94
95
90
96
93
94
97
96
95
97
94
96
94
96
93
98
97
92
93
CHCl3, -10oC
CHO
3-MeC6H4
4-MeC6H4
2-FC6H4
4-BrC6H4
4-ClC6H4
4-MeC6H4
3-MeC6H4
4-MeC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Et
3
7 examples, 74-91% yield
96-98 de, 99% ee
4d
5
Ph
Ph
OTMS
6
CHO
O
Our work
7d
8
4-MeC6H4
4-MeC6H4
2-FC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2-ClC6H4
3-BrC6H4
2-FC6H4
4-MeC6H4
4-OMeC6H4
4-NO2C6H4
2-Furanyl
N-Boc-3-indolyl
C6H5
O
N
H
Cl
R1
O
C
R2
R1
9
CH2Cl2, Et3N, RT
R2
10
11
12
13d
14
15d
16
17d
18d
19d
20
21
22
22 examples, 62-85% yields,
>30:1 dr, 90-99% ee
Scheme 1. Asymmetric cyclopropanation of
a
,b-unsaturated aldehyde using
organocatalysts.
conditions, only single diastereomer was formed, and no other dia-
stereomeric products were detectable according to 1H NMR of
crude reaction mixture (Table 1, entry 4, 94% conversion, >30:1
dr, 93% ee).
n-Pr
C6H5
Having established the optimized reaction conditions, the gen-
erality of this cascade process was explored. The cascade reactions
a
Reaction conditions:
a,b-unsaturated aldehydes 1 (0.3 mmol), chloroaceto-
phenones 2 (0.9 mmol), I (0.06 mmol) and triethylamine (0.3 mmol) in CH2Cl2
(0.6 mL) were stirred under room temperature for 24 h.
were carried out with
phenones 2, catalyst I and triethylamine in dichloromethane at
room temperature. As showed in Table 2, the reaction appeared
quite tolerant for aromatic
a,b-unsaturated aldehydes 1, chloroaceto-
b
Isolation yield.
c
The enantiomerexcesswas detected on HPLC usingChiralpakÒ AS-H, IC, Whelk-O1
column.
a,b-unsaturated aldehydes. Aromatic
d
The enantiomer excess was detected on HPLC after conversion to the corre-
sponding alcohols 4.
Table 1
Optimization studies
CHO
O
Cl
O
Cat. (20 mol%)
O
+
HO
Solvent, Additive, RT
1a
2a
3a
O
R
I: R = Ph
Cat.:
R
II: R = 3,5-(CF3)2C6H3
III: R =1-Naphthyl
Br
N
OTMS
H
4e
Entrya
Cat
Solvent
Additive
None
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
II
III
THF
9
nd
nd
nd
93
91
93
93
nd
nd
nd
93
93
92
nd
nd
nd
nd
MeOH
CH2Cl2
CH2Cl2
THF
EtOAc
Toluene
CH3CN
DMF
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
None
None
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
LiOH
DIPEA
DBU
25
34
94
93
91
87
45
47
10
70
75
65
37
36
n.r.
n.r.
Scheme 2. X-ray crystal structure of 4e.
substrates bearing electron- withdrawing or electron-donating
groups in ortho-, meta-, and para-position of the benzene ring,
could be successfully employed to afford the cascade products in
good yields with excellent enantioselectivities (Table 2, entries
1–12). A similar trend was also observed with the structural vari-
ations of substrates 2 (Table 2, entries 13–18). Heteroaromatic ke-
tones such as furan and indole, also successfully engaged in the
cascade process (Table 2, entries 19–20). Unfortunately, the enan-
tiometric excesses of the products (3d, 3g, 3m, 3o, 3q, 3r, 3s) could
not be determined directly by chiral phase HPLC analysis. Accord-
ingly, the products were reduced to corresponding alcohols and
then analyzed to reveal that they were formed in excellent enanti-
oselectivities (93–98%). Gratifyingly, this cascade process was also
LiOAc
DABCO
Et3N
Et3N
a
Reaction conditions: Unless noted, a mixture of 1a (0.1 mmol), 2a (0.3 mmol),
catalyst (20 mol %), and additive (0.1 mmol) in the solvent (0.2 mL) was stirred at
room temperature for 24 h.
b
Conversion was determined by GC.
c
The enantiomer excess was detected on HPLC using ChiralpakÒ AS-H.

W. Li et al. / Tetrahedron Letters 52 (2011) 2715–2718
2717
OH
O
Et3N
Cl
Cl
Ph
R2
R2
N
Ph
OTMS
OH-
O
R1
R1
H
H2O
O
Ph
Ph
OTMS
Ph
Ph
OTMS
N
Cl
R2
N
H
R1
H
R1
CHO
Et3N
H2O
Et3N
R2
O
Ph
Ph
OTMS
OH-
N
HCl
R1
R2
O
Scheme 3. Proposed catalytic mechanism of the organocatalytic asymmetric domino Michael/a-alkylation reaction.
tolerated for aliphatic
a,b-unsaturated aldehydes. For examples,
References and notes
pentenal and hexenal all achieved excellent entioselectivities with
slightly lower yields (Table 2, entries 21–22).
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3e (Scheme 2).11 To account for the observed stereochemical out-
come of the reaction, the catalytic mechanism was proposed and
depicted in Scheme 3. We supposed that the Michael addition of
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chloroacetophenone to
through iminium intermediate could be well controlled and then
enamine-based intramolecular -alkylation reaction occurred
a,b-unsaturated aldehyde catalyzed by I
a
smoothly to generate cyclopropane motif.
In summary, we have developed an environmentally friendly
and high diastereo- and enantioselective method to construct
cyclopropane motif. Through iminium/enamine catalysis with I,
the domino Michael/a-alkylation reactions could be achieved in
high yields with excellent diastereo- and enantioselectivities. Fur-
ther researches on iminium/enamine catalysis are undergoing and
the results will be presented in the future.
Acknowledgments
We thank Innovation Program of Shanghai Municipal Education
Commission (11ZZ56), National Natural Science Foundation of
China (20902018) and Shanghai Pujiang Program (08PJ1403300)
for financial support.
Supplementary data
Supplementary data associated with (experimental procedures
and compound characterization data) this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.079.

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W. Li et al. / Tetrahedron Letters 52 (2011) 2715–2718
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10. General Procedure for Asymmetric Domino Michael/
a-Alkylation Reaction: To a
solution of CH2Cl2 (0.6 mL) were added ,b-unsaturated aldehydes
a
1
6. (a) Rios, R.; Sundén, H.; Vesely, J.; Zhao, G. L.; Dziedzic, P.; Córdova, A. Adv.
Synth. Catal. 2007, 349, 1028; (b) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am.
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611.
(0.3 mmol), chloroacetophenones 2 (0.9 mmol), catalyst I (0.06 mmol) and
triethylamine (0.3 mmol). The reaction mixture was stirred at room
temperature for 24 h and then the solvent was removed under vacuum. The
residue was added 1 M hydrochloric acid (5.0 mL) and extracted with CH2Cl2
for three times. The combined organic phases were dried over anhydrous
Na2SO4, filtered and evaporated under vacuum. The residue was purified by
silica gel chromatography to yield the desired product.
11. The crystallographic data of 4e for this paper has been deposited in the
Cambridge Structural Database, Cambridge Crystallographic Data Centre,
Cambridge CB2 1EZ, United Kingdom (CSD reference no. 805086).