The first catalytic asymmetric morita-baylis-hillman reaction of acrolein with aromatic aldehydes

Article abstract of DOI:10.1002/cjoc.201200937

We report the first example of catalytic asymmetric Morita-Baylis-Hillman reaction of acrolein with aromatic aldehydes. The use of 10 mol% of Hatakeyama's catalyst β-isocupreidine C4, in combination with 20 mol% of 2,6-dimethoxybenzoic acid, could catalyz

Full text of DOI:10.1002/cjoc.201200937

FULL PAPER
DOI: 10.1002/cjoc.201200937
The First Catalytic Asymmetric Morita-Baylis-Hillman Reaction
of Acrolein with Aromatic Aldehydes
Zeng, Xingpinga(曾兴平)
Ji, Congbina(计从斌)
Liu, Yunlina(刘运林)
Zhou, Jian*,a(周剑)
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China
Normal University, Shanghai 200062, China
We report the first example of catalytic asymmetric Morita-Baylis-Hillman reaction of acrolein with aromatic
aldehydes. The use of 10 mol% of Hatakeyama’s catalyst β-isocupreidine C4, in combination with 20 mol% of
2,6-dimethoxybenzoic acid, could catalyze the reaction to give the desired products in up to 81% ee.
Keywords Morita-Baylis-Hillman reaction, acrolein, β-isocupreidine, 2,6-dimethoxybenzoic acid, organocatalysis
Introduction
with acrolein underwent very slowly, so the more reac-
tive p-nitrobenzaldehyde 1a was undertaken for condi-
tion optimization, and typical results were shown in Ta-
ble 1.
The catalytic asymmetric Morita-Baylis-Hillman
(MBH) reaction is a powerful tool for the selective
atom-economical synthesis of highly functionalized al-
lylic alcohols which are valuable building blocks in
synthetic organic and natural product chemistry.[1] Ac-
cordingly, much effort has gone to this field,[2] and tre-
mendous progress has been made in the past decade
since Hatakeyama and co-workers discovered a power-
ful catalyst, β-isocupreidine 1 (β-ICD), for this valuable
reaction.[3] Notable achievements include the use of
multifunctional organocatalysts and chiral Lewis acids
for the addition of different activated alkenes to alde-
hydes.[2] Surprisingly, the use of acrolein as the nucleo-
philic reaction partner to react with aldehydes has not
been reported in the catalytic enantioselective MBH
reaction,[4] as far as we know, although the use of
acrylic esters, acrylonitrile, methyl vinyl ketone or cy-
clic enones as the nucleophiles has been extensively
studied. Considering the resulting MBH adducts contain
a versatile aldehyde group, the use of acrolein as the
nucleophile to develop catalytic asymmetric MBH reac-
tions would be highly desirable.
Recently, during our efforts in the catalytic asym-
metric synthesis of 3,3-disubstituted oxindoles,[5] we
developed the highly enantioselective catalytic MBH
reaction of isatins with acrolein.[5a] Later, it was found
that the racemic version of this reaction could be run in
ethylene glycol without the use of any catalyst.[6] The
high reactivity that acrolein showed in the reaction with
isatins encouraged us to develop a catalytic asymmetric
MBH reaction of acrolein and aldehydes. However, ini-
tial studies revealed that the reaction of benzaldehyde
Results and Discussion
A variety of cinchona alkaloid-based catalysts were
examined, but only Hatakeyama’s catalyst β-ICD C4
could promote the reaction and afford product 3a in
78% yield, with 64% ee (Entry 2, Table 1). Other bi-
functional catalysts such as C1—C2 did not work at
－30 ℃, and C3 catalyzed this reaction very slowly
(Entry 1, Table 1). The study of solvent effects revealed
that acetone was the most suitable solvent, when using
C4 as the catalyst (Entries 2—5, Table 1). A variety of
Brønsted acids were used as additives to further im-
prove the ee (Entries 6—11, Table 1). While the addi-
tion of hydrogen-bond donor A1—A3 decreased the ee
of 3a (Entries 6—8, Table 1), the addition of (R)-A4
obviously improved the ee to 72%, but the yield of 3a
was only 45% even the reaction was run for 48 h (Entry
9, Table 1). The addition of (S)-A4 greatly decreased
the ee of 3a from 64% to 38% (Entry 10, Table 1),
which further confirmed the addition of Brønsted acid
additives could influence the stereochemical control of
this reaction. Surprisingly, the addition of benzoic acid
A5 could improve the ee to 74%, but the reaction was
slowed down (Entry 11, Table 1).
The finding that the addition of carboxylic acid
could improve the enantioselectivity was interesting.
Generally, the accepted mechanism of tertiary amines
catalyzed MBH reaction is that the tertiary amines func-
tion as Lewis bases to activate nucleophilic elec-
*
E-mail: jzhou@chem.ecnu.edu.cn; Tel.: 0086-021-62234560; Fax: 0086-021-62234560
Received September 23, 2012; accepted October 31, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200937 or from the author.
Chin. J. Chem. 2012, 30, 2631—2635
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Zeng et al.
FULL PAPER
Table 1 Condition optimization
OH
CHO
CHO
Cat. (10 mol%)
CHO
+
solvent, -30 oC
O2N
2 (2.0 equiv.)
1a
3a
O2N
Ar
EtO
EtO
O
N
HN
S
N
P
N
N
O
N
N
HO
O
HN
MeO
HO
HO
O
C1
C2
C3
C4
N
N
Ar = 3,5-(CF3)2C6H3
Ar1
Ar1
O
OH
CF3
CF3
OH
OH
CO2H
OH
OH
S
O
Ar1 Ar1
Ar1 = 2-naphthyl
A1
NO2
F3C
N
N
CF3
H
H
A5
A2
A3
A4
Entrya
Cat.
C3
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
Additive (20 mol%)
Solvent
Acetone
Acetone
CH3CN
EtOAc
Time/h
240
12
Yieldb/%
trace
78
eec/%
25
1
2
—
—
64
3
—
12
33
21
4
—
12
58
46
5
—
THF
12
67
13
6
A1
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
72
72
53
7
A2
72
74
53
8
A3
48
97
55
9
(R)-A4
(S)-A4
A5
48
45
72
10
11
48
89
38
72
78
74
a Run on a 0.25 mmol scale. b Isolated yield. c Determined by chiral HPLC analysis.
tron-deficient olefins.[1,7] Accordingly, the addition of
hydrogen-bond donors such as phenols to activate the
electrophilic reaction partner is a common method to
improve the reactivity and enantiofacial control.[1]
However, to the best of our knowledge, the addition of a
carboxylic acid, in combination with a tertiary amine, to
improve the reaction outcome has not been reported.[8]
This is reasonable because the addition of carboxylic
acid would protonate the tertiary amine moiety of the
catalyst, which resulted in the catalyst poison. In light of
this, the observation that the addition of benzoic acid
would improve the ee was very impressive and would
have potential use in the development of catalytic
asymmetric MBH reaction.
On the basis of this finding, a series of different sub-
stituted benzoic acids were synthesized and tried in the
reaction of 1a and 2, using acetone as the solvent at −30
℃, with 10 mol% of C4 and 20 mol% of additive, as
shown in Table 2. The phenyl substituent of benzoic
acid indeed affected the reaction. Benzoic acids with
electron-withdrawing groups greatly decreased the reac-
tivity (Entries 1－2, Table 2), and A6 as the additive
terminated the reaction, possibly due to its high acidity
which completely protonated the amine catalyst. Ben-
zoic acids A9－A18, with different electron-releasing
groups at different position were examined (Entries 4－
13, Table 2), and the highest ee was obtained by using
3,6-dialkoxyl substituted acids A15 and A16 (Entries 10
－11, Table 2), and up to 77% ee was obtained for ad-
duct 3a. It should be mentioned that when benzoic acid
derivatives were used, the reaction was greatly slowed
down, as compared with that in the absence of additive
(Entry 2, Table 1). As A15 could be easily synthesized,
it was used as the additive for further screenings.
The ratio of β-ICD C4 and A15 was also found to
influence the reaction outcome (Entries 1－4, Table 3).
The use of 20 mol% of A15 and 10 mol% of β-ICD C4
afforded the product 3a in acceptable yield with im-
proved ee (Entry 2, Table 3). We further examined the
influence of the amount of acrolein, and found that the
use of 4.0 equiv. of acrolein could improve the yield of
3a to 87%, without the loss of ee (Entry 6, Table 3).
Based on the above screenings, the optimum condi-
tion was determined to run the reaction at −30 ℃ using
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Chin. J. Chem. 2012, 30, 2631—2635

The First Catalytic Asymmetric Morita-Baylis-Hillman Reaction of Acrolein with Aromatic Aldehydes
Table 2 Effects of different acid additives
Table 3 Effects of different amount of A15 and acrolein
OH
CHO
+
C4 (10 mol%)
OH
C4 (10 mol%)
A15 (X mol%)
acetone, -30 oC, 4 d
CHO
CHO
CHO
CHO
CHO
Additive (20 mol%)
+
acetone, -30 oC
O2N
O2N
1a
2 (2.0 equiv.)
3a
O2N
2 (Y equiv.)
4 d
O2N
1a (1.0 equiv.)
3a
CO2H
CO2H
Cl
Entrya
X
10
20
40
100
20
20
20
Y
Yieldb/%
eec/%
CO2H
NO2
CO2H
CO2H
1
2
3
4
5
6
7
2.0
2.0
2.0
2.0
3.0
4.0
5.0
88
71
68
45
82
87
76
74
77
77
77
77
77
77
A9
CO2H
OR
A8
A6
A7
CO2H
CO2H
CO2H
O
O
4
A10
A11
A12: R = n-Hexyl
A13: R = s-Bu
Bu-t
CO2H
CO2H
CO2H
Run on a 0.25 mmol scale. Isolated yield. c Determined by
chiral HPLC analysis.
a
b
O
BnO
OBn
RO
OR
O
A14
A18
A15: R = Me
A16: R = Et
A17: R = n-Hexyl
This protocol had a limitation that less reactive aryl
aldehydes, without strong electron-withdrawing effect,
were inefficient for the reaction with acrolein. The reac-
tion of aryl aldehydes 1j—1k and acrolein could not
take place with the addition of A15, and both reactions
were accordingly carried out in the absence of A15.
Products 3j—3k were obtained in only moderate yield
and ee (Entries 11—12, Table 4). It was also found that
aryl aldehydes, with electron-releasing substituents,
failed to react with acrolein to give the corresponding
products under this condition.
Entrya
Additive
A6
Yieldb/%
NR
25
eec/%
1
2
—
71
75
74
75
73
75
76
75
77
77
76
70
A7
3
39
A8
4
91
A9
5
95
A10
A11
A12
A13
A14
A15
A16
A17
6
48
7
89
Table 4 Substrate scope
C4 (10 mol%)
8
74
OH
CHO
+
A15 (X mol%)
ArCHO
CHO
9
44
Ar
acetone, -30 oC
1 (1.0 equiv.)
2 (4.0 equiv.)
10
11
12
13
71
3
79
Entrya
Ar
X
Time/d
Yieldb/% eec/%
3
45
1
2d
3
4-NO2C6H4 (1a) 20
4-NO2C6H4 (1a) 20
3-NO2C6H4 (1b) 20
2-NO2C6H4 (1c) 20
4-CNC6H4 (1d) 20
4
6
4
5
4
4
5
5
5
5
5
4
87
45
34
25
60
36
28
57
33
52
29
10
77
81
78
60
73
73
69
69
75
68
56
30
3a
3a
3b
3c
3d
3e
3f
68
A18
Run on a 0.25 mmol scale. Isolated yield. c Determined by
chiral HPLC analysis
a
b
4
acetone as the solvent, with 10 mol% of β-ICD C4 and
20 mol% of A15. Under this condition, differently sub-
stituted aromatic aldehydes were examined, and it was
observed that electron-withdrawing groups would fa-
cilitate this reaction. With nitro substituent at any posi-
tion of the phenyl ring, aldehydes 1a—1c could work
(Entries 1—4, Table 4), even the nitro group at the ortho
position. Up to 81% ee could be obtained for product 1a
when running the reaction at ―40 ℃, but the yield is
lower (Entry 2, Table 4). With one cyano, trifluoro-
methyl or two chloro groups on the phenyl ring, substi-
tuted benzaldehydes 1d—1i could work to give corre-
sponding products 3d—3i in moderate to good yield
(Entries 5—10, Table 4).
5
6
3-CNC6H4 (1e)
4-CF3C6H4 (1f)
20
20
7
8
2,4-Cl2C6H3 (1g) 20
3,4-Cl2C6H3 (1h) 20
3,5-Cl2C6H3 (1i) 20
3g
3h
3i
9
10
11e
12f
3-ClC6H4 (1j)
0
3j
2-naphthyl (1k)
0
3k
a Run on a 0.30 mmol scale. b Isolated yield. c Determined by
chiral HPLC analysis. d At －40 ℃. e Run on a 1.0 mmol scale,
－20 ℃. f Run on a 1.0 mmol scale, 25 ℃.
Chin. J. Chem. 2012, 30, 2631—2635
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Zeng et al.
FULL PAPER
OH
OH O
1)
2)
NaClO2, NaH2PO4,
CHO
CHO
2-methyl-2-butene
OEt
t-BuOH, r.t.
O2N
NO2
H SO (cat.)/EtOH
2
4reflux
4 (81% ee)
3a (81% ee)
70%, 2 steps
OH
OH
O
O
DCM, r.t.
R
R
Ph3P
+
O2N
O2N
5a: R = OEt
5b: R = Me
3a (77% ee)
6a: R = OEt (45%, 76% ee)
6b: R = Me (41%, 77% ee)
Chem. 2011, 29, 2732.
The thus obtained MBH adducts 3 could be readily
transformed to other building blocks. For example, the
aldehyde group of product 3a could be oxidized to give
the correspongding product 4. By comparing the optical
rotation of product 4 with literature report,[9] the abso-
lute configuration of product 3a was determined to be R,
and those of other adducts were tentatively assigned by
analogy. The Wittig reaction of product 3a and ylide 5
could give multifunctional products 6 in moderate yield,
without loss of enantioselectivity.
[2] For selected examples of catalytic asymmetric MBH reactions, see:
(a) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry 1995, 6,
1241; (b) Markó, I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997,
53, 1015; (c) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem.
Commun. 1998, 2533; (d) Shi, M.; Jiang, J. K. Tetrahedron: Asym-
metry 2002, 13, 1941; (e) Yang, K. S.; Lee, W. D.; Pan, J. F.; Chen,
K. J. Org. Chem. 2003, 68, 915; (f) McDougal, N. T.; Schaus, S. E. J.
Am. Chem. Soc. 2003, 125, 12094; (g) Imbriglio, J. E.; Vasbinder, M.
M.; Miller, S. J. Org. Lett. 2003, 5, 3741; (h) Krishna, P. R.; Kannan,
V.; Reddy, P. V. N. Adv. Synth. Catal. 2004, 346, 603; (i) Hayashi, Y.;
Tamura, T.; Shoji, M. Adv. Synth. Catal. 2004, 346, 1106; (j)
Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589; (k) Aggarwal, V. K.; Fulford, S. Y.;
Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1706; (l)
Matsui, K.; Takizawa, S.; Sasai, H. Tetrahedron Lett. 2005, 46, 1943;
(m) Ito, K.; Nishida, K.; Gotanda, T. Tetrahedron Lett. 2007, 48,
6147; (n) Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.;
Nagasawa, K. Tetrahedron 2008, 64, 9423; (o) Cabrera, S.; Alemán,
J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2008, 47, 121; (p) Senapati, B. K.; Hwang, G. S.; Lee, S.; Ryu, D. H.
Angew. Chem., Int. Ed. 2009, 48, 4398; (q) Bugarin, A.; Connell, B.
T. Chem. Commun. 2010, 2644; (r) Gong, J. J.; Yuan, K.; Song, H.
L.; Wu, X. Y. Tetrahedron 2010, 66, 2439; (s) Guan, X. Y.; Wei, Y.;
Shi, M. Chem. Eur. J. 2010, 16, 13617; (t) Shi, M.; Liu, X. G. Org.
Lett. 2008, 10, 1043; (u) Shi, M.; Chen, L. H. Chirality 2007, 19,
124; (v) Yang, W.; Sha, F.; Zhang, X.; Yuan, K.; Wu, X. Chin. J.
Chem. 2012, 30, DOI:10.1002/cjoc. 201200740; (w) Gao, J.-L.; Liu,
Y.-K.; Xue, S. Chin. J. Chem. 2008, 26, 1689.
Conclusions
In conclusion, we have developed the first example
of catalytic asymmetric Morita-Baylis-Hillman reaction
of acrolein with aromatic aldehydes, which affords
highly functional products with an aldehyde group for
versatile elaboration. The combination of Hatakeyama’s
catalyst β-isocupreidine with 2,6-dimethoxybenzoic
acid has been identified as a useful catalyst system for
the reaction, which gives the desired products in up to
81% ee. The development of more efficient system to
improve the reactivity, enantioselectivity and substrate
scope is now in progress in our laboratory.
Acknowledgement
[3] (a) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S. J.
Am. Chem. Soc. 1999, 121, 10219; (b) Nakano, A.; Takahashi, K.;
Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357.
The financial support from the 973 program
(2011CB808600), NSFC (20902025), Specialized Re-
search Fund for the Doctoral Program of Higher Educa-
tion (20090076120007), Innovation Program of SMEC
(12ZZ046), and the Fundamental Research Funds for
the Central Universities (East China Normal University
11043) are highly appreciated.
[4] For the reaction of acrolein with aldimines, see: (a) Matsui, K.; Ta-
kizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680; (b) Shi, M.;
Chen, L. H.; Li, C. Q. J. Am. Chem. Soc. 2005, 127, 3790; (c) Shi,
M.; Xu, Y. M.; Shi, Y. L. Chem. Eur. J. 2005, 11, 1794; (d) Abermil,
N.; Masson, G.; Zhu, J. Adv. Synth. Catal. 2010, 352, 656; For a
review on aza-MBH reaction, see: (e) Masson, G.; Housseman, C.;
Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 4614.
[5] (a) Liu, Y. L.; Wang, B. L.; Cao, J. J.; Chen, L.; Zhang, Y. X.; Wang,
C.; Zhou, J. J. Am. Chem. Soc. 2010, 132, 15176; (b) Zhou, F.; Cao,
Z.-Y.; Zhang, J.; Yang, H.-B.; Zhou, J. Chem.-Asian J. 2012, 7, 233;
(c) Zhou, F.; Ding, M.; Zhou, J. Org. Biomol. Chem. 2012, 10, 3178;
(d) Cao, J.-J.; Zhou, F.; Zhou, J. Angew. Chem., Int. Ed. 2010, 49,
4976; (e) Ding, M.; Zhou, F.; Liu, Y.-L.; Wang, C.-H.; Zhao, X.-L.;
Zhou, J. Chem. Sci. 2011, 2, 2035; (f) Qian, Z.-Q.; Zhou, F.; Du,
T.-P.; Wang, B.-L.; Ding, M.; Zhao, X.-L.; Zhou, J. Chem. Commun.
2009, 6753; (g) Cao, Z.-Y.; Zhang, Y.; Ji, C.-B.; Zhou, J. Org. Lett.
2011, 13, 6398; (h) Zhou, F.; Ding, M.; Liu, Y.-L.; Zhou, J. Adv. Syn.
Catal. 2011, 353, 2945; (i) Ding, M.; Zhou, F.; Qian, Z.-Q.; Zhou, J.
References
[1] For reviews, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811; (b) Basavaiah, D.; Rao, K. V.; Reddy, R.
J. Chem. Soc. Rev. 2007, 36, 1581; (c) Singh, V.; Batra, S. Tetrahe-
dron 2008, 64, 4511; (d) Declerck, V.; Martinez, J.; Lamaty, F. Chem.
Rev. 2009, 109, 1; (e) Ma, G. N.; Jiang, J. J.; Shi, M.; Wei, Y. Chem.
Commun. 2009, 5496; (f) Mansilla, J.; Saá, J. M. Molecules 2010, 15,
709; (g) Wei, Y.; Shi, M. Acc. Chem. Res. 2010, 43, 1005; For syn-
thetic application of MBH adducts, see: (h) Sun, X.; Peng, J.; Zhang,
S.; Zhou, Q.; Dong, L.; Chen, Y. Acta Chim. Sinica 2012, 70, 1682;
(i) Wu, C.; Zeng, H.; Liu, Z.; Liu, L.; Wang, D.; Chen, Y. Chin. J.
2634
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Chin. J. Chem. 2012, 30, 2631—2635

The First Catalytic Asymmetric Morita-Baylis-Hillman Reaction of Acrolein with Aromatic Aldehydes
Org. Biomol. Chem. 2010, 8, 2912; (j) Liu, Y.-L.; Zhou, J. Acta
Chim. Sinica 2012, 70, 1451.
Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 15608; (b) Koba-
yashi, S.; Sugiura, M.; Ogawa, C. Adv. Synth. Catal. 2004, 346,
1023.
[6] (a) Liu, Y. L.; Zeng, X. P.; Zhou, J. Chem. Asian. J. 2012, 7, 1759.
For independent work of other groups on addition of arylates to
isatins, see: (b) Guang, X. Y.; Wei, Y.; Shi, M. Chem. Eur. J. 2010,
16, 13617; (c) Zhong, F.; Chen, G. Y.; Lu, Y. Org. Lett. 2011, 13, 82;
(d) Wang, C. C.; Wu, X. Y. Tetrahedron 2011, 67, 2974; (e) Qian, J.
Y.; Wang, C. C.; Sha, F.; Wu, X. Y. RSC. Adv. 2012, 2, 6042.
[7] For Lewis base catalysis, see for reviews: (a) Denmark, S. E.;
[8] For the use of benzoic acid as the additive in the tertiary phosphines
catalyzed aza-MBH reaction, see: (a) Garnier, J. M.; Liu, F. Org.
Biomol. Chem. 2009, 7, 1272; (b) Anstiss, C.; Garnier, J. M.; Liu, F.
Org. Biomol. Chem. 2010, 8, 4400.
[9] Yuan, K.; Song, H. L.; Hu, Y.; Wu, X. Y. Tetrahedron 2009, 65,
8185.
(Zhao, X.)
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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