Chiral bifunctional organocatalysts in asymmetric aza-Morita-Baylis-Hillman reactions of ethyl (arylimino)acetates with methyl vinyl ketone and ethyl vinyl ketone

Article abstract of DOI:10.1021/jo701764e

(Chemical Equation Presented) The bifunctional chiral phosphine Lewis base (R)-2′-diphenylphosphino-[1,1′-binaphthalene]-2-ol is an effective organocatalyst in the asymmetric aza-MBH reaction of ethyl (arylimino)acetates 1 with MVK and EVK to give the cor

Full text of DOI:10.1021/jo701764e

Chiral Bifunctional Organocatalysts in
Asymmetric Aza-Morita-Baylis-Hillman
Reactions of Ethyl (Arylimino)acetates with
Methyl Vinyl Ketone and Ethyl Vinyl Ketone
Min Shi,*,† Guang-Ning Ma,‡ and Jun Gao†
FIGURE 1. Structures of imines.
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China, and School of
Chemistry & Molecular Engineering, East China UniVersity of
Science and Technology, 130 MeiLong Road,
to high enantioselectivities have been reported.2,3 These findings
suggest an alternative strategy to improve enantioselectivity in
asymmetric aza-MBH reactions, such as using more syntheti-
cally useful imines as substrates. We have reported some
preliminary results regarding the use of ethyl (arylimino)acetates
1 (Figure 1) as the reactive imine electrophiles,4 with MVK
and EVK to produce the corresponding highly functionalized
adducts ethyl 3-acetyl-2-arylaminobut-3-enoates and ethyl 2-aryl-
amino-3-propionylbut-3-enoates 2 in good yields, using tri-
phenylphosphine as a Lewis base promoter.5 Since this class
of adducts can be transformed to various nitrogen-containing
compounds by simple reactions, we investigated the corre-
sponding asymmetric aza-MBH reaction of ethyl (arylimino)-
acetates 1 with MVK and EVK in the presence of bifunctional
chiral phosphine Lewis bases (R)-LB1, (S)-LB1, and (S)-H8-
LB2, and monofunctional organocatalyst (R)-MOP (Figure 2).
For optimization studies, the aza-MBH reaction of imine 1a
with MVK catalyzed by LB1 (10 mol %) was selected as the
model reaction. We initiated our investigation by screening a
Shanghai 200237, China
mshi@mail.sioc.ac.cn
ReceiVed August 13, 2007
(2) (a) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. Engl. 2002, 41, 4507-
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Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org.
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Soc. 2005, 127, 3680-3681. (f) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am.
Chem. Soc. 2005, 127, 3790-3800 and references cited therein. (g) Shi,
M.; Xu, Y.-M.; Shi, Y.-L. Chem. Eur. J. 2005, 11, 1794-1802. (h) Raheem,
I. T.; Jacobsen, E. N. AdV. Synth. Catal. 2005, 347, 1701-1705. (i)
Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003, 5, 3741-
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Li, H.; Yu, X. H.; Zu, L. S.; Wang, W. Org. Lett. 2005, 7, 4293-4296. (l)
Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J. Org. Chem.
2002, 67, 510-514. (m) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org.
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Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1706-1708. (o) Shi, Y.-L.;
Shi, M. AdV. Synth. Catal. 2007, 349, 2129-2135. (p) Qi, M.-J.; Shi, M.
Tetrahedron 2007, 63, 10415-10424.
(3) For selected papers regarding asymmetric MBH reactions, see: (a)
Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998, 2533-
2534. (b) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125,
12094-12095. (c) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama,
S. J. Am. Chem. Soc. 1999, 121, 10219-10220. (d) Yang, K.-S.; Lee, W.-
D.; Pan, J.-F.; Chen, K.-M. J. Org. Chem. 2003, 68, 915-919. (e) Matsui,
K.; Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H. Tetrahedron: Asymmetry
2006, 17, 578-583. (f) Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006,
761-765. (g) Liu, Y.-H.; Chen, L.-H.; Shi, M. AdV. Synth. Catal. 2006,
348, 973-979. (h) Gausepohl, R.; Buskens, P.; Kleinen, J.; Bruckmann,
A.; Lehmann, C. W.; Klankermayer, J.; Leitner, W. Angew. Chem., Int.
Ed. 2006, 45, 3689-3692. (i) Berkessel, A.; Roland, K.; Neudo¨rfl, J. M.
Org. Lett. 2006, 8, 4195-4198. (j) Nakano, A.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Org. Lett. 2006, 8, 5357-5360. (k) Utsumi, N.; Zhang,
H.; Tanaka, F.; Barbas, C. F., III Angew. Chem., Int. Ed. 2007, 46, 1878-
1880.
The bifunctional chiral phosphine Lewis base (R)-2′-diphe-
nylphosphino-[1,1′-binaphthalene]-2-ol is an effective orga-
nocatalyst in the asymmetric aza-MBH reaction of ethyl
(arylimino)acetates 1 with MVK and EVK to give the
corresponding adducts in moderate to good yields and good
to high enantiomeric excesses under mild conditions.
Morita-Baylis-Hillman reactions involving simple Michael
acceptors such as methyl vinyl ketone (MVK) or methyl acrylate
have hitherto been characterized by poor enantioselectivity, thus
offering a challenging and potentially fruitful area of investiga-
tion to broaden the scope of this general class of reactions.1
Recently, aza-Morita-Baylis-Hillman (aza-MBH) reactions of
N-sulfonated imines (ArCH ) NTs) or N-phosphorated imines
[ArCH ) NP(O)R2] (Figure 1) with various Michael acceptors,
such as MVK and ethyl vinyl ketone (EVK), have received
much attention, and several excellent reaction systems using
chiral nitrogen and phosphine Lewis bases to achieve moderate
* Address correspondence to this author. Fax: 86-21-64166128.
† Chinese Academy of Sciences.
‡ East China University of Science and Technology.
(1) For reviews of the Morita-Baylis-Hillman reaction, see: (a)
Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001-8062.
(b) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653-4670. (c)
Ciganek, E. Org. React. 1997, 51, 201-350. (d) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. ReV. 2003, 103, 811-892. (e) Iwabuchi, Y.;
Hatakeyama, S. J. Synth. Org. Chem. Jpn. 2002, 60, 2-14. (f) Cai, J.-X.;
Zhou, Z.-H.; Tang, C.-C. Huaxue Yanjiu 2001, 12, 54-64. (g) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049-3051. (h) Masson, G. R.;
Housseman, C.; Zhu, J. P. Angew. Chem., Int. Ed. 2007, 46, 4614-4628.
(4) For the preparation of ethyl (arylimino)acetates, see: Borrione, E.;
Prato, M.; Scorrano, G.; Stivanello, M. J. Heterocycl. Chem. 1988, 25,
1831-1836.
(5) Gao, J.; Ma, G.-N.; Li, Q.-J.; Shi, M. Tetrahedron Lett. 2006, 47,
7685-7688.
10.1021/jo701764e CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/08/2007
J. Org. Chem. 2007, 72, 9779-9781
9779

TABLE 2. Asymmetric Aza-MBH Reaction of 1 with MVK or
EVK under the Optimized Conditionsa
time yieldb
eec
(%)
FIGURE 2. Bifunctional organocatalysts (R)-LB1, (S)-LB1, and (S)-
H8-LB2 and the monofunctional organocatalyst (R)-MOP.
entry
Ar
R
product
(h)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
p-CH3C6H4 (1a)
m-CH3C6H4 (1b)
Et
Me
Et
Me
Et
Me
Et
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2r
2s
48
48
48
60
60
60
60
48
48
60
60
60
60
60
60
48
48
99
82
86
65
69
76
60
92
89
81
66
80
85
75
67
53
66
94e
92e
90e
90e
94e
90e
88e
91e
92d
66e
92d
93f
86e
89e
90e
93e
97e
TABLE 1. Asymmetric Aza-MBH Reaction of 1a with MVK
under a Variety of Conditionsa
p-BrC6H4 (1c)
p-ClC6H4 (1d)
C6H5 (1e)
Me
Et
p-Cl, o-CH3C6H3 (1f) Me
Et
Me
Et
Me
Et
Me
Et
yeildb
(%)
eec
(%)
p-CH3OC6H4 (1g)
m-CF3C6H4 (1h)
p-FC6H4 (1i)
temp
(°C)
time
(h)
entry
solvent
chiral LB
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
MeCN
THF
DMSO
DMF
toluene
Et2O
CH2Cl2
Et2O
Et2O
toluene
Et2O
Et2O
Et2O
Et2O
(R)-LB1
(R)-LB1
(R)-LB1
(R)-LB1
(R)-LB1
(R)-LB1
(R)-LB1
(R)-MOP
(R)-LB1
(R)-LB1
(R)-LB1
(R)-LB1
(R)-LB1
(S)-H8-LB2
(S)-LB1
25
25
25
25
25
25
25
25
0
-10
-10
-20
-30
-10
-10
48
48
48
48
48
48
48
48
48
48
48
60
72
48
48
58
68
trace
complex
complex
80
n.d.d
n.d.d
n.d.d
84
a Ethyl (arylimino)acetate (0.5 mmol), MVK or EVK (0.75 mmol), LB1
(0.05 mmol, 22.5 mg), molecular sieves (100 mg), and 1.5 mL of ether
were used at -10 °C under argon atmosphere. b Isolated yields. c Deter-
mined by chiral HPLC. d Using Chiralpak AS-H column. e Using Chiralpak
OD-H column. f Using Chiralpak AD-H column.
83
84
79
83
n.r.d
81
n.d.d
88
98
98
90
90
81
80
89
92
91
90
-92
-93
or -30 °C in ether did not improve the ee of 2a (Table 1, entries
12 and 13). With use of (S)-H8-LB2 and (S)-LB1 as the catalysts
in ether at -10 °C, 2a was obtained in 92% ee and 93% ee
with the opposite enantioselectivity and 81% and 80% yield,
respectively (Table 1, entries 14 and 15).
Et2O
a Ethyl (p-methylphenylimino)acetate (0.5 mmol), MVK (0.75 mmol),
LB1 (0.05 mmol, 22.5 mg) or H8-LB2 (0.05 mmol, 23.2 mg), molecular
sieves (100 mg), and 1.5 mL of solvent were used. b Isolated yields.
c Determined by chiral HPLC, using Chiralpak OD-H column. d n.d. ) not
determined; n.r. ) no reaction.
With the optimal reaction conditions identified, we next
investigated the substrate scope of this interesting asymmetric
aza-MBH reaction of 1 with Michael acceptors MVK and EVK.
The results are summarized in Table 2. Substrate generality for
this catalytic asymmetric reaction is satisfactory and the reaction
can tolerate various substituents on the aromatic ring, whether
they are electron donating or withdrawing. All reactions
proceeded smoothly to give the corresponding adducts 2 in
moderate to high yields (53-99%) and good to high ee (66-
97%) under the optimal conditions (Table 2). For the reaction
of a sterically hindered imine with MVK, the corresponding
adduct 2k was obtained in moderate enantiomeric excess (66%
ee) (Table 2, entry 10).
In conclusion, we have devised an effective bifunctional chiral
phosphine Lewis base-catalyzed asymmetric aza-MBH reaction
of ethyl (arylimino)acetates 1 with MVK or EVK under mild
conditions to give the corresponding adducts in moderate to
high yields as well as good to high enantioselectivities. The
further transformation of these adducts is being investigated and
efforts are in progress to elucidate additional mechanistic details
of these reactions and to understand their scope and limitations.
series of solvents and temperatures in the presence of 4 Å
molecular sieves.6 The results are summarized in Table 1.
As can be seen from Table 1, we found that the solvent
employed significantly affected the reaction. For example, the
corresponding adduct 2a was obtained in 58% yield and 68%
ee at room temperature (25 °C) in acetonitrile, and only a trace
of 2a or complex product mixtures were obtained in THF,
DMSO, or DMF under otherwise identical conditions (Table
1, entries 1-4). To our delight, we found that 2a could be
obtained in 80% yield and 84% ee, and 83% yield and 84% ee
in toluene and ether, respectively (Table 1, entries 5 and 6). In
dichloromethane, 2a also could be obtained in 79% yield and
83% ee (Table 1, entry 7). With MOP (10 mol %) as the catalyst
in the same reaction under the standard conditions, no reaction
occurred (Table 1, entry 8). This result suggests that the phenol
group of LB1 is crucial in this asymmetric aza-MBH reaction.2b,f
Lowering the reaction temperature improved the ee of 2a. At 0
°C in ether, 2a was obtained in 81% yield and 88% ee (Table
1, entry 9). At -10 °C, 2a was formed in 98% yield and 89%
ee and 98% yield and 92% ee in toluene and ether, respectively
(Table 1, entries 10 and 11). Carrying out the reaction at -20
Experimental Section
Typical Reaction Procedure. To a mixture of corresponding
ethyl (arylimino)acetate (0.5 mmol), methyl vinyl ketone (63.0 µL,
0.75 mmol), organocatalyst LB1 (22.5 mg, 0.05 mmol), and 4Å
molecular sieves (100 mg) was added anhydrous ether (1.5 mL)
and the reaction solution was stirred under argon atmosphere at
(6) Ethyl (arylimino)acetates 1 are more moisture sensitive than N-
sulfonated imines and N-phosphorated imines. It is necessary to remove
any moisture by using molecular sieves 4Å.
9780 J. Org. Chem., Vol. 72, No. 25, 2007

-10 °C for the required time indicated in the tables. After the
reaction solution was filtered and concentrated under reduced
pressure, the residue was purified by flash chromatography on silica
gel (eluent: EtOAc/petroleum ether ) 1/18) to afford the corre-
sponding pure product.
National Natural Science Foundation of China for financial
support (20472096, 203900502, 20672127, and 20732008).
Supporting Information Available: Analytical and spectro-
scopic data, including 1H and 13C NMR spectra, for the compounds
shown in Tables 1 and 2, and detailed experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Shanghai Municipal Com-
mittee of Science and Technology (04JC14083, 06XD14005),
the Chinese Academy of Sciences (KGCX2-210-01), and the
JO701764E
J. Org. Chem, Vol. 72, No. 25, 2007 9781