Asymmetric catalytic aza-Morita-Baylis-Hillman reaction (aza-MBH): An interesting functional group-caused reversal of asymmetric induction

Article abstract of DOI:10.1039/b814500h

A highly efficient aza-Morita-Baylis-Hillman reaction (aza-MBH reaction) of N-tosyl salicylaldehyde imines with α,β-unsaturated ketones has been achieved by using β-isocupreidine (β-ICPD) as the catalyst (10 mol%) to give the corresponding adducts in good to high yields (90%-quant.) and excellent ee's (up to 99% ee), with adducts showing the opposite absolute configuration to that of those obtained in the similar aza-MBH reaction of N-tosyl aldimines with α,β-unsaturated ketones. The Royal Society of Chemistry.

Full text of DOI:10.1039/b814500h

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Asymmetric catalytic aza-Morita–Baylis–Hillman reaction (aza-MBH):
an interesting functional group-caused reversal of asymmetric inductionw
Min Shi,* Ming-Juan Qi and Xu-Guang Liu
Received (in College Park, MD, USA) 20th August 2008, Accepted 19th September 2008
First published as an Advance Article on the web 15th October 2008
DOI: 10.1039/b814500h
A highly efficient aza-Morita–Baylis–Hillman reaction (aza-MBH
reaction) of N-tosyl salicylaldehyde imines with a,b-unsaturated
ketones has been achieved by using b-isocupreidine (b-ICPD) as
the catalyst (10 mol%) to give the corresponding adducts in good to
high yields (90%–quant.) and excellent ee’s (up to 99% ee), with
adducts showing the opposite absolute configuration to that of those
obtained in the similar aza-MBH reaction of N-tosyl aldimines with
a,b-unsaturated ketones.
Asymmetric catalysis by the use of bifunctional organo-
Scheme
1 Proposed asymmetric aza-MBH reaction of salicyl
catalysts via hydrogen bonding has become one of the most
active research areas in the past decade.1 A synergistic activa-
tion by the functionalities on the catalyst can lead to specific
control of the transition state and result in chiral products
with high enantioselectivity. Recently, the aza-Morita–
Baylis–Hillman (aza-MBH) reaction of N-sulfonated imines
(ArCH = NTs) with various Michael acceptors such as methyl
vinyl ketone (MVK) has received much attention.2 We and
others have successfully developed several excellent catalytic
systems by using chiral nitrogen and phosphine Lewis bases as
multifunctional organocatalysts and have achieved high
enantioselectivities for this reaction.3 Another interesting find-
ing is that the absolute configuration of the adducts derived
from the asymmetric aza-MBH reaction of N-sulfonated
imines with MVK or ethyl vinyl ketone (EVK) is opposite to
that obtained by reaction with acrolein, methyl acrylate,
phenyl acrylate and a-naphthyl acrylate in the presence of
b-isocupreidine (b-ICPD) under similar reaction conditions.3g
Since the hydrogen bonding interactions between imines and
bifunctional organocatalysts have been proven to be powerful,
it is conceivable that by introducing functionalities on the aryl
groups of the imine substrates, such as in salicyl N-tosylimines
1 (Scheme 1), high yields, ee’s and reversible asymmetric
induction would be realized. In this paper, we are pleased to
report that an interesting reversal of absolute configuration
can be achieved by introducing an ortho-phenol group onto
imine substrates for aza-MBH reaction using b-isocupreidine
(b-ICPD)4 as the catalyst.
N-tosylimines with MVK catalyzed by bifunctional organocatalyst
b-ICPD.
An initial examination was carried out using b-ICPD in this
reaction. Gratifyingly, by adding b-ICPD (10 mol%) to the
reaction of imine 1a with MVK 2a in THF at ꢀ30 1C, the
product 3a was obtained in a quantitative yield and 91% ee as
the S-configuration (Scheme 2).5 The resulting stereochemistry
of the product 3a was found to be opposite to that obtained in
the previous system in which N-tosyl imines (such as 1a0) were
employed to react with 2a in the presence of b-ICPD, provid-
ing the corresponding aza-MBH adducts (such as 3a0) in
R-configuration (Scheme 2).3a,g
As for the aza-MBH reaction of N-tosylimines 4a and 4b
with 2a in the presence of b-ICPD in THF at 20 1C, we found
that all these reactions were sluggish, affording the corres
ponding adducts 5a and 5b in low yields and ee’s after the
reaction was conducted for 8 days (Scheme 3).6 These results
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Lu, Shanghai 200032, China. E-mail: Mshi@mail.sioc.ac.cn;
Fax: +86-21-64166128
w Electronic supplementary information (ESI) available: 13C and
1H NMR spectroscopic and analytical data for 3 and X-ray crystal
data of 6a and 7a as well as chiral HPLC traces. CCDC 601323 and
632081. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b814500h
Scheme 2 aza-MBH reaction of salicyl N-tosylimine 1a with MVK 2a
as well as aza-MBH reaction of N-sulfonated imine 1a0 with MVK 2a.
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Scheme 3 aza-MBH reaction of N-tosylimines 4a and 4b with MVK
2a catalyzed by b-ICPD (10 mol%) in THF at room temperature.
suggest that the ortho-phenolic hydroxy group adjacent to the
CQN double bond in salicyl N-tosylimine plays a key role in
the aza-MBH reaction with 2a, providing the corresponding
adduct in high yield and ee.
In optimization studies, aza-MBH reactions of imine 1a
with 2a catalyzed by b-ICPD (10 mol%) were carried out in a
series of solvents such as dichloromethane (DCM), acetonitrile
(MeCN), ethyl acetate (EA) and dioxane as well as at various
temperatures. We found that the best reaction conditions are
to carry out the reaction in THF at ꢀ30 1C. All these results
have been outlined in the ESIw (Table SI-1) and indicate that
solvents DCM, MeCN, EA and dioxane are not as effective as
THF for this reaction. With these optimized reaction condi-
tions in hand, we next investigated the substrate scope of the
reaction of 1 with Michael acceptors 2a and ethyl vinyl ketone
(EVK, 2b). The results of these experiments are summarized in
Table 1. As shown in Table 1, the asymmetric induction is
satisfactory and the reaction can tolerate various substituents
on the aromatic rings of 1 for acceptors 2a and 2b. Most of the
reactions proceeded smoothly to give the corresponding ad-
ducts 3 in good to high yields (90%–99.5% yields) and
excellent ee’s (90%–99.9% ee) with S-configuration under
these optimal conditions, whether they are electron-rich or
-poor aryl groups (Table 1, entries 1–8 and 10–13). As for
salicyl N-tosylimine 1j (R1 = H, R2 = R4 = Me, R3 = Cl),
Scheme 4 aza-MBH reaction of salicyl N-tosylimine 1a with MVK 2a
catalyzed by b-ICN (10 mol%) and b-IQD (10 mol%) in THF at room
temperature.
the reaction was sluggish and the corresponding adduct 3j was
obtained in a trace amount under the standard conditions
(Table 1, entry 9). The ee’s of 3a–3i and 3k–3n were deter-
mined by chiral HPLC analyses after converting to the corres
ponding acetates 6 upon treatment with acetyl chloride in the
presence of Et3N in DCM as shown in the ESI.w
It should be noted that using salicyl N-tosylimine 1a as the
substrate, we examined its reaction with 2a in the presence of
b-ICN (10 mol%) and b-IQD (10 mol%) as the mono-
functional organocatalysts, which have similar chiral scaffolds
to the bifunctional counterpart b-ICPD (Scheme 4). Unfortu-
nately, these reactions were sluggish at room temperature
(20 1C) and the corresponding adducts 3a were obtained in
poor chemical yields (16% and 9%) and moderate to good
enantiomeric excesses (55% ee and 80% ee) after 7 and 12 days
in tetrahydrofuran (THF), respectively, as the S-configuration,
suggesting that the bifunctional counterpart b-ICPD is
essential for this reaction to achieve high yields and ee’s.
A plausible reaction mechanism is shown in Scheme 5.
Michael addition of b-ICPD to a,b-unsaturated ketone 2a
gives enolate A which is in equilibrium with enol B prior to
Mannich reaction with N-sulfonated imine 1a or 1a0 to furnish
an equilibrium mixture of several diastereomers. In the case of
N-sulfonated imine 1a0, as we described in our previous
papers,3a,g two betaine intermediates in an equilibrium which
are stabilized by intramolecular hydrogen-bonding between
the amidate ion and phenolic OH are nearly ideal for the
subsequent E2 or E1cb elimination for stereoelectronic
reasons.3g As indicated in a Newman projection of intermedi-
ate C, according to the generally accepted mechanism of
Morita–Baylis–Hillman reaction this affords adduct 3a0 in
R-configuration,1 which has been strongly consolidated by
Santos’s finding on the basis of ESI/MS/MS spectroscopic
investigation recently.7 Therefore, the formation of intermedi-
ate C0 is disfavored. In the case of salicyl N-tosylimine 1a, the
corresponding intermediate D would be more stable than
intermediate E, because the ortho-phenol containing aromatic
moiety in the chiral pocket can form a stronger net type or
branched hydrogen bonding system,8 which affords the
Table 1 aza-MBH reaction of salicyl N-tosylimines 1 with activated
alkenes catalyzed by b-ICPD (10 mol%) in THF at ꢀ30 1C
Yield
R5 Time/h (%)a
Entry R1
R2
R3
R4
1
ee (%)b
1
2
3
4
5
6
7
8
OMe H
H
H
H
H
1b Me 48
1c Me 96
3b: 99.5 93 (S)
H
H
H
Br
Cl
Cl
H
H
H
H
OMe
H
H
H
H
H
F
Me
H
H
3c: 98
3d: 95
3e: 96
3f: 95
3g: 90
3h: 96
3i: 93
92 (S)
99.9 (S)
92 (S)
90 (S)
95 (S)
90 (S)
94 (S)
—
OMe H 1d Me 24
Me
H
Cl
H
H
H
H
H
H
H
1e Me 30
1f Me 72
1g Me 72
1h Me 72
1i Me 96
9
Cl
H
Me 1j Me 96
1a Et 64
3j: Trace
10
11
12
13
a
H
3k: 99.9 92 (S)
OMe H 1d Et 64
H
H
3l: 97
3m: 96
3n: 95
95 (S)
94 (S)
92 (S)
OMe H
Br
H
H
1b Et 64
1f Et 96
H
b
Isolated yields. Determined by chiral HPLC after acylation.
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20732008), and the National Basic Research Program of
China (973)-2009CB825300.
Notes and references
1 For selected reviews concerning organocatalysis, see: (a) P. I. Dalko
and L. Moisan, Angew. Chem., Int. Ed. Engl., 2001, 40, 3726–3748;
(b) M. Benaglia, A. Puglisi and F. Cozzi, Chem. Rev., 2003, 103,
3401–3430; (c) A. Berkessel and H. Groger, Metal-Free Organic
¨
Catalysis in Asymmetric Synthesis, Wiley-VCH, Weinheim, 2004; (d)
‘‘Special Issue: Asymmetric Organocatalysis’’, Acc. Chem. Res.,
2004, 37, pp. 487–631.
2 For selected reviews on the Morita–Baylis–Hillman reaction, see:
(a) D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev.,
2003, 103, 811–892; (b) G. Masson, C. Housseman and J. Zhu,
Angew. Chem., Int. Ed., 2007, 46, 4614–4628; (c) D. Basavaiah, K.
V. Rao and R. J. Reddy, Chem. Soc. Rev., 2007, 36, 1581–1588;
(d) Y. L. Shi and M. Shi, Eur. J. Org. Chem., 2007, 18, 2905–2916;
(e) P. Langer, Angew. Chem., Int. Ed., 2000, 39, 3049–3051.
3 For selected papers on the asymmetric aza-MBH reaction, see:
(a) M. Shi and Y.-M. Xu, Angew. Chem., Int. Ed. Engl., 2002, 41,
4507–4510; (b) M. Shi and L. H. Chen, Chem. Commun., 2003,
1310–1311; (c) S. Kawahara, A. Nakano, T. Esumi, Y. Iwabuchi
and S. Hatakeyama, Org. Lett., 2003, 5, 3103–3105; (d) D. Balan
and H. Adolfsson, Tetrahedron Lett., 2003, 44, 2521–2524; (e) K.
Matsui, S. Takizawa and H. Sasai, J. Am. Chem. Soc., 2005, 127,
3680–3681; (f) M. Shi, L.-H. Chen and C.-Q. Li, J. Am. Chem. Soc.,
2005, 127, 3790–3800 and references cited therein; (g) M. Shi, Y.-M.
Xu and Y.-L. Shi, Chem.–Eur. J., 2005, 11, 1794–1802;
(h) Y.-H. Liu, L.-H. Chen and M. Shi, Adv. Synth. Catal., 2006,
348, 973–979; (i) K. Matsui, K. Tanaka, A. Horii, S. Takizawa and
H. Sasai, Tetrahedron: Asymmetry, 2006, 17, 578–583; (j) K. Matsui,
S. Takizawa and H. Sasai, Synlett, 2006, 761–765; (k) V. K.
Aggarwal, D. K. Dean, A. Mereu and R. Williams, J. Org. Chem.,
2002, 67, 510–514; (l) V. K. Aggarwal, I. Emme and S. Y. Fulford,
J. Org. Chem., 2003, 68, 692–700; (m) V. K. Aggarwal, S. Y. Fulford
and G. C. Lloyd-Jones, Angew. Chem., Int. Ed., 2005, 44,
1706–1708; (n) Y.-L. Shi and M. Shi, Adv. Synth. Catal., 2007,
349, 2129–2135; (o) G. Li, H.-X. Wei, J. Gao and T. D. Caputo,
Tetrahedron Lett., 2000, 41, 1–5.
Scheme 5 Proposed reaction mechanism.
corresponding aza-MBH adduct in the S-configuration. How-
ever, in intermediate E, the ortho-phenol group is unable to
join in the transition state to influence the reaction since it
takes up a position outside of the chiral environment. As for
N-tosylimines 4a or 4b, the phenolic hydroxy group is located
at a position outside the hydrogen bonding network system
and only acts as an electron-donating group on the benzene
ring, retarding the reaction rate.
4 (a) C. von Riesen and H. M. R. Hoffmann, Chem.–Eur. J., 1996, 2,
680–684; (b) Y. Iwabuchi, M. Nakatani, N. Yokoyama and S.
Hatakeyama, J. Am. Chem. Soc., 1999, 121, 10219–10220.
5 The absolute configuration of 3 was determined by X-ray diffraction
of its acetate 6a and ester 7a as shown in the ESI.w The crystal data
of 6a have been deposited in the CCDC with number 601323.
Empirical Formula: C20H21NO2S; formula weight: 387.44; crystal
color, habit: colorless, prismatic; crystal system: monoclinic; lattice
It should be noted that when using acrolein, acrylate, or
acrylonitrile as the Michael acceptor in this reaction, none of
the corresponding aza-MBH adducts could be obtained in the
presence of DABCO or b-ICPD under identical conditions.9
Therefore, we could not examine the absolute configuration
with these Michael acceptors.
type: primitive; lattice parameters:
a
=
8.8105(13) A,
b = 9.4689(13) A, c = 12.1148(17) A, a = 901, b = 103.853(2)1,
g = 901, V = 981.3(2) A3; space group: P2(1); Z = 2; Dcalc = 1.311
g cmꢀ3; F000 = 408; diffractometer: Rigaku AFC7R; residuals: R;
Rw: 0.0636, 0.1529. The crystal data of 7a have been deposited in the
CCDC with number 632081. Empirical Formula: C25H22BrNO5S;
formula weight: 528.41; crystal color, habit: colorless, prismatic;
crystal system: orthorhombic; lattice type: primitive; lattice para-
meters: a = 8.9781(11) A, b = 10.3536(12) A, c = 25.647(3) A, a =
In conclusion, we have succeeded in an effective b-iso-
cupreidine Lewis base-catalyzed asymmetric aza-MBH reac-
tion of N-tosyl salicylaldehyde imines 1 with a,b-unsaturated
ketones under mild conditions. The aza-MBH adducts have
been obtained in good to high yields and high enantio-
selectivities. More importantly, an interesting reversal of
asymmetric control has been achieved by introducing an
ortho-phenol group to the imine substrates. Further study on
the mechanism and scope of this asymmetric reaction is
underway in our laboratories.
901,
b = 901, g = 901, V =
2384.0(5) A3; space group:
P2(1)2(1)2(1); Z = 4; Dcalc = 1.472 g cmꢀ3; F000 = 1080;
diffractometer: Rigaku AFC7R; residuals: R; Rw: 0.0407, 0.0785.
6 Electron-donating groups on the benzene ring can significantly
retard the reaction rate of the MBH reaction.
7 L. S. Santos, C. H. Pavam, W. P. Almeida, F. Coelho and M. N.
Eberlin, Angew. Chem., Int. Ed., 2004, 43, 4330–4333.
8 (a) D. Eisenberg and W. Kauzman, The Structure and Properties of
Water, Oxford Univ. Press, 1969; (b) J. O. Lundgren and I.
Olovsson, The Hydrogen Bond, II, Structure and Spectroscopy, ed.
P. Schuster, North-Holland Pub. Co., Holland, 1976, p. 471.
9 M.-J. Qi and M. Shi, Tetrahedron, 2007, 63, 10415–10424.
We thank the Shanghai Municipal Committee of Science
and Technology (04JC14083, 06XD14005), the Chinese Acad-
emy of Sciences, the National Natural Science Foundation of
China for financial support (20472096, 20672127 and
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