Highly diastereo- and enantioselective one-pot Michael-Aldol reactions of α,β-unsaturated aldehydes with imidazole derivatives

Article abstract of DOI:10.1039/c1cc12300a

Highly diastereo- and enantioselective one-pot Michael-Aldol reactions of α,β-unsaturated aldehydes with imidazole derivatives have been developed. The cascade reactions products could be obtained with three stereocenters in high yields and excellent dias

Full text of DOI:10.1039/c1cc12300a

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Highly diastereo- and enantioselective one-pot Michael–Aldol reactions
of a,b-unsaturated aldehydes with imidazole derivativesw
Wenjun Li, Xin Li, Wenbin Wu, Xinmiao Liang and Jinxing Ye*
Received 20th April 2011, Accepted 2nd June 2011
DOI: 10.1039/c1cc12300a
Highly diastereo- and enantioselective one-pot Michael–Aldol
reactions of a,b-unsaturated aldehydes with imidazole derivatives
have been developed. The cascade reactions products could be
obtained with three stereocenters in high yields and excellent
diastereo- and enantioselectivities.
the cascade organocatalytic reactions to afford the complex
compounds in excellent stereoselective manner and simple one-
pot operation. Herein, we designed a new class of nucleophilic
imidazole derivatives 2, which contain two nucleophilic points in
the molecules. We considered that the carbon atom of substituted
acetophenone is more acidic and nucleophilic than the carbon
atom of imidazole ring, which could attack the a, b-unsaturated
aldehydes 1 firstly. As showed in Scheme 1, the Michael–Aldol
reaction is composed of iminium Michael reaction and enamine
aldol reaction. It should be noted that this enamine aldol reaction
mechanism differed from the reported studies. Imidazole could
also be regarded as an enamine. Once the first step finished,
the imidazole ring could take part in the cascade reaction
spontaneously without secondary amine catalyst. The high
stereoselectivities of the domino organocatalytic reaction was
mainly determined by the activation of a, b-unsaturated
aldehydes 1 by catalyst I, which provided the efficient shielding
of the fragment in the catalytic process.
Recently, heterocyclic compounds have drawn special attention
because of their biological activities. As one of the most important
kind of heteroaromatic compounds, imidazole derivatives have
exhibited considerable biological activities such as anti-
inflammatory, antifungal, antiallergic, antileishmanial and
analgesic activities.1 Notably, they are also useful precursors to
N-heterocyclic carbenes (NHC), which serve as powerful ligands
in various transition-metal complexes.2 Furthermore, in the field
of organocatalysis, chiral imidazole derivatives have been proven
to be wonderful organocatalysts in the enantioselective kinetic
resolutions.3 However, to the best of our knowledge, the research
on imidazole derivative in cascade organocatalytic reactions has
been rare. Therefore, the use of imidazole derivative in cascade
organocatalytic reaction with the formation of multiple stereo-
centers in excellent diastereo- and enantioselectivity remains a
challenging task. Up to now, the field of organocatalysis has been
developing rapidly.4 One of the challenges in organocatalysis is to
devise novel and significant cascade reactions and implement them
in one pot with excellent diastereo- and enantioselectivities.5
Gratifyingly, organic chemists have developed many kinds of
organocatalysts to overcome this difficulty. Of those developed
organocatalysts, diarylprolinol silyl ether,6 which was originally
developed by Jørgensen7 and Hayashi,8 has been recognized as a
powerful one. Among the developed strategy, the iminium-
enamine catalysis is the most employed method in asymmetric
organocatalytic domino reactions involving a,b-unsaturated
aldehydes,9 which displays widely application prospect in the
future.
To explore the possibility of the proposed cascade Michael–
Aldol process, we started our investigations by reacting
cinnamaldehyde 1a with imidazole derivative 2a in the presence
of catalyst I in dichloromethane. To our delight, by performing
the cascade reaction in dichloromethane, we were able to obtain
54% of conversion with 10 : 1 dr and 95% ee in the presence of
catalyst I (Table 1, entry 1). Screening of the catalysts showed
that they exhibited significantly different catalytic activities.
Using catalysts II and III would result in poor conversions
We are interested in devising and searching for the novel and
interesting nucleophiles, which could exhibit high reactivities in
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.
E-mail: yejx@ecust.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the Michael addition products.
CCDC 805085. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc12300a
Scheme 1 One-pot, domino and organocatalytic Michael–Aldol
reactions.
c
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Table 1 Optimization of the reaction conditions for the one-pot,
domino and organocatalytic Michael–Aldol reactiona
observed even in the protonic solvents such as MeOH (Table 1,
entry 17).
With the best reaction conditions in hand (20 mol% of I,
20 mol% of 2-NO2PhCOOH in CH2Cl2), the one-pot, domino
and organocatalytic Michael–Aldol processes between a variety
of a,b-unsaturated aldehydes 1 and imidazole derivatives 2 were
next investigated.z The results were summarized in Table 2.
In general, the domino Michael–Aldol processes took place
efficiently in high yields (65–95%) with good to excellent enantio-
selectivities (87–499%) and excellent dr values (6 : 1–30 : 1). The
reactions were applicable to a,b-unsaturated aldehydes 1, which
bear both aryl and alkyl groups with imidazole derivatives 2a
(Table 2, entries 1–11). Aromatic a,b-unsaturated aldehydes,
regardless of electron-rich, electron-deficient groups on o-, m-,
p-position of benzene ring, took part in this cascade process in
excellent results (Table 2, entries 1–9, 76–95% yields, 98–499%
ee, 6 : 1–30 : 1 dr). For less reactive alkyl a,b-unsaturated
aldehydes, a slightly inferior results were obtained (Table 2,
entries 10–11, 65–67% yields, 87–95% ee, 30 : 1 dr). Further-
more, excellent results were also independent of the structural
variations of imidazole derivatives 2. Substrates 2b–2d, bearing
various substituent groups on R2, reacted with cinnamaldehyde
1a in high efficiency (Table 2, entries 12–14, 83–86% yields,
92–99% ee, 10 : 1–30 : 1 dr). When S-methyl was replaced with
S-benzyl (R3 = Bn), the dr would decrease to 13 : 1 with good
yield and enantioselectivity (Table 2, entry 15). To our delight,
when the substrate 2f (R2 = R4 = n-Pr) was employed, excellent
a
Unless otherwise noticed, all reactions were carried out with 1a
(0.10 mmol), 2a (0.15 mmol), catalyst (20 mol%) and additive
(20 mol%) in CH2Cl2 (0.3 mL) at room temperature for 72 h.
1
b Determined by the crude H NMR. c Determined by chiral HPLC.
Table 2 One-pot, domino and organocatalytic Michael–Aldol reactions
between a,b-unsaturated aldehydes and imidazole derivativesa
(Table 1, entries 2–3). Having identified catalyst I as the best
catalyst, we attempted to improve the conversion through
introducing different additives to the cascade Michael–Aldol
reaction. To our delight, the conversion would increase to
78–79% in the presence of lithium acetate and lithium benzoate
(Table 1, entries 4–5). Further investigations revealed that the
I-catalyzed cascade reaction was more sensitive to an additive
acid, which could be attributed to the convenient formation of
iminium in the acidic environment. For instance, in a strong acid
such as TFA, up to 85% of conversion with 30 : 1 dr and 95% ee
were obtained (Table 1, entry 6). Similar results were observed in
the presence of 4-methylbenzenesulfonic acid (Table 1, entry 7).
We were pleased to find that the conversion would increase to
90% in the presence of benzoic acid with dr and ee maintained
(Table 1, entry 8). Further screenings indicated that benzoic acid
analogues which contained the substituent groups on the
benzene ring were more suitable for this cascade reaction. When
2-methoxybenzoic acid and 4-chlorobenzoic acid were employed,
the reaction conversion would be improved to 93% and 92%
without sacrificing dr and ee (Table 1, entries 9–10). It should be
noted that the best results (499% conversion, 30 : 1 dr, 98% ee)
were obtained when 2-nitrobenzoic acid was used as the additive
(Table 1, entry 11). An investigation of the effects of the reaction
medium led to the selection of dichloromethane as the ideal
solvent for the cascade Michael–Aldol reaction. Slightly inferior
results were obtained in other solvents (Table 1, entries 12–17).
Notably, 82% conversion with excellent dr and ee were still
a
Unless otherwise noticed, all reactions were carried out with a, b-
unsaturated aldehydes
(0.45 mmol), catalyst I (0.06 mmol), 2-NO2PhCOOH (0.06 mmol) in
1 (0.30 mmol), imidazole derivatives 2
CH2Cl2 (0.9 mL) under room temperature for 72 h. b Isolated yield.
c Determined by the crude H NMR. d Determined by chiral HPLC.
1
c
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Notes and references
z General procedure for cascade one-pot Michael–Aldol reactions: To
a solution of CH2Cl2 (0.9 mL) were added a,b-unsaturated aldehydes 1
(0.30 mmol), imidazole derivatives 2 (0.45 mmol), catalyst I (0.06
mmol) and 2-NO2PhCOOH (0.06 mmol). The reaction mixture was
stirred at room temperature for 72 h and then the solvent was removed
under vacuum. The residue was purified by silica gel chromatography
to yield the desired product.
1 (a) J. W. Black, G. I. Durant, J. C. Emmett and C. R. Ganellin,
Nature, 1974, 248, 65; (b) S. A. Laufer, W. Zimmermann and J. Ruff,
J. Med. Chem., 2004, 47, 6311; (c) A. S. Kiselyov, M. Semenova and
V. V. Semenov, Bioorg. Med. Chem. Lett., 2006, 16, 1440.
2 (a) H. Lebel, M. K. Janes, A. B. Charette and S. P. Nolan, J. Am.
Chem. Soc., 2004, 126, 5046; (b) E. A. B. Kantchev, C. J. O’Brien
and M. C. Organ, Angew. Chem., Int. Ed., 2007, 46, 2768;
(c) N. Marion and S. P. Nolan, Acc. Chem. Res., 2008, 41, 1440;
(d) J. C. Y. Lin, R. T. W. Huang, C. S. Lee, A. Bhattacharyya,
W. S. Hwang and I. J. B. Lin, Chem. Rev., 2009, 109, 3561.
3 (a) Y. Zhao, A. W. Mitra, A. H. Hoveyda and M. L. Snapper, Angew.
Chem., Int. Ed., 2007, 46, 8471; (b) C. E. Muller, L. Wanka, K. Jewell
and P. R. Schreiner, Angew. Chem., Int. Ed., 2008, 47, 6180;
(c) B. S. Fowler, P. J. Mikochik and S. J. Miller, J. Am. Chem. Soc.,
2010, 132, 2870.
4 For reviews on organocatalysis, see: (a) Acc. Chem. Res., 2004, 37,
special issue on organocatalysis; (b) P. I. Dalko and L. Moisan, Angew.
Chem., Int. Ed., 2004, 43, 5138; (c) J. Seayad and B. List, Org. Biomol.
Chem., 2005, 3, 719; (d) S. Bertelsen and K. A. Jøgensen, Chem. Soc.
Rev., 2009, 38, 2178; (e) B. Westermann, M. Ayaz and S. Berkel,
Angew. Chem., Int. Ed., 2010, 40, 846; (f) C. Grondal, M. Jeanty and
D. Enders, Nat. Chem., 2010, 2, 167.
Scheme 2 Assuming process of the asymmetric Michael–Aldol
reaction.
ee and dr with high yield were also obtained (Table 2, entry 16,
74% yield, 99% ee, 30 : 1 dr). Substrate 2g, in which S was
replaced with O (X = O), reacted with a,b-unsaturated aldehydes
smoothly to give the cascade products in excellent results
(Table 2, entries 17–21, 80–84% yields, 99–499% ee,
20 : 1–30 : 1 dr). In order to determine the absolute configuration
of the cascade products, enantiopure 3h containing the bromine
atom was fortunately obtained. The absolute configuration of
the product 3h was determined to be (5S,6S,8R) based on X-ray
crystal structure analysis (see supporting informationw).10
The domino organocatalytic formation of products 3 could
be explained by activation of a,b-unsaturated aldehyde 1 by
catalyst I. As illustrated in Scheme 2, a,b-unsaturated
aldehyde 1 reacted with catalyst I to give the iminium inter-
mediate. The imidazole derivative 2a could isomerize to its
enol form 2a0. Then the Michael reaction took place between
imidazole derivative 2a0 with iminium intermediate to give the
Michael adduct 4, which released the catalyst I to afford the
compound 5 in excellent enantioselectivity. The final enamine
Aldol reaction proceeded spontaneously on the formation of
intermediates 5 to give the cascade products 3 with excellent
diastereo- and enantioselectivities. In this cycle, excellent
diastereo- and enantioselectivities were obtained because
of the efficient shielding of the fragment in catalyst I in the
first step.
5 For review on organocatalytic cascade reaction, see: D. Enders,
C. Grondal and M. R. M. Huttl, Angew. Chem., Int. Ed., 2007,
46, 1570. For selected examples of organocatalytic cascade reactions,
see: (a) D. B. Ramachary, N. S. Chowdari and C. F. Barbas III,
Angew. Chem., Int. Ed., 2003, 42, 4233; (b) H. Sunden, I. Ibrahem,
L. Eriksson and A. Cordova, Angew. Chem., Int. Ed., 2005, 44, 4877;
(c) D. Enders, M. R. M. Huttl, C. Grondal and G. Raabe, Nature,
2006, 441, 861; (d) H. Sunden, I. Ibrahem, G. L. Zhao and L. Eriksson,
Chem.–Eur. J., 2007, 13, 574; (e) D. Enders, M. R. M. Huttl,
J. Runsink, G. Raabe and B. Wendt, Angew. Chem., Int. Ed., 2007,
46, 467; (f) P. Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli and
P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48, 7892; (g) D. Zhu,
M. Lu, L. Dai and G. Zhong, Angew. Chem., Int. Ed., 2009, 48, 6089;
(h) B. Tan, Z. Shi, P. J. Chua, Y. Li and G. Zhong, Angew. Chem., Int.
Ed., 2009, 48, 758; (i) Y. Wang, X. F. Liu and L. Deng, J. Am. Chem.
Soc., 2006, 128, 3928; (j) H. Jiang, P. Elsner, K. L. Jensen,
A. Falcicchio, V. Marcos and K. A. Jøgensen, Angew. Chem., Int.
Ed., 2009, 48, 6844; (k) Q. Cai, Z. Zhao and S. L. You, Angew. Chem.,
Int. Ed., 2009, 48, 7428; (l) Y. Wang, D. Yu, Y. Liu, H. Wei, Y. Luo,
D. J. Dixon and P. Xu, Chem.-Eur. J., 2010, 16, 3922.
6 For reviews, see: (a) C. Palomo and A. Mielgo, Angew. Chem., Int.
Ed., 2006, 45, 7876; (b) A. Mielgo and C. Palomo, Chem.–Asian J.,
2008, 3, 922.
7 (a) M. Marigo, T. C. Wabnitz, D. Fielenbach and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2005, 44, 794; (b) M. Marigo, D. Fielenbach,
A. Braunton, A. Kjærsgaard and K. A. Jørgensen, Angew. Chem., Int.
Ed., 2005, 44, 3703.
In summary, we have developed a novel and simple organo-
catalytic domino Michael–Aldol reaction between a,b-unsaturated
aldehyde and imidazole derivative employing iminium-
enamine catalysis. This process could provide the products
with three stereocenters in one pot in high yields with excellent
diastereo- and enantioselectivities (up to 499% ee, 30 : 1 dr).
A broad substrate scope has been successfully employed in this
process, including aromatic and alkyl a,b-unsaturated aldehydes
1 and various imidazole derivatives 2. Further researches on this
field are undergoing within our group.
8 Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem.,
Int. Ed., 2005, 44, 4212.
9 For selected examples of organocatalytic cascade reactions using
iminium-enamine catalysis, see: (a) J. W. Yang, M. T. H. Fonsecca
and B. List, J. Am. Chem. Soc., 2005, 127, 15036; (b) Y. Huang,
A. M. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem.
Soc., 2005, 127, 15051; (c) M. Marigo, T. Schulte, J. Franzen and
K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 15710; (d) A. Carlone,
S. Carbera, M. Marigo and K. A. Jørgensen, Angew. Chem., Int. Ed.,
2007, 46, 1101; (e) G. L. Zhao, R. Rios, J. Vesely, L. Eriksson and
A. Cordova, Angew. Chem., Int. Ed., 2008, 47, 8468.
This work was supported by the National Natural Science
Foundation of China (20902018), the Innovation Program of
Shanghai Municipal Education Commission (11ZZ56), the
Shanghai Pujiang Program (08PJ1403300), and the Funda-
mental Research Funds for the Central Universities.
10 The crystallographic data of 3h for this paper has been deposited in
the Cambridge Structural Database, Cambridge Crystallographic
Data Centre, Cambridge CB2 1EZ, United Kingdom (CSD
reference no. 805085).
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8325–8327 8327