Published on Web 10/31/2006

Highly Enantioselective Organocatalytic Biginelli Reaction

Xiao-Hua Chen,†,§ Xiao-Ying Xu,†,§ Hua Liu,†,§ Lin-Feng Cun,† and Liu-Zhu Gong*,†,‡
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry,
UniVersity of Science and Technology of China, Hefei, 230026, China, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu, 610041, China, and Graduate School of Chinese Academy of Sciences,
Beijing, China
Received July 23, 2006; E-mail: [email protected]

Multicomponent reactions in which three or more reactants are Scheme 1. Proposed Chiral Phosphoric Acid-Catalyzed Biginelli
combined in a single vessel to generate new molecules that contain Reaction
portions of each reactant undoubtedly maintain great importance
in organic and medicinal chemistry due to the synthetic efficiency
and molecular diversity required in the discovery of new lead
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compounds.1 The Biginelli reaction,2 one of the most useful

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multicomponent reactions, offers an efficient way to access

multifunctionalized 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs)
and related heterocyclic compounds. Such heterocycles show a wide
scope of important pharmacological properties and make up a large
family of medicinally relevant compounds.3 Asymmetric Biginelli
reactions have therefore received renewed attention.4 Compounds
containing the DHPM moiety have an inherent stereogenic center,
and the influence of the absolute configuration of the stereogenic
center on the biological activity has been extensively investigated.3
The individual enantiomers have been found to exhibit different
or opposite pharmaceutical activities.5 The procedure most often substituents on the phosphoric acids considerably impacted the
used for manufacturing optically pure 3,4-dihydropyrimidin-2-(1H)- reaction behavior. In general, increasing the size of 3,3′-substituents
ones relies on resolution and chiral auxiliary-assisted asymmetric on the catalyst resulted in decreased yields and enantioselectivities
synthesis.6 Despite its importance for preparing enantioenriched (entries 1-4 and 5-7), which is in contrast to the substituent effect
DHPMs, the catalytic asymmetric Biginelli reaction has rarely been of the other phosphoric acid-catalyzed reactions.12 For instance,
studied.7,8 To date, only one asymmetric variant with a chiral the catalyst 7c, which is highly efficient in catalyzing the hydro-
ytterbium catalyst provided synthetically useful enantioselectivity.8 phosphonylation of imines,12b afforded only 25% yield and 52%
There has been no report of organocatalytic asymmetric Biginelli ee (entry 3). Trace amounts of the product were obtained with 7d,
dihydropyrimidine synthesis, which essentially avoids the metal which bears two 2-naphthyl substituents at the 3,3′-positions (entry
contamination in the preparation of these medicinally relevant 4). Surprisingly, the configuration of the product was inverted using
compounds.9 Herein, we will report the first organocatalytic highly the highly hindered Brønsted acid 7c (entry 3). Of binol-derived
enantioselective Biginelli reaction. phosphoric acids 7, 7a turned out to be the most enantioselective
Traditionally, Brønsted acids are primarily used for promoting (80% ee), albeit affording only a moderate yield (entry 1). To our
the Biginelli reaction.2,4 Recently, chiral Brønsted acids have delight, the yield and enantioselectivity were both improved from
appeared to be efficient organocatalysts for asymmetric additions 67 to 84% and 80 to 85% ee, respectively, when the H8-binol-
of nucleophiles to imines.10 Among them, chiral phosphoric acids
have received increasing attention since their first application in Table 1. Screening Catalysts and Optimization of Reaction
the asymmetric catalysis11and have frequently been the catalyst of Conditionsa
choice for transformations related to enantioselective activation of
imines.12 In light of these successes as well as the mechanism of
the Biginelli reaction,13 we envisioned that chiral phosphoric acids
would effectively catalyze the asymmetric Biginelli reaction by
forming chiral N-acyliminium phosphate ion pairs 5, to which entry catalyst yield (%)b ee (%)c
enantioselective addition of â-keto esters 3 should occur to generate 1 7a 67 80
optically active 4 via the enantioenriched intermediate 6 (Scheme 2 7b 41 53
1). 3 7c 25 -52
4 7d <10
Validation of the hypothesis started by evaluating the ability of 5 8a 84 85
binol- and H8-binol-based phosphoric acids 7 and 8 to catalyze the 6 8b 45 70
Biginelli reaction of 4-nitrobenzaldehyde (1a), thiourea (2a), and 7 8c 24 68
ethyl acetoacetate (3a). Indeed, the reaction proceeded in the 8 8a 75 82d
presence of 10 mol % of chiral phosphoric acids to afford the 9 8a 94 85e
10 8a 93 82f
desired optically active product 4aa. As shown in Table 1, the 3,3′-
†
a The reaction was carried out on a 0.2 mmol scale, and the ratio of
Chengdu Institute of Organic Chemistry.
‡ University of Science and Technology of China. 1a/2a/3a is 1/1.2/3. b Isolated yield based on the aldehyde. c Determined
§ Graduate School of Chinese Academy of Sciences. by HPLC. d Addition of 5 Å MS. e The reaction time is 6 days. f At 35 °C.
14802 9 J. AM. CHEM. SOC. 2006, 128, 14802-14803 10.1021/ja065267y CCC: $33.50 © 2006 American Chemical Society
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Table 2. Organocatalytic Enantioselective Biginelli Reaction with reactions of urea (2b) with various aldehydes and â-keto esters
Phosphoric Acid 8aa were carried out to give corresponding DHPMs with up to 97% ee
(entries 22-24).
Individual enantiomers of monastrol show distinct pharmaceutical
properties.5b The enantioenriched monastrol could be readily
prepared in high optical purity (91% ee), commencing with the
entry 4 R1 2 R2 yield (%)b ee (%)c Biginelli reaction of meta-TBSO-benzaldehyde (1q) with thiourea
1 4ba 3-FC6H4 2a Et 86 91 (2a) and ethyl acetoacetate (3a) (See Supporting Information).
2 4ca 3-NO2C6H4 2a Et 80 88 In summary, we have discovered the first organocatalytic
3 4da 2-ClC6H4 2a Et 77 91
asymmetric Biginelli reaction. The optimal chiral phosphoric acid,
4 4ea 3-ClC6H4 2a Et 73 90
5 4fa 2-NO2C6H4 2a Et 52 90 derived from H8-binol, afforded the reaction in high yields with
6 4ga 3-BrC6H4 2a Et 85 91 excellent enantioselectivities of up to 97% ee. A wide variety of
7 4ha 3,5-Br2C6H3 2a Et 66 96 substrates, including aldehydes and â-keto esters, could be tolerated.
8 4ia 3,5-(CF3)2C6H3 2a Et 56 97 This reaction has an advantage of avoiding the contamination of
9 4ja 4-MeO2CC6H4 2a Et 67 90
10 4ka 1-BrC10H6 2a Et 64 91 transition metals in the manufacture of the medicinally relevant
11 4la c-C6H11 2a Et 40 92 chiral 3,4-dihydropyrimidin-2-(1H)-ones.
12 4ma PhCHdCH 2a Et 44 88
13 4na 3-MeOC6H4 2a Et 83 90
Acknowledgment. We are grateful for financial support from
14 4gb 3-BrC6H4 2a Me 85 91 NSFC (20472082, 203900505, and 20325211).
15 4hb 3,5-Br2C6H3 2a Me 51 96 Supporting Information Available: Experimental details and
16 4gc 3-BrC6H4 2a i-Pr 65 92
17 4bc 3-FC6H4 2a i-Pr 70 94 characterization of new compounds and complete ref 5c. This material
18 4jd 3-BrC6H4 2a t-Bu 64 92 is available free of charge via the Internet at http://pubs.acs.org.
19 4bd 3-FC6H4 2a t-Bu 65 94
20 4oc 2-FC6H4 2a i-Pr 86 91 References
21 4od 2-FC6H4 2a t-Bu 84 92
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Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b) Ramón, D. J.; Yus,
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24 4pb 3,5-F2C6H3 2b Me 84 93d S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
(2) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
a The reaction was carried out on a 0.2 mmol scale, and the ratio of
(3) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
1/2/3 is 1/1.2/3. b Isolated yield based on aldehyde. c Determined by HPLC.
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reactions related to these substrates (entries 14-21). Biginelli JA065267Y

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