Application of (1 S ,4 S )-2,5-diazabicyclo[2.2.1]heptane derivatives in asymmetric organocatalysis: the Biginelli reaction

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Introduction
Multicomponent reactions (MCRs) are those involving three or more reagents that are combined in a single chemical step to afford a product containing segments of the starting substrates. 1 Multicomponent reactions are of great interest to synthetic organic chemists because the desired product may be obtained in a single experimental step, reducing the time and cost of the process.A salient example of MCR is the Biginelli reaction 2a developed in 1893 by the Italian chemist Pietro Biginelli, who described the preparation of 3,4-dihydropyrimidin-2(1H)-one (DHPM) via the cyclocondensation of ethyl acetoacetate, benzaldehyde and urea under acidic conditions (Scheme 1). 2 It has been found that several DHPM derivatives possess biological activity, which has led to their use as antihypertensive, antiviral, antibacterial or anticancer agents. 3Furthermore, DHPMs are chiral compounds and it has been discovered that the configuration at the stereogenic carbon C(4) determines their biological properties.For example, only the enantiomer (R)-SQ 32 926 exhibits an antihypertensive effect, 4 and only (S)-Monastrol 5 and (R)-Mon-97 6 present potential anticancer activity (Figure 1).Recently, several examples of enantioselective Biginelli reactions in which asymmetric catalysis with either chiral organometallic complexes 7 or chiral organocatalysts 8 is employed, have been described.Of particular relevance to the present report are the advances in highly enantioselective Mannich reactions catalyzed by L-proline. 9Indeed, alternative chiral amines have proved efficient as organocatalysts in several asymmetric transformations. 10By contrast, L-proline and its corresponding hydrochloride have been used in the Biginelli reaction, but the isolated DHPMs were found to be racemic. 11n this context, our research group has developed several novel derivatives of (1S,4S)-2,5diazabicyclo[2.2.1]heptane as chiral ligands in asymmetric Diels-Alder reactions and in the enantioselective diethylzinc addition to benzaldehyde, and as chiral Brønsted acids in α-amination of ethyl α-cyano-α-phenylacetate. 10d, 12 The present report describes the application of three (1S,4S)-2,5-diazabicyclo[2.2.1]heptane derivatives as chiral organocatalysts in the Biginelli reaction (Figure 2).

Results and Discussion
Initially, the potential activities of chiral diamines 1 and 2 (10 mol%, solvent methanol) as organocatalyst in the Biginelli reaction were examined (Table 1).On the other hand, when organocatalyst 3 was used under the same reaction conditions, the corresponding DHPM was obtained in 56% yield and 32% ee (Table 2, entry 1).Motivated by this promising result (cf.entries 1 and 4 in Table 1), we deemed it important to further explore this chiral salt as organocatalyst.For instance, the concentration of 3 was increased to one half equivalent (50 mol%); nevertheless, the enantioselectivity did not increase (Table 2, entry 2).In other experiment, the methanol solvent was replaced by an isopropanol-methanol 6:1 mixture to find that the yield of product increased substantially to 88%, although the enantiomeric excess remained essentially unchanged, 34% ee (Table 2, entry 3).Additional DHPMs were then prepared following the reaction conditions that provided the highest yield of the desired product, 10 mol% of catalyst 3, at room temperature during 5 days, and employing different aldehydes.The results are collected in Table 3, finding that electron-donating substituents such as p-methoxy and m-hydroxy afforded the expected DHPM in good yield and enantioselectivities as high as 46% (entries 1-4).Interestingly, lower enantioselectivity was observed when the same substituents occupy the meta position or para position (entries 7 and 8 in Table 3).By contrast, moderate electron-withdrawing groups such as chlorine and bromine lead to lower enantiomeric excess, 26% and 28% respectively (entries 10 and 11 in Table 3), whereas the strongly electron-withdrawing nitro substituent afforded racemic DHPM (entries 12 and 13 in Table 3).Finally, use of methyl acetoacetate instead of ethyl acetoacetate gave similar results (entry 3 in Table 2 and entry 14 in Table 3).Table 3. Use of organocatalyst 3 in the Biginelli reaction and effect of substitution at the aromatic ring in the aldehyde substrate Seeking to reduce the reaction time in the Biginelli cyclocondensation catalyzed by (1S,4S)-2methyl-2,5-diazabicyclo[2.2.1]heptane•2HBr 2, the effect of microwave irradiation (MW) was explored. 13,14An exploratory experiment employing 6-7 W and 45 ºC during 8 h provided the corresponding product in 42% yield and 27% ee (Scheme 2).Unfortunately, neither the chemical yield nor the enantiomeric excess could be improved at other temperatures.Scheme 2

Table 2. Use of organocatalyst 3 under various solvent and catalyst concentration conditions
Based on mechanistic considerations advanced mainly by List and Kappe 15 we would consider that the amino catalytic mechanism advanced in Scheme 3 is plausible to interpret the enantioinduction observed in the present reactions.In summary, (1S,4S)-2,5-diazadicyclo[2.2.1]heptane derivatives 1-3 catalyze the enantioselective Biginelli cyclocondensation of methyl and ethyl acetoacetate with aromatic aldehydes and urea.The excellent yields and significant enantioselectivities observed in these reactions show that the chiral diamines employed in the present work are promising organocatalysts in asymmetric synthesis.

Experimental Section
General Procedures.Optical rotations were measured in a Perkin-Elmer 241 polarimeter.NMR spectra were recorded in Bruker Advance 300 (300 MHz) spectrometer.Microwave irradiation was achieved in a singlemode Discover (CEM Corporation) reactor provided with BenchMate and CoolMate accessories.HPLC analyses were carried out with a Waters 600 E equipment fitted with UV/Visible Waters 2487 detector 230 nm (wavelength) and Chirobiotic T (Astec, Whippany, USA) (0.46 x 25 cm) column, employing acetonitrile-water (70:30) mobile phase, and 1 mL/min flow.All Biginelli products obtained in this work (4a-o) were known. 16The absolute configuration of the major enantiomer in DHPMs 4b, 4k and 4o was assigned as (S) by comparison with the reported optical rotations for the (R) enantiomers.7c The similarity in the sign of the optical rotation for the rest of the DHPMs prepared in this work (dextrorotatory) as well as the similarity in chiral HPLC retention times led to the tentative assignment of the (S) configuration in the major enantiomer.

Table 1 .
Use of chiral organocatalysts 1 and 2 in the Biginelli reaction of several aromatic aldehydes with ethyl acetoacetate and urea a Determined by chiral HPLC (see Experimental Section).