Abstract
The effect of aqueous ethanol medium on the outcome of a Diels–Alder (DA) reaction with regard to yields, reaction time, and the stereoselectivity observed has been studied. When the reaction between anthrone and (R)-(+)-N-α-methylbenzylmaleimide was carried out in aqueous ethanol in presence of achiral base no diastereoselectivity could be obtained. Moderate diastereoselectivity could be achieved in presence of chiral bases. Use of biodegradable aqueous ethanol solvent for the reaction and stereoselective nature of the reactions studied provide a greener approach.
Introduction
There are many advantages in replacing hazardous organic solvents with environmentally favorable solvents. One of the prime concerns for a modern chemist is the designing of the “ideal” solvents or solvent systems as reaction media that fulfill the desired standards of efficiency and economy. An equally important criterion of “environmental safety” for selecting solvents as reaction media has been established in an irrevocable manner. Due to the realization of the alarming hazards, the emphasis has shifted to employment of greener solvents such as water or even organic solvents such as ethanol, ethyl lactate, and so on Citation1–5.
Any such solvent substitution is pointless unless the replacement by the greener solvent exhibits comparable efficiency in terms of yield, reaction rate, and selectivity.
Water is the most desirable solvent in the green context and many successful examples of reactions in aqueous medium are known Citation6–19. Though water has been used successfully as a reaction medium, the use of organic solvents still remains as part of the total process as many of these reactions involve extraction in organic solvents as the last step Citation20–28. A large volume of organic solvents is often required for the extraction that negates most of the advantage of carrying out the reactions in aqueous medium. Moreover, aqueous medium is not suitable for all types of substrates.
Aqueous-ethanol mixture for the reaction medium has worked wonderfully in many instances Citation1–4 Citation11 Citation25. This offers homogenous medium for many reactions and provides rate accelerations in several others.
Engberts and coworkers have shown that the addition of a small amount of alcohol to an aqueous medium enhances the rates of DA reactions Citation29. The enhancement in rate constants is discussed in terms of enforced pairwise hydrophobic interactions between diene and dienophile. The hydrophobic interactions and the phenomenon of hydrophobic hydration are discussed in greater detail by Franks Citation30. Recently, Bentley et al. Citation31 studied the solvolysis of p-methoxybenzoyl chloride in aqueous alcohol and suggested that preferential solvation by either alcohol or water at the reaction site is not a major factor influencing rate. A large number of studies, explaining the effect of binary aqueous organic mixtures on rates of DA reaction and other organic reactions Citation32–36 are available.
Asymmetry is ubiquitous in every part of nature and has a great impact in many fields. Chiral maleimide adducts can also be converted to derivatives of hydroanthracene-dicarboximides by efficient synthetic protocol. Derivatives of hydroanthracene-dicarboximides find applications in different fields due to their easy modulation and their chemical stability. These have been employed in anticancer chemotherapy Citation37 Citation38 and also as precursors of pharmacophores such as α, β-unsaturated lactam or lactone compounds Citation39 Citation40. The use of chiral auxiliaries for achieving stereocontrol has been popularized through the work of groups such as Evans and Oppolzer, and is now widely used in the academic and industrial organic chemistry communities Citation41 Citation42.
The reaction between anthrone enolate, generated with chiral Brønsted bases with enantiomerically enriched maleimide seemed particularly attractive. This diastereoselective Diels–Alder reaction has been reported by some groups in organic solvents such as chloroform, dichloromethane Citation43. This polar reaction involving diene and dienophiles could be expected to exhibit rate enhancement in polar solvents. It was considered interesting to study the effect of aqueous-ethanol mixture on overall reaction time, yield, and stereoselectivity. Here we wish to report diastereoselective reaction between anthrone and (R)-(+)-N-α-methylbenzylmaleimide using various chiral Brønsted bases in aqueous ethanol (%v/v, 1:1) as a green approach (). The (S)-(–)-2-(α-hydroxyethyl)-benzimidazole(3a) was found to be extremely useful for some stereodiscrimination processes studied in this laboratory Citation44 Citation45 previously. This encouraged us to attempt the chiral influence of the same molecule on this reaction. Another benzimidazole derivative, namely, (S)-(+)-2-(α-hydroxybenzyl)-benzimidazole(3b) Citation46 Citation47, along with chiral bases such as (R)-(+)-Phenyl ethyl amine(3c), quinine(3d) Citation48–50, and cinchonine(3e) Citation51 Citation52 were chosen for the present study.
Results and discussion
As the aim was to use a greener solvent, the reaction was first attempted in pure water, however, the reaction did not take place in pure water as the reaction mixture remained heterogeneous. The ethanol was then used to obtain the homogeneous reaction mixture. The 50:50 mixture of water:ethanol was found to be the most suitable for the reaction under study.
Initially in water:ethanol mixture, triethyl amine as an achiral base was employed in Diels–Alder reaction between anthrone (1) and (R)-(+)-N-α-methylbenzylmaleimide (2) and it was noticed that though the reaction was found to be over in a mere 15 minutes and occurred with excellent yields, no diastereoselectivity could be observed. It was clear that in the ethanol-water mixture the chiral center present in chiral maleimide was unable to give any facial selectivity. The external chiral influence was then attempted along with the chiral maleimide part. Thus, a series of chiral Brønsted bases, namely, (S)-(–)-2-(α-hydroxyethyl)-benzimidazole(3a), (S)-(+)-2-(α-hydroxybenzyl)-benzimidazole(3b), (R)-(+)-phenyl ethyl amine(3c), quinine(3d), and cinchonine(3e) were screened for diastereoselectivities Diels–Alder reaction between anthrone (1) and (R)-(+)-N-α-methylbenzylmaleimide (2).
The reaction was found to be very rapid and a white solid appeared almost immediately after the reaction was initiated by chiral/achiral base. The reactions required about 15 minutes for completion at room temperature. Here, we observed that the anthrone enolate reacted very cleanly with dienophile in aqueous ethanol. Excellent yields were obtained (>97%). The percentage was determined by employing HPLC analyses. Overall, modest diastereoselectivity was observed for the reactions. We observed that only Diels–Alder adducts as the major product were formed and we did not detect any Michael addition products as has been reported by Tokioka et al. Citation43.
It is proposed that the reaction begins with deprotonation of the anthrone with chiral base. Enolate generated from the anthrone and protonated chiral base form an ion pair. The external chiral base in its protonated form along with chiral maleimide form diastereomeric species. It is likely that the chiral maleimide reacts in a conformation in which phenyl group is directed away from the reacting diene, whereupon the lower face of the maleimide is offered for the reaction. This situation is proposed to be responsible for the formation of S,S,R diastereoisomer as the major product.
Double asymmetric Diels–Alder reactions were also studied by Baldwin Citation53 and Tokioka et al. Citation43 with anthrone or acyclic diene as the diene component, which were carried out in chloroform. Stereoselectivities are a result of a more organized transition states. Aprotic solvents such as chloroform are generally preferred for these reactions, which happens to be environmentally unfriendly. It is for the first time that for this type of cyclo-additions modest diastereoelectivity could be obtained in greener aqueous ethanol medium.
The diastereomeric excesses of Diels–Alder adduct were determined by HPLC using stationary phase Kromasil-5-CelluCoat and polar mobile phase details of which are given in .
Table 1. Double asymmetric cyclo-addition of anthrone with chiral (R)-(+)-N-α-methylbenzylmaleimide catalyzed by various chiral bases.
Experimental
General procedures and methods
The 1H and 13C NMR spectra were recorded on a Bruker ACF300 (300MHz) spectrometer. Chemical shifts were reported in parts per million (ppm). The residual solvent peak was used as an internal reference. Infrared spectra were recorded on a Shimadzu FTIR-4200 spectrometer. Optical rotations were recorded on a JASCO DIP-360. Polarimeter and diastereomeric excesses were determined by HPLC analysis on a thermo fisher spectra system UV1000 HPLC units. All melting points are uncorrected. Temperatures are recorded in °C. All other reagents and solvents are commercial grade and are used as supplied without further purification unless otherwise stated.
Typical procedure for chiral base-catalyzed diastereoselective cycloaddition
To a 25 ml RBF containing chiral base (S)-(–)-2-(α-hydroxyethyl)-benzimidazole (20 mol%) and a stirring bar, 5 mL water, 5 mL ethanol, anthrone (97 mg, 0.5 mmol) and (R)-(+)-N-α-methylbenzylmaleimide (101 mg, 0.5 mmol) were added in this sequence. As soon as stirring started at RT, white solid appeared, the reaction was monitored with TLC. After stirring for 15 minutes, on completion the reaction mixture was acidified with 5 mL dil. The HCl filtered and washed with water. Yield: 0.195 g (98.48%), Mp: 208–210°C.
The formation of D-A adduct was confirmed by IR, 1H NMR, and 13C NMR.
IR (KBr, cm−1) spectrum for adduct 4a exhibited the following frequencies ν =3350, 3025, 1687, 1457, 1364. The 1H NMR spectrum obtained for adduct 4a catalyzed by (S)-(–)-2-(α-hydroxyethyl)-benzimidazole showed signals at δ=1.163(d, 3H, J=7.2 Hz, 71.26% SSR-diastereomer), 1.261(d, 3H, J=7.2 Hz, 28.74% RRR-diastereomer), 3.004(d, 1H, J=8.7 Hz, 35.09% RRR-diastereomer), 3.057(d, 1H, J=8.7 Hz, 64.91% SSR-diastereomer), 3.227(dd, 1H, J=3.6Hz, 9.0 Hz, diastereomeric), 3.288(dd, J=3.8Hz, 8.9 Hz, diastereomeric), 4.506(s, 1H, 33.87% RRR-diastereomer, OH), 4.553(s, 1H, 66.13% SSR-diastereomer, OH), 4.708(d, J=3.3 Hz, 1H), 4.947(q, 1H, J=7.2 Hz), 6.922–7.684(m, 13H),13C NMR δ=15.73, 15.85, 44.50, 44.56, 47.10, 47.17, 49.90, 50.04, 50.17, 120.72, 121.02, 123.63, 124.53, 126.68, 126.78, 126.96, 127.06, 127.13, 127.17, 127.27, 127.45, 127.57, 128.28, 136.60, 138.29, 138.38, 139.18, 140.92, 141.00, 142.64, 176.04, 177.78.
Conclusions
When double asymmetric influence was attempted in the form of chiral center in maleimide and in presence of a chiral base, facial selectivity was obtained. The environmentally friendly water-alcohol mixture was used for such system. This is a “greener” procedure compared to earlier base catalyzed double asymmetric Diels–Alder reaction carried out in organic solvents. The reactions were over within 15 minutes, suggesting that the solvent was influencing the rate of the reaction significantly, without formation of Michael adduct. The procedure is operationally simple and for the first time diastereoselectivity could be achieved in an environmentally-friendly aqueous ethanol mixture.
Acknowledgements
The authors wish to thank DST, New Delhi and University of Mumbai, India for financial support.
Related Research Data
References
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