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Journal of Chemistry
Volume 2013, Article ID 349519, 5 pages
Research Article

An Alternative Route for Synthesis of Chiral 4-Substituted 1-Arenesulfonyl-2-imidazolidinones: Unusual Utility of (4S,5S)- and (4R,5R)-4,5-Dimethoxy-2-imidazolidinones and X-Ray Crystallography

1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
2Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
3Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt

Received 4 October 2013; Accepted 19 November 2013

Academic Editor: Narcis Avarvari

Copyright © 2013 Ibrahim A. Al-Swaidan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


An unusual synthesis of (S)-1-arenesulfonyl-4-(1-adamantyl)-2-imidazolidinones 15a–d and (R)-1-arenesulfonyl-4-tert-butyl-2-imidazolidinones 19a–d has been developed from trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 as chiral synthons. Diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were successfully subjected to regioselective reduction using bulky organocuprates that afforded 1-apocamphanecarbonyl-5-methoxy-2-imidazolidinones 10 and 11. This new finding was used for synthesis of chiral 4-substituted 2-imidazolidinones 15a–d and 19a–d through the corresponding intermediates 13 and 17 by treatment with steric bulky tert-butylcuprate or 1-adamantylcuprate.

1. Introduction

Methods involving the use of heterocyclic chiral auxiliaries have been very successful for a wide range of asymmetric transformations [15]. Chiral 2-imidazolidinones [4, 5] have been described as chiral auxiliaries for use in diastereocontrolled reactions and a number of enantiopure 2-imidazolidinones [68]. The most direct route for synthesis of 2-imidazolidinones is from the corresponding 1,2-diamines via carbonylation with phosgene or its synthetic equivalents [9]. The application of the 2-imidazolidinones in asymmetric synthesis requires that it should be readily available on a useful scale and preferably in both enantiomeric forms. A route to obtain optically active 4-tert-butyl-2-imidazolidinones 3 and 4-(1-adamantyl)-2-imidazolidinones 4 from a 2-imidazolidinone heterocycle has been described. The method involves the conversion of 4-methoxy-2-imidazolidinones 1, using organocuprates (tert-butylcuprate, 1-adamantylcuprate, phenylcuprate, and benzylcuprate), into 4-alkyl- and 4-aryl-derivatives 2, followed by optical resolution through either a stoichiometric or catalytic process (Scheme 1) [10]. It was also reported that (4S,5S)- and (4R,5R)-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones (DMIm 6, 7) are good candidates as chiral synthons. (DMIm 6, 7) could be used for the chiral synthesis of 1,2-diamino acids 8, sterically congested 1,2-diamines 9 [11] (Scheme 2), and for synthesis of biological active molecules [12, 13].

Scheme 1: General method for optical resolution of 4-substituted 2-imidazolidinones.
Scheme 2: The utility of DMIm 6 and 7 for the synthesis of 1,2-diamino acids 8 and -symmetric 1,2-diamines 9.

2. Results and Discussion

We now describe the conversion of (4S,5S)-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinone 6 and (4R,5R)-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 7 to chiral (S)-1-arenesulfonyl-4-(1-adamantyl)-2-imidazolidinones 15a–d and (R)-1-arenesulfonyl-4-tert-butyl-2-imidazolidinones 19a–d through regioselective controlled reductive removal of one methoxy group under the effect of tert-butyl- or 1-adamantylcuprates (RCu(CN)MgBr/LiCl) in the presence of BF3·OEt2 [10, 14] at 0°C.

As can be seen in Table 1 and Scheme 3, regioselective reduction of 6 or 7 using bulky organocuprates afforded 1-apocamphanecarbonyl-5-methoxy-2-imidazolidinones 10 and 11. It is clear that the regioselective reduction is greatly dependent on the nature of the organocuprate and the N-substituent. Apparently, a small structural variation in the N-substituents induces a large effect on the regioselective reduction. The 1-adamantyl and tert-butyl groups represent the organocuprate of choice for the regioselective reduction and efficiency (Table 1, entries 2 and 4). The same pattern was observed when the reaction was carried out in ether or CH2Cl2, while no reaction was observed using toluene [15] as a solvent.

Table 1: The BF3-promoted region/stereoselective demethoxylation of DMIm with organocupratesa.
Scheme 3: Regioselective reduction of 6 and 7 into the corresponding 5-methoxy-2-imidazolidinones 10 and 11.

The generality and validity of this reaction, with bulky chiral 1-arenesulfonyl-4-methoxy-5-adamantyl-2-imidazolidinones 13 and 1-arenesulfonyl-4-methoxy-5-tert-butyl-2-imidazolidinones 17, were examined and checked, as shown in Table 2, Scheme 4. Generally, no reactions were observed using less hindered arenesulfonyl moieties (Table 2, entries 1-2), while high yields were obtained with bulky arenesulfonyl derivatives (Table 2, entries 3–8). A trimethylbenzenesulfonyl moiety (Table 2, entries 5 and 6) gave a higher yield than 2,4-dimethoxybenzenesulfonyl derivatives (Table 2, entries 3 and 4). Increasing the bulkiness at the o-position from 2,6-dimethyl to 2,6-diisopropyl induced a large effect on the reaction yield (Table 2, entries 7 and 8 versus 5 and 6).

Table 2: Stereoselective demethoxylation of sterically congested imidazolidinonesa  13 and 17 with organocupratesb.
Scheme 4: Conversion of 6 and 7 into the corresponding 4-substituted 1-arenesulfonyl-2-imidazolidinones 15 and 19.

It is clear that the N-substituents and organocuprate [16, 17] can significantly affect the chelate structures, which may play a crucial role in the reduction step. This could occur through a β-hydride ion transfer, where both reduction [18] and alkylation [1113] outcomes are possible, but the only one observed is reduction. Such reduction process was controlled to a large extent by the steric crowding enforced by either the bridge 7-gem-dimethyl groups of apocamphane carboxylic acid (Mac) or o-substituents of the arenesulfonyl moieties at the reaction site under high temperature.

Compounds 14 and 18 (Scheme 4) were subjected to regioselective controlled arenesulfonylation, after the removal of 3-arenesulfonyl moiety with tributyltin hydride in boiling toluene [18], to afford the chiral auxiliaries (S)-1-arenesulfonyl-4-(1-adamantyl)-2-imidazolidinones 15a–d and (R)-1-arenesulfonyl-4-tert-butyl-2-imidazolidinones 19a–d [10]. The stereochemistry was determined by a comparison of compounds 15 and 19 with authentic samples obtained according to Scheme 1 [10] and by X-ray crystallographic analysis of compound 19b prepared according to Scheme 3 after its conversion to (4R)-(-)-1-(2,4,6-trimethylbenzenesulfonyl)-3-n-butyryl-4-tert-butyl-2-imidazolidinone 20. In the crystal structure, compound 20 crystallizes in the P1 space group and exists in three independent conformationally different molecules in the unit cell as indicated in our previous report [19].

3. Experimental

3.1. General

NMR spectra were measured in CDCl3 on a Bruker NMR spectrometer operating at 500 MHz for 1H. Chemical shifts are expressed in values (ppm) relative to TMS as an internal standard.

3.2. General Method for the Reduction of DMIm-Mac 6, 7 and Compounds 13, 17 (Tables 1 and 2)

To a solution of the compounds (6, 7, 13, or 17) (0.1 mmol) in THF (2 mL), BF3·OEt2 (0.4 mmol) was added. The whole mixture was then added to a suspension of dried LiCl (0.88 mmol), CuCN (0.44 mmol), and organometals (0.4 mmol) in THF (4 mL), which was previously stirred at 0°C under nitrogen atmosphere for 30 min. The mixture was then stirred for an additional 3 h. The reaction was quenched by the addition of a saturated solution of NH4Cl (4 mL), extracted into ethyl acetate (3 × 15 mL), and purified using column chromatography (Hexane-AcOEt; 3: 1) to afford the 4-methoxy-2-imidazolidinones 10, 11 or 4-substituted 3-arenesulfonyl-2-imidazolidinones 14, 18 (Schemes 3 and 4). Compound (4S)-10: (81%) mp 67-68°C (hexane); = −27.4° (c 1.00, CDCl3); 1H-NMR (CDCl3, 500 MHz): δ 5.79 (s, 1H), 5.34 (s, 1H), 4.82–4.80 (d, 1H, J = 8.5 Hz), 4.37–4.35 (dd, 1H, J = 3.6, 7.9 Hz), 3.65–3.51 (t, 1H, J = 9.2 Hz), 3.49 (s, 3H), 3.18 (s, 3H), 2.40–2.36 (m, 1H), 1.98–1.86 (m, 4H), 1.67–1.63 (m, 2H), 1.22 (s, 3H), 1.18 (s, 3H); Anal. C15H24N2O4: calcd 60.79, 8.16, 9.45%, found 60.78, 8.18, 9.55%. Compound (4R)-11: (76%), mp 68-69°C (hexane); = +26.2° (c 0.09, CDCl3); 1H-NMR (CDCl3, 500 MHz): δ 5.93 (s, 1H), 5.47 (s, 1H), 4.94 (s, 1H), 4.56–4.54 (dd, 1H, J = 3.6, 7.9 Hz), 3.75 (s, 1H), 3.46 (s, 3H), 3.21 (s, 3H), 1.77–1.75 (m, 1H), 1.69–1.64 (m, 6H), 1.31 (s, 3H), 1.10 (s, 3H); Anal. C15H24N2O4: calcd 60.79, 8.16, 9.45%, found 60.71, 8.15, 9.40%.

Compounds 12, 13, 16, and 17 were synthesized according to the literature procedure [11].

4. Conclusion

The enantioselective synthesis of sterically congested (S)-1-arenesulfonyl-4-(1-adamantyl)-2-imidazolidinones 15a–d and (R)-1-arenesulfonyl-4-tert-butyl-2-imidazolidinones 19a–d was achieved from the chiral synthons 4,5-dimethoxy-2-imidazolidinones 6 and 7 under regioselective controlled reduction with bulky organocuprates at 0°C in the presence of BF3·OEt2. Subsequent regioselective N-substitution with a variety of arenesulfonyl chloride provided chiral 4-substituted 1-arenesulfonyl-2-imidazolidinones 15a–d, 19a–d. The crystal structures of (4R)-(-)-1-(2,4,6-trimethylbenzenesulfonyl)-3-n-butyryl-4-tert-butyl-2-imidazolidinone 20 were reported. This compound 20 crystallized in layers formed by crystallographic independent molecules. These crystallographic motifs are the consequence of the interplay of the diverse intermolecular interactions in the crystal packing. The crystal packing showed that three molecules of compound 20 are stacked as a result of intermolecular interaction.

Conflict of Interests

The authors have declared that there is no conflict of interests.


The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group Project no. RGP-VPP-163.


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