Hindawi Publishing CorporationJournal of ChemistryVolume 2013, Article ID 349519, 5 pageshttp://dx.doi.org/10.1155/2013/349519

Research ArticleAn Alternative Route for Synthesis of Chiral 4-Substituted1-Arenesulfonyl-2-imidazolidinones: Unusual Utility of(4S,5S)- and (4R,5R)-4,5-Dimethoxy-2-imidazolidinones andX-Ray Crystallography

Ibrahim A. Al-Swaidan,1 Amer M. Alanazi,1 Adel S. El-Azab,1,2 and Alaa A.-M. Abdel-Aziz1,3

1 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia2Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt3 Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt

Correspondence should be addressed to Alaa A.-M. Abdel-Aziz; alaa moenes@yahoo.com

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 AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

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 and7 as chiral synthons. Diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 weresuccessfully 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–dthrough 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 auxiliarieshave been very successful for a wide range of asymmetrictransformations [1–5]. Chiral 2-imidazolidinones [4, 5] havebeen described as chiral auxiliaries for use in diastere-ocontrolled reactions and a number of enantiopure 2-imidazolidinones [6–8]. The most direct route for synthe-sis of 2-imidazolidinones is from the corresponding 1,2-diamines via carbonylation with phosgene or its syntheticequivalents [9]. The application of the 2-imidazolidinonesin asymmetric synthesis requires that it should be read-ily available on a useful scale and preferably in bothenantiomeric forms. A route to obtain optically active4-tert-butyl-2-imidazolidinones 3 and 4-(1-adamantyl)-2-imidazolidinones 4 from a 2-imidazolidinone heterocyclehas been described. The method involves the conversionof 4-methoxy-2-imidazolidinones 1, using organocuprates(tert-butylcuprate, 1-adamantylcuprate, phenylcuprate, and

benzylcuprate), into 4-alkyl- and 4-aryl-derivatives 2, fol-lowed by optical resolution through either a stoichio-metric or catalytic process (Scheme 1) [10]. It was alsoreported that (4S,5S)- and (4R,5R)-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones (DMIm 6, 7) are goodcandidates as chiral synthons. (DMIm 6, 7) could be usedfor the chiral synthesis of 1,2-diamino acids 8, stericallycongested 1,2-diamines 9 [11] (Scheme 2), and for synthesisof biological active molecules [12, 13].

2. Results and Discussion

We now describe the conversion of (4S,5S)-1-apocamphane-carbonyl-4,5-dimethoxy-2-imidazolidinone 6 and (4R,5R)-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 7to chiral (S)-1-arenesulfonyl-4-(1-adamantyl)-2-imidazolidi-nones 15a–d and (R)-1-arenesulfonyl-4-tert-butyl-2-imid-azolidinones 19a–d through regioselective controlled

2 Journal of Chemistry

NH2

HOOCOMe

MeO

HN NR2

NR2

R1

O

HN

R1

O

Optical resolution

(1) Stoichiometric with“Mac acid”

(2) Catalytic with1 2

3

4

HN NAc

R1

O

O

HN

NAc

OH·BH3 system

Scheme 1: General method for optical resolution of 4-substituted 2-imidazolidinones.

NH2

NH2

N

N

OMe

OMe

OMe

OMe

MeO

MeO

HN

R1R1

O

O O

O

HN

HN

NHO

6

7

8

9

5

H2N

H2N

CO2Me

Scheme 2: The utility of DMIm 6 and 7 for the synthesis of 1,2-diamino acids 8 and 𝐶

2-symmetric 1,2-diamines 9.

Table 1

(S)

Table 1

HN N

O

OMe

O OMe

O

HN N

OMe

O OMe

(MAC)

(MAC)

10

11 (R)

HN N

O

OMeMeO

O OMe

HN N

O

OMeMeO

O OMe

6

7

Scheme 3: Regioselective reduction of 6 and 7 into the correspond-ing 5-methoxy-2-imidazolidinones 10 and 11.

reductive removal of one methoxy group under the effect oftert-butyl- or 1-adamantylcuprates (RCu(CN)MgBr/LiCl) inthe presence of BF

3⋅OEt2[10, 14] at 0∘C.

As can be seen in Table 1 and Scheme 3, regioselectivereduction of 6 or 7 using bulky organocuprates afforded1-apocamphanecarbonyl-5-methoxy-2-imidazolidinones 10and 11. It is clear that the regioselective reduction is greatlydependent on the nature of the organocuprate and the N-substituent. Apparently, a small structural variation in the

Table 1:The BF3-promoted region/stereoselective demethoxylationof DMIm with organocupratesa.

R2M, CuCN, LiCl

, THF , 0∘C

3h10 or 11

HN

O

MeO OMe∗ ∗

HNN-Mac

O

OMe∗

NR1

BF3·OEt2

Entry R1b R2M Yield % (A.C.)c

1 Ac𝑡-BuLi 0

2 Mac 76 (R)3 Ac 1-AdamantylMgBr 04 Mac 81 (S)aThe reaction was performed by using Grignard reagent (4.0 eq), CuCN(4.4 eq), and BF3⋅OEt2 (2.0 eq) in the presence of LiCl (8.8 eq) at 0

∘C, for 3 h,unless otherwise stated.b(4𝑅, 5𝑅)-enentiomer was used with 𝑡-BuLi, while (4𝑆, 5𝑆)-enentiomer wasused with 1-adamantylMgBr.cAbsolute configuration.

N-substituents induces a large effect on the regioselectivereduction. The 1-adamantyl and tert-butyl groups representthe organocuprate of choice for the regioselective reductionand efficiency (Table 1, entries 2 and 4). The same patternwas observed when the reaction was carried out in ether orCH2Cl2, while no reaction was observed using toluene [15]

as a solvent.The generality and validity of this reaction, with bulky

chiral 1-arenesulfonyl-4-methoxy-5-adamantyl-2-imidazoli-dinones 13 and 1-arenesulfonyl-4-methoxy-5-tert-butyl-2-imidazolidinones 17, were examined and checked, as shownin Table 2, Scheme 4. Generally, no reactions were observedusing less hindered arenesulfonyl moieties (Table 2, entries 1-2), while high yields were obtained with bulky arenesulfonylderivatives (Table 2, entries 3–8). A trimethylbenzenesulfonylmoiety (Table 2, entries 5 and 6) gave a higher yield than2,4-dimethoxybenzenesulfonyl derivatives (Table 2, entries 3

Journal of Chemistry 3

OMe

OMe(Mac)

OMe(Mac)

OMe

ii)LiBH4 ,MeOH

ii)LiBH4 ,MeOHii) RSO2Cl,NaHTHF, reflux, 3h

(65–75%)

ii) RSO2Cl,NaHTHF, reflux, 3h

(67–77%)

HN N

O

SO2R

HNHN

N

O

SO2RNHNH NNN

OOOO

OMe

HN N

OO

RO2SRO2S

OMe

NHN

O

RO2S NHNO

RO2S1-AdamantylCuCNLi

THF, −78∘C, 6h(69%)

THF, −78∘C, 6h(69%)

7

6

16

12

R = a; 2,4,6-triisopropylbenzeneR = b; 2,4,6-trimethylbenzeneR = c; 4-methylbenzeneR = d; 2,4-dimethoxybenzene

1-AdamantylCuCNLiLiCl,

t-BuCuCNLiLiCl,

t-BuCuCNLiLiCl,

LiCl,

(87%)

(i)Bu3SnH,AIBN,

(90%)

(i)Bu3SnH,AIBN,(i)RSO2Cl,NaHTHF, reflux, 1–3h

(62–73%)

(i)RSO2Cl,NaHTHF, reflux, 1–3h

(61–77%)

THF, 0∘C, 3hTable 2

THF, 0∘C, 3hTable 2

THF, rt, 3h (quant.)

THF, rt, 3h (quant.)

18a–d

14a–d 15a–d

19a–d

13a–d

17a–d

toluene, heat, 3h

toluene, heat, 3hBF3·OEt2

BF3·OEt2

BF3·OEt2

BF3·OEt2

Scheme 4: Conversion of 6 and 7 into the corresponding 4-substituted 1-arenesulfonyl-2-imidazolidinones 15 and 19.

Table 2: Stereoselective demethoxylation of sterically congested imidazolidinonesa 13 and 17 with organocupratesb.

, THF, 0∘C3h

13or17 14 or 18

NHNH

OMe∗∗∗

N

OS

O O

N

OS

O ORM, CuCN, LiCl

R1

R2R1

R2

BF3·OEt2

Entry R1 RM R2 Yield %1 t-Bu t-BuLi p-Tolyl 02 1-Adamantyl 1-AdamantylMgBr p-Tolyl 03 t-Bu t-BuLi Dimethoxybenzene 714 1-Adamantyl 1-AdamantylMgBr Dimethoxybenzene 665 t-Bu t-BuLi Trimethylbenzene 796 1-Adamantyl 1-AdamantylMgBr Trimethylbenzene 817 t-Bu t-BuLi Triisopropylbenzene 908 1-Adamantyl 1-AdamantylMgBr Triisopropylbenzene 93a(4𝑅, 5𝑅)-enentiomer was used with 𝑡-BuLi, while (4𝑆, 5𝑆)-enentiomer was used with 1-adamantylMgBr.bThe reaction was performed by using Grignard reagent (4.0 eq), CuCN (4.4 eq), and BF3⋅OEt2 (2.0 eq) in the presence of LiCl (8.8 eq) at 0∘C, for 3 h, unlessotherwise stated.

and 4). Increasing the bulkiness at the o-position from 2,6-dimethyl to 2,6-diisopropyl induced a large effect on thereaction yield (Table 2, entries 7 and 8 versus 5 and 6).

It is clear that the N-substituents and organocuprate [16,17] can significantly affect the chelate structures, which mayplay a crucial role in the reduction step. This could occurthrough a 𝛽-hydride ion transfer, where both reduction [18]and alkylation [11–13] outcomes are possible, but the only oneobserved is reduction. Such reduction process was controlledto a large extent by the steric crowding enforced by either thebridge 7-gem-dimethyl groups of apocamphane carboxylicacid (Mac) or o-substituents of the arenesulfonyl moieties atthe reaction site under high temperature.

Compounds 14 and 18 (Scheme 4) were subjectedto regioselective controlled arenesulfonylation, after the

removal of 3-arenesulfonyl moiety with tributyltin hydridein boiling toluene [18], to afford the chiral auxiliaries (S)-1-arenesulfonyl-4-(1-adamantyl)-2-imidazolidinones 15a–dand (R)-1-arenesulfonyl-4-tert-butyl-2-imidazolidinones19a–d [10]. The stereochemistry was determined by acomparison of compounds 15 and 19 with authenticsamples obtained according to Scheme 1 [10] and by X-ray crystallographic analysis of compound 19b preparedaccording 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, compound20 crystallizes in the P1 space group and exists inthree independent conformationally different moleculesin the unit cell as indicated in our previous report[19].

4 Journal of Chemistry

3. Experimental

3.1. General. NMR spectra were measured in CDCl3on a

Bruker NMR spectrometer operating at 500MHz for 1H.Chemical shifts are expressed in 𝛿 values (ppm) relative toTMS as an internal standard.

3.2. General Method for the Reduction of DMIm-Mac 6, 7 andCompounds 13, 17 (Tables 1 and 2). To a solution of the com-pounds (6, 7, 13, or 17) (0.1mmol) in THF (2mL), BF

3⋅OEt2

(0.4mmol) was added.The whole mixture was then added toa suspension of dried LiCl (0.88mmol), CuCN (0.44mmol),and organometals (0.4mmol) in THF (4mL), which waspreviously stirred at 0∘C under nitrogen atmosphere for30min. The mixture was then stirred for an additional 3 h.The reaction was quenched by the addition of a saturatedsolution of NH

4Cl (4mL), extracted into ethyl acetate (3 ×

15mL), 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); [𝛼]

𝐷

26 = −27.4∘ (c 1.00, CDCl3); 1H-NMR (CDCl

3,

500MHz): 𝛿 5.79 (s, 1H), 5.34 (s, 1H), 4.82–4.80 (d, 1H, J= 8.5Hz), 4.37–4.35 (dd, 1H, J = 3.6, 7.9Hz), 3.65–3.51 (t,1H, J = 9.2Hz), 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. C

15H24N2O4: calcd 60.79, 8.16, 9.45%, found

60.78, 8.18, 9.55%. Compound (4R)-11: (76%), mp 68-69∘C(hexane); [𝛼]

𝐷

25 = +26.2∘ (c 0.09, CHCl3); 1H-NMR (CDCl

3,

500MHz): 𝛿 5.93 (s, 1H), 5.47 (s, 1H), 4.94 (s, 1H), 4.56–4.54(dd, 1H, J = 3.6, 7.9Hz), 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. C

15H24N2O4: calcd 60.79, 8.16, 9.45%, found 60.71, 8.15,

9.40%.Compounds 12, 13, 16, and 17were synthesized according

to the literature procedure [11].

4. Conclusion

The enantioselective synthesis of sterically congested (S)-1-arenesulfonyl-4-(1-adamantyl)-2-imidazolidinones 15a–dand (R)-1-arenesulfonyl-4-tert-butyl-2-imidazolidinones19a–dwas achieved from the chiral synthons 4,5-dimethoxy-2-imidazolidinones 6 and 7 under regioselective controlledreduction with bulky organocuprates at 0∘C in the presenceof BF

3⋅OEt2. Subsequent regioselective N-substitution

with a variety of arenesulfonyl chloride provided chiral4-substituted 1-arenesulfonyl-2-imidazolidinones 15a–d,19a–d. The crystal structures of (4R)-(-)-1-(2,4,6-trimeth-ylbenzenesulfonyl)-3-n-butyryl-4-tert-butyl-2-imidazolidi-none 20 were reported. This compound 20 crystallized inlayers formed by crystallographic independent molecules.These crystallographic motifs are the consequence ofthe interplay of the diverse intermolecular interactionsin the crystal packing. The crystal packing showed thatthree molecules of compound 20 are stacked as a result ofintermolecular interaction.

Conflict of Interests

Theauthors have declared that there is no conflict of interests.

Acknowledgment

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

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