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邱声祥

A Facile and Ef?cient Synthesis of Bis(oxazoline)s

Wei Jie Li*and Sheng Xiang Qiu

Program for Natural Product Chemical Biology and Drug Discovery,South China Botanical Garden,Chinese Academy of Sciences,Guangzhou 510650,People’s Republic of China

*E-mail:weijieli1688@https://www.wendangku.net/doc/0118526384.html,

Received November 11,2009

DOI 10.1002/jhet.477

Published online 23August 2010in Wiley Online Library

(https://www.wendangku.net/doc/0118526384.html,).

Thiophene-2,5-dicarboxylic acid,benzene-1,3-dicarboxylic acid,or furan-2,5-di-carboxylic acid,respectively,reacted with various b -amino alcohols in toluene under re?ux within 24h,to form nine bis(oxazoline)s (1–3)in good yields through water deprivation via a one-pot reaction.The synthetic method is facile and ef?cient and deserves great application potentials in the research and development in the area of bis(oxazoline)s.

J.Heterocyclic Chem.,47,1340(2010).

INTRODUCTION

Since Butula et al.prepared the ?rst optically active bis(oxazoline)in 1976,the design and development of effective chiral bis(oxazoline)ligands have played a sig-ni?cant role in advancement of asymmetric catalysis and have attracted a great deal of attention because they hold special structural characters and provide high enan-tioselectivities in a variety of asymmetric catalytic reactions [1–6].Chiral bis(oxazoline)ligands have wide-spread uses in asymmetric hydrosilylation [7],cyclopro-pantion reaction [8],Friedel-Crafts reaction [9],Diels-Alder reaction [10],Aldol addition [11],Michael reac-tion [12],Henry reaction [13],allylic oxidation [14],1,3-dipolar cycloaddition [15],and so on.

Chiral bis(oxazoline)s have various structures,which determine the diversity of their synthetic methods.At present,two general synthetic routes are summarized from various synthesis [2,3,16]:(a)Reaction of dintriles with chiral amino alcohol or diols afford the target com-pound via a one or multiple-step reaction in the pres-ence of Lewis acid or base.(b)Dicarboxylic acids or their derivatives (diacyl halide,diacylamide or diesters)react with chiral amino alcohol,via the corresponding bis(b -hydroxylamide)s as the successive intermediates,that cyclize to produce the target compounds.The latter method requires activating agents,with thionyl chloride,also cyclizing agent being the most commonly used,which results in more side reactions and low yields.Therefore,a simpler and more ef?cient synthesis

approach should be explored to meet the needs of bis(oxazoline)ligands.

In this article,we report the results of the reaction of dicarboxylic acids with b -amino alcohols under re?ux through water deprivation to obtain chrial bis(oxazo-line)s 1a –1e ,2a –2c ,and a novel achiral bisoxazoline 3(Fig.1and Scheme 1–3)via a one-pot reaction.This method afforded high yields with simple workup procedure.

RESULTS AND DISCUSSION

Gao et al .reported that chiral bis(oxazoline)s 1a –1e were synthesized from thiophene-2,5-dicarboxylic acid by sequential amidation with a chiral ethanolamine,con-version of hydroxyl to chloro group,and base-promoted oxazoline ring formation [17,18].Kanazawa et al.described the synthetic procedure of chiral 1,3-bis[40-substitutedoxazolin-20-yl]benzene including bis(oxazo-line)s 2a –2c ,which isophthaloyl dichloride reacted with chiral b -amino alcohols at 0 C to form the correspond-ing diamide-dialcohols as the successive intermediates and then cyclized to obtain the target compounds in the presence of methanesulfonyl chloride at 0 C [19].As described above,the syntheses of chiral bis(oxazoline)s involve multistep reactions,which result in more side reactions and low yields.

To address above issues,we successfully developed a new,facile,and ef?cient method for the synthesis of

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bis(oxazoline)s starting from dicarboxylic acids.With this convenient method,bis(oxazoline)s1or2were read-ily synthesized in high yields from thiophene-2,5-dicar-boxylic acid(TDA)or benzene-1,3-dicarboxylic acid (BDA)and b-amino alcohols(Scheme1and2).Brie?y,a mixture of dicarboxylic acid and b-amino alcohol was re?uxed in toluene through water deprivation for24h. After cooling to ambient temperature,the solvent was removed under reduced pressure,and the residue was puri?ed by silica gel column chromatography to give the desired product in high yield.The conditions and results of reaction of carboxylic acids with b-amino alcohols have been listed in Table1(entries1–8).

Instead of thiophene-2,5-dicarboxylic acid(TDA)or benzene-1,3-dicarboxylic acid(BDA),furan-2,5-dicarbox-ylic acid(FDA)reacted with2-aminoethanol to afford a new achiral bis(oxazoline)3in high yield under the same reaction condition(Scheme3and Table1,entry9).

In conclusion,a facile one-pot synthetic method of bis(oxazoline)s(1–3)was described,which is simple and ef?cient,deserving great application potentials in the research and development in the area of bis(oxazoline)s.

EXPERIMENTAL

General.Melting points were determined by the capillary method and are uncorrected.1H-NMR spectra were measured on a Varian UNITY INOVI-500NMR spectrometer,a Bruker Avance DPX300NMR spectrometer or a Bruker DRX-400 NMR spectrometer,using TMS as internal standard.Mass spectra were taken on a MDS Sciex API2000LC/GC/MS instrument.Elemental analyses were carried out on a Perkin-Elmer240C elemental analyzer.Optical rotation values were measured on a POLARTRONIC HNQW5polarimeter.

All solvents used for the synthesis were of analytical grade and were dried and freshly distilled under a nitrogen atmos-phere prior to use.Chiral b-amino alcohols,furan-2,5-dicar-boxylic acid,and benzene-1,3-dicarboxylic acid were pur-chased from Fluka Chemical Co.Thiophene-2,5-dicarboxylic acid was synthesized in our own laboratory.Other reagents were all of analytical grade.

General procedure for the synthesis of2,5-bis[40(S)-substi-tuted-oxazolin-20-yl]thiophene(1a–1e).Thio-phene-2,5-dicar-boxylic acid(100.0mg,0.58mmol),chiral b-amino alcohol (1.16mmol),and toluene(20mL)were added to a three-neck ?ask with a water segregator,a re?ux condenser,and a mag-netic stirring bar.The mixture was re?uxed and dehydrated for24h.After cooling to room temperature,the solvent was removed under reduced pressure,and the residue was puri?ed by silica gel column chromatography with dichloro-methane and ethanol(50:1)as eluent to give the pure title compound.

(à)-2,5-Bis[40(S)-ethyloxazolin-20-yl]thiophene(1a).This com-pound was obtained as colorless solid;yield96%;mp90–91 C([18]89–90 C);[a]20D?à95.3(c1.0,CH2Cl2);1H-NMR(300MHz,CDCl3):d0.99(t,J?7.4Hz,6H,CH3), 1.58–1.65(m,2H,CH2),1.67–1.74(m,2H,CH2),4.06(dd, J?7.4,10.2Hz,2H,OCH2),4.19–4.28(m,2H,NCH),4.50 (dd,J?8.4,10.2Hz,2H,OCH2),7.56(s,2H,

thiophene-H).

ESI-MS:m /z (MH +)279.Anal.Calcd.for C 14H 18N 2O 2S:C,60.41;H,6.52;N,10.06.Found:C,60.23;H,6.54;N,10.02.(à)-2,5-Bis[40(S)-isopropyloxazolin-20-yl]thiophene(1b).This compound was obtained as colorless solid;yield 91;mp 66–

67 C ([18]66–68 C);[a ]20D ?à29.7(c 0.5,CH 3COCH 3);1

H-NMR (500MHz,CDCl 3):d 0.91(d,J ?7.0Hz,6H,CH 3),1.15(d,J ?7.0Hz,6H,CH 3),1.84–1.91(m,2H,CH),4.08–4.15(m,4H,OCH 2),4.39(dd,J ?8.0,9.0Hz,2H,NCH),7.57(s,2H,thiophene-H).ESI-MS:m /z (MH +)307.Anal.Calcd.for C 16H 22N 2O 2S:C,62.71;H,7.24;N,9.14.Found:C,62.55;H,7.26;N,9.11.

(+)-2,5-Bis[40(S)-tert-butyloxazolin-20-yl]thiophene(1c).This compound was obtained as colorless solid;yield 89%;mp

119–120 C ([17]120–121 C);[a ]20D

?+5.9(c 0.6,CH 3COCH 3);1

H-NMR (500MHz,CDCl 3):d 0.98(s,18H,CH 3),4.02(dd,J ?7.5,10.0Hz,2H,OCH 2),4.24(dd,J ?8.0,8.5Hz,2H,NCH), 4.35(dd,J ?8.5,10.0Hz,2H,OCH 2),7.53(s,2H,thiophene-H).ESI-MS:m /z (MH +)335.Anal.Calcd.for C 18H 24N 2O 2S:C,64.64;H,7.84;N,8.38.Found:C,64.41;H,7.86;N,8.35.

(+)-2,5-Bis[40(S)-phenyloxazolin-20-yl]thiophene(1d).This compound was obtained as colorless solid;yield 93%;mp

127–128 C;[a ]20D ?+59.5(c 0.4,CH 2Cl 2);

H-NMR (500MHz,CDCl 3):d 4.32(dd,J ?8.0,16.0Hz,2H,NCH),4.78(dd,J ?8.5,10.0Hz,2H,OCH 2),5.39(dd,J ?8.0,10.0Hz,2H,OCH 2),7.27–7.36(m,10H,Ph-H),7.68(s,2H,thiophene-H).ESI-MS:m /z (MH +)375.Anal.Calcd.for C 22H 18N 2O 2S:C,70.57;H,4.85;N,7.48.Found:C,70.46;H,4.84;N,7.46.(+)-2,5-Bis[40(S)-benzyloxazolin-20-yl]thiophene(1e).This compound was obtained as colorless solid;yield 93%;mp

108–110 C ([18]107–109 C);[a ]20D

?+91.5(c 0.3,CH 3COCH 3);1

H-NMR (500MHz,CDCl 3):d 2.74(dd,J ?8.5,13.5Hz,2H,CH 2-Ph),3.21(dd,J ?5.0,13.5Hz,2H,CH 2-Ph),4.14(dd,J ?7.0,9.0Hz,2H,OCH 2),4.37(dd,J ?8.5,9.0Hz,2H,OCH 2),4.58–4.61(m,2H,NCH),7.22–7.31(m,10H,Ph-H),7.52(s,2H,thiophene-H).ESI-MS:m /z (MH +)403.Anal.Calcd.for C 24H 22N 2O 2S:C,71.62;H,5.51;N,6.96.Found:C,71.34;H,5.53;N,6.94.

General procedure for the synthesis of 1,3-bis[40(S )-sub-stitutedoxazolin-20-yl]benzene

(2a–2c).Benzene-1,3-dicar-boxylic acid (100.0mg,0.60mmol),chiral b -amino alcohol (1.20mmol),and toluene (20mL)were added to a three-neck ?ask with a water segregator,a re?ux condenser,and a mag-netic stirring bar.The mixture was re?uxed and dehydrated for 24h.After cooling to room temperature,the solvent was removed under reduced pressure and the residue was puri?ed by silica gel column chromatography with dichloromethane and ethanol (50:1)as eluent to give the pure title compound.(à)-1,3-Bis[40(S)-isopropyloxazolin-20-yl]benzene(2a).This compound was obtained as colorless solid;yield 93%;mp 58–

60 C;[a ]20D ?à141.5(c 0.3,CHCl 3);

H-NMR (500MHz,CDCl 3):d 0.94(d,J ?7.0Hz,6H,CH 3),1.06(d,J ?7.0Hz,6H,CH 3), 1.87–1.94(m,2H,CH), 4.11–4.19(m,4H,OCH 2),4.38–4.45(m,2H,NCH),7.45–8.51(m,4H,benzene-H).ESI-MS:m /z (MH +)301.Anal.Calcd.for C 18H 24N 2O 2:C,71.97;H,8.05;N,9.33.Found:C,71.75;H,8.08;N,9.31.(à)-1,3-Bis[40(S)-phenyloxazolin-20-yl]benzene(2b).This com-pound was obtained as colorless solid;yield 94%;mp 122–

124 C ([19]120–124 C);[a ]20D ?à73.1(c 0.3,CH 2Cl 2);

H-NMR (500MHz,CDCl 3):d 4.42(dd,J ?8.0,8.5Hz,2H,OCH 2),4.92(dd,J ?8.0,10.0Hz,2H,OCH 2),5.48(dd,J ?7.0,10.0Hz,NCH),7.27–7.41(m,10H,Ph-H),7.57(t,J ?7.5Hz,1H,benzene-H),8.39(dd,J ?1.5,7.5Hz,2H,ben-zene-H),8.76(t,J ?1.5Hz,1H,benzene-H).ESI-MS:m /z (MH +)369.Anal.Calcd.for C 24H 20N 2O 2:C,78.24;H,5.47;N,7.60.Found:C,78.01;H,5.49;N,7.58.

(à)-1,3-Bis[40(S)-benzyloxazolin-20-yl]benzene(2c).This com-pound was obtained as colorless solid;yield 94%;mp 105–

107 C ([19]106–107 C);[a ]20D ?à4.1(c 0.5,CHCl 3);

H-NMR (300MHz,CDCl 3):d 2.73–3.28(m,4H,CH 2Ph),4.17(dd,J ?7.5,8.5Hz,2H,OCH 2),4.37–4.41(m,2H,OCH 2),4.58–4.63(m,2H,NCH),7.10–7.36(m,10H,Ph-H),7.50–8.49(m,4H,benzene-H).ESI-MS:m /z (MH +)397.Anal.Calcd.for C 26H 24N 2O 2:C,78.76;H,6.10;N,7.07.Found:C,78.52;H,6.12;N,7.05.

Synthesis of 2,5-bis(oxazolin-20-yl)furan (3).Furan-2,5-dicarboxylic acid (100.0mg,0.64mmol),2-aminoethanol (78.3mg,1.28mmol),and toluene (20mL)were added to a three-neck ?ask with a water segregator,a re?ux condenser,and a magnetic stirring bar.The mixture was re?uxed and dehydrated for 24h.After cooling to room temperature,the solvent was removed under reduced pressure,and the residue was puri?ed by silica gel column chromatography with

Scheme

Table 1

The conditions and results of dicarboxylic acid reacted with b -amino alcohol in toluene through water deprivation.a

Entry Dicarboxylic acid

b -Amino alcohol Bis(oxazoline)

Yield (%)

1TDA (S )-2-aminobutan-1-ol

1a 962TDA L -leucinol 1b 913TDA L -tert-leucinol 1c 894TDA L -phenylglycinol 1d 935TDA L -phenylalaninol 1e 936BDA L -leucinol 2a 937BDA L -phenylglycinol 2b 948BDA L -phenylalaninol 2c 949

FDA

2-aminoethanol

Dicarboxylic acid/b -amino alcohol ?1/2(mole ratio).Reaction time:24h.

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W.J.Li and S.X.Qiu

dichloromethane and ethanol(50:1)as eluent to give the pure

title compound as colorless liquid;yield88%;1H-NMR(400

MHz,DMSO-d6):d2.94(t,J?5.2Hz,4H,NCH2),3.62(t,J ?5.2Hz,4H,OCH2),6.73(s,2H,furan-H).13C-NMR(400 MHz,DMSO-d6):41.5,57.9,113.5,151.1,163.3.ESI-MS:m/

z(MK+)245.Anal.Calcd.for C10H10N2O3:C,58.25;H,4.89; N,13.59.Found:C,58.14;H,4.91;N,13.57.

Acknowledgment.This work is?nancially supported by the Guangdong Provincial Research Foundation for Basic Research, China(Grant No.04J004).

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A Facile and Ef?cient Synthesis of Bis(oxazoline)s