preparation of polymers containing the 1,3,4-oxadiazoline-5-thione structure and their application...

Preparation of Polymers Containing the 1,3,4- Oxadiazoline-5-thione Structure and Their

Application to the Activation of N-Protected at-Amino Acids

HIROYUKI FUKUDA, TAKESHI ENDO, MASAYOSHI SUYAMA, and MAKOTO OKAWARA, Research Laboratory of Resources Utilization,

Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 227, Japan

Synopsis

Two new monomers with pendent 1,3,4-oxadiazoline-5-thione structures were prepared. Ho- mopolymerization of 2-isopropenyl-1,3,4-oxadiazoline-5-thione (V) and copolymerization with styrene (Ml)(rl= 0.02, r2 = 1.56, Q = 4.12, e = 1.06) were examined. Further, 2-(4-methacryloylaminophenyl)-l,3,4-oxadiazoline-5-thione (VIII) having a phenylcarbamoyl group between the isopropenyl and 1,3,4-oxadiazoline-5-thione ring as a spacer was also synthesized and polymerized. The resultant polymers were allowed to react with N-protected a-amino acids such as Z-AlaOH, Z-LeuOH and Z-PheOH by the DCC method. The polymers containing amino acids thus obtained were reacted with ethyl glycinate to give the corresponding dipeptides in excellent yields without racemization.

INTRODUCTION

2-Substituted 1,3,4-oxadiazoline-5-ones (I) are known as antibacterial or in- secticidal compounds, and a large number of their derivatives have been prepared and examined in the field of pharma~ology.l-~ From a different view of point, we have been studying the chemistry of these compounds, and have reported on them.”7 Further, we have reported that 4-acetyl derivatives (11) of 2-phenyl-l,3,4-oxa(thia)diazoline-5-ones(thiones) reacted with various amines under mild conditions to afford acetamide derivatives quantitatively.* From the ki- netic studies of aminolyses of I1 with cyclohexylamine, it is found that the acetyl derivatives I1 are 102-107 times more reactive than p-nitrophenyl acetate, known as an active ester, and the thione structures (X = S ) are more effective for activation of acetyl group than the structures I1 with (X = 0). The unusually rapid aminolyses of I1 are explained by the intramolecular base catalyzed reactions at their transition states, as illustrated in 111.

In this paper, we wish to report the preparation and polymerization of 2-isopropenyl-1,3,4-oxadiazoline-5-thione (V), and 2-(4-methacryloylamino-

N-NH R-< I

0-c 0 II

I

Journal of Polymer Science: Polymer Chemistry Edition, Vol. 16,457-468 (1978) 0 1978 John Wiley & Sons, Inc. 0360-6376/78/0016-0457$01.00

458 FUKUDA ET AL.

0 0- I ,CH3

I1 a x - - - . H

N-N-C II

N-N-CCH, P h 4 : I + RNH, - Ph-< 1 'Hg-R ---) CH,CONHR

Y-c=x Y-c I

I11 x = o , s Y = 0,s

+ Ph-{-r (1) Y-c = x

phenyl)-1,3,4-oxadiaoline-5-thione (VIII) having a phenylcarbamoyl group between isogropenyl and 1,3,4-oxadiazoline-5-thione as a spacer, as well as the activation of N-protected a-amino acids by use of the resultant polymers.

EXPERIMENTAL

Materials

Styrene, DVB, and all solvents used for the present study were purified by the usual procedure. Hydrazine hydrate, carbon disulfide, DCC, AIBN, and other reagents were of commercial grade. Benzoyl hydraides and methacryloyl hy- drazide4 were synthesized according to the method previously reported.

Preparation of 2-Phenyl-1,3,4-oxadiazoline-5-thione (IV)

To a mixture of 1.36 g (0.01 mole) of benzoyl hydrazide, 4 ml of carbon disulfide, and 0.02 mole of tertiary amine in 20 ml of THF, 2.06 g (0.01 mole) of DCC was added with stirring under prescribed conditions. After evaporation of the solvent, the residue was poured into 50 ml of ethyl acetate, and the insoluble material was filtered off. The extraction from the filtrate was carried out five times with 20 ml of 10% aqueous sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid under cooling in an ice bath and the deposited precipitate was recrystallized from methanol. Yields are shown in Table I; mp 217-219OC (lit17 mp 218-220OC).

Preparation of 2-Isopropenyl- 1,3,4-oxadiazoline-5-thione (V)

To a mixture of 10 g (0.1 mole) of methacryloyl hydrazide, 40 ml of carbon disulfide, and 16 g (0.2 mole) of pyridine in 100 ml of THF, a solution of 20.06 g (0.1 mole) of DCC in 100 ml of THF was added dropwise with stirring under cooling at -10 to -15OC. After the reaction was continued for 15 hr at -15OC, THF was removed under reduced pressure, and the residue was poured into 150 ml of ethyl acetate, and the insoluble material was filtered off and washed with 50 ml of ethyl acetate. The solution was extracted five times with 30 ml of 10% aqueous sodium hydroxide. The aqueous layer was acidified with concentrated hydrochloric acid under cooling in an ice bath. The precipitate was extracted three times with 50 mi of ethyl acetate, and the solution was dried over sodium sulfate. Ethyl acetate was removed under reduced pressure. The crude product was recrystallized from benzene to yield 10.4 g (73.4%) of V; mp 87-88"C.

1,3,4-OXADIAZOLINE-5-THIONE POLYMERS 459

ANAL. Calcd for (CsH&OS): C, 42.23%; H, 4.25% N, 19.71%; S, 22.51%. Found. C, 42.23% H, 4.15% N, 20.04%; S, 22.39%.

Preparation of 2- (4- Aminophenyl) - 1,3,4-0xadiazoline-5- thione (V)

A mixture of 40 g (0.27 mole) of 4-aminobenzoylhydrazide (mp 220-224°C) (lit1* mp 22OoC), prepared from ethyl 4-aminobenzoate and hydrazine hydrate, 60 g (0.86 mole) of carbon disulfide and 30 g (0.54 mole) of potassium hydroxide in 200 ml of ethanol-water (1:l v/v) was refluxed for 36 hr under a nitrogen atmosphere, and the solvent and unreacted carbon disulfide were removed under reduced pressure. The residue was dissolved in 150 ml of water and neutralized with concentrated hydrochloric acid under cooling in an ice bath. The precipitate was filtered off and recrystallized from methanol to yield pale yellow crystals, yield 45 g (88%); mp 236236°C.

ANAL. Calcd for (C&NaOS): C, 53.61% H, 3.94%; N, 15.63%; S, 17.89%. Found: C, 53.82%; H, 4.06%; N, 15.57% S, 17.84%.

Preparation of 2-(4-Methacryloylaminophenyl)- 1,3,4-oxadiazoline-5- thione (VIII)

To a solution of 19.3 g (0.1 mole) of VI in 100 ml of pyridine, 10.5 g (0.1 mole) of methacryloyl chloride was added dropwise from a dropping funnel with stirring at 0°C over a period of 30 min. After the reaction was continued at 0°C for 4 hr, the reaction mixture was allowed to heat at 50°C for 6 hr. After the precipitated pyridine hydrochloride was filtered off, pyridine was removed under reduced pressure. The residue was dissolved in 100 ml of water and acidified with 6N hydrochloric acid. The precipitate was collected and recrystallized from methanol to obtain 7.8 g (29.5%) of pale yellow crystals of VIII. When the filtrate was allowed to stand at room temperature for 3 weeks, the yellow crystal was separated out and recrystallized from methanol to give 17.1 g (65.5%) of the product; total yield 24.9 g (95%); mp 214216°C.

ANAL. Calcd for (C12HllN302S): C, 55.15%; H, 4.25%; N, 16.08% S, 12.26%. Found C, 55.08%; H, 4.12%; N, 16.08%; S, 11.81%.

Polymerization of V and VIII

The polymerization was carried out in sealed tubes with AlBN initiator. The polymers were isolated by pouring the reaction mixture into ether or ether- hexane (1:l v/v). They were filtered off and dried under reduced pressure.

The copolymerization was performed in a similar manner. The crosslinked copolymers were prepared by the polymerization of 5.68 g (0.04 mole) of V, 12.48 g (0.12 mole) of styrene and 2.12 g of 55% DVB (6 mole %to the total monomers) under nitrogen atmosphere. The copolymer contents were determined from elementary analysis.

Preparation of XVI-XVIII by the Reaction of IV with Z-AmOH

To a mixture of 0.53 g (3 mmole) of IV and 3.3 mmole of Z-AmOH in 15 ml of THF, 0.67 g (3.3 mmole) of DCC was added with stirring at 0°C. After the reaction was continued for 15 hr with stirring at O"C, the dicyclohexylurea pre-

460 FUKUDA ET AL.

cipitated was filtered off, and THF was removed a t reduced pressure. The residue was recrystallized from ethyl acetate-petroleum ether. The results were summarized in Table IV.

Preparation of Dipeptides by the Reaction of XVI and Ethyl Glycinate

To a solution of 5 mmole of XVI in 2 ml chloroform or ethyl acetate, a sus- pension solution of 0.07 g (5 mmole) of ethyl glycinate hydrochloride and 0.05 g (5 mmole) of triethylamine in 3 ml of chloroform was added at 0°C with stirring. The reaction was continued at 0°C for 2 hr. After the reaction mixture was allowed to stand overnight a t room temperature, 30 ml of chloroform was added. The mixture was washed with water and saturated aquedus solution of sodium hydrogen carbonate. The solution was dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane. The results are listed in Table V.

Preparation of N-Protected a- Amino Acylated Polymers

To a solution of 3.84 mmole of polymers and 4.6 mmole of Z-AmOH in 20 ml of DMF, 0.95 g (4.6 mmole) of DCC was added with stirring at 0°C. The reaction was continued for 15 hr at 0°C with stirring. The precipitated dicyclohexylurea was filtered off, and DMF was evaporated under reduced pressure. The residue was dissolved in 7 ml of THF and cooled at -20°C for 2 hr. Dicyclohexylurea was filtered off and filtrate was poufed into ether-petroleum ether (3:l v/v), and then the polymer was isolated. The results are shown in Table VI.

Reaction of N-Protected a-Amino Acylated XIIIA, Polymer and Ethyl Glycinate

A 1.25-g portion of XIIIA, was swelled in 10 ml of ethyl acetate, 0.63 g (4.5 mmole) of ethyl glycinate hydrochloride, and 0.46 g (4.5 mmole) of triethylamine was added with stirring at 0°C. The reaction was continued for 15 hr at 0°C. The polymer and triethylamine hydrochloride were filtered off and washed three times with 5 ml of ethyl acetate. After the filtrate was washed with aqueous sodium hydrogen carbonate, water, and brine, and dried over sodium sulfate; the solvent was evaporated in uucuo. The residue was recrystallized from ethyl acetate-petroleum ether. The reaction of XVA, and ethyl glycinate was also carried out in a similar way. These results are shown in Table VII.


DCC RCONHNH, + CS, - RCONHNHCSSH - R3N

N-NH

0-c=s - R-Z \ I + @-NH~-NH-Q (2)

IV: R = C,H, S V: R = CH,=C(CH,)

RESULTS AND DISCUSSION

Preparation of 2-Isopropenyl-1,3,4-oxadiazoline-5-thione (V)

Preparation of V by the ordinary ring transformation method, that is, the thermal treatment of potassium 0-acyldithiocarbazate, did not succeed. On the other hand, V may be expected to form by removal of hydrogen sulfide from P-methacryloyldithiocarbazic acid under mild conditions. Jochims has reportedg the dicyclohexylcarbodiimide (DCC) is useful for the dehydrosulfidation of di- thiocarbamic acid in preparation of isothiocyanates. Therefore, the synthesis of 2-phenyl- (IV as a model compound) and 2-isopropenyl- 1,3,4-oxadiazoline- 5-thione by the reactions of hydrazides (benzoyl or methacryloyl), carbon disulfide, and DCC in tetrahydrofuran (THF) in the presence of tertiary amines was carried out under various conditions. Pyridine was the most effective for obtaining 2-substituted-l,3,4-oxadiazoline-5-thiones by this method. These reactions could proceed via either formation of isothiocyanate derivatives or the activation of P-acyldithiocarbazic acids by DCC, as shown in the scheme [eq.

The results are summarized in Table I. The structure of V was confirmed by elemental analysis and infrared absorption spectra, 3120 (NH), 1640 (C=C), 1575 (C=N), and 1370 cm-l (C=S).

@)I.

TABLE I Preparation of 2-Substituted 1,3,4-0xadiazoline-5-thiones (IV, V).

R Base Yield, %

C6H5 Noneb 62.5 C6H5 None 62.9 C6H5 Et3N 67.7

C H d C H 3 None 60.4 CHFCCH~ Et3N 64.5 CHz=CCH3 Pyridine 66.4

c6 H.5 Pyridine 79.4

a Hydrazide, 0.01 mole; DCC, 0.01 mole; C&,4 ml; mine , 0.02 mole; THF, 20 ml; -15 to -1OOC; time, 15 hr.

Room temperature.

462 FUKUDA ET AL.

H,NNH,

COOEt CONHNH,

6 "

0-y I S=C-N-C-C=CHj

II 0

VII

CH3 I

VI CH, I

cH2=(7 CO

(3) I Pyridine. 5OoC

d C + N I I

S=C-NH WI

f CHZ- k-k

V O / G N t I Radical polymerization

I I s=c-NH IX

(4)

Preparation of 2-(4-Methacryloylaminophenyl)- 1,3,4-oxadiazoline-5- thione (VIII)

The preparation of VIII, which has a phenylcarbamoyl group as the spacer, was attempted in order to facilitate the reactivity in dipeptide synthesis. 2- (4-Aminophenyl)-l,3,4-oxadiazoline-5-thione (VI) was obtained in 88% yield by the reaction of 4-aminobenzoylhydrazide, prepared from ethyl 4-aminobenzoate and hydrazine, carbon disulfide, and potassium hydroxide by refluxing in aqueou ethanol under a nitrogen atmosphere. The confirmation of VI was performed by elemental analysis and infrared absorption bands at 3120 (NH), 1605 (C=N or C-N) and 1350 cm-l (C=S). The reaction of VI with meth- acrylic anhydride was carried out in dimethylformamide (DMF) at 0°C. However, contrary to our expectation, the poorly crystallizable substance isolated was assumed to be VII from its infrared absorption band at 1760 cm-l (C=O), plus the lack of absorption at the a i d e region. However, VIII could be obtained successfully in 95% yield by heating VII at 5OoC for 6 hr in pyridine. The elemental analysis is satisfactory for VIII, and the infrared spectra of VIII showed


TABLE I1 Copolymerization of 2-Isopropenyl-l,3,4-oxadiazoline-5-thione (Mz) and Styrene (Ml)*

Mz x lmb Time, Conversion, N in m2 x l o 0 C MI i- Ma min % coDolvmers, % m1 + m:,

5.0 45 2.8 9.10 38.6 10.0 45 4.6 11.05 48.3 15.0 65 9.1 12.04 53.5 28.6 65 8.3 13.63 62.2 40.0 45 11.7 14.68 68.1 50.0 90 13.0 15.14 70.8 60.0 45 11.0 16.20 77.2 70.0 60 10.7 17.23 83.6 85.0 60 11.7 17.84 87.5

a Initiator: AIBN, 3 mole % for total monomers; 70%; solvent, THF. b MI, Mz = initial concentration of two monomers (mole).

ml, mz = concentration of monomers in the copolymer (mole).

CH3 I

CH, = C CHz=F I O X W I I

O=C-NH X XI

XI1 XI11

the characteristic absorption at 3360 (NH, amide), 3120 (NH, heterocycle), 1673 (C-0, amide), 1630 (C=C), and 1350 cm-l (C=S).

TABLE 111 Monomer Reactivity Ratios and Alfrey-Price Q and e Values

Monomers (MZP r l r2 Q e

V 0.02 1.56 4.12 1.06 X 0.31 0.13 0.43 0.51 XI 0.19 0.45 1.20 0.25

a MI, styrene.

464 FUKUDA ET AL.

TABLE IV Reactions of N-Protected a-Amino Acids with 2-Phenyl-1,3,4-oxadiazoline-5-thione (IV)

Yield, MP, IR spectra, cm-l % "C [a18 C 4 C=N C=S

XVI 80 163-164 -40.8' 1760 1690 1630 1320 XVII 73 140-141 +48.98 1785 1710 1640 1320 XVIII 83 133-134 -31.6b 1760 1685 1630 1315

a c = 5 , T H F . c = 5, CH2Clz.

CH3 1 I

CH3

t CHz- C H M C H z - C % I I I

+CHz-C+

C=O

NH I

6 y4 NH I Q

W G N 1 1

S=C-NH XIV

Q O O G N I I

SIC-NH

Polymerization of Monomers V and VIII

The homopolymerization of V was carried out in THF or DMF at 70°C with azobisisobutyronitrile (AIBN) initiator. The homopolymer (IX) obtained, a pale yellow powder, is soluble in acetone, THF, DMF, and N-methylpyrrolidone (NMP) but insoluble in ether, benzene, and hexane. The infrared spectrum of IX shows the characteristic absorption bands at 1605 (C=N) and 1320 cm-l (C=S). The shift of the C=N absorption to higher wave number is ascribed to the disappearance of conjugation between C=N and C=C bonds. Next, copolymerization of V(M2) with styrene (M1) was examined in THF at 70°C. The results are shown in Table 11. The monomer reactivity ratios rl and r2 were estimated by the Fineman-Ross method, and the Alfrey-Price Q and e values were calculated. These parameters were compared with those for the monomers with analogous structure, as shown in Table 111. It can be seen that the 1,3,4- oxadiazoline-5-thione ring is more electron-attractive than 1,3,4-oxadiazoline-

TABLE V Reactions of XVI with Ethyl Glycinate

[a18 Products Yield, % MP, O C Founda Lit.

Z- Ah-GlyOEt 100 99-101 -2Oi7 -20.Sb Z-Phe-GlyOEt 93.2 102-103 -16.2 -16.9 Z-Leu-GlyOEt 99.5 101-102 -26.6 -27.2d

a c = 1, EtOH. Data of Panneman et al.14 Data of Young et al.15 Data of Anderson et al.16


Ph

Z-AlaOH. DCC XVI

Ph I

OO'%N

Ph I

0Nc\N Z-PheOH. DCC t S=C-NH I I S=C-N-Phe-z I I (5)

Iv XVII

Ph I Z-LeuOH, DCC

I 1 S=C-N-Leu-Z

x VIII

XVI _r Z-Ma-GlyOEt + IV

XVII - Z-Phe-GlyOEt + IV

XVIII - Z-Leu-GlyOEt + IV

(6)

(7)

(8)

HGlyOEt

HGlyOEt

HGlyOEt

&one (X)4 and 1,3,4-dioxazoline-5-one (XI) structures. Moreover, soluble copolymer XI1 and crosslinked copolymer XI11 were prepared for the application to peptide synthesis.

Moreover, the homopolymerization and copolymerization of VIII with styrene

TABLE VI Reactions of Polymers IX, XII, XIII, XIV, and XV with N-Protected a-Amino Acids (Z-AmOH)

Conver- IR spectra s, N, % Polymer Z-AmOH sion,% C=O,cm-l Found Calcd Found Calcd

IX Ala 748 1760 1720 13.08 13.04 10.85 11.06 IY Phe 708 17601720 11.15 11.15 9.41 9.45 IX Leu 71a 1760 1720 11.97 11.97 10.16 10.12 XI1 Ala 448 1760 1720 10.11 10.11 9.60 9.50 XI1 Phe 41a 1760 1720 9.17 9.17 8.72 8.71 XI1 Leu 2ti8 1760 1720 9.94 99.94 10.23 10.10 XI11 Ala 43,b 4 9 1760 1720 5.97 5.86 5.52 552 XI11 Phe 48: 47' 1760 1720 5.51 5.48 5.06 5.06 XI11 Leu 40,b 36c 1760 1720 5.74 5.58 5.33 5.33 XIV Ala 92a 1760 1720 1665 12.20 12.20 7.02 7.15 XIV Phe lW 1760 1720 1665 10.24 10.23 5.76 5.91 XIV Leu 778 1760 1720 1665 11.71 11.71 7.26 7.12 XV Ala 67b 1760 1720 1665 6.63 6.88 4.28 4.29 xv Phe 78b 1760 1720 1665 6.31 6.38 3.86 3.86 XV Leu 73b 1760 1720 1665 6.76 6.64 4.05 4.07

a Determined from elemental analysis of N%. b Determined from elemental analysis of S%. c Determined from the increase of the polymer weight.

466 FUKUDA ET AL.

I I Am; Ala, Phe, Leu

wc>y Z-Am-OH O / k N I - 1 1

IX IXA, S=C-NH S=C-N-Am-Z

I 0 4 HGly-OEt

Z-Am-GlyOEt + XI11 or XV I t S=C-N-Am-Z

XIIIA, or XVA,

were conducted in THF at 70°C for 27 hr with AIBN as an initiator. The resultant polymers, XIV and XV, are pale yellow powders and soluble in dipolar aprotic solvents but insoluble in the usual organic solvents.

Activation of N-Protected Amino Acids and Syntheses of Dipeptides by Use of 1,3,4-0xadiazoline-5-thione Function

As mentioned before, 2-phenyl-4-acetyl-l,2,4-oxa(thia)diazoline-5-ones- (thiones) (11) are highly reactive to aminolysis. Therefore, the polymers obtained here, if they can combine amino acids, are expected to be polymeric reagents for peptide synthesis. Besides the enhanced activation, another advantage might be presumed in that racemization could be suppressed effectively in the aminolysis step if it passed through transition state 111, as observed in several ex- amples of bifunctional catalysis.12J3 Thus, with IV as a model compound, the formation of amino acid amides of IV and amidation of other N-protected amino acids were investigated.

The coupling reactions of IV with N-protected a-amino acids such as Z-AlaOH, Z-PheOH, and Z-LeuOH were performed in THF at 0°C for 15 hr with DCC as a dehydration reagent. 4-(Z-~-Alanyl) -( XVI), 4-(Z-~-phenylalanyl) - (XVII),

TABLE VII Reactions of Polymers of XIIIA,, and XVA,,, with Ethyl Glycinatea

b1B Polymers Products Yield, % Foundb Literature

X I I I b c (Am = Ala) Z- Ala-Gly OEt 87.7 -20.8 - 2 1 2

XIIIA,~ (Am = Leu) Z-Leu-GlyOEt 71.7 -26.4 -27.28 XVA,~ (Am = Ala) Z- Ala-GlyOEt 97.2 -21.4 -21.2e

XIIIA,~ (Am = Phe) Z-Phe-GlyOEt 82.0 -15.1 -16.9

XVA,~ (Am = Phe) Z-Phe-GlyOEt 95.5 -16.9 -16.9 XVA,~ (Am = Leu) Z-Leu-GlyOEt 92.7 -27.3 -27.28

a A t O O C , 15 hr; solvent, ethyl acetate (in the case of XIHA,,,), DMF (in the case of X V A . b c 1 in EtOH.

Polymer (amino acid content), 0.7 mmole; HCl HGlyOEt, 1.4 mmole; Et3N, 1.4 mmole. Polymer, 1.25 g; HCl HGlyOEt, 0.63 g; Et3N, 0.46 g.

e Data of Panneman et al.14 ‘Data of Young et al.15 8 Data of Anderson et a1.16


and 4-(Z-phenylleucyl)-2-phenyl-1,3,4-oxadiaoline-5-thione (XVIII) were obtained in reasonable yields. The structures of XVI, XVII, and XVIII were confirmed by elemental analyses and infrared spectra, as shown in Table IV. XVI, XVII, and XVIII were allowed to react easily with ethyl glycinate in chloroform or ethyl acetate at 0°C to give Z-Ala-GlyOEt, Z-Phe-GlyOEt, and Z- Leu-GlyOEt in quantitative yields. The optical rotations of obtained dipeptides showed that no racemization occurred in any instance, as indicated in Table V.

The coupling reactions of homopolymers IX and XIV with Z-AlaOH, Z- PHeOH and Z-LeuOH by DCC were carried out in DMF at 0°C for 15 hr. The coupling reactions of copolymers XII, XIII, and XV with N-protected a-amino acids by the DCC method were also performed. The infrared spectra of N - protected a-amino acylated polymers ( I X b , XIIb , XIIIA,, XIVA,, XVA,) thus obtained showed characteristic absorption bands at 1760 (C=O), 1720 (C=O), and 1320 cm-l (C=S). The degrees of conversion, determined by the elemental analyses for N and S, agreed with calculated values, and the conversions estimated by the weight increases of the polymers are nearly the same as those by elemental analyses. These results are listed in Table VI. It is obvious from Table VI that the conversions of acylated polymer XIVA, having a spacer are fairly high compared with that of acylated polymer IXA, with a pendent 1,3,4-oxadiazoline-5-thione structure directly bound to the polymer main chain. These facts suggest that the reduced reactivity in IXA, might be ascribed to the steric hindrance of main chain. In addition, the,conversions in the copolymers (XIIb, XIIIA,, X V b ) are lower than that of the corresponding homopolymers ( I X b , XIVb). These facts would roughly suggest that the length between the polymer chain and the functional group is more important than that between the pendent functional groups in the case of activation of the bulky amino acids by the polymers.

Finally, acylation reactions of ethyl glycinate with acylated polymers (IXA,, XIIA,, XIIIA,, XIVA,, XVA,) at 0°C for 15 hr were examined. The reactions were carried out in ethyl acetate (in the case of XIIIA,) or DMF (in the case of X V b ) by using two moles of ethyl glycinate to give the corresponding dipeptide in excellent yields. The results are tabulated in Table VII. From the mea- surement of specific rotation of dipeptides obtained, racemization seems to have scarcely taken place.

These experimental results demonstrate that the polymers containing 1,3,4-oxadiazoline-5-thione are excellent polymeric reagents for the activation of carboxylic acids including amino acids.

References 1. H. Taniyama, B. Hirai, and H. Uchida, Yakugaku Zusshi, 76,1300 (1956). 2. H. Gehlen and P. Demin, East Germ. Pat. 63,503 (1965); Chem. Abstr., 70,77978~ (1969). 3. I. Hirao, Y. Kato, and T. Hirata, BULL Chem. SOC. Jpn., 44,1927 (1971). 4. T. Endo, T. Inoue, and M. Okawara, Makromol. Chem., 169,109 (1973). 5. T. Endo, T. Inoue, and M. Okawara, Kobunshi Kagaku, 30,400 (1973). 6. T. Endo, S. Takahashi, and Okaware, Nippon Kagaku Kaishi, 1973,1209. 7. H. Fukuda, T. Endo, and M. Okawara, Nippon Kagaku Kaishi, 1973,1987. 8. H. Fukuda, T. Endo, and M. Okawara, Nippon Kagaku Zasshi, 1976,315. 9. J. C. Jochims, Chem. Ber., 101,1746 (1968).

10. T. Endo, N. Mizushima, H. Fukuda, and M. Okawara, Nippon Kaguku Kaishi, 1975,390. 11. C . Ainsworth, J. Am. Chem. Soc., 78,4475 (1956).

468 FUKUDA ET AL.

12. B. 0. Hankford, J. H. Jones, G. T. Young, and T. F. N. Johnson, J. Chem. SOC., 1965,6814. 13. J. H. Jones and G. T. Young, J. Chem. SOC., 1968,436. 14. H. J. Panneman, A. F. Marx, and J. F. Arens, Rec. Trau. Chim., 78,487 (1958). 15. R. W. Young, K. H. Wood, R. J. Joyce, and G. W. Anderson, J. Am. Chem. SOC., 78,2128

16. G. W. Anderson, J. Blodinger, and A. W. Welcher, J. Am. Chem. SOC., 74,5309 (1952). 17. E. Hoggarth, J. Chem. SOC., 1952,4811. 18. Beilsteins Handbuch, Vol. I , (14), 570.

(1956).

Received November 11,1976 Revised February 12,1977

preparation of polymers containing the 1,3,4-oxadiazoline-5-thione structure and their application...

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