3034 J . Org. Chem., Vol. 38, No. 17, 1973
SHEEHAN AND GUZIEC
order rate coefficient was calculated according to the following stoichiometry. 2PhCHO
+ NHzCH~COZ-+PhCH-CHC02- + HzO d H I&=CHPh
A blank reaction under the reaction conditions without glycine shows a decrease in benzaldehyde below 47, in 2.5 hr which is negligibly small compared with the phenylserine formation (over 70% conversion in 2.5 hr). Phenylserine was isolated from the reaction solution in a yield of 447,: mp 187-189" (lit. mp 192OH), 1830 (Con-), 760 and 194'); vmaY (KBr) 3500-2500 ("a+, 710 cm-l (monosubstituted phenyl). Formation of the Schiff Base.-Condensation of ethyl glycinate with benzaldehyde in benzene containing anhydrous MgS04 as a dehydrating agent at room temperature gives X-benzylideneglycine ethyl ester almost quantitatively. This product was confirmed by ir and nmr: vmtLX (KBr) 1740 (C=O), 1840 (C=X), 1180 [CC(=O)O)], 750 and 688 cm-l (monosubstituted phenyl); T (CCla) 1.81 (s, CH=N, 1 H), 2.27-2.63 (m, aromatic H , 5 H ) , 5.73 [s, (C=N)CHn-, 2 HI, 5.85 [q, -CHg(CHa)] 2 HI, 8.75 (t, CH3,3 H). Condensation of glycine with benzaldehyde in benzene or ethanol containing anhydrous MgSOc gives N-benzylidenemethylbut amine and ~V-benzylidene(2-phenyl-2-hydroxyethyl)amine, N-benzylideneglycine could not be isolated. The infrared spectrum of the former was consistent with that of the authentic sample and the latter was identified by ir and nmr: mp 106108'; vmax (KBr) 3350-3000 (NH, OH), 1650 (C=N), 750 and
690 cm-1 (monosubstituted phenyl); T (DMSO) 1.74 (e, CH=N, 1 H), 2.24-2.57 (m, aromatic H , 10 H), 4.59 (b, OH, 1 H), 5.06 (9, CH, 1 H), 6.20 (d, CHz, 2H). The infrared spectrum of the ethanolic mixture of benzaldehyde, glycine, and potassium hydroxide at an early stage of reaction had C=N absorption at 1640 cm-1. Reaction of Ethyl N-Benzylideneg1ycinate.-To a solution of KOH (5.61 g, 0.1 mol) and ethyl N-benzylideneglycinate (9.56 g, 0.05 mol) in absolute ethanol (75 ml), there was added a solution of benzaldehyde (5.31 g, 0.05 mol) in absolute ethanol (25 ml). The mixture was allowed to stand a t room temperature. A crystalline product was separated. Ethanol was decanted and the residual crystals were dissolved in a mixture of 2 N hydrochloric acid (20 ml) and benzene (20 ml). The solution was concentrated under vacuum until all ethanol was removed. After neutralization with concentrated ammonia, crystalline phenylserine (2.52 g, 27%) was obtained, which was identified by ir and melting point with the authentic specimen. Phenylserine ethyl ester was separated from ethanol solution by means of tlc: vmax (KBr) 3450-3300 (NH2, OH), 1730 (C=O), 1210-1190 [CC(=O)O], 750 and 700 cm-l (monosubstituted phenyl); 7 (CDCla) 2.70 (m, aromatic H), 4.97 (s, OH, 1 H), 5.35 (d, CH, 1 H), 5.73 (d, CH, 1 H), 6.06 (9, CH2, 2 H), 7.24 (s, NHz, 2 H), 9.24 (t, CHa, 3 H ) . Registry No.-Glycine, 56-40-6; benzaldehyde, 100-52-7; phenylserine, 1078-17-7; ethyl glycinate, 459-73-4; N-benzylideneglycine ethyl ester, 40682-54-0 ; A'-benz ylidenemethylamine, 622-29-7; N-benzylidene(2-phenyl-2-hydroxyethyl)amine, 2555812-7; phenylserine ethyl ester, 40682-56-2.
Amino Group Protection in Peptide Synthesis. The 4,5-Diphenyl-4-oxazolin-2-one Group1 JOHN C. SHEEHAN" AND FRANK S. GVZIEC, JR. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 08159 Received March 16, 19'73 The preparation and properties of 4,5-diphenyl-4-oxazolin-2-one (Ox) derivatives (1) of amino acids are described and these derivatives evaluated as protected intermediates in peptide synthesis. The Ox group -one of the few protecting groups which mask both hydrogens of a primary amino function-is unreactive undei the usual conditions used t o remove protecting groups, but may be cleaved under mild reductive or oxidative conditions. The use of Ox protection for the €-aminogroup of lysine is described.
The previously described properties of the 4,5diphenyl-4-oxazolin-2-ones2 (1) have indicated the Ph
0
NR
K0 1
potential of this heterocyclic system3 as a protecting group for primary amines, one of the few protecting groups which mask both hydrogens of a primary amine function. Compounds of this type are extremely stable and unreactive under a variety of rigorous conditions. Methods existed for the preparation of this cyclic system through the easily prepared benzoin urethanes. The oxazolinones are highly crystalline, yet reasonably soluble in organic solvents; because of the cis-stilbene moiety present in the system, they are also highly fluorescent. Finally, possibilities existed for (1) Dedicated t o Professor Dr. Theodor Wieland on the occasion of his 60th birthday, June 5 , 1973. (2) J. C. Sheehan and F. Guziec, Jr., J. Amer. Chem. S o c . , 94, 6561 (1972). (3) Reviewed by R. Filler, "Advances in Heterocyclic Chemistry," Vol. I V , Academic Press, New York, N. Y., 1965, p 103.
the removal of the protecting group under mild oxida. t'ive or reductive conditions. The proposed preparation of the 4,5-diphenyl-4oxazolin-2-one (Ox) derivatives involved a two-step reaction sequence: the preparation of benzoin urethanes, followed by cyclization and simultaneous dehydration of the urethanes t o oxazolinones in an acid medium.
RNHJ
-
- KNR Ph
I
0II Ph 0 I1 PhC-CHOCNHR 2
Wp:H
0
0 3
--I
I n contzast t o the usual met'hods of preparing urethanes, a novel method is available for the preparation of the benzoin urethanes. Treatment of benzoin with phosgene in the presence of N,N-dimethylaniline, followed by thermal cyclization of the intermediate, unstable chloroformat'e affords a cyclic unsaturated carbonate (4) in good yields4 Treatment of this (4) A minor by-product is desyl chloride, formed in a reaction analogous t o the thionyl chloride-pyridine chlorination of alcohols. This compound becomes the major product of the reaction unless N,N-dimethylaniline hydrochloride is removed prior t o the chloroformate cyclization.
J . Org. Chern., Vol. 58,No. 17, 1978 3035
4,5-DIPHENYL-4-OXAZOLIN-2-ONE GROUP
TABLE I Ox AMINOACIDDERIVATIVES~ Registry no.
.4mino acid
Registry no!
Yield?
Mp,c
oc
Optical rotation, deg ( c , MeOH)
GlY 40691-13-2 79 178-1 79 77 202-204d (subl) [ a I z 6 D -31.5 (1.02) L-Ala 37628-69-2 L-Phe 37628-66-3 84 196-197d (subl) [ a I z 6 D -176 (1.02) L-Val 37628-67-4 75 234-236d (subl) [a]'*D -69.3 (0.99) L-Leu 407 19-38-8 85 203-204d [aIz6D -24.6 (1.02) L-Ile 40719-39-9 74 225-226d (subl) [aIz6D -44.8 (1.08) L-Tyr 407 19-40-2 70 198-202ddec [ a ] " D -150 (1.00) L-Met 40719-41-3 82 168-169 [ C Y ] ~ ~- 5 D1 . 6 ( 1 . 0 1 ) 73 196-1986 dec [ a I z 4 D - 4 . 3 (0.97) 40719-42-4 L-Ser (DCHA salt) 67 163.5-165' [aIz6D -32.4 (1.04) 50719-43-5 L-Gln 82 147-14ge [ a l Z s D$ 4 . 5 ( 1 . 0 3 ) 40719-44-6 CU-Z-L-LYS (DCHA salt) All melting points are uncorrected. b Based on a single recrystallization. a All compounds gave satisfactory elemental analyses. f Recrystallized from acetone-water. e Recrystallized from absolute ethanol-ether. d Recrystallized from ethyl acetate-pentane. Of Ox derivative. 56-40-6 56-4 1-7 63-91-2 72-18-4 61-90-5 73-32-5 60-18-4 63-68-3 4071 9-34-4 56-85-9 40719-35-5
Q
0
Ph
II
I
PhC-CHOH
+ COClz + PhNMez
r o 1 - 11 PhH
1
P h 0 1
1
PhC-CHOCC1
II
hydroxyoxazolidinone form, or as the desyl urethanes (2) [ir 1735-1725cm-'; nmr 6 8.1-7.8 (m, 2H), 6 7.7-6.7 0
Ph 0
II I
'"M'" OK 0 0
4
-*
+ RNH.,
3
carbonate with a primary amine affords the benzoin urethane in high yield. Although urethanes of simple primary amines could be prepared without difficulty using the cyclic carbonate in organic solvents, the normal conditions of amino acid acylation in aqueous solvents led t o significant hydrolysis of the cyclic carbonate. The catalytic nature of this hydrolysis resulted in poor yields in the acylation reaction. The use of tetramethylammonium or l11,3,3-tetramethylguanidine salts of amino acids in anhydrous dimethylformamide, however, offered a reasonable alternative to aqueous systems. The tetramethylammonium salts of amino acids react with the cyclic carbonate to afford the benzoin urethanes in consistently high yields (70-85Oj,). The use of tetramethylguanidine as a base in the acylation, however, led to high yields of the urethanes only when the amino acid salts were very soluble in dimethylformamide. In those cases where the amino acid salts were only moderately soluble, low yields of the urethanes were obtained due to the acylation of tetramethylguanidine by the cyclic carbonate.
MezN
/
(m, 8 H) 1, depending on the conditions of the acylation and work-up. Acylation or work-up conditions involving aqueous base led to the predominant formation of the desyl urethanes, while immediate acidification of an anhydrous acylation mixture led to the isolation of the urethane in the hydroxyoxazolidinone form. Because the dehydration of the hydroxyoxazolidinoncs to oxazolinones occurs under conditions (trifluoroacetic acid, 1-2 hr, quantitative yield) much milder than those required for the cyclization and dehydration of desyl urethanesj5 the conditions favoring hydroxyoxazolidinone formation were used in a general procedure for the preparation of oxazolinone derivatives of amino acids. The most convenient procedure for the synthesis of 4,5-diphenyl-4-oxazolin-2-one (Ox) derivatives of amino acids therefore involved the treatment of an amino acid tetramethylammonium salt in dimethylformamide at room temperature with 1 equiv of the cyclic carbonate, acidification and isolation of the resulting hydroxyoxazolidinone mixture, and dehydration of this mixture to the desired oxazolinone in trifluoroacetic acid. Pure Ox derivatives of a variety of amino acids could be obtained in consistently high yields using this procedure (Table I). A single rccrystallization in each case afforded analytically pure derivatives.
0 Ph 0
Me2N
\
