Studies on the use of <i>N</i>-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline for the synthesis of acylamino acid anilides and <i>p</i>-nitroanilides

Fm, Chen; Nl, Benoiton

doi:10.1139/o78-006

Cited by 5 publications

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“…Their use to eliminate side-reactions has been recommended (7). Our realization that (Boc-Val),02 was resistant to aqueous washes (8) led us to develop a simple procedure for preparing anhydrides 3 using a soluble carbodiimide. Reaction of 1 with 0.5 equiv.…”

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Further studies on the synthesis of symmetrical anhydrides and 2,4-disubstituted-5(4H)-oxazolones from N-alkoxycarbonylamino acids using soluble carbodiimide

Paquet¹,

Chen²,

Benoiton³

1984

Can. J. Chem.

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[err-butyl, trichlorocthyl, p-nitrobcnzyl, p-mcthoxybenzyl, and 9-fluorcnylmethyl, and N-ethoxycarbonylaminoisobutyric acid have been prepared using 0.5 equivalents of N-ethyl-N'-(3-dirncthylaminopropyl)carbodiimide hydrochloride in dichloromcthane followed by rcmoval of sideproducts by washing with aqueous solutions. When an excess of carbodiimidc was used. 2-alkoxy-5(4H)-oxazolonc was also generated. exccpt when R = trichloroethyl. High yields of pure 5(4H)-oxazolone wcre obtained when R = ethyl. Thc Chem. 62. 1335Chem. 62. (1984. On a prtparC les anhydrides symitriques purs de la N-alkoxycarbonyl (ROC0)-valinc (ou R = Cthyl, rerr-butyl, trichlorotthyl, p-nitrobenzyl, p-mCthoxybenzy1 et fluorenyl-9 mtthyl) et de I'acide N-Cthoxycarbonyl aminoisobutyrique en utilisant 0.5 tquivalents de chlorhydrate de N-tthyl, N'-(dimtthylamino-3 propy1)carbodiimide dans le dichloromtthane et en enlevant cnsuite les produits sccvndaires par lavage avec des solutions aqueuses. Lorsqu'on utilise un excks de carbodiimide, il y a aussi formation de I'alkoxy-2 (4H)-oxazolone-5 (sauf lorsque R = trichloroithyl). On a obtenu de bons rendements de la (4H)-oxazolonc-5 lorsquc R = Cthyl. La (fluorenyl-9 methyloxy)-2 (4H)-oxazolone-5 subit lentement une tlimination au cours des nlanipulations ou de I'entreposage.[Traduit par Ic journal]The solid phase method of peptide synthesis according to Merrifield ( 1 ) involves the carbodiimide-mediated reaction of i an N-alkoxycarbonylamino acid (1) with the amino group of a I polymer-supported peptide chain. The activated intermediates undergoing aminolysis are the 0-acylisourea (2) which is 1 formed initially, the symmetrical anhydride (3) produced by the reaction of 2 with 1 , and in some cases the 2-alkoxy-5(4H)-oxazolone (4) generated by cyclization of 2(2) or the reaction of carbodiimide with 3(3) (see refs. 4 and 5 for reviews). In the modified version, the symmetrical anyhrides are preformed by reaction of 1 with 0.5 equiv. of dicyclohexylcarbodiimide and used without isolation after removal of the dialkylurea by filtration (see ref. 4).Purified anhydrides 3 (R' = (CH,)?C) are available from the acid salt and phosgene (6). Their use to eliminate side-reactions has been recommended (7). Our realization that (Boc-Val),02 was resistant to aqueous washes (8) led us to develop a simple procedure for preparing anhydrides 3 using a soluble carbodiimide. Reaction of 1 with 0.5 equiv. of EDC in dichloromethane followed by washing the solution with aqueous acid and sodium hydrogen carbonate gave excellent yields of 3 (Rr = (CH3)3C and C6HSCH,) except for derivatives of valine and isoleucine (9). It transpired that-in the latter cases a second neutral product, the 2-alkoxy-5(4H)-oxazolone (4), was also 'On sabbatical leave, 198 1 -1982. Permanent address: Food Research Institute, Canada Department of Agr~culture, Ottawa, Ont , Canada KIA 0C6.'~hbrevlorions: Alb, am~norsobutyrrc acrd; Boc, rerr-butoxycarbonyl; Eoc, ethoxycarbonyl; Fmc. 9-fluorenylmethlyoxycarbonyl; Mbc, p-methoxybenzyloxycarbonyl...

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confidence: 99%