Synthesis and transformations of stereoisomeric ethyl 2‐isothiocyanato‐1‐cyclopentanecarboxylatesm

Abstract

Ethyl vis‐ and trans‐2‐isothiocyanato‐1‐cyclopentanecarboxylates 2 and 7 were prepared by the reaction of the corresponding alicyclic ethyl 2‐amino‐1‐carboxylates and thiophosgene. The cis‐isothiocyanato compound 2 underwent ring closure with amines in one or two steps, resulting in 3‐substituted‐cis‐2‐thioxocyclopenta[d]pyrimidin‐4‐ones 3a‐g. The trans isomer 7 failed to cyclize, but gave carboxamide 8a,b or thiourea ester derivatives 9a,b.

The Chemistry of 2-Aminocycloalkanecarboxylic Acids

“…The N -unsubstituted or N -methyl-substituted carboxamide 108 can be prepared from the ester 107 with methanol containing 25% ammonia or methylamine. − Further N -substituted derivatives of 108 were obtained from Boc- or Z-protected amino acids with a mixed anhydride method, using isobutyl chloroformate and the corresponding amine. ,− From ester 107 with hydrazine, the hydrazides have been produced . Alkylation of the amino group of β-amino acids can be performed easily: reductive alkylation on the amino group with oxo compounds and sodium borohydride afforded N -alkyl-substituted derivatives 109 . ,, The amino group in 107 was readily transformed to a thiocyanate 108 with thiophosgene in the presence of triethylamine. , Lithium aluminum hydride reduction can be performed either on the acid 106 or under milder conditions on the ester 107 , or on their N -acyl derivatives , in diethyl ether or THF, which results in excellent yields of the corresponding amino alcohols 111 (Scheme ) (see e.g., refs −207).…”

“…The reactions of amino ester 123 (ROEt) with potassium cyanate or phosgene afforded pyrimidine-2,4-dione 123 , while those with potassium thiocyanate led to 2-thioxopyrimidin-4-one 128 . ,− When acid or ester 123 was reacted with phenyl or methyl isothiocyanate or isocyanate, urea or thiourea adducts were formed, which underwent ring closure without difficulty when reacted in the presence of acid or base, resulting in N -substituted pyrimidinones 127 and 128 , respectively. ,, Further derivatives of 127 were prepared from carboxamide 123 (RNH 2 ) by cyclization with 1,1‘-carbonyldiimidazole. , An alternative route to 128 involves the treatment of 2-isocyanatocyclopentanecarboxylates with amines. , …”

“…62,201,202 The amino group in 107 was readily transformed to a thiocyanate 108 with thiophosgene in the presence of triethylamine. 203,204 Lithium aluminum hydride reduction can be performed either on the acid 106 or under milder conditions on the ester 107, or on their N-acyl derivatives, in diethyl ether or THF, which results in excellent yields of the corresponding amino alcohols 111 (Scheme 26) (see e.g., refs [205][206][207].…”

“…195,197 An alternative route to 128 involves the treatment of 2-isocyanatocyclopentanecarboxylates with amines. 203,204 With lactim ethers, acid 123 gave tricycles 129 (n ) 1-3), 246 while ester 123 related with haloalkyl isothiocyanates to produce sulfur-containing tricycles 130 in a domino cyclization reaction. 247 With a formaldehyde-formic acid mixture, the carboxamide of 123 gave perhydroquinazoline 131.…”

Synthesis of Alicyclic 2-Methylenethiazolo[2,3-b]quinazolinone Derivatives via Base-Promoted Cascade Reactions

“…21,22 This involved addition of a mixture of N,N′-diisopropylcarbodiimide (DIC) and hydroxybenzotriazole (HOBt) to the corresponding Boc-protected amino acids 1a-8a in tetrahydrofuran, followed by the addition of propargylamine (Scheme 1). On the other hand, according to the literature, [23][24][25] several alicyclic ethyl-2-isothiocyanatocarboxylates (9b-18b) were obtained in relatively high yields from the corresponding 2-amino esters (9a-18a) upon reaction with thiophosgene (Scheme 2).…”