Preparation of Morpholine-2-one and 1,4-Oxazepan-2-one Derivatives by Cyclization Reaction between N-Bts Amino Alcohol and Chloroacetyl Chloride

Abstract

Sulfonamide is one of the most stable nitrogen protective group, and various sulfonamides have been developed and applied for organic synthesis. However, deprotection of most sulfonamides has drawbacks due to harsh reaction conditions. Benzothiazole-2-sulfonyl (Bts) was first reported as an amine protective group in amino acid synthesis. Compared to other sulfonyl groups, Bts is an attractive choice because it requires milder deprotection conditions. Initially, Bts chloride, the reagent for Bts protection for simple amines, was prepared using Cl2 gas, which is toxic and inconvenient. Recently, an improved methodology using aqueous sodium hypochlorite instead of toxic Cl2 was reported and making Bts protection much easier. The Bts group is known to have an electron withdrawing property, and Bts protected amide shows a different reactivity compared to other N-protected amide derivatives. Although usual amide bond is strong enough not to be easily hydrolyzed or aminolized, N-Bts amide linkage can be broken by attack of simple amine nucleophiles. This is another benefit of Bts protection, and the ring opening reaction of 1-Bts piperazin-2-one derivative as a peptide nucleic acid (PNA) monomer with a PNA oligomer anchored on solid phase has been usefully applied for solid phase PNA synthesis. In this paper, a facile cyclization reaction of N-Bts amino alcohol with chloroacetyl chloride is described. We speculated that if the Bts group could effectively withdraw electrons from nitrogen, nucleophilicity of Bts attached amine would be reduced, and a different reactivity toward electrophiles would be observed compared to normal amine derivatives. These subtle reactivity differences could be an effective means of obtaining different regioselectivity. Detailed data pertaining to change of nucleophilicity due to Bts protection has not been reported thus far. To investigate this hypothesis, Bts, Ts (toluensulfonyl), and Boc (t-butyl carbamate) protected amino alcohols were prepared, and reactions with chloroacetyl chloride were performed (Scheme 1). Between two chlorides in chloroacetyl chloride, acyl chloride is known to be more reactive toward usual nucleophiles. In the case of unprotected amino alcohol, the amine should react with acyl chloride prior to OH, and OH can subsequently attack α-carbon to produce a morpholine-3-one. However, for N-protected amino alcohol, OH should be acylated prior to the acylation of Nprotected amine. If the N-protected amine has sufficient reactivity to perform intramolecular cyclization to attack αcarbon, a morpholine-2-one derivative can be prepared. In the reaction of N-Bts amino alcohol (2a, b), The OH group reacted with acyl chloride to form ester 3a, b. After workup to remove remaining chloroacetyl chloride, and stirring in DMF with K2CO3, it was found that N-Bts amine could substitute a chloride at α-carbon, and morpholine-2one (4a) or 1,4-oxazepan-2-one (4b) derivative was produced. When N-Ts amino ethanol (5a) was reacted with chloroacetyl chloride dropwise, a different outcome was obtained. A mixture of O-acylated (6a) and diacylated compound 8 was produced in 1:4 ratios. The production of diacylated compound 8 as a major product means that N-Ts amine has enough nucleophilicity to react with acyl chloride, and its reactivity is higher than N-Bts amine. When O-acylated product (6a) was separated and stirred with K2CO3, morpholine-2-one derivative (7a) was obtained.