Sulfinamides as Highly Effective Amine Protecting Groups and Their Use in the Conversion of Amino Alcohols into Morpholines

Abstract

1,2‐Amino alcohols have been converted into morpholines by using sulfinamides as temporary protecting/activating groups on the amine. We have developed a procedure for the selective synthesis of monoprotected N‐sulfinyl amino alcohols through a double sulfinylation/hydrolysis strategy. Following the reaction of the sulfinamides with bromoethyldiphenylsulfonium triflate, protected morpholines were obtained in high yields. Subsequent treatment with HCl liberated the morpholine hydrochloride salts. The usefulness of this high yielding and efficient methodology has been demonstrated in the formal synthesis of the antidepressant drug (S,S)‐reboxetine.

Bond-Forming and -Breaking Reactions at Sulfur(IV): Sulfoxides, Sulfonium Salts, Sulfur Ylides, and Sulfinate Salts

“…Shortly thereafter, the group of Aggarwal investigated the sulfinyl moiety as a possible nitrogen protecting group alternative to the commonly used tosylamides, which are not always easy to remove. 301 To this end, the p -tolylsulfinyl p -tolyl sulfone 475 was used to install the sulfinamide group, which proved competent in the subsequent annulation (Scheme 79b). Facile removal under acidic conditions was demonstrated in high yields, using hydrogen chloride in ether.…”

Recent Developments in Vinylsulfonium and Vinylsulfoxonium Salt Chemistry

“…The same group extended the above annulation methodology using diphenylvinylsulfonium triflate 1 , generated in situ from its precursor (2-bromoethyl)diphenylsulfonium triflate 3 , to undergo reaction with several β -amino alcohols/thiols/amines 54 / 56 / 58 and produce an array of morpholines 59 , piperazines 57 , and thiomorpholines 55 [ 43 , 44 ]. Important disubstituted morpholines were synthesized with a range of nitrogen-protecting groups ( 59 vs. 57 ) in excellent yields ( Scheme 17 ).…”

A Concise and Efficient Synthesis of Substituted Morpholines

“…We also successfully applied our synthetic approach to the synthesis of several fused morpholines. Saturated and unsaturated fused morpholines 5u-x (Table 1, entries [21][22][23][24] were synthesized in good to moderate yields from the corresponding amino alcohols and chloroacetyl chloride.…”

“…All the products except 5g and 5k have been reported in the literature. 1c,12d, [22][23][24][25][26][27][28][29][30][31] The 1 H NMR spectra of the two new molecules 5g and 5k are presented in the Supporting Information. All the morpholine products have been used to synthesize new chemical entities of medicinal interest; this information is documented elsewhere.…”