Convenient and efficient synthesis of disubstituted piperazine derivatives by catalyst-free, atom-economical and tricomponent domino reactions

Abstract

Synthesis of disubstituted piperazine derivatives is accomplished by a one-pot ring opening and tri-component domino reaction. The method features operational simplicity, mild conditions and moderate to high yields.

Reactions of Polychlorinated Pyrimidines with DABCO

“…Interestingly, among our efforts to displace the C2 chloride in the presence of DABCO, we observed the formation of a colorless side-product, identified as 2,4,5-trichloro-6-[4-(2-chloroethyl) piperazin-1-yl]pyrimidine (5), which was isolated in 17% yield along with 60% recovered starting material (Scheme 3). Reaction of tetrachloropyrimidine 4 with 1 equiv.…”

“…Molbank 2019, 2019 2 of 4 11], and often the chloroethyl moiety was not isolated but converted in situ to other derivatives by nucleophilic displacement of the chloride [2][3][4][5].…”

“…One strategy to access these compounds is starting from the familiar tertiary amine 1,4-diazabicyclo[2.2.2]octane (DABCO). DABCO acts as a nucleophile in a variety of displacement reactions and often leads to the formation of quaternary ammonium salts that, in the presence of other nucleophiles, can ring open forming substituted N-ethylpiperazines [2][3][4][5].…”

“…Trichloro-2-[4-(2-chloroethyl)piperazin-1-yl]pyrimidine(5) One portion 1,4-diazabicyclo[2.2.2]octane (DABCO, 56.0 mg, 0.500 mmol) was added to a stirred mixture of 2,4,5,6-tetrachloropyrimidine (4) (109 mg, 0.500 mmol) in MeCN (5 mL) at ca. 20 • C. The mixture was protected with a CaCl 2 drying tube and stirred at this temperature until complete consumption of the starting material (TLC, 48 h).…”

Synthesis of N‐alkyl‐N′‐aryl or Alkenylpiperazines: A Copper‐Catalyzed C–N Cross‐Coupling in the Presence of Aryl and Alkenyl Triflates and DABCO

“…As opposed to the carboamination approach, this process uses inexpensive and readily available alcohols and only a catalytic amount of ruthenium catalyst. In 2015, Xie and co‐workers reported a novel method for the synthesis of N ‐alkyl‐ N ′‐alkenylpiperazines in a reaction involving DABCO, electron‐deficient acetylenes, and aryl acids. This N ‐alkenylation reaction utilized highly activated acetylenic esters as the alkenyl source which limits the reaction scope.…”