A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones

Abstract

A rapid and versatile one-pot, 2 x 10 min microwave protocol for the preparation of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The alpha-aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as beta-strand inducing core structures in a medicinal chemistry context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-containing Hepatitis C virus NS3 protease inhibitors is reported.

Heterocycles from α‐Aminonitriles

“…[77] The same authors prepared vari-ous other spiroheterocyclic products from similar a-aminonitrile substrates. [84] They treated aaminonitriles 159 with gaseous HCl and oxalyl chloride and achieved closure of the six-membered ring under microwave irradiation (Scheme 34). Treatment of ureas 152 with anhydrous phosphoric acid results first in the kinetically favored ring closure by attack of the oxygen on the nitrile carbon to furnish phosphate salts of 4-methyl-4-phenyl-2-phenylimino-5-imino-4,5-dihydro-1,3-oxazoles.…”

Microwaves in Heterocyclic Chemistry

“…Larhed and co-workers reported a rapid and versatile one-pot microwave method (2 × 10 min) for the preparation of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones [81]. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinones containing hepatitis C virus NS3 protease inhibitors was realized.…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…their widespread biological activities [234][235][236][237][238][239]. In this context, Gising et al [237] have reported a rapid and versatile one-pot MW-assisted two steps synthesis of N-1 and C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones 258.…”

“…In this context, Gising et al [237] have reported a rapid and versatile one-pot MW-assisted two steps synthesis of N-1 and C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones 258. In the first step, the reaction of a primary amine 254, an aldehyde 255 and trimethylsilyl cyanide (256) in 1,2-dimethoxyethane under MW-irradiation leads to substituted α-aminonitriles 257.…”