Pd-Catalyzed Benzylic C–H Amidation with Benzyl Alcohols in Water: A Strategy To Construct Quinazolinones

Abstract

A novel method for the synthesis of 4-phenylquinazolinones via a palladium-catalyzed domino reaction of o-aminobenzamides with benzyl alcohols is developed. This protocol involves N-benzylation, benzylic C-H amidation, and dehydrogenation in water, which may play an important role in the smooth generation of the (η(3)-benzyl)palladium species by activation of the hydroxyl group of the benzyl alcohol.

Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water

“…These results suggested that 3-benzylated 4a is not the intermediate in our catalytic system. These results and our previous report [25][26][27][28] suggest the following mechanism for the formation of bis(indolyl)methanes 3 from indole carboxylic acid 1 and benzyl alcohol 2 in water (Scheme 4 -benzyl)palladium complex through reductive elimination in our catalytic system (see Scheme 4). We were delighted to observe that indeed toluene 5 was obtained in the reaction mixture (Sceme 5, A).…”

“…Recently, direct application of benzyl alcohols as electrophiles in various reactions was achieved via Brønsted/Lewis acid [10][11][12], transition metal [13,14] or water-promoted [15][16][17] We have developed a unique strategy for benzylation and C-H activation [18][19][20][21][22][23][24] by the (η 3 -benzyl)palladium system from a palladium catalyst and benzyl alcohol in water [25][26][27][28]. Water activates the benzyl alcohol via hydration of the hydroxyl group for generation of the (η 3 -benzyl)palladium species, which can then undergo innovative direct transformation reactions.…”

Acceptorless dehydrogenative condensation of o-aminobenzamides with aldehydes to quinazolinones in water catalyzed by a water-soluble iridium complex [Cp*Ir(H2O)3][OTf]2

“…2 (0.005 mmol, 1 mol%) was added and the mixture was then cooled to ambient temperature, concentrated in 25 vacuo and purified by flash column chromatography with hexanes/ethyl acetate to afford the corresponding products. 29 33 Procedure for the hydrogen evolution experiment (Scheme 4). 29 33 Procedure for the hydrogen evolution experiment (Scheme 4).…”

Synthesis of quinazolines and quinazolinones via palladium-mediated approach

“…Isocyanide insertion of tert -butyl isocyanide on complex 15 produces Pd(II) species 16 A convenient one-pot method to synthesize 4(3 H )-quinazolinones has been developed [23] . The aminocarbonylation of bromobenzene 8 using substituted amines 19 in the presence of Pd(OAc) 2 and Mo(CO) 6 [24] . Results for the reaction of o -aminobenzamides 22 with several benzyl alcohols 23 using Pd(OAc) 2 (5 mol%) and sodium (diphenylphosphino)benzene-3-sulfonate (TPPMS; 10 mol%) in water for 16 h under air in a sealed tube are summarized in Scheme 11 .…”

“…Hikawa et al [24] reported in 2012 that 2,3-disubstituted-4(3 H )quinazolinones 37 are obtained in excellent yields by the reaction of 2-amino-N -methylbenzamide ( 36 ), a benzyl alcohol 23 , Pd(OAc) 2 (5 mol%), and TPPMS (10 mol%) in water for 16 h under air in a sealed tube ( Scheme 17 ).…”