Copper-Catalyzed Domino Reaction Research Articles

Synthesis of Eleven-Membered Cyclic Urea Fused Quinazolinones

AbstractStraightforward synthesis of quinazolinones having N-fused medium-sized ring urea was accomplished. Key intermediates were tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates derived from copper-catalyzed domino reaction of tert-butyl [2-(2-iodobenzamido)ethyl]carbamates and cyclic enaminones. Steric hindrance of cyclic enaminones played an important role in the formation of quinazolinone ring. The eleven-membered ring urea moiety was readily achieved by direct cyclization using 1,1′-carbonyldiimidazole (CDI) of diamino intermediate generated by readily reductive amination and deprotection of tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates.

Isoquinolone-4-Carboxylic Acids by Ammonia-Ugi-4CR and Copper-Catalyzed Domino Reaction.

Highly substituted isoquinolone-4-carboxylic acid is an important bioactive scaffold; however, it is challenging to access it in a general and short way. A Cu-catalyzed cascade reaction was successfully designed involving the Ugi postcyclization strategy by using ammonia and 2-halobenzoic acids as crucial building blocks. Privileged polysubstituted isoquinolin-1(2H)-ones were constructed in a combinatorial format with generally moderate to good yields. The protocol, with a ligand-free catalytic system, shows a broad substrate scope and good functional group tolerance toward excellent molecular diversity. Free 4-carboxy-isoquinolone is now for the first time generally accessible by a convergent multicomponent reaction protocol.

Synthesis of pyrazolo[1,5-c]quinazoline derivatives through the copper-catalyzed domino reaction of o-alkenyl aromatic isocyanides with diazo compounds.

A novel copper-catalyzed domino reaction between o-alkenyl aromatic isocyanides and diazo compounds has been developed under mild reaction conditions. Various o-alkenyl aromatic isocyanides were prepared from readily available reactants. The reaction provides a general and efficient method for the synthesis of pyrazolo[1,5-c]quinazolines by the formation of two rings and three new bonds in a single step from readily available acyclic starting materials. A mechanism involving a tandem (3+2) cyclization/elimination/intramolecular aza-addition sequence was proposed.

Copper-catalyzed domino reaction of carbodiimides and benzoic acid derivatives for the synthesis of quinazolinediones

Quinazolinediones were obtained from 2-iodobenzoic acids and carbodiimide derivatives under mild reaction conditions via a copper-catalyzed domino reaction. The absence of an external base was essential to avoid the generation of amide by-products. Both alkyl- and aryl-substituted carbodiimides gave the corresponding quinazolinediones. However, the use of aryl-substituted carbodiimides resulted in low yields due to an undesired elimination process.

Copper-Catalyzed Cascade Synthesis of [1,2,4]-Triazoloquinazolinones

An efficient and practical method for the synthesis of 1,2,4-triazolo[5,1-b]quinazolin-9(3H)-ones has been developed via the copper-catalyzed domino reactions of readily available substituted N′-acetyl-2-bromobenzohydrazides with cyanamide. The protocol uses inexpensive CuI as the catalyst, and no other ligand or additive was required. The target products were prepared in good to excellent yields with tolerance of various functional groups.

Synthesis of Pyrimidine Fused Quinolines by Ligand-Free Copper-Catalyzed Domino Reactions.

Herein, we report two novel methods for the synthesis of pyrimidine fused quinolines using a one-pot C-C and C-N bond forming strategy from the reaction of 6-aminouracils with 2-bromobenzaldehydes or 2-bromobenzyl bromide derivatives in the presence of 10 mol % CuCl2 without using any ligand. The reaction of 2-bromobenzaldehyde or its derivatives with 6-aminouracils in the presence of K2CO3 as base and a catalytic amount of CuCl2 in DMF medium under microwave heating conditions provides corresponding pyrimidine fused quinoline derivatives in good yields within 30 min. Alternatively, pyrimidine fused quinoline derivatives have been synthesized from the reaction of 2-bromobenzyl bromides with 6-aminouracil derivatives in the presence of molecular oxygen, CuCl2 (10 mol %), and K2CO3 as base in DMF under reflux conditions. Structures of all the products were unambiguously confirmed by spectroscopic techniques and by recording single crystal XRD of 3a.

Synthesis of quinolines via copper-catalyzed domino reactions of enaminones

Quinoline derivatives were obtained from enaminones and 2-bromo- or 2-iodobenzaldehydes via copper-catalyzed domino reactions consisting of the aldol reaction, C(aryl)-N bond formation and elimination. The electronic effect of aldehydes played a major role in the reaction outcome. Two simple protocols are disclosed to achieve various quinolines from both cyclic and acyclic enaminones in good yields. With the less-reactive acyclic enaminones, diethyl-2-(2-bromobenzylidene)malonate was shown to be more compatible than the benzaldehydes.

Synthesis of Pyrido-Fused Quinazolinone Derivatives via Copper-Catalyzed Domino Reaction.

A simple and efficient synthesis of 11H-pyrido[2,1-b]quinazolin-11-ones by Cu(OAc)2·H2O-catalyzed reaction of easily available substituted isatins and 2-bromopyridine derivatives has been developed. The reaction involves C-N/C-C bond cleavage and two C-N bond formations in a one-pot operation. This methodology is complementary to previously reported synthetic procedures, and two plausible reaction mechanisms are discussed.

ChemInform Abstract: Copper‐Catalyzed Domino Reactions: Conjugate Alkylative Aldol Addition/Lactonization of α,β‐Unsaturated Diesters.

Abstract A novel copper-catalyzed domino reaction of α,β-unsaturated dicarboxylate (itaconate, fumarate) with carbonyl (ketone or aldehyde) and diethyl zinc was achieved in high yield, wherein diethyl zinc has been employed as an alkyl Michael donor. In the case of maleate, diethyl zinc acts as a reducing reagent that provides a hydride for Michael addition, and thus affords the corresponding lactones following the conjugate reduction-induced domino reaction.

Copper-catalyzed synthesis of 2,3-disubstituted indoles from ortho-haloanilines and β-keto esters/β-diketone

Tetrazole-1-acetic acid was identified as an efficient ligand to promote copper-catalyzed domino reaction of ortho-iodo/bromo-anilines with β-keto esters/β-diketone for 2,3-disubstituted indoles' synthesis with high yields under mild conditions. The protocol, with easy-available catalytic system, shows good substrate tolerance towards various functional groups.

Copper-catalyzed domino reactions: conjugate alkylative aldol addition/lactonization of α,β-unsaturated diesters

A novel copper-catalyzed domino reaction of α,β-unsaturated dicarboxylate (itaconate, fumarate) with carbonyl (ketone or aldehyde) and diethyl zinc was achieved in high yield, wherein diethyl zinc has been employed as an alkyl Michael donor. In the case of maleate, diethyl zinc acts as a reducing reagent that provides a hydride for Michael addition, and thus affords the corresponding lactones following the conjugate reduction-induced domino reaction.

Copper-Catalyzed Dimerization/Cyclization of Itaconates.

A copper-catalyzed domino reaction between itaconate esters and diethyl zinc (or silane) is developed, affording itaconate dimerization products, multi-ester-substituted cyclopentanones, in moderate to high yields.

Intramolecular decarboxylative coupling as the key step in copper-catalyzed domino reaction: facile access to 2-(1,3,4-oxadiazol-2-yl)aniline derivatives.

A copper-catalyzed domino protocol for the synthesis of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives has been developed from simple and available isatins and hydrazides. This domino process integrated consecutive condensation, base-promoted ring-opening and the key copper-catalyzed decarboxylative coupling for intramolecular C-O bond formation.

A copper-catalyzed domino reaction to construct functionalized indolizinones

An efficient one-step copper-catalyzed domino reaction to 3,8α-disubstituted indolizinone derivatives has been developed for the first time, in which cheap and readily available pyridine ketones and terminal alkynes are the starting materials.

ChemInform Abstract: Copper‐Catalyzed Domino Reactions for the Synthesis of Cyclic Compounds

AbstractReview: [54 refs.

Copper-catalyzed domino reactions for the synthesis of cyclic compounds.

Copper-catalyzed domino reactions are one of the most useful strategies for the construction of various cyclic compounds. In this Synopsis, we mainly focus on the latest advances in copper-catalyzed cross-coupling or addition-initiated domino reactions in the synthesis of cyclic compounds, including double alkenylation of N- or S-nucleophiles, alkenylation or alkynlation followed by cyclization of amides or amines, addition and cyclization of heteroallenes affording heterocycles, and coupling and cyclization of 1,3-dicarbonyl compounds toward heterocycles.

Copper-catalyzed domino synthesis of 2-imino-1H-imidazol-5(2H)-ones and quinoxalines involving C-C bond cleavage with a 1,3-dicarbonyl unit as a leaving group.

Although 2-imino-1H-imidazol-5(2H)-ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as "privileged scaffolds" in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper-catalyzed domino reactions for the synthesis of 2-imino-1H-imidazol-5(2H)-ones and quinoxalines involving CC bond-cleavage with a 1,3-dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2-imino-1H-imidazol-5(2H)-ones includes aza-Michael addition, intramolecular cyclization, CC bond-cleavage, 1,2-rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza-Michael addition, intramolecular cyclization, elimination reaction, and CC bond-cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.

Assembly of 4H-chromenes, imidazobenzothiazines and quinazolines via copper-catalyzed domino reactions using 2-halobenzyl tosylates as substrates

The use of 2-halobenzyl tosylates as substrates in copper-catalyzed domino intermolecular substitution/intramolecular arylation processes for the efficient and selective preparation of heterocycles is reported for the first time. Reaction of 2-halobenzyl tosylates with β-ketoesters delivers 4H-chromenes with yields ranging between 59 and 89%. Imidazobenzothiazines are formed with yields up to 82% upon reaction of 2-halobenzyl tosylates with 2-mercaptoimidazoles. When 2-halobenzyl tosylates are reacted with benzamidines the corresponding quinazolines are obtained.

Copper-catalyzed domino reaction between 1-(2-halophenyl)methanamines and amidines or imidates for the synthesis of 2-substituted quinazolines

The CuI-catalyzed domino reaction between 1-(2-bromophenyl)methanamines and amidines using K3PO4 as the base, pivalic acid as the additive, and aerial oxygen as the oxidant gives access to substituted quinazolines in a single step with yields in the range between 43 and 90%. It is assumed that the reaction proceeds as a Cu(I)-catalyzed intermolecular N-arylation followed by an intramolecular nucleophilic substitution and a Cu(II)-catalyzed oxidation. The amidines can be replaced with imidates and the reaction can also be run with 1-(2-iodophenyl)methanamine.

Copper-Catalyzed Domino Reaction of 2-Haloanilines with Hydrazides: A New Route for the Synthesis of Benzo[e][1,2,4]triazine Derivatives

A copper-catalyzed domino reaction for the synthesis of benzo[e][1,2,4]triazine derivatives has been developed using readily available substituted 2-haloanilines and hydrazides as the starting materials. The procedure of the present method is mild, facile, and efficient.