One-Pot Three-Component Reaction for the Synthesis of 3,4-Dihydroquinazolines and Quinazolin-4(3H)-ones.

A highly efficient and straightforward one-pot synthesis of diversely substituted 3,4-dihydroquinazolines and quinazolin-4(3H)-ones has been achieved through a domino three-component assembly reaction of arenediazonium salts, nitriles, and bifunctional aniline derivatives. This new protocol involves three C-N bond formations through the initial formation of N-arylnitrilium intermediates from arenediazonium salts and nitriles, followed by the sequential nucleophilic addition and cyclization reactions with bifunctional anilines, leading to such N-heterocyclic compounds of biological and pharmacological importance. This method offers a simple, expedient, and robust approach with the use of amenable and easily accessible reactants/reagents under metal-free mild conditions, good functional group tolerance, and high efficiency. The synthetic applications were also demonstrated by derivatization of the products obtained from these processes and syntheses of a diverse range of valuable polycyclic N-heterocycles.

Simple Tandem Olefin Isomerization/Intramolecular Hydroamination of Alkenyl Amines with Various Allylic Tethers.

A simple and efficient AgOTf-promoted tandem olefin isomerization/intramolecular hydroamination of 1,1-disubstituted alkenyl amines has been developed. This one-pot process represents a facile and attractive route for the synthesis of diverse 2-alkyl-substituted 1,3-X,N-heterocycles through chemo- and regioselective C(sp3)-N bond formation with atom economy. Advantages such as the operationally simple and practical procedure that uses a readily available catalyst under aerobic conditions, good to excellent chemical yields, the high functional group tolerance, the broad substrate scope, and high efficiency and selectivity are noteworthy.

Pd-Catalyzed Regioselective Intramolecular Allylic C-H Amination of 1,1-Disubstituted Alkenyl Amines.

Pd-Catalyzed intramolecular allylic C-H amination of 1,1-disubstituted alkenyl amines with various allylic tethers (X = O, NMs, CH2) was developed. This process allows for the divergent synthesis of 1,3-X,N-heterocycles through a regioselective allylic C-H cleavage and π-allylpalladium formation. Particularly noteworthy is the use of substrates containing a labile allylic moiety and new simple catalytic systems capable of promoting highly chemo- and regioselective allylic C-H amination by overcoming significant challenges.

Transition-metal-catalyzed ortho-selective C-H functionalization reactions of free phenols.

Phenols are important readily available chemical feedstocks and versatile synthetic building blocks for diverse synthetic transformations. Their motifs are prevalent in a diverse array of natural products, pharmaceuticals, functional materials, and privileged chiral ligands. Consequently, the development of facile and direct site-selective C-H bond functionalization of free phenols is of great importance and considerable interest to both industry and academic research. Over the past decades, transition-metal-catalyzed C-H bond functionalization has become as a powerful synthetic tool in organic synthesis. In this review, we provide a brief overview of recent progress in the transition-metal-catalyzed direct ortho-selective C-H functionalization of free phenols.

Facile one-pot synthesis of 2-aminoindoles from simple anilines and ynamides.

A highly effective and straightforward one-pot synthesis of diversely substituted 2-aminoindoles has been developed, involving sequential Au(i)-catalyzed regioselective hydroamination and CuCl2-mediated oxidative cyclization. This protocol offers an operationally easy, simple, robust, and sustainable approach with the use of readily available starting materials, good functional group tolerance, and high practicality and efficiency.

Divergent Syntheses of Indoles and Quinolines Involving N1-C2-C3 Bond Formation through Two Distinct Pd Catalyses.

Pd-catalyzed annulative couplings of 2-alkenylanilines with aldehydes using alcohols as both the solvent and hydrogen source have been developed. These domino processes allow divergent syntheses of two significant N-heterocycles, indoles and quinolines, from the same substrate by tuning reaction parameters, which seems to invoke two distinct mechanisms. The nature of the ligand and alcoholic solvent had a profound influence on the selectivity and efficiency of these protocols. Particularly noteworthy is that indole formation was achieved by overcoming two significant challenges, regioselective hydropalladation of alkenes and subsequent reactions between the resulting Csp3-Pd species and less reactive imines.

Zn(II)-Catalyzed One-Pot Synthesis of Coumarins from Ynamides and Salicylaldehydes.

A highly efficient and straightforward synthesis of diversely substituted coumarins from ynamides and salicylaldehydes in the presence of Zn(II) catalyst has been developed. The sulfonamide moiety of ynamides was successfully recycled in this process, serving as an effective traceless directing group for high regioselectivity in the bond-forming event. The advantages of this protocol are good functional group tolerance, broad substrate scope, simple and high-yielding reaction, recovery/reuse of the sulfonamides, low catalyst loading of inexpensive catalyst, and, by these merits, a more cost-effective and greener process.

Pd(II)/Cu(II)-Catalyzed Regio- and Stereoselective Synthesis of ( E)-3-Arylmethyleneisoindolin-1-ones Using Air as the Terminal Oxidant.

Regio- and stereoselective synthesis of ( E)-3-arylmethyleneisoindolin-1-ones via Pd(II)/Cu(II)-catalyzed one-pot C-C/C-N bond forming sequence between amides and styrenes is reported. This method provides facile and rapid access to a diverse range of such compounds using readily available starting materials under mild aerobic conditions with good functional group tolerance and high selectivity and efficiency. Further elaboration of the products obtained from this process enabled very short and efficient syntheses of aristolactam and indoloisoquinolinone alkaloids.

Palladium-Catalyzed Regioselective Synthesis of 3-Arylindoles from N-Ts-Anilines and Styrenes.

A Pd-catalyzed intermolecular oxidative annulation between N-Ts-anilines and styrenes was developed. This method offers a straightforward and robust approach to a wide range of 3-arylindoles using readily available starting materials with good functional-group tolerance and high regioselectivity and efficiency. Further elaboration of the products obtained from this process provided access to highly functionalized and structurally diverse indoles, for example, 3-(indol-3-yl)carbazoles, 1,9-dihydropyrrolo-[2,3-b]carbazoles, and 3'-aryl-3,5'-biindoles.

Pd(II)/Ag(I)-Promoted One-Pot Synthesis of Cyclic Ureas from (Hetero)Aromatic Amines and Isocyanates.

A simple and facile one-pot reaction has been developed to afford a diverse range of N,N'-disubstituted benzimidazolones and imidazopyridinones containing two differently substituted N atoms. A cooperative Pd(II)/Ag(I) system promotes the sequential addition/intramolecular C-H amidation reaction of (hetero)aromatic amines and isocyanates, leading to the formation of two C-N bonds. A mechanism involving radical intermediates generated by single-electron transfer (SET) in the presence of a Ag2CO3 oxidant and Pd(OAc)2 Lewis acid is proposed. This protocol offers an operationally easy, simple, and robust approach with the use of readily available starting materials, good functional group tolerance, and high efficiency.

Metal-Free One-Pot Synthesis of N,N'-Diarylamidines and N-Arylbenzimidazoles from Arenediazonium Salts, Nitriles, and Free Anilines.

A highly efficient and facile metal-free, one-pot reaction has been developed to afford diversely substituted N-arylbenzimidazoles through chemoselective in situ generation of N,N'-diarylamidines from arenediazonium salts, nitriles, and free anilines. The advantages of this protocol consist of the operationally easy and simple one-pot procedure under metal-free and mild conditions, the direct use of inexpensive and commercially available chemicals, and thus, a cost-effective and greener process.

The cooperative FeCl3/DDQ system for the regioselective synthesis of 3-arylindoles from ß-monosubstituted 2-alkenylanilines.

A highly regioselective synthesis of 3-arylindoles by using the cooperative FeCl3/DDQ system has been developed. This new protocol represents an attractive route for the synthesis of 3-arylindoles from readily accessible non-indole precursors, ß-aryl-substituted 2-styrylanilines, using an inexpensive catalyst and oxidant. Noteworthy is the unique synergetic and synergistic effect of FeCl3 and DDQ on the 1,2-aryl migratory process.

Unusual 1,2-aryl migration in Pd(ii)-catalyzed aza-Wacker-type cyclization of 2-alkenylanilines.

Inspired by the Hegedus aza-Wacker indole synthesis, we were intrigued with the fate of the aminopalladation intermediate if syn ß-hydrogen is made inaccessible or unavailable. In contrast to our previously reported ß-carbon elimination, cyclization of a variety of 2-alkenylaniline substrates under electrophilic palladium conditions unexpectedly afforded C3-substituted indoles. This unusual 1,2-migratory process was found to be operative across a variety of substrates with predictable migratory aptitude. A mechanistic proposal was put forward to rationalize the observed substrate dependence, and this unexpected finding could provide an opportunity for other related processes.

Metal-free C-H amination for indole synthesis.

An effective metal-free C-H amination of N-Ts-2-alkenylanilines by using DDQ as an oxidant has been developed to afford a diverse range of substituted indoles. This protocol is operationally simple and robust, obviates the need of expensive transition-metal catalysts, and offers a broad substrate scope. A mechanism involving a radical cation generated by SET and a migratorial process via a phenonium ion intermediate is proposed.

NHC-catalyzed oxidative cyclization reaction for the synthesis of 3-substituted phthalides.

An efficient NHC-catalyzed domino oxidation/oxa-Michael addition reaction of 2-alkenylbenzaldehydes has been developed to afford 3-substituted phthalides bearing a C3-stereogenic center with a broad substrate scope and wide functional group tolerance. The preliminary results of the asymmetric process have been provided as well.

Asymmetric domino multicatalysis for the synthesis of 3-substituted phthalides: cinchonine/NHC cooperative system.

It is demonstrated that two organocatalysts, achiral NHC and chiral bifunctional cinchonine, are mutually compatible and operating concurrently and effectively to promote the asymmetric domino oxidation/oxa-Michael addition reaction. This protocol allowed access to both enantiomers of a product by using two natural, inexpensive pseudoenantiomeric cinchona alkaloids, cinchonine and cinchonidine, as well as to phthalides containing a chiral quaternary carbon center in good enantioselectivities.

C-H activation: a complementary tool in the total synthesis of complex natural products.

The recent advent of transition-metal mediated C-H activation is revolutionizing the synthetic field and gradually infusing a "C-H activation mind-set" in both students and practitioners of organic synthesis. As a powerful testament of this emerging synthetic tool, applications of C-H activation in the context of total synthesis of complex natural products are beginning to blossom. Herein, recently completed total syntheses showcasing creative and ingenious incorporation of C-H activation as a strategic manoeuver are compared with their "non-C-H activation" counterparts, illuminating a new paradigm in strategic synthetic design.

Pd-catalyzed sequential C-C bond formation and cleavage: evidence for an unexpected generation of arylpalladium(II) species.

A Pd(II)-catalyzed reaction engaging alkenyl ß-keto esters is reported that leads to the formation of 1-naphthols and an unexpected generation of arylpalladium(II) species. Interception of the in situ generated arylpalladium(II) species in a Mizoroki-Heck reaction, together with additional mechanistic studies, provided strong evidence in support of the first aromatization-driven ß-carbon elimination process. A single Pd catalyst served to promote a series of both C-C bond forming and cleavage events in an unprecedented manner.

Cyclization reaction for the synthesis of polysubstituted naphthalenes in the presence of Au(I) precatalysts.

Au(I)-catalyzed cyclization of alkenyl carbonyl compounds leading to a variety of substituted naphthalenes has been developed. This process exploits a dual function of the Au(I) catalyst: (1) the oxophilic nature of the Au(I) catalyst, counterintuitive to the π-acidic reactivities generally associated with Au catalysts, and (2) olefin isomerization supported by the outcome of isotope scrambling experiments. It cannot be completely excluded that TfOH is a true operative catalyst in this protocol. In view of the practicality, the unnecessity of isomerically pure starting material in this reaction is particularly attractive and valuable.

Pd-catalyzed intramolecular oxidative C-H amination: synthesis of carbazoles.

A Pd-catalyzed oxidative C-H amination of N-Ts-2-arylanilines under ambient temperature using Oxone as an inexpensive, safe, and easy-to-handle oxidant has been developed. This process represents a green and practical method for the facile construction of carbazoles with a broad substrate scope and wide functional group tolerance.