A machine-learning tool to predict substrate-adaptive conditions for Pd-catalyzed C-N couplings.

Machine-learning methods have great potential to accelerate the identification of reaction conditions for chemical transformations. A tool that gives substrate-adaptive conditions for palladium (Pd)-catalyzed carbon-nitrogen (C-N) couplings is presented. The design and construction of this tool required the generation of an experimental dataset that explores a diverse network of reactant pairings across a set of reaction conditions.

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine.

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N'-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an "azatropic shift" with retention of configuration, the product of which may be hydrolysed to the target amine.

Expedient Access to Polyaromatic Biaryls by Unconventional Ag-Catalyzed Cycloaromatization of Alkynylthiophenes and Au-Catalyzed Double C-H Activation.

An unconventional approach for the regioselective synthesis of polyaromatic biaryls via site-selective Ag-catalyzed twofold electrophilic cycloisomerization followed by Au-catalyzed double C-H activation is described. The developed process allows the synthesis of highly decorated biaryls with excellent regioselectivity. As revealed by DFT computations, the reaction represents a rare example of C1-C5 - and C1-C6 - cycloaromatization.

C(sp)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (SAr).

The asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums.

Enantioselective one-carbon expansion of aromatic rings by simultaneous formation and chromoselective irradiation of a transient coloured enolate.

Enantioenriched seven-membered carbocycles are motifs in many molecules of structural and biological interest. We report a simple, practical, transition metal-free and mechanistically unusual method for the enantioselective synthesis of substituted cycloheptatrienes. By forming a coloured enolate with an appropriate absorption band and selectively irradiating , we to initiate a tandem, asymmetric anionic and photochemical ring expansion of readily accessible -benzylbenzamides.

Tandem 6π-Azatriene Electrocyclization of Fused Amino-cyclopentenones: Synthesis of Functionalized Pyrrolo- and Indolo-quinoxalines.

A tandem 6π-azacyclization approach for the synthesis of diversified pyrrolo/indolo[1,2-]quinoxalines from amino-cyclopentenones has been developed. The reaction proceeds through a trifluoroacetic-acid-mediated 6π-electrocyclization and concomitant opening of the cyclopentenone ring. The advantageous features of the developed chemistry include transition-metal-free conditions, operational simplicity, and a broad substrate scope.

Synthesis of cyclopentaquinolinone and cyclopentapyridinone from ortho-alkynyl-N-arylaldehyde via superbase-promoted C-N, C-O and C-C bond formation.

An environmentally benign, transition metal-free, superbase-mediated intramolecular annulation of o-alkynylaldehydes with primary amines forms highly functionalized amino-substituted cyclopentaquinolinones and cyclopentapyridinones via C-N, C-C, and C[double bond, length as m-dash]O bond formation. Contrary to the traditional approaches of ring closures, a different mode of annulation is disclosed. The protocol involves the in situ generations of imine intermediate followed by potassium hydroxide-promoted intramolecular cyclization and subsequent dimethyl sulfoxide induced dehydrogenation leads to the formation of N-heterocycles.

Dual function of carbon tetrachloride: synthesis of chlorinated heterocycles.

An efficient tandem approach to invent highly chlorinated and structurally diversified dihydropyridine fused heterocycles from easily accessible ortho-alkynylaldehydes and primary amines under metal-free conditions via four sequential bond formations is described. The proposed tandem route proceeds via a carbon tetrachloride-mediated 6-endo-dig ring closure followed by nucleophilic attack of the trichloromethyl anion.

Connective synthesis of 5,5-disubstituted hydantoins by tandem α-amination and α-arylation of silyl ketene acetals.

5,5-Disubstituted hydantoins, formally the cyclisation products of quaternary amino acids, were formed connectively from simple ester-derived starting materials by a one-pot tandem method. Amination of the silyl ketene acetal derivative of a methyl ester takes place by silver-catalysed addition to the N[double bond, length as m-dash]N bond of an azocarboxamide, generating a -amino-'-aryl urea derivative of a substituted aminoester. Treatment with a base forms an ester enolate which undergoes arylation by intramolecular migration of an aryl ring to the α-position of the ester.

On water: iodine-mediated direct construction of 1,3-benzothiazines from ortho-alkynylanilines by regioselective 6-exo-dig cyclization.

Herein, we report the 6-exo-dig ring closure of ortho-alkynylanilines with readily available aroyl isothiocyanate. An environmentally benign, metal- and base-free, iodine promoted cascade synthesis of highly functionalized (benzo[1,3]thiazin-2-yl)benzimidic acids has been accomplished via in situ generated ortho-alkynylthiourea. The established methodology employs the abundant chemical feedstock of ortho-alkynylanilines and aroyl isothiocyanates and could be applied in the late-stage synthesis of pharmaceutically active 1,3-benzothiazine containing molecules.

On Water: Metal-Free Synthesis of Highly Functionalized Benzothiazolylidene from ortho-Haloanilines.

An environmentally benign, transition-metal-free organic base promoted one-pot cascade synthesis of highly functionalized benzo[ d]thiazol-2(3 H)-ylidene benzamide in the presence of water was accomplished by three-component reaction of ortho-iodoanilines, acrylates, and aroyl isothiocyanates. The protocol involves the in situ generation of thiourea intermediate followed by triethylamine induced intramolecular SN displacement reaction and subsequent Michael addition onto acrylate leads to the formation of benzo[ d]thiazol-2(3 H)-ylidene benzamide. Benzo[ b]thiazole is also generated in good yields using amidation and intramolecular aromatic nucleophilic substitution chemistry.

Base-Mediated Deuteration of Organic Molecules: A Mechanistic Insight.

A base-promoted, step-economical, and cost-effective strategy for introducing heavy isotopes into the organic molecules has been developed. The schemes involve the selective deuteration of various electronically distinct molecules that are formed because of deuterioamination, deuteriothiolation, deuteriophenoxylation, and deuterioalkoxylation as well as tandem cyclization using dimethyl sulfoxide (DMSO)- as a deuterium source. The reaction involves a metal-, ligand-, and additive-free route and provides a high level of deuterium incorporation in the presence of DMSO- as an inflammable and ecological reagent.

Pd-Catalyzed one-pot sequential cross-coupling reactions of tetrabromothiophene.

Unsymmetrical one-pot sequential cross-coupling reactions of sterically hindered tetrabromothiophene with arylboronic acid and an alkyne/alkene to afford selective bi-, tri-, and tetrasubstituted aryl/alkynyl-thiophenes with the aid of a palladium catalyst were described. The reaction proceeds via a site-selective Suzuki/Sonogashira coupling, followed by selective Sonogashira, Suzuki and Heck coupling reactions. This methodology has demonstrated an important framework for the synthesis of organic scaffolds.

Ag(i)-Catalyzed cycloisomerization reactions: synthesis of substituted phenanthrenes and naphthothiophenes.

This paper describes silver catalyzed synthesis of substituted phenanthrenes and naphthothiophenes from ortho-alkylated biaryl derivatives via 6-endo-dig intramolecular alkyne-arene coupling. The mechanistic study reveals that 6-endo-dig cyclization proceeds through initial π-coordination of the alkyne unit followed by a Friedel-Crafts-type electrophilic aromatic cyclization at the adjacent arene ring. X-ray crystallographic studies further supported the formation of carbocycles.

Base-Mediated Hydroamination of Alkynes.

Inter- or intramolecular hydroamination reactions are a paradigmatic example of modern sustainable organic chemistry, as they are a catalytic, 100% atom-economical, and waste-free process of fundamental simplicity in which an amine is added to an alkyne substrate. Many enamines are found in many natural and synthetic compounds possessing interesting physiological and biological activities. The development of synthetic protocols for such molecules and their transformation is a persistent research topic in pharmaceutical and organic chemistry.

Palladium meets copper: one-pot tandem synthesis of pyrido fused heterocycles via Sonogashira conjoined electrophilic cyclization.

An efficient step-economical tandem approach for the direct synthesis of pyrido fused indole, quinoline, benzofuran and benzothiophene derivatives using a bimetallic Pd/Cu catalytic system has been described. The three component reaction of o-halo aldehydes, alkynes and tert-butylamine leads to the synthesis of biologically active polyheterocycles. The present strategy involves the dual role of tert-butylamine and copper(i) in Sonogashira coupling followed by electrophilic cyclization through imine formation.

Palladium-Catalyzed Intramolecular Fujiwara-Hydroarylation: Synthesis of Benzo[a]phenazines Derivatives.

An atom-economical Pd-catalyzed approach for the synthesis of benzophenazine derivatives using substituted 2-aryl-3-(aryl/alkylethynyl) quinoxaline in the presence of trifluoroacetic acid at 65 °C has been described. The chemistry involves in situ generation of cationic Pd(II) species, which functionalized the aromatic C-H bonds via electrophilic metalation followed by concomitant intramolecular trans-insertion of C-C triple bond to aryl-Pd complex. The results were supported by various control experiments including with electron-deficient arenes and deuterium labeling studies.

Regioselective 5-endo-dig Electrophilic Iodocyclization of Enediynes: A Convenient Route to Iodo-substituted Indenes and Cyclopenta-Fused Arenes.

An efficient iodine-mediated regioselective tandem approach for the synthesis of symmetric and asymmetric iodo-substituted indenes and stereoselective cyclopenta [b]pyridine/thiophenes from easily accessible enediynes that proceeds by in situ formation of an iodonium intermediate followed by a regioselective 5-endo-dig cyclization has been described. The intramolecular electrophilic iodocyclization was selectively triggered by a distribution of electronic density along the alkyne bond. Subsequently, the iodo-substituted indenes were diversified by employing palladium-catalyzed cross-coupling reactions and the coupled products were further confirmed by X-ray crystallographic studies.

Regioselective Synthesis of C-3-Functionalized Quinolines via Hetero-Diels-Alder Cycloaddition of Azadienes with Terminal Alkynes.

A highly efficient metal and protection-free approach for the regioselective synthesis of C-3-functionalized quinolines from azadienes (in situ generated from 2-aminobenzyl alcohol) and terminal alkynes through [4 + 2] cycloaddition has been developed. An unprecedented reaction of 2-aminobenzyl alcohol with 1,3- and 1,4-diethynylbenzene provided the C-3 tolylquinolines via [4 + 2] HDA and oxidative decarboxylation. The -NH2 group directed mechanistic approach was well supported by the control experiments and deuterium-labeling studies and by isolating the azadiene intermediate.

Pd-catalyzed one-pot sequential unsymmetrical cross-coupling reactions of aryl/heteroaryl 1,2-dihalides.

Efficient, step-economic, Pd(ii)-catalyzed one-pot sequential Sonogashira/Sonogashira, Sonogashira/Suzuki, Sonogashira/Heck, Suzuki/Sonogashira, Suzuki/Suzuki, Suzuki/Heck, Heck/Sonogashira, Heck/Suzuki and Heck/Heck cross coupling reactions of sterically hindered aryl/heteroaryl 1,2-dihalides have been developed. The present methodology allows the conversion of easily available aryl/heteroaryl 1,2-dihalides into synthetically useful unsymmetrically substituted arenes/heteroarenes in good to excellent yields under mild reaction conditions. This methodology is a powerful tool for building a versatile substrate which can be utilized for the synthesis of various organic scaffolds.

Metal- and Protection-Free [4 + 2] Cycloadditions of Alkynes with Azadienes: Assembly of Functionalized Quinolines.

A base promoted, protection-free, and regioselective synthesis of highly functionalized quinolines via [4 + 2] cycloaddition of azadienes (generated in situ from o-aminobenzyl alcohol) with internal alkynes has been discovered. The reaction tolerates a wide variety of functional groups which has been successfully extended with diynes, (2-aminopyridin-3-yl)methanol, and 1,4-bis(phenylethynyl)benzene to afford (Z)-phenyl-2-styrylquinolines, phenylnaphthyridine, and alkyne-substituted quinolines, respectively. The proposed mechanism and significant role of the solvent were well supported by isolating the azadiene intermediate and deuterium-labeling studies.

Tandem Approach to Benzothieno- and Benzofuropyridines from o-Alkynyl Aldehydes via Silver-Catalyzed 6-endo-dig Ring Closure.

An operationally simple silver-catalyzed tandem strategy for the synthesis of benzothienopyridines 7a-t and benzofuropyridines 8a-p by the reaction of o-alkynyl aldehyde 4a-t and 5a-p with tert-butylamine 6 under mild reaction conditions is described. The present methodology provides a facile conversion of easily accessible o-alkynyl aldehydes into medicinally useful heterocycles in good to excellent yields under mild and environmentally friendly reaction conditions with excellent regioselectivity. The developed chemistry has been successfully extended for the selective synthesis of C-4 deuterated benzothienopyridines 7u-v and benzofuropyridines 8q-r.

Pd(II)-Catalyzed C-H Activation of Styrylindoles: Short, Efficient, and Regioselective Synthesis of Functionalized Carbazoles.

A novel Pd(II)-catalyzed approach for the direct synthesis of highly functionalized carbazoles from unprotected styrylindoles has been developed. The reaction features a variety of olefin substrates, which are readily switchable by subtle tuning of the reaction conditions. Investigations of the mechanism suggest that the C-H activation proceeds via enamine formation.

Palladium-Catalyzed Triple Successive C-H Functionalization: Direct Synthesis of Functionalized Carbazoles from Indoles.

A novel Pd(II)-catalyzed approach for the direct synthesis of differentially substituted carbazoles from free (NH) indoles via regioselective triple successive oxidative Heck (Fujiwara-Moritani reaction) has been achieved. It is demonstrated that both electron-deficient and electron-rich alkenes could be used successively for the incorporation of two different functional groups into the product. The proposed mechanistic pathway was well supported by isolating the first and second successive oxidative Heck intermediates as well as by trapping with styrene-d3.

Pd-catalyzed Heck-conjoined amidation and concomitant chemoselective Michael-addition: an efficient tandem approach to highly functionalized tetrahydroquinazolines from o-haloanilines.

An efficient palladium-catalyzed tandem approach for the synthesis of highly functionalized tetrahydroquinazolines 4a–q, and 5a–f by the reaction of o-haloanilines 1a–g with acrylates 2a–d and isothiocyanates 3aa–3ah/isocyanates 3ba–3bfvia Heck-conjoined amidation/thioamidation and concomitant chemoselective Michael-addition is described. A competitive experiment showed that isothiocyanates were more reactive than isocyanates. The developed methodology offers an efficient chemoselective process for the synthesis of highly functionalized tetrahydroquinazolines under mild and operationally simple reaction conditions from inexpensive and commercially available starting substrates.