Monika Patel

On Water: Silver-Catalyzed Domino Approach for the Synthesis of Benzoxazine/Oxazine-Fused Isoquinolines and Naphthyridines from o-Alkynyl Aldehydes

An operationally simple domino approach for the silver-catalyzed synthesis of oxazine/benzoxazine-fused isoquinolines 5a-q and naphthyridines 6a-v by the reaction of o-alkynyl aldehydes 3a-aa with amines having embedded nucleophiles 4a-d under mild reaction condition in water is described. The reaction shows selective C-N bond formation on the more electrophilic alkynyl carbon resulting in the formation of 6-endo-dig cyclized product. The competitive experiments show the viability of an intramolecular nucleophilic attack over an intermolecular attack of the external nucleophile. This methodology accommodates wide functional group variation, which proves to be useful for structural and biological assessment.

Silver-Catalyzed Tandem Synthesis of Naphthyridines and Thienopyridines via Three-Component Reaction

An efficient approach for the silver-catalyzed regioselective tandem synthesis of highly functionalized 1,2-dihydrobenzo[1,6]naphthyridines 6a-z and 7a-e by the reaction of ortho-alkynylaldehydes 3a-n with amines 4a-d and ketones 5a-c/active methylene compounds 5d-g, under mild reaction conditions, is described. The scope of the developed chemistry was successfully extended for the direct synthesis of 1,2-dihydrobenzo[4,5]thieno[2,3-c]pyridines 8a-e, which is known as the sulfur analogue of β-carbolines. Naphthyridines 6a-z and thienopyridines 8a-e were obtained via dual activation concept using l-proline as organocatalyst; however, naphthyridines 7a-e were synthesized without using organocatalyst. The reaction shows selective N-C bond formation on the more electrophilic alkynyl carbon, resulting in the regioselective 6-endo-dig-cyclized products. Reactivity behavior of electron-deficient and electron-rich ortho-alkynylaldehydes in the synthesis of naphthyridines and thienopyridine by three-component reaction is supported by the control experiment.

Base-mediated selective synthesis of diversely substituted N-heterocyclic enamines and enaminones by the hydroamination of alkynes.

Regio- and stereoselective alkynylation of various N-heterocycles 1a-l using potassium and cesium salts in DMSO is described. Terminal alkynes 2a-k and internal alkynes 4a-f provided the kinetically stable Z-enamines 3a-l and 5a-i in good to excellent yields using KOH at 120 °C. Addition of heterocyclic amines to 1,3- and 1,4-diethynylbenzene 6a-b provided the mixture of E/Z isomers with KOH; however, with Cs(2)CO(3) selectively Z-isomers 7ab-db were obtained by the hydroamination at one triple bond. This developed methodology also provides an easy and novel access for the synthesis of enaminones 10a-c. The detailed work also supports the formation of cis-isomer by preferential addition of o-haloarylalkynes followed by intramolecular C2 arylation in the copper-catalyzed tandem synthesis of indolo and pyrrolo[2,1-a]isoquinolines.

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.

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. Hydroamination is conspicuously superior to the other accessible methods, such as the imination of ketones or the aminomercuration/demercuration of alkynes, that involve the stoichiometric use of toxic reagents. Additionally, the hydroamination of alkyne substrates has been successfully employed as a key step in synthesizing target molecules through total syntheses containing substituted indoles, pyrroles, imidazoles, and other heterocycles as core moieties. Many research groups have explored inter- or intramolecular hydroamination of alkynes for the synthesis of diversely substituted nitrogen heterocycles using expensive metal catalysts. However, in contrast to metal-catalyzed hydroamination, the base-mediated hydroamination of alkynes has not been extensively studied. Various inorganic (such as hydroxides, phosphates, and carbonates) and organic bases have been proven to be valuable reagents for achieving the hydroamination process. This method represents an attractive strategy for the construction of a broad range of nitrogen-containing compounds that prevents the formation of byproducts in the creation of a C-N linkage. The presence of a base is thought to facilitate the attack of nitrogen nucleophiles, such as indoles, pyrroles, and imidazoles, on unsaturated carbon substrates through the activation of the triple bond and thus transforming the electron-rich alkyne into an electrophile. In the past few years, we have been involved in the development of methods for the nucleophilic addition of N-heterocycles onto terminal and internal alkynes using alkali base catalysts to achieve new carbon-nitrogen bond-forming reactions. During our study, we discovered the regioselective preferential nucleophilic addition of N-heterocycles onto the haloarylalkyne over N-arylation of the aryl halide. In this Account, we summarize our latest achievements in regio-, stereo-, and chemoselective hydroamination chemistry of N-nucleophiles with alkynes using a superbasic medium to produce a broad range of highly functionalized vinyl and styryl enamines, which are valuable and versatile synthetic intermediates for the synthesis of bioactive compounds. Interestingly, the stereoselectivity of the addition products (kinetically stable Z and thermodynamically stable E isomers) was found to be dependent upon time. It is worthwhile to note that hydroaminated products formed by the addition reaction can further be utilized for the synthesis of indolo-/pyrrolo[2,1-a]isoquinolines, naphthyridines, and bisindolo/pyrrolo[2,1-a]isoquinolinesvia tandem cyclization. This chemistry is expected to find application in organic synthesis for constructing a diverse variety of fused π-conjugated compounds, enaminones, and C-C coupled products.

Pd(II)‐Catalyzed CH 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.

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.

On water: catalyst-free chemoselective synthesis of highly functionalized tetrahydroquinazolines from 2-aminophenylacrylate

A green and catalyst-free atom-ecomonic straightforward tandem approach for the synthesis of highly functionalized tetrahydroquinazolines by the reaction of 2-aminophenylacrylates with isothiocyanates using water as an environmentally friendly solvent via amidation and concomitant chemoselective Michael-addition is described.

Base-mediated chemo- and stereoselective addition of 5-aminoindole/tryptamine and histamines onto alkynes.

Transition-metal-free chemo- and stereoselective addition of 5-aminoindole (1a), tryptamine (1b), and histamine (1c) to alkynes 2a-s to synthesize the indolyl/imidazolyl enamines 3a-p, 5a-o, and 6a-e using superbasic solutions of alkali-metal hydroxides in DMSO is described. The addition of N-heterocycles onto alkynes takes places chemoselectively without affecting the 1° amino groups (aromatic and aliphatic) of 5-aminoindole, tryptamine, and histamine. The stereochemistry of the products was found to be dependent upon reaction time; an increase in reaction time leads to the formation of a mixture of E/Z isomers and the thermodynamically stable E addition product. The chemoselective addition of N-heterocycle 1a onto alkyne over thiophenol 7 and phenol 8 is supported by control experiments. Competitive experiments showed that 5-aminoindole was more reactive than tryptamine, and histamine was found to be the least reactive. The present methodology provides an efficient chemoselective method to synthesize a variety of (Z)-enamines of 5-aminoindole, tryptamine, and histamine without affecting the 1° amino group. The presence of the free amino group in enamines could be further used for synthetic elaboration, which proved to be highly advantageous for structural and biological activity assessments.

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. The reactivity and selectivity of unprotected azadiene in metal-free base-assisted hetero-Diels-Alder reaction is exploited to quickly assemble an important class of C-3-functionalized quinolines, which are difficult to access.