Efficient Pd-catalyzed domino synthesis of 1-phenyl-1H-indol-2-amine and 5-amino-indolo[1,2-a]quinazoline derivatives

Abstract

An efficient and practical one-pot domino synthesis of 1-phenyl-1H-indol-2-amine and 5-amino-indolo[1,2-a]quinazoline derivatives from readily available 2-(2-bromophenyl)acetonitriles was developed. The overall protocol involves a Buchwald-Hartwig type coupling and a base-promoted intramolecular nucleophilic reaction. The reaction scope, advantages and limitations are discussed.

Discovery of an orally bioavailable and selective PKMYT1 inhibitor RP-6306

“…To explore the SAR of the phenyl ring in the tricyclic scaffold, all four possible bromophenyl regioisomers of analog 6 were prepared (compounds 26-29) to enable further diversification of each position by transition metal-mediated transformations. Although all four bromo analogs (26)(27)(28)(29) displayed low nanomolar potencies in the enzymatic assay, compound 29 was found to have superior potency in the cell-based activity assay (Table 4). The three most promising bromo regioisomers (26, 28, and 29) were each derivatized to provide representative nitrile, pyrazole and cyclopentene analogs 30-38.…”

Copper Catalyzed Intramolecular N-Arylation of Ketene Aminals at Room Temperature: Synthesis of 2-Amino-3-cyanoindoles

“…16 However, this reaction failed to give the expected 2aminoindole in the presence of copper(I) iodide. 16 Thus, in the context of the limitations of the existing methods such as low yields, 15 tedious workup, 12i multistep synthesis, 12j 3cyanoindole precursor, 12j and high temperature, 12f developing a mild and practical method for the synthesis of 2-amino-3cyanoindoles is vital.…”

“…Further, a one-step protocol for the synthesis of 2-amino-3-cyano-5-hydroxyindoles was developed through the Nenitzescu reaction of ketene aminals with 1,4-benzoquinone resulting in moderate yields . Recently, the palladium catalyzed direct N-arylation followed by in situ cyclization of resulting intermediate to 2-amino-3-cyanoindoles was reported . However, this reaction failed to give the expected 2-aminoindole in the presence of copper­(I) iodide .…”

“…Recently, the palladium catalyzed direct N-arylation followed by in situ cyclization of resulting intermediate to 2-amino-3-cyanoindoles was reported . However, this reaction failed to give the expected 2-aminoindole in the presence of copper­(I) iodide . Thus, in the context of the limitations of the existing methods such as low yields, tedious workup, multistep synthesis, 3-cyanoindole precursor, and high temperature, developing a mild and practical method for the synthesis of 2-amino-3-cyanoindoles is vital.…”

Formal [4+1] Cycloaddition of o‐Aminobenzyl Chlorides with Isocyanides: Synthesis of 2‐Amino‐3‐Substituted Indoles

“…While many powerful reactions have been developed for the synthesis of indoles, [4] synthetic methods allowing efficient construction of 2aminoindoles remained limited. [5][6][7][8][9][10][11] Listed in Scheme 1 are some of the recently developed methodologies including 1) Pd-catalyzed Buchwald -Hartwig N-arylation of 2-haloindoles with anilines (Scheme 1,a); [12,13] 2) Pd-catalyzed heteroannulation of Nalkynyl-2-haloanilides with amines (Scheme 1,b); [14] 3) Pd-catalyzed coupling of ynamides and o-iodoanilines (Scheme 1,c); [15] 4) Pd-catalyzed domino N-arylation followed by base-promoted cyclization (Scheme 1,d); [16] 5) copper-catalyzed reaction of substituted N-(2halophenyl)-2,2,2-trifluoroacetamides with alkyl 2-cyanoacetate or malononitrile (Scheme 1,e); [17] 6) goldcatalyzed intermolecular reaction of azides with ynamides (Scheme 1,f). [18,19] In spite of these significant achievements, the development of practical and cost-effective methods are still highly demanding.…”