Chiral Anion Phase Transfer of Aryldiazonium Cations: An Enantioselective Synthesis of C3‐Diazenated Pyrroloindolines

Abstract

Herein is reported the first asymmetric utilization of aryldiazonium cations as a source of electrophilic nitrogen. This is achieved through a chiral anion phase-transfer pyrroloindolinization reaction that forms C3-diazenated pyrroloindolines from simple tryptamines and aryldiazonium tetrafluoroborates. The title compounds are obtained in up to 99% yield and 96% ee. The air-and water-tolerant reaction conditions accommodate electronic and steric diversity of the aryldiazonium electrophile and of the tryptamine core. Keywordsphase-transfer catalysis; cyclization; asymmetric catalysis; photolysis; amination Chiral anion phase-transfer (CAPT) catalysis has recently arisen as an effective strategy in enantioselective catalysis (Figure 1a). [1] In particular, electrophilic halo-functionalization reactions of alkenes using Selectfluor (Figure 1b) and its derivatives have proven broadly effective, delivering a wide scope of valuable halogenated products in high yields and excellent enantioselectivities. [1f-m] Inspired by the substrate generality exhibited by CAPT halo-functionalization and other oxidative reactions, [1n-o] it has been a long-standing goal in our group to identify additional cationic electrophiles amenable to this strategy (Figure 1b).We were specifically interested in cations comprised of electrophilic nitrogen atoms, as asymmetric electrophilic C-N bond formation remains a synthetic challenge. [2] Aryldiazonium salts were recognized as candidates, as their N-electrophilicity has been exploited to diazenate several classes of carbon nucleophiles in a non-stereoselective fashion, including aromatics, [3] enolates, [4] and heteroaromatics. [5] Reports of GombergBachmann-Hey biaryl syntheses [3b] and azo-coupling reactions [3a,c] that utilize aryldiazoniums under phase-transfer conditions further encouraged our efforts in this area. ** We gratefully acknowledge NIHGMS (R01 GM104534) for financial support. H.M.N. would like to acknowledge the UNCF and Merck for generous funding. S.H.R. would like to acknowledge the Amgen Foundation for generous funding. The authors would like to thank Pascal Tripet for useful discussions.

Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives

“…In 2014, under the catalysis of chiral anion phase-transfer (CAPT), Toste and coworkers realized the CADA reaction of tryptamines 22 using aryldiazonium cations as a source of electrophilic nitrogen, which was in situ generated from aryldiazonium tetrafluoroborates 23 (Scheme 5). 14 By this approach, a series of C3-diazenated pyrroloindolines 24 were synthesized in overall high yields and excellent enantioselectivities. The authors suggested that the interaction of CPA (R)-C7 with aryldiazonium tetrafluoroborates 23 provided a soluble chiral ion pair, which controlled the enantioselectivity in the step of nucleophilic addition of tryptamines 22 to aryl-diazonium, thus generating an enantioenriched intermediate D to undergo the subsequent intramolecular cyclization to give products 24.…”

“…13 Scheme 5 Organo-CADA reaction of tryptamines with aryldiazonium cations by Toste and coworkers. 14 reduced into N-Me groups by Red-Al, leading to the total synthesis of (−)-psychotriasine.…”

Highly Enantioselective [3+2] Coupling of Indoles with Quinone Monoimines Promoted by a Chiral Phosphoric Acid

“…Chiral phosphoric acids are versatile catalysts for many asymmetric reactions 8. In particular, many efficient strategies for asymmetric C3 functionalization of indoles and functionalization of enamines (enamides) by phosphoric acids have been well established 3a,g,j,k,o. 9 Herein we report a highly enantioselective [3+2] coupling of 3‐substituted indoles with quinone monoimines promoted by a chiral phosphoric acid.…”

Highly Enantioselective [3+2] Coupling of Indoles with Quinone Monoimines Promoted by a Chiral Phosphoric Acid

“…[2] Among these transformations, dearomative annulation of indoles is the most straightforward method and has attracted much attention. [3] The benzofuroindoline core is a unique motif found in some important natural alkaloids, [4][5][6] such as diazonamides [4] and azonazine [5] (Figure 1). Since diazonamide A has been found to be a very potent anticancer agent owing to its high antitumor activity (IC50 < 5 nm), [4b,c] it has received considerable attention from chemists for the synthesis of these benzofuroindoline skeletons.…”