An Arylation Strategy to Propargylamines: Catalytic Asymmetric Friedel–Crafts‐type Arylation Reactions of C‐Alkynyl Imines

Abstract

The first arylation strategy for the synthesis of enantioenriched propargylamines is disclosed. This approach, which is complementary to previous alkynylation and alkylation strategies,involves aC(sp 2 ) À C(sp 3 )bond formation, and is based on the first asymmetric Friedel-Crafts-type arylation reaction of C-alkynyl imines.A symmetric Friedel-Crafts reactions with electron-deficient phenols,alongstanding unsolved challenge,h ave thus been realized for the first time, enabled by the combination of our recently introduced Calkynyl N-Boc-protected N,O-acetals as electrophiles and chiral phosphoric acids as catalysts.T he synthetic utility of the resulting structurally diverse and polyfunctional chiral propargylamines was demonstrated by as eries of selective transformations,i ncluding controlled reduction of the alkynyl group and iterative cross-couplings.

PPTS‐Catalyzed Bicyclization Reaction of 2‐Isocyanobenzaldehydes with Various Amines: Synthesis of Diverse Fused Quinazolines

“…On the basis of the above experimental results together with related reports, [11][12][13]17] a possible mechanism for the formation of 3, 5 and 7 is proposed in Scheme 5 (with the formation of 3 aa as example). Initially, in the presence of PPTS, the in situ condensation of 2-isocyanobenzaldehyde 1 a and o-phenylenediamine 2 a generates aldimine A.…”

“…On the basis of the above experimental results, along with the consideration of Friedel-Crafts alkylation reaction of imines with arenes, [17] we reasoned that the imine intermediate generated in situ from the reaction of 2-isocyanobenzaldehyde 1 a with 2-(1Hpyrrol-1-yl)aniline 6 a can undergo a sequential intramolecular Friedel-Crafts alkylation and intramolecular cyclization to afford polycyclic fused quinazoline derivatives (Table 4). As expected, the polycyclic fused quinazoline 7 a was obtained in 87% yield when 2isocyanobenzaldehyde 1 a (0.2 mmol) was treated with 6 a (0.2 mmol) under the optimized reaction conditions as above.…”

An overview of the applications of chiral phosphoric acid organocatalysts in enantioselective additions to CO and CN bonds

“…In 2016, Shao and co-workers reported the addition of phenols 133 to propargyl imines formed in situ from N,O acetals 132 (Scheme 38). 132 The reaction is performed in the presence of 5 mol% of (R)-BPA2 catalyst and provides access to a wide number of chiral propargyl amines 134 in high yields (62-94%) and enantiomeric excesses up to 92%. In addition, some simple modifications of the methodology also allows the efficient addition of 1-or 2-naphthols, a few indole derivatives, pyrrole and 2-methoxyfuran with similar results.…”

Recent advances in aza Friedel–Crafts reaction: strategies for achiral and stereoselective synthesis

“…Shao and co-workers described an unusual synthesis of chiral propargylimine compounds 51 using low electron starting compounds such as phenol derivatives 52 . 61 However, the use of electron-neutral phenols in the asymmetric aza-FC reaction remained elusive due to its lower nucleophilicity compared with naphthols and indoles. Herein the reaction could occur at two different reaction sites ( ortho and para positions).…”