Stereoselective 1-arylation of isoquinolines via chiral N-acylisoquinolinium salts

Abstract

Reaction of isoquinolines with (R)-menthyl chlorocarbonate or (S)-α-Cbz-aminoacyl fluorides and arenes or heteroarenes gave access to 2-acyl-1-aryl-1,2-dihydroisoquinolines in a Mannichtype reaction via intermediate N-acylisoquinolinium salts. As an alternative, aryl metal compounds could be used. Modest stereoselectivities were achieved. Further reduction and hydrolysis of the products gave access to 1-aryl-1,2,3,4-tetrahydroisoquinolines.

A practical route to tertiary diarylmethylamides or -carbamates from imines, organozinc reagents and acyl chlorides or chloroformates

“…While several common Lewis acids (TiCl 4 , AlCl 3 , CeCl 3 and BF 3 ·Et 2 O) were trialled unsuccessfully, a different strategy based on the formation of solid bonds indicated that carbonyl derivatives such as acetyl chloride or methyl chloroformate were, in contrast, efficient activators of the C=N double bond, albeit used in stoichiometric amounts. This result is consistent with some previous studies reporting the activation of imines under an acyliminium form and the subsequent addition of either aromatic [ 17 – 23 26 – 27 ] or non-aromatic [ 34 – 35 ] organometallic nucleophiles onto carbon.…”

“…The most commonly employed reagents are organoindium [ 17 – 18 ], organolithium [ 19 – 20 ], organomagnesium [ 21 – 22 ], organotin [ 23 ], or organozinc compounds [ 24 – 25 ]. However, although these are recognized as mild multi-purpose reagents, sole examples of their use in nucleophilic additions on acylimium salts consist, to the best of our knowledge, of the phenylation of quinolinium salts using diphenylzinc [ 26 – 27 ].…”

Amino acid fluorides: viable tools for synthesis of peptides, peptidomimetics and enantiopure heterocycles

“…6.2 Heterocycles 6.2.1 1,4-Benzodiazepines. Ellman and Bunin reported solid phase synthesis of 1,4-benzodiazepine derivatives (155) (Scheme 33), where Fmoc-amino acid uorides were found to couple extremely well with PS supported 2-aminobenzophenones (152) in the presence of an acid scavenger, 4methyl-2,6-di-tert-butylpyridine (153). 150 Other protocols including carbodiimides/HOBt or pentauorophenyl ester gave poor yields.…”

“…A subsequent reaction with electron rich arenes or heteroarenes resulted in a Mannich type reaction yielding 2-acyl-1-aryl-1,2-dihydroisoquinolines (164) in modest to high diastereomeric ratio (dr ¼ 6 : 1). 153 However, in some cases tricyclic imidazo-isoquinolines (165) were formed by an intramolecular attack of the N-atom at the iminium carbon. Grignard reagents/diorgano zinc compounds could be used with electron decient arenes, albeit with moderate yields and stereoselectivity.…”