Diastereo‐ and Regioselective Intramolecular Heck Reaction of α‐Amino Alcohol Derivatives for the Synthesis of Enantiomerically Pure Isoquinolines and Benzazepines at Ambient and High Pressure

Abstract

Alkylation and acylation of the alkenes 9b, c and 10a, b, which are easily prepared from the corresponding a-amino alcohols, with 2-halobenzyl and 2-halobenzoyl halides respectively, gives 11-15. These compounds cyclize with excellent diastereo-and regioselectivity to the enantiomerically pure N-heterocycles 18-20 in an intramolecular Heck reac-tion using 5 mol-% of Pd(OAc)2 in the presence of PPh3, TPAB and KOAc. Under the same conditions substrate 17 leads to the enantiomerically pure benzazepine 24. The reaction of the bromoarene derivatives 14-15 must be performed under high pressure to give good results.

The Heck Reaction as a Sharpening Stone of Palladium Catalysis

“…The increase of oxidative addition with pressure rate makes it possible to perform reactions with substrates, practically unreactive under normal pressure, e.g., to perform differential Heck reaction by substituting a better leaving group (nonaflate) at normal pressure and poorer leaving group (chlorine) at high pressure 189 as well as to use bromoderivatives in place of iododerivatives (Scheme ). ,

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Oxazolidines as Intermediates in the Asymmetric Synthesis of 3-Substituted and 1,3-Disubstituted Tetrahydroisoquinolines

“…Diastereoselective alkylation of C-3 substituted THIQs afforded chiral trans -1,3-disubstituted derivatives . The Pictet–Spengler and intramolecular Heck reactions, electrophile-induced cyclization, nucleophilic addition to 3-substituted isoquinolines followed by ionic hydrogenation, and three-component reductive amination using an organocatalyst followed by intramolecular Michael addition have been disclosed for the synthesis of 1,3-disubstituted THIQs. A key factor to be addressed in the synthesis of these molecules is the control of relative and absolute stereochemistries at C-1 and C-3.…”

Controlled Synthesis of Cis or Trans Isomers of 1,3-Disubstituted Tetrahydroisoquinolines and 2,5-Disubstituted Pyrrolidines

“…Owing to the importance of the 1,2,3,4-tetrahydroisoquinoline moiety, other methods have been developed that do not rely on the electronic characteristics of the aromatic ring. For example, the intramolecular Heck reaction has successfully been used to assemble the tetrahydroisoquinoline skeleton in complex alkaloids (Figure ) . Electrophile-induced cyclization of o -allylbenzylamides has also been employed (Figure ) .…”