Synthesis of 1,2-Dihydroisoquinolines by a Modified Pomeranz–Fritsch Cyclization

Abstract

Isoquinolines (IQs) and their derivatives are present in many natural products and biologically active small molecules. Herein, we report a modified procedure for the classical Pomeranz-Fritsch protocol, which expands the scope of 1,2-dihydroisoquinoline (DHIQs) products. 1,2-DHIQs are an attractive branch point for the synthesis of IQs, but because of their innate reactivity, they have remained difficult to prepare. We demonstrate that the Fujioka/Kita conditions, combining trimethylsiyltriflate (TMSOTf) and an amine base, activate dimethylacetals required for Pomeranz-Fritsch cyclization under sufficiently mild conditions to prepare a broad range of 1,2-DHIQ products. We also demonstrate the synthetic value of these DHIQs by further functionalization to either reduced tetrahydroisoquinoline (THIQ) or fully aromatized IQ natural products. Scheme 1. A) Redox States of Isoquinoline Compounds. B) Unique properties of 1,2-DHIQ. C) This Work: An Improved Pomeranz-Fritsch Synthesis of 1,2-DHIQ and other isoquinoline compounds.

Comprehensive Strategies for the Synthesis of Isoquinolines: Progress Since 2008

“…Ji and Lumb have also reported the similar Pomeranz‐Fritsch cyclization towards the synthesis of 1,2‐dihydroisoquinolines under Fujioka/Kita conditions [327] …”

“…[37e] Ji and Lumb have also reported the similar Pomeranz-Fritsch cyclization towards the synthesis of 1,2-dihydroisoquinolines under Fujioka/Kita conditions. [327] Zhao et al have reported 1,1'-disubstituted and spiro-tetrahydroisoquinoline alkaloid 567 synthesis by employing biomimetic phosphate buffer following Pictet-Spengler reaction sequence. The tetrahydroisoquinolines were obtained in high yields (Scheme 329).…”

(3 + 2) Cycloaddition Reaction of the Endocyclic N-Silyl Enamine and N,N′-Cyclic Azomethine Imine

“…The use of the endocyclic enamine functional group of the partially reduced N -heteroarene has been challenging because it is readily rearomatized . A typical solution for this issue is the use of a protecting group; however, additional protection/deprotection steps are often required to achieve this. − Recently, our group reported the cyclic amidine syntheses via dearomative hydrosilylation of readily available N -heteroarenes 1 (Scheme b). , The first B­(C 6 F 5 ) 3 catalyzed dearomative monohydrosilylation step could provide the unique endocyclic N -silyl enamine 2 as an intermediate. − Although the N–Si bond of 3 is unstable under ambient conditions, 3 is stable enough to use in situ . The transient silyl protecting group was easily cleaved during the workup process.…”

Total Synthesis of (S)-Cularine via Nucleophilic Substitution on a Catechol

“…A substituent at C8 precludes the most common syntheses based on Pictet–Spengler or Bischler–Napieralski cyclizations to form the C1–C8a bond. Therefore, we devised an alternative that capitalized on Ellman’s chiral sulfonamide technology to install the lone chiral center at C1 and our recently reported modification of the Pomeranz–Fritsch cyclization to install the isoquinoline ring by forming the C4–C4a bond.…”

“…Ellman’s auxiliary was then removed to allow reductive alkylation with a glyoxal dimethyl acetal ( 11 ) before tosyl protection of the amine provided 7 with >99% ee and in 83% yield on a scale of 7–9 g . To effect the desired Pomeranz–Fritsch cyclization, we employed our recently reported conditions, consisting of 3 equiv of TMS-OTf and 4 equiv of 2,6-lutidine. We were pleased to find that the cyclization of 7 to 15 proceeded in 83% yield on a 14 g scale without erosion of the ee .…”