Ruthenium Hydride/Brønsted Acid-Catalyzed Tandem Isomerization/N-Acyliminium Cyclization Sequence for the Synthesis of Tetrahydro-β-carbolines

Abstract

This paper describes an efficient tandem sequence for the synthesis of 1,2,3,4-tetrahydro-β-carbolines (THBCs) relying on a ruthenium hydride/Brønsted acid-catalyzed isomerization of allylic amides to N-acyliminium ion intermediates which are trapped by a tethered indole nucleophile. The methodology provides not only a convenient "aldehyde-free" alternative to the classical Pictet-Spengler reaction but also attractive possibilities for total synthesis, including rapid generation of molecular complexity and formation of quaternary stereogenic centers. TBHCs can also be accessed by harnessing the Suzuki cross-coupling reaction to the isomerization/N-acyliminium cyclization sequence. Finally, diastereo- and enantioselective versions of the title reaction have been examined using substrate control (with dr >15: 1) and asymmetric catalysis (ee up to 57%), respectively.

The Pictet-Spengler Reaction Updates Its Habits

“…and further 2 h heating to give the tricycle product 110d (or the other corresponding cyclization products) in 98% yield and diastereomeric ratio > 20:1, or the other cyclization products [123]. (2012) As disclosed earlier, Nielsen and coworkers performed the metal-catalyzed isomerization of N-acyl-N-allyl tryptamines that were previously described (Scheme 32, down) [124].…”

“…Notably, N b -benzyl substituents in L-tryptophan derivatives proved to be more important than the N b -acetyl groups for the diastereoselectivity in a substrate-controlled version of the above tandem sequence. (2013) In a third step, ruthenium hydride RuHCl-(CO)(PPh3) was found as an effective promoter of the isomerization 111β111α since the Wilkinson's catalyst [124] was no more efficient for the isomerization of the double bond of acylated allylamines 111. The combination of the ruthenium catalyst (10% mol) together with the chiral phosphoric acid (PhO)2PO2H (30% mol) proved to be the most efficient for the transformation of the allylic amides 111ab into THBCs 112ab, but high temperature (toluene at reflux) was needed for the completion of the reaction.…”

“…25, x FOR PEER REVIEW 28 of Ruthenium-catalyzed RCM/isomerization/N-acyliminium cyclization tandem sequence. As disclosed earlier, Nielsen and coworkers performed the metal-catalyzed isomerization of N-acyl-N-allyl tryptamines that were previously described (Scheme 32, down)[124].Scheme 31. Ruthenium-catalyzed RCM/isomerization/N-acyliminium cyclization tandem sequence.…”

Rhodium catalyzed, one-pot, three component redox-neutral process towards fused ring heterocycles

“…5 Nielsen and co-workers have reported a ruthenium/Brønsted acid catalyzed tandem isomerization/Nacyliminium ion cyclisation sequence for the synthesis of tetrahydro-β-carbolines whilst Sorimachi and Terada have reported ruthenium/Brønsted acid catalyzed cascade isomerization/Friedel-Crafts type reactions. [6][7] We have been involved in generating azomethine ylides via a rhodium catalyzed isomerization process using either two or three component processes. 8 Herein, we report a novel three component rhodium catalyzed isomerization/1,3-dipolar cycloaddition cascade for the synthesis of fused-ring cycloadducts as endo/exo isomers, with the formation of three new bonds and four stereocenters using either acyclic allylamines (Scheme 1a) or cyclic allylamines (Scheme 1b, c).…”

Synthesis of Heterocycles through Transition‐Metal‐Catalyzed Isomerization Reactions

“…Very recently, Nielsen and co-workers extended their original tandem isomerization/cyclization methodology [26] for the construction of tetrahydro-b-carbolines to also include N-acyliminium intermediates (Scheme 9). [31] The combination of [RuClH(CO)(PPh 3 ) 3 ] (10 mol %) and diphenyl phosphate (30 mol %) constituted a highly tolerant catalytic system, affording the desired products 56 in high yields for different amides, carbamates, sulfonamides, and phosphoramidates (70-96 %). Notably, standard protecting groups such as Boc and Fmoc gave the desired products in excellent yields (95 and 82 %, respectively), thereby allowing for further modifications of the products.…”