Asymmetric Hydrogenation of 1-aryl substituted-3,4-Dihydroisoquinolines with Iridium Catalysts Bearing Different Phosphorus-Based Ligands

Abstract

Starting from the chiral 5,6,7,8-tetrahydroquinolin-8-ol core, a series of amino-phosphorus-based ligands was realized. The so-obtained amino-phosphine ligand (L1), amino-phosphinite (L2) and amino-phosphite (L3) were evaluated in iridium complexes together with the heterobiaryl diphosphines tetraMe-BITIOP (L4), Diophep (L5) and L6 and L7 ligands, characterized by mixed chirality. Their catalytic performance in the asymmetric hydrogenation (AH) of the model substrate 6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline 1a led us to identify Ir-L4 and Ir-L5 catalysts as the most effective. The application of these catalytic systems to a library of differently substituted 1-aryl-3,4-dihydroisoquinolines afforded the corresponding products with variable enantioselective levels. The 4-nitrophenyl derivative 3b was obtained in a complete conversion and with an excellent 94% e.e. using Ir-L4, and a good 76% e.e. was achieved in the reduction of 2-nitrophenyl derivative 6a using Ir-L5.

Chiral 8-Amino-5,6,7,8-tetrahydroquinoline Derivatives in Metal Catalysts for the Asymmetric Transfer Hydrogenation of 1-Aryl Substituted-3,4-dihydroisoquinolines as Alkaloids Precursors

“…L4 was purchased from ThermoFischer Scientific. Substrates I – XI were synthesized according to reported procedures and their spectra were in accordance to data reported in the literature [ 15 ]. HPLC spectra of products I – XI under optimized reaction conditions can be found in the Supplementary Materials, Figures S1–S9 .…”

“…The products were analyzed by 1 H NMR to determinate the molar conversion whereas the enantiomeric excess was evaluated by HPLC analysis and the absolute configuration was assigned by comparison with literature references [ 15 ]. 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline ( I ): R -isomer: 11.1 min (min); S -isomer: 15.4 min (maj); column: Chiralcel OD-H, eluent: 2-propanol/hexane = 30/70 (0.01% DEA), flow = 0.7 mL/min, λ = 285 nm.…”

“…Moreover, the aqueous media usually employed in the ATH protocol generally avoid the use of the most performing but moisture sensitive diphosphine ligands, refs. [ 15 , 16 , 17 , 18 , 19 ] thus evoking the need for new catalysts able to broaden the scope toward the most challenging dihydroisoquinolines (DHIQs). The related reduction products, namely tetrahydroisoquinolines (THIQs), indeed account for an important class of alkaloids and semi-synthetic derivatives endowed with multiple relevant biological properties ( Figure 1 ) [ 20 , 21 , 22 , 23 , 24 ].…”

New sp3 diphosphine-based rhodium catalysts for the asymmetric conjugate addition of aryl boronic acids to 3-azaarylpropenones

“…In the last decades in our laboratory different types of chiral diphosphines have been synthesized having different sources of chirality and the corresponding metal complexes have been successfully applied to many enantioselective organic transformations. [23][24][25] In this paper, we reported the use of these phosphorus based chiral scaffolds in coordination with a rhodium center in the asymmetric catalyzed 1,4 conjugate addition of different substituted arylboronic acids to 3azaarylpropenones. A preliminary screening with atropoisomeric ligands on (E)-chalcone had already stated the importance of the 3-aza core for affecting both the reactivity and the enantioselectivity of the rhodium system in this type of reaction.…”

“…Conversely, the addition of phenylboronic acid was evaluated for four different 3-azaarylpropenones as substrates, hereafter called 1 ((E)-1-phenyl-3-(pyridin-2-yl)prop-2-en-1-one), 2 ((E)-1-phenyl-3- and 4 ((E)-3-(1-methyl-1H-imidazol-4-yl)-1-phenylprop-2-en-1-one) respectively. 26 In order to get a prognostic insight into the reactivity of different rhodium based catalytic systems in this type of reaction, we employed diphophine ligands characterized by varied types of chirality: phosphorus based ligands bearing only an atropoisomeric chirality as in (S)-TetraMe-BITIANP (L1) and (S)-BITIANP (L2), 23,27 ; diphosphines endowed with a mixed chirality (both sp 3 and atropoisomeric) as in (S,S,Sax)-DIOPHEP (L3) 28 and (R,Rax)-ISAPHOS C1 (L4) and (S,Rax,Rax)-ISAPHOS C2 (L5) 29,30 ; or only a sp 3 chirality as in the case of (R,R)-ZEDPHOS (L6). 20 Table 1.…”