Catalytic Asymmetric Hydrogenation of 2,3,5-Trisubstituted Pyrroles

Abstract

Supporting InformationGeneral and Materials. All NMR spectra were measured with Bruker AVANCE 400 (9.4 T magnet) spectrometer. In 1 H NMR spectra, chemical shifts (ppm) referenced to internal tetramethylsilane (0.00 ppm, in CDCl 3 ) or residual solvent (7.15 ppm, in C 6 D 6 ). In 13 C NMR spectra, chemical shifts (ppm) referenced to the carbon signal of the deuterated solvents (77.0 ppm in CDCl 3 or 128.0 ppm in C 6 D 6 ). IR spectra were measured with JASCO FT/IR-4100. Elemental and high resolution mass (HRMS) analyses were performed by Service Centre of Elementary Analysis of Organic Compounds and Institute for Materials Chemistry and Engineering (ICME) in Kyushu University, respectively.Flash column chromatographies and medium-pressure liquid chromatographies (MPLC) were performed with silica gel 60 (230-400 mesh, Merck) and C.I.G. pre-packed column CPS-223L-1 (Kusano, Tokyo, Japan), respectively.Acetonitrile (MeCN), ethyl acetate (EtOAc), 2-propanol (i-PrOH), and triethylamine (Et 3 N) were dried with calcium hydride. Methanol (MeOH) was dried with Mg(OMe) 2 . These solvents and reagents were distilled under nitrogen atmosphere. Tetrahydrofuran (THF) (HPLC grade, without inhibitor) was deoxidized by purging with nitrogen for 30 min and was dried with an alumina column system (GlassContour Co.). Ru(η 3 -methallyl) 2 (cod), 1 (S,S)-(R,R)-PhTRAP, 2 Methyl N-(tert-butoxycarbonyl)pyrrole-2-carboxylate (1a), 3 were prepared according to literature procedures. All other materials were purchased and used without further purification. Preparations of N-Boc Pyrroles 1. General Procedure of N-Boc Protection of Pyrroles.Under nitrogen atmosphere, (Boc) 2 O (2.40 g, 11 mmol) was added to a solution of a pyrrole (10 mmol) and DMAP (61 mg, 0.5 mmol) in dry MeCN (3.3 ml) at room temperature. The mixture was stirred until the pyrrole disappeared completely or the reaction mixture ceased evolving carbon dioxide (monitored by a bubbler tube). After water was added, the resulting mixture was extracted with EtOAc. The organic phase was washed with brine, dried with Na 2 SO 4 , and evaporated under reduced pressure. The residue was purified with a flash column chromatography (EtOAc/hexane) to give the desired N-Boc-pyrroles 1. S2Methyl N-(tert-Butoxycarbonyl)-3,5-dimethylpyrrole-2-carboxylate (1b). N MeO 2 C Me Me Boc 1bThe general procedure was followed with use of methyl 3,5-dimethylpyrrole-2-carboxylate 4 (1.25 g, 8.2 mmol). The reaction was conducted for 17 h. The crude product was purified with a flash column chromatography (EtOAc/hexane = 1/10) to give 1b (1.47 g, 71% yield) as pale yellow oil: 1

Catalytic Asymmetric Hydrogenation of 3-Substituted Benzisoxazoles

“…A small amount of 1a reacted with hydrogen, but no saturation of the C-N double bond was observed in either reaction, which afforded only the achiral imine 3a, formed through the hydrogenolytic cleavage of the N-O bond of 1a [49,50]. The ruthenium catalyst failed to reduce the C-N double bond even in the presence of N,N,N',N'-tetramethylguanidine (TMG) (entries 3 and 4), even though in our previous reports the base additive brought about a remarkable acceleration of hydrogenations of heteroaromatics [22][23][24][25]28,30,31]. We were pleased that the hydrogenation of the benzisoxazole was accompanied by the reduction of the C-N double bond in the presence of stoichiometric Boc 2 O, which afforded N-Boc-protected (R)-1-(2-hydroxyphenyl)-1-propylamine 4a with 25% ee (entry 5).…”

“…In a series of our studies, a trans-chelating chiral bisphosphine, PhTRAP (Figure 1) [20,21], was mainly used as the chiral ligand. PhTRAP-rhodium or ruthenium complex allowed indoles [22][23][24][25][26][27] and pyrroles [28,29] to be reduced with hydrogen to the corresponding chiral indolines and pyrrolidines with high enantiomeric excesses, respectively. Moreover, the chiral ruthenium catalyst recently proved to be useful for the asymmetric hydrogenation of imidazoles and oxazoles, which contain two heteroatoms in their aromatic rings [30,31].…”

Deaza-modification of MR1 ligands modulates recognition by MR1-restricted T cells

“…6,7-Dimethyl-8-D-ribityldeazalumazine (DZ). Ribitylaminouracil 2a (26 mg, 0.10 mmol) and the sodium salt of commercially available 2-methyl butan-3-one-ol [38] (26 mg, 0.20 mmol) were refluxed in 0.5 M HCl (1.0 mL) at 100°C for 2 h. After the reaction was complete, DZ (8.0 mg, 0.025 mmol, 25 % yield) was isolated by preparative HPLC using gradient B. 1 H-NMR was consistent with reference spectra [20].…”

Catalytic Homogeneous Asymmetric Hydrogenation: Successes and Opportunities

“…Thus, the olefin of CC-5 is reduced without interference of its carboxylic acid. 161,162 The hindered olefinic groups in substituted pyrroles 163,164 (not included in Table 5) and indoles related to CC-14 163 undergo very enantioselective AH using certain ruthenium or palladium diphosphine catalysts. Ruthenium complexes with homochiral NHC ligands are very effective for the AH of hindered olefins including substituted benzofurans (CC-12), 165 indolizines, 166 quinoxalines, 103 thiophenes and benzothiophenes, 167 flavones and chromones, 168 vinylthioethers, 169 and isocoumarins.…”