Asymmetric Hydrogenation of 1-Alkyl and 1-Aryl Vinyl Benzoates: A Broad Scope Procedure for the Highly Enantioselective Synthesis of 1-Substituted Ethyl Benzoates

Abstract

The enantioselective hydrogenation of enol esters of formula CH2C­(OBz)­R with rhodium catalysts based on phosphine–phosphite ligands (P–OP) has been studied. The reaction has a broad scope, and it is suitable for the preparation of products possessing a wide variety of R substituents. For the cases where R is a primary alkyl, high catalyst activity (S/C = 500) and enantioselectivities (95–99% ee) were obtained with a catalyst characterized by an ethane backbone and a PPh2 fragment. In contrast, for R = t-Βu, a catalyst possessing a benzene backbone provided the best results (97% ee). Derivatives with a cycloalkyl R substituent were particularly difficult substrates for this reaction. A broader catalyst screening was required for these substrates, which identified a catalyst possessing a P­(m-xylyl)2 fragment as the most appropriate one, affording enantioselectivities between 90 and 95% ee. Outstanding enantioselectivities (99% ee) and high catalyst activity (S/C = 500–1000) were also obtained in the case of substrates bearing a Ph or a fluoroaryl R substituent. In addition, the system is also appropriate for the preparation of other synthetically useful esters as those for R = benzyl, 2-phenylethyl or N-phthalimido alkyl chains. Likewise, the hydrogenation of divinyl dibenzoates proceeded with very high diastero- and enantioselectivity, generating rather low amounts of the meso isomer (3–6%). On the other hand, substrates with Br and MeO substituents at the phenyl benzoate ring, suitable for further functionalization, have also been examined. The results obtained indicate no detrimental effect of these substituents in the hydrogenation. Alternatively, the methodology has been applied to the highly enantioselective synthesis of deuterium isotopomers of 1-octyl benzoate bearing CDH2, CD2H, or CD3 fragments. Finally, as a practical advantage of the present system, it has been observed that the high performance of the catalysts is retained in highly concentrated solutions or even in the neat substrate, minimizing both the amount of solvent added and the volume of the reaction.

Metal-Catalyzed Intra- and Intermolecular Addition of Carboxylic Acids to Alkynes in Aqueous Media: A Review

“…The most active catalyst of the series, i.e., [RuCl 2 (η 3 :η 3 -C 10 H 16 )(PPh 3 )] (31a), showed also a wide scope allowing the preparation of a large variety of enol esters 32 by selective Markovnikov addition of different carboxylic acids to both aliphatic and aromatic terminal alkynes, as well as to 1,3-enynes (Scheme 19) [68,72,73]. As a general trend, the reactions proceeded faster, and with higher yields, when aliphatic terminal alkynes were employed as substrates.…”

“…Further evidence of the versatility of [RuCl2(η 3 :η 3 -C10H16)(PPh3)] (31a) was gained in the reactions of the terminal diynes 33 with benzoic acid. Thus, as shown in Scheme 20, the corresponding enynes 34 or the diesters 35 could be selectively synthesized with 31a just by adjusting the diyne/benzoic acid ratio employed [68,72,73]. The only limitation encountered with the ruthenium catalyst 31a is that it is completely inactive with internal alkynes; substrates which, as commented in the introduction of this article, show a much lower reactivity in these intermolecular hydrocarboxylation reactions.…”

“…Further evidence of the versatility of [RuCl 2 (η 3 :η 3 -C 10 H 16 )(PPh 3 )] (31a) was gained in the reactions of the terminal diynes 33 with benzoic acid. Thus, as shown in Scheme 20, the corresponding enynes 34 or the diesters 35 could be selectively synthesized with 31a just by adjusting the diyne/benzoic acid ratio employed [68,72,73]. Further evidence of the versatility of [RuCl2(η 3 :η 3 -C10H16)(PPh3)] (31a) was gained in the reactions of the terminal diynes 33 with benzoic acid.…”

The intermolecular hydro-oxycarbonylation of internal alkynes: current state of the art

“…Enol ester derivatives represent a relevant class of compounds widely used as mild acylating reagents, [1][2][3][4] as monomers for the production of diverse types of polymers and copolymers, [5][6][7][8] and as starting materials in a large variety of reactions, including asymmetric hydrogenation, [9][10][11][12] cycloaddition, [13][14][15][16] cyclization, [17][18][19][20] hydroformylation, [21][22][23] cross-coupling, [24][25][26][27] Michael addition, [28][29][30][31] aldol-type, [32][33][34] Mannich-type 35 and amide bond-forming processes, 36 to name a few. The enol ester motif is also found in a number of natural products with relevant biological properties.…”

Ruthenium‐Catalyzed Hydrocarboxylation of Internal Alkynes

“…[1,2] Such esters can be applied as monomers in numerous polymerization reactions [3,4] and are important intermediates in organic synthesis. [5][6][7][8][9][10][11] The first metal found to catalyze this reaction was mercury. [12][13][14] However, due to its high toxicity, alternatives to mercury have been explored with an emphasis on both effectivity and lack of toxicity.…”