Alpha-branched Aldehydes Research Articles

ChemInform Abstract: Preparation of Chiral Allenylmetal Reagents from Enantioenriched Allenyl Iodides and Propargylic Mesylates. A Comparison of Indium, Bismuth, and Tin Derivatives.

Chiral allenylmetal halides were prepared starting from enantioenriched ( approximately 95% ee) 1-octyn-3-ol mesylate (1) and 3-butyn-2-ol mesylate (7). Addition of these transient metallo species to aldehydes in situ afforded mainly anti homopropargylic alcohol adducts of varying ee. Three approaches were explored. In the first, the mesylates were converted to allenylstannanes with Bu(3)SnLi.CuBr and the allenylmetal halide was prepared from the resulting enantioenriched allenylstannane by transmetalation with InBr(3), BiBr(3), and SnCl(4) in the presence of cyclohexanecarboxaldehyde. The configurational stability of the transient allenylmetal halide was estimated from the ee of the derived adduct. The second approach involved metalation of the allenyl iodides prepared from mesylates 7 and 1 through S(N)2' displacement with LiCuI(2). From these experiments, it was determined that allenylindium bromides and allenyltin bromides are configurationally stable under the reaction conditions. The adduct obtained from the allenylbismuth bromide was nearly racemic. A superior procedure was developed in which the propargylic mesylates 7 and 1 were converted to allenylindium iodide intermediates through treatment with InI and 5 mol % of a Pd(0) dppf catalyst in THF-HMPA, THF-DMSO, or THF-DMPU. Under these conditions, alpha-branched aldehydes were converted to anti adducts ( approximately 95:5 anti/syn) of >90% ee. Additions to unbranched aldehydes were less diastereoselective, but afforded adducts of high ee. Additions of enantiomeric allenylindium iodide reagents to (R)-beta-ODPS-alpha-methylpropanal (13) afforded diastereomeric adducts (anti,anti and anti,syn) 14, 15 and 18, 19 with excellent diastereoselectivity indicative of a high degree of reagent control. A convenient procedure for the preparation of InI from In and I(2) is also described.

N-Heterocyclic Carbene (NHC)-Catalyzed Direct Amidation of Aldehydes with Nitroso Compounds

NHC-catalyzed direct amidation of aldehydes with nitroso compounds is a powerful method for the synthesis of N-arylhydroxamic acids. A variety of aryl, alkyl, alkenyl, and heterocyclic aldehydes were found to give excellent yields of the corresponding N-arylhydroxamic acids. This chemistry was also extended to the synthesis of chiral N-arylhydroxamic acids by kinetic resolution of alpha-branched aldehydes, a domino amidation-redox amination reaction of acrolein, and a three-component reaction for the synthesis of N-arylaziridines.

Terminal Olefins from Aldehydes through Enol Triflate Reduction

The transformation of aldehydes into terminal olefins through reduction of the corresponding enol triflates is described. The method is effective with both linear and alpha-branched aldehydes.

Rearrangement of 3,3-Disubstituted Indolenines and Synthesis of 2,3-Substituted Indoles

Synthesis of 2,3-substituted indoles from phenylhydrazine and alpha-branched aldehydes via rearrangement of 3,3-disubstituted indolenine intermediates is reported. [reaction: see text]

Catalytic Asymmetric Reductive Amination of Aldehydes via Dynamic Kinetic Resolution

A novel organocatalytic asymmetric reductive amination of aldehydes has been developed. Treating racemic alpha-branched aldehydes with p-anisidine and a Hantzsch ester in the presence of our previously developed phosphoric acid catalyst, TRIP, gave beta-branched secondary amines in excellent yields and enantioselectivities via an efficient dynamic kinetic resolution. The process is applicable to several different aromatic aldehydes and amines but gives slightly reduced enantiomeric ratios with aliphatic aldehydes.

Non‐Biaryl Atropisomers in Organocatalysis

A new class of 6'-hydroxy cinchona alkaloids, with a non-biaryl atropisomeric functionalisation at position 5' of the quinoline core can be prepared by an easy amination procedure. These are the first derivatives for which the principle of atropisomerism is engrafted in the classical core of the cinchona alkaloids. The aminated cinchona alkaloids are effective organocatalysts for the Michael addition of beta-keto esters to acrolein and methyl vinyl ketone, in up to 93 % ee (ee=enantiomeric excess), as well as for the asymmetric Friedel-Crafts amination of a variety of 2-naphthols, permitting the preparation of the latter in up to 98 % ee. The aminated 8-amino-2-naphthol itself is the first chiral organocatalyst based on non-biaryl atropisomerism. The two enantiomers of this chiral primary amine can be used for the direct alpha-fluorination of alpha-branched aldehydes. The fluorinated compounds can thereby be accessed in up to 90 % ee.

A Positional Scanning Approach to the Discovery of Dipeptide-Based Catalysts for the Enantioselective Addition of Vinylzinc Reagents to Aldehydes

[reaction: see text] A combinatorial library of dipeptide N-acylethylenediamine-based ligands was synthesized by parallel solid-phase methods. These ligands were screened in crude form as catalysts for the asymmetric addition of vinylzinc reagents to aldehydes to give chiral allylic alcohols. Three sites of diversity on the ligands were optimized using a positional scanning approach. The optimized structure from the library, ligand 54, was found to catalyze the formation of 10 different (E)-allylic alcohols with enantioselectivities ranging from 90% to 95% ee. This ligand was effective for both aromatic and alpha-branched aldehydes, and vinylzinc reagents derived from both bulky and straight chain terminal alkynes.

Enantioselective direct aldol addition of acetone to aliphatic aldehydes.

The asymmetric direct aldol addition of acetone to aliphatic aldehydes catalyzed by D-proline, L-proline, and its derivatives was studied. While excellent results could be obtained in neat acetone using alpha-branched aldehydes, unbranched and beta-branched aldehydes gave moderate results. Two dipeptide derivatives, L-Pro-L-Try-CH(2)OH and L-Pro-L-Trp-OCH(3), were prepared and tested in this reaction and both were found to be able to induce enantioselectivities. The ee-values in the case of some aldehydes approached that obtained with L-proline. Immobilization of L-proline on a polystyrene resin by its carboxylic group provided a catalyst which is able to induce enantioselectivity, can be easily removed from the reaction mixture, and reused without a significant decrease in the enantioselectivity of the beta-hydroxyketones obtained in the cross-aldol additions.