Amination alkylation of aldehydes

The strategies presented in Table 8.1 can be generalized in the following manner (1) carbanion addition to aldimine or ketimine derivatives (2) sequential amination-alkylation of aldehydes (carbanion addition to in situ formed aldimine derivatives) (3) transfer hydrogenation or hydrogenation of imines (4) reductive amination of ketones and (5) N-acetylenamide reduction. Because of the difficulty of their synthesis, a-alkyl,-alkyl substituted amines are highlighted whenever possible. 

ALKYLATIONS OF ALDEHYDES via REACTION OF THE MACNESIOEN AMINE SALT OF AN ALDEHYDE 2,2-DIMETHYL-3-PHENYLPROPIONALDEHYDE... 

Direct catalytic intermolecular a-allylic alkylation of aldehydes and cyclic ketones has been achieved using a one-pot combination of a transition metal catalyst, Pd(PPh3)4, and an organocatalyst a secondary amine which facilitates enamine catalysis.300... 

This method is effective for aldehydes bearing a or /1-alkyl substituents and alkyl zincs other than Et2Zn. It is noteworthy that only negligible alkylation of aldehyde (< 2%) is observed under these conditions. The produced amines can be further elaborated to optically enriched acylated amines with high efficiency and without any detectable loss of enantiopurity (Scheme 9.25). 

Asymmetric alkylation of aldehydes. Aldimines derived from the S-( - )-amine and propionaldehyde undergo alkylation (LD A, 1 equiv. of MgBt2) in a stereoselective manner (equation 1). 

Chiral Ligand of L1A1H4 for the Enantioselective Reduction of Alkyl Phenyl Ketones. Optically active alcohols are important synthetic intermediates. There are two major chemical methods for synthesizing optically active alcohols from carbonyl compounds. One is asymmetric (enantioselective) reduction of ketones. The other is asymmetric (enantioselective) alkylation of aldehydes. Extensive attempts have been reported to modify Lithium Aluminum Hydride with chiral ligands in order to achieve enantioselective reduction of ketones. However, most of the chiral ligands used for the modification of LiAlHq are unidentate or bidentate, such as alcohol, phenol, amino alcohol, or amine derivatives. 

Similar studies have been carried out for control of absolute stereochemistry in the alkylation of aldehydes via imine anions. Fraser examined the reactions of the imine anion derived from a-phenylethyl-amine with lithium as the counterion where optimum conditions aftbrded approximately 70% optical... 

Hydrogenation of aromatic nitro compounds to aromatic amines Hydrogenation of aldehydes and ketortes to alcohols Hydrogenation of atomic olehnic groups Hydrogenation of unsaturatcd nitriles to unsaturated amines Hydrogenation of diolefins artd alkynes to monoolehns Hydration of ethylene oxide alkylation of aromatics with olehns oxidation of alcohols to aldehydes Oxidation of ethylene to ethylene oxide Synthesis of HCN from NH, and CH4 Oxidation of CH3OH to HCHO... 

Treatment of the diamide 77 with dibutyltin dichloride affords the 2,2-bis(2-[4(/ ),5(5)-diphenyl-1,3-oxazolinyl])propane 78, while successive reaction of 77 with mesyl chloride and aqueous ethanolic sodium hydroxide yields the diastereomer 79 <96TI3649>. The (+)- and (-)-forms of the chiral oxazoline 80 were used as ligands for palladium catalysed allylic amination reactions thus the acetate 81 and benzylamine gave the optically active amine 82 in excellent enantiomeric excess <97JOC55Q8>. The enantioselective catalytic alkylation of aldehydes RCHO (R = n-heptyl, Ph, cyclohexyl or PhCH=CH) with allyluibutyltin in the presence of chiral bis(oxazolinyl)zinc complexes, c.g., 83, leads to alcohols 84 in 40 6% enantiomeric excess <97TL145>. 

Enamines and metalloenamines provide a valuable alternative to the use of eno-lates for the selective alkylation of aldehydes and ketones. Enamines are a,p-unsaturated amines and are obtained simply by reaction of an aldehyde or ketone with a secondary amine in the presence of a dehydrating agent, or by heating in benzene or toluene solution in the presence of toluene-/7-sulfonic acid (TsOH) as a catalyst, with azeotropic removal of water (1.31). Pyrrolidine and morpholine are common secondary amines useful for forming enamines. All of the steps of the reaction are reversible and enamines are readily hydrolysed by water to reform the carbonyl compound. All reactions of enamines must therefore be conducted under anhydrous conditions, but once the reaction has been effected, the modified carbonyl compound is liberated easily from the product by addition of dilute aqueous acid to the reaction mixture. 

The use of enamine catalysis in the enantioselective a-functionalization of carbonyl compounds has been reviewed, including aldol, Mannich, and alkylation processes," and a short review has examined enantioselective a-alkylation of aldehydes Benzodithiolylium tetrafluoroborate (133) is a water-stable salt and can be added enantioselectively to aldehydes at the a-position in the presence of simple chiral organocatalysts, giving the corresponding alcohol. The sulfurs can be readily cleaved with H2/Raney Ni, rendering the process a formal tf-methylation of aldehydes." a ,/3-Unsaturated aldehydes undergo enantioselective a- and y-alkylation via dien-amine activation, using a diarylprolinol TMS ether as catalyst." ... 

Z.-J. Zheng, L.-X. Liu, G. Gao, H. Dong, J.-X. Jiang, G.-Q. Lai, L.-W. Xu, RSC Adv. 2012, 2, 2895-2901. Amine-fiinctional polysUoxanes (AFPs) as efficient polymeric organocatalyst for amino catalysis efficient multicomponent Gewald reaction, a-allyhc alkylation of aldehydes, and Knoevenagel condensation. 

Nicewicz and MacMillan reported an elusive asymmetric intermolecular a-alkylation of aldehydes by elegantly merging Ru photoredox catalysis with chiral amine organocatalysis [30]. The reaction mechanism proposed for the synergistic catalysis is illustrated in Scheme 2. 

More recently, a novel one-pot synthesis of enantioenriched polysubstituted cyclopenta[fc]indoles 127 starting with the a-alkylation of aldehydes 125 was established by Xu et al. [51], In the presence of a primary-amine-derived thiourea T1 and a carboxylic acid Al, the reaction between ot,a-disubstituted aldehydes 125 and 3-indolyhnethanol 124 proceeded smoothly to afford alkylation products, which underwent two further consecutive Friedel-Crafts reactions catalyzed by aphosphoric acid PAl to afford the desired polysubstituted cyclic products 127 with excellent stereoselectivities (Scheme 2.36). 

The process whereby aldehydes are produced from arylmethyl (also alkyl and other) halides by the action of hexamine is known as the Sommelet reaction. The reaction is essentially the conversion of an amine into an aldehyde the hexamine serves the dual role of converting the halide into the amine and the amine into the aldehyde, but its function is different in the two steps. When starting from a halide, the reaction proceeds in three stages —... 

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