Hydroxy aldehydes from imines

Desilylation. The powerful desilylation ability of BU4NF makes it useful for generating various carbanion equivalents. Synthetic exploitations of this reactivity include access to homoallylamines from imines and an allylsilane, to p-hydroxy-a-diazoalkanoic esters from a-silyl-a-diazoacetic esters and aldehydes, and a-fluorovinylation of carbonyl compounds by 1-fluoro-l-methyldiphenylsilylsilylethylene. Benzyne is formed by treatment of phenyl 2-trimethylsilylphenyliodonium triflate" with BU4NF. 

Absolute stereochemistry is a central problem in the synthesis of such biologically significant natural products as )S-lactams. The cycloaddition of an enantiomerically pure a-hydroxy-A-(trimethylsilyl)imine 114, prepared from the mandelic aldehyde 113, constitutes a useful approach to the complete enantio- and diastereoselective synthesis of optically pure azetidinones. 

The nuclear magnetic resonance spectra of SchifF bases formed from primary amines and ortAo-hydroxy aldehydes and ketones show that the Schiff bases derived from l-hydroxy-2-acetonaphthone and from 2-hydroxy-1-naphthaldehyde exist as keto amines (7a) although their formation involves loss of most of the resonance energy of one of the aromatic rings When R is a phenyl group, the phenol-imine tautomer (7b) predominates Schiff bases derived from ortho-hydroxy aldehydes and ketones have the phenol-imine structure (8) . Evidently, in such compounds the keto-amine tautomer... 

Recently, Kobayashi and co-workers reported an interesting variant for the synthesis of homoallylic amines, dubbed an ammonia fixation reaction [128]. With this method, allylboronates are reacted with aldehydes in a solution of ethanolic ammonia. Despite the highly basic conditions, optically pure protected a-hydroxy aldehydes such as 89 can be employed without any observed racemization, and this approach was apphed to the synthesis of aminosugar derivatives via aminoalcohol product 90 (Equation 47). Unfortunately, the addition of a chiral camphor-based allylboronate to benzaldehyde led only to a low enantioselectivity (34% ee). Reactions with the ( )- and (2)-pinacol crotylboronates lead to the same diastereoselectivity seen in the corresponding reactions with aldehydes, affording the respective anti and syn products from a reaction mechanism that most likely involves the intermediacy of primary imines. 

Aromatic A-TMS-ketene imines undergo efficient aldol-type reaction with O-protected a-hydroxy aldehydes, giving iy -selectivity at ambient temperature, reversing at -78 °C to anti- Transfer of the TMS group from the ketene imine prevents (g) retro-reaction. 

Silyl cyanides react enantioselectively with such electrophiles as aldehydes, ketones, imines, activated azines, or,/ unsaturated carbonyl compounds, epoxides, and aziridines in the presence of chiral Lewis acid catalysts to give functionalized nitriles, versatile synthetic intermediates for hydroxy carboxylic acids, amino acids, and amino alcohols (Tables 3-6, 3-7, 3-8, and 3-9, Figures 3-6, 3-7, and 3-8, and Scheme 3-154). ° Soft Lewis acid catalytst, the reaction of epoxides with trimethylsilyl cyanide often leads to isonitriles, which are derived from silylisonitrile spiecies (Schemes 3-155 and 3-156). Soft Lewis base such as phosphine oxide also catalyzes the reaction and cyanohydrin silyl ethers of high ee s are isolated. 

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Polar C=Y double bonds (Y = NR, O, S) with electrophilic carbon have been added to suifinic acids under formation of sulfones. As in the preceding section one must distinguish between carbonyl groups and their derivatives on the one hand, and carboxylic acids (possessing leaving groups at the electrophilic carbon) on the other. Aldehydes " of sufficient reactivity—especially mono-substituted glyoxals - —and their aryl or arylsulfonyl imines have been added to suifinic acids (in a reversible equilibrium) to yield a-hydroxy or a-amino sulfones the latter could also be obtained from the former in the presence of primary amines (equation 26). 

The carbonyl ylide generated from metal carbene can also add to C=0 or C=N bonds. The [2 + 3]-cycloaddition of carbonyl ylide with G=0 bond has been used by Hodgson and co-workers in their study toward the synthesis of zaragozic acid as shown in Scheme n 27a,27d Recently, a three-component reaction approach to syn-a-hydroxy-f3-amino ester based on the trapping of the carbonyl ylide by imine has been reported.The reaction of carbonyl ylide with aldehyde or ketone generally gives l,3-dioxolanes. Hu and co-workers have reported a remarkable chemoselective Rh2(OAc)4-catalyzed reaction of phenyl diazoacetate with a mixture of electron-rich and electron-deficient aryl aldehydes. The Rh(ii) carbene intermediate reacts selectively with electron-rich aldehyde 95 to give a carbonyl ylide, which was chemospecifically trapped by the electron-deficient aldehyde 96 to afford 1,3-dioxolane in a one-pot reaction (Equation (12)). 

Two mechanisms have been proposed for the Knoevenagel reaction. In one, the role of the amine is to form an imine or iminium salt (378) which subsequently reacts with the enolate of the active methylene compound. Under normal circumstances elimination of the amine would give the cinnamic acid derivative (379). However, when an o-hydroxy group is present in the aromatic aldehyde intramolecular ring closure to the coumarin can occur. The timing of the various steps may be different from that shown (Scheme 118). 

In 1997, Kobayashi and colleagues reported the first truly catalytic enantioselective Mannich-type reactions of aldimines 24 with silyl enolates 37 using a novel chiral zirconium catalyst 38 prepared from zirconium (IV) fert-butoxide, 2 equivalents of (R)-6,6 -dibromo-l,l -bi-2-naphthol, and N-methylimidazole (Scheme 13) [27, 28], In addition to imines derived from aromatic aldehydes, those derived from heterocyclic aldehydes also worked well in this reaction, and good to high yields and enantiomeric excess were obtained. The hydroxy group of the 2-hydroxyphenylimine moiety, which coordinates to the zirconium as a bidentate ligand, is essential to obtain high selectivity in this method. 

Boron aldol reactions have been used to stereoselectively construct the anti-3-hydroxy-2-methylcarbonyl system from carboxylate esters,58 and to combine a-hetero-substituted thioacetates with aldehydes or silyl imines enantio- and/or diastereo-selectively.59... 

In 2000, the group of Banik et al. reported the enantiospecific synthesis of 3-hydroxy-2-azetidinones by microwave assisted Staudinger reaction [51]. Chiral imines, derived from chiral aldehydes and achiral amines, reacted with methoxy- or acet-oxy-acetyl chloride to afford a single, optically pure c/s-p-lactam, (Scheme 7). 

These are the most favourable of all and the precursors, such as the hydroxy acids, e.g. 15, cannot usually be isolated, though the carboxylate salts are stable. The only important thing is to get the oxidation level of the precursor right. Using cyclic amines as examples, a fully saturated ring 45 would come from an alkylation reaction on 46 X = a leaving group. Imines 47 or enamines 49 would come from aldehydes or ketones 48. 

The original Kabachnik-Fields procedure employing ammonia as the amine component used ammonia in ethanol and the reactions were performed in sealed vessels at circa 100°C.90,123 This method avoids such conditions by using ammonium acetate as the source of ammonia, and it is also thought to act as an acid catalyst for imine formation other ammonium salts were unsatisfactory. Addition of water to produce a homogeneous reaction mixture resulted in diethyl 1-hydroxy-1-benzylphosphonate formation (i.e. from direct attack of diethyl phosphite 25 on benzaldehye, a common side reaction in the Kabachnik-Fields reaction). The yields of this reaction are serviceable, and better for aromatic than aliphatic aldehydes. The product 58 may be further purified by crystallization as the hydrochloride salt by treatment of 58 with hydrogen chloride in ethanol/diethyl ether.122... 

Lithium aldimine (131), an acyl anion equivalent derived from an isocyanide and an organolithium reagent, adds to aldehydes giving, after quenching with water, a-amino ketones (134) via the Amadori rearrangement (Scheme 33)." The a-amino ketone (134) results from a double tautomerization of a-hydroxy imine (132), formed initially after quenching with water. Thus, the imine (132) isomerizes to enolamine (133), which in turn tautomerizes to the observed product (134). 

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