Unusual tethering effects in the Schmidt reaction of hydroxyalkyl azides with ketones: cation-pi and steric stabilization of a pseudoaxial phenyl group

The Lewis acid-promoted reactions of chiral 2-aryl-3-azido-1-propanols with 4-substituted cyclohexanones lead to iminium ethers and ultimately caprolactams (following a hydrolysis step). In this study, it is shown that these reactions afford variable ratios of products, depending on the electronic nature of the phenyl group. These results are interpreted in the context of a cation-pi stabilizing effect in the product-determining reaction intermediate. Remarkably, the best selectivity was obtained when an azidopropanol reagent containing a quaternary center was used; a control experiment showed that the high selectivity observed in this result depended upon the free rotation of the pseudoaxial aromatic group in the intermediate that affords the major product.     

Ab initio approach to understanding the stereoselectivity of reactions between hydroxyalkyl azides and ketones

A new stereoselective version of the Schmidt reaction has been discovered by Aubé and co-workers (J. Am. Chem. Soc. 2003, 125, 7914-7922). Quantum chemical calculations reported in this paper were carried out to examine the observed diastereoselectivities. The azide attack step is found to be reversible, but a thermodynamic preference for the equatorial attack product is observed. The final stereoselectivity of the reaction is determined by the axial/equatorial ratio of the chiral substituent in the resulting intermediate. In the case of 2-R-hydroxypropyl azides, interesting axial/equatorial preferences are observed. In particular, the phenyl substituent shows a preference for the axial position resulting from a novel interaction with a N(2) cationic group.     

Intramolecular reactions of benzylic azides with ketones: competition between Schmidt and Mannich pathways.

The Lewis acid-promoted reactions of benzylic azides with ketones can proceed by two major pathways. The azido-Schmidt reaction involves simple addition of azide to the ketone followed by rearrangement and ring expansion. In addition, benzylic azides can undergo prior rearrangement to afford iminium ions that can subsequently participate in a Mannich reaction. A series of ketones containing an alpha CH2(CH2)nCH(N3)Ph substituent (n = 1-3) was prepared to investigate the dependence of products on ketone ring size and tether length. For all ketones examined, good yields of bicyclic lactams arising from intramolecular Schmidt reaction were obtained when a four-carbon linker was used (n = 1 in the above formulation), but Mannich products predominated for the longer tethers examined (n = 2, 3).     

Electronic and steric effects on the intramolecular Schmidt reaction of alkyl azides with secondary benzyl alcohols

The intramolecular Schmidt reaction of simple azido secondary benzyl alcohols has been realized for the first time. Investigation of the electronic and steric effects of the substrates on the product outcome was conducted. Unique intramolecular Schmidt rearrangements were observed with the formation of a cinnamaldehyde derivative and aryl aldehydes, respectively. Using this protocol, an efficient synthesis of dihydrobenzotriazine derivatives was achieved. Moreover, a practical approach to 2-aryl-1-pyrrolines was also accessed.     

Asymmetric Mukaiyama aldol reaction of nonactivated ketones catalyzed by allo-threonine-derived oxazaborolidinone

Asymmetric Mukaiyama aldol reaction of nonactivated ketones is realized for the first time by using an oxazaborolidinone catalyst derived from O-benzoyl-N-tosyl-allo-threonine. By employing a dimethylsilyl ketene S,O-acetal as a nucleophile, a variety of acetophenone derivatives afford the corresponding tertiary beta-hydroxy carbonyl compounds with high enantioselectivity up to 98% ee.     

Lewis acid-mediated reactions of alkyl azides with alpha,beta-unsaturated ketones

[reaction: see text] Alkyl azides react with saturated ketones upon treatment with Lewis acids to afford ring-expansion products through the azido-Schmidt reaction, but this reaction does not proceed when alpha,beta-unsaturated ketones are used. In this study, alkyl azides were reacted with enones in the presence of Lewis acids to give enaminones (vinylogous amides), which formally involve a ring contraction reaction. The mechanism and scope of this reaction is discussed.     

The reaction of certain heterocyclic azides with triphenylphosphine

Azidobenzothiazole and azidobenzimidazole and certain of its derivatives react with triphenyl-phosphine to give isolatable adducts which decompose thermally to give the corresponding phosphinimines. 2-Azidobenzoxazole gives an adduct which loses nitrogen at 15–20° and gives the phosphinimine directly. Methylation of the phosphinimines occurs at the hetero nitrogen, whereas benzoylation occurs at the exo nitrogen atom. The structures of the alkylation and aroylation products of the phosphinimines were established.     

The Schmidt reaction with pyridine carboxylic acids

The Schmidt reaction in oleum is used to prepare 2, 3-and 4-aminopyridines.     

Asymmetric direct aldol reaction of 1,2-diketones and ketones mediated by proline derivatives

The direct aldol reaction of 1,2-diketones and ketones mediated by proline derivatives yields the corresponding 2-hydroxy 1,4-diketones in high regioselectivity, diastereoselectivity and good enantioselectivity. This reaction provides an easy access to optically active tertiary alcohols, which are flanked by two carbonyl groups for further elaborations.     

Asymmetric hydrogenation of tert-alkyl ketones

A combined system of RuCl2(tolbinap)(pica) and an alkaline or organic phosphazene base catalyzes asymmetric hydrogenation of sterically congested tert-alkyl ketones (TolBINAP = 2,2'-bis(di-4-tolylphosphino)-1,1'-binaphthyl, PICA = alpha-picolylamine). Hydrogenation with RuH(eta1-BH4)(tolbinap)(pica) does not require any strong base. Alcoholic solvents strongly affect the catalytic efficiency. The reaction proceeds smoothly in ethanol under 1-20 atm of H2 and at room temperature with a substrate to catalyst molar ratio of up to 100 000. Various aliphatic, aromatic, heteroaromatic, and olefinic tert-alkyl ketones are convertible to the corresponding chiral carbinols in high enantiomeric purity. Olefinic and heteroaromatic functions are left intact. Certain cyclic ketones are also usable. The mode of enantioface selection is consistent and predictable.     

Regiochemical studies of the ring expansion reactions of hydroxy azides with cyclic ketones

The regiochemistry of ring expansions of 2-substituted cyclic ketones using 1,2-azidoethanol and 1,3-azidopropanol was examined. It was determined that the reactions of ketones with an adjacent methyl or ethyl group are generally unselective, but that bulkier substituents lead to preferential migration of the more highly substituted carbon. In addition, it was found that ketones bearing inductively electron-withdrawing substituents (OMe, Ph, Br) undergo selective migration of the less highly substituted carbon. For some substrates, alternative reaction pathways were also identified.     

Asymmetric hydrogenation of ketones with polymer-supported chiral 1,2-diphenylethylenediamine

[reaction: see text] A poly(ethylene glycol)-supported chiral diamine (PEG-2), in which the polymer is attached to the phenyl rings, has been synthesized and shown to be highly effective in asymmetric hydrogenation of unfunctionalized aromatic ketones with the possibility of reuse. PEG-2 can also serve as a chiral scaffold on which various immobilized chiral catalysts could be easily built.     

Asymmetric reduction of perfluoroalkyl ketones with chiral lithium alkoxides

Reduction of perfluoroalkyl ketones with chiral lithium alkoxides gave chiral α-perfluoroalkyl alcohols in high enantiomeric excesses. Interestingly, reaction of 2,2,2-trifluoroacetophenone (1) with lithium (S)-1-phenylethoxide (2) gave (S)-2,2,2-trifluoro-1-phenylethanol (3), while the same reaction of perfluorooctan-1-one (7) with 2 gave (R)-1H-1-phenylperfluorooctanol (8). Based on the speculation of mechanism, the order of steric effects on this reaction is estimated as C₇F₁₅ > substituted phenyl > CF₃.     

Asymmetric direct aldol reaction of functionalized ketones catalyzed by amine organocatalysts based on bispidine

Organocatalysts containing primary-secondary amine based on bispidine and amino acid have been designed to catalyze the asymmetric direct aldol reaction of functionalized ketones including alpha-keto phosphonates, alpha-keto esters, as well as alpha,alpha-dialkoxy ketones as aldol reaction acceptors. The corresponding products with chiral tertiary alcohols were obtained in moderate to high yields (up to 97%) and high enantioselectivities (up to 98% ee). A theoretical study of transition structures demonstrated that protonated piperidine was important for the reactivity and enantioselectivity of this reaction.     

Catalytic enantioselective Reformatsky reaction with ketones

Chiral tertiary alcohols were obtained with good yields and enantioselectivities via a catalytic Reformatsky reaction with ketones, including the challenging diaryl ketones, using chiral BINOL derivatives.