Department of Chemistry, Tianjin University, Tianjin 300072, China; Department of Applied Chemistry, China Agricultural University, Beijing 100193, China; UMR 6014 CNRS, Laboratoire COBRA de l’IRCOF, Université et INSA de Rouen, Rue Tesniere, F-76130 Mont Saint Aignan, France; and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China

Asymmetric construction of stereogenic carbon centers featuring a trifluoromethyl group from prochiral trifluoromethylated substrates.

The SAMP-/RAMP-hydrazone methodology in asymmetric synthesis

The well-known properties of the carbonyl group render aldehydes and ketones prominent substrates in both C-C and C-heteroatom bond forming methodologies of organic synthesis. In practical syntheses, nitrogen analogues of aldehydes and ketones such as enamines, imines, or hydrazones, acting as synthetic equivalents of the carbonyl * To whom correspondence should be addressed. E-mail: lazny@uwb.edu.pl. Chem. Rev. 2010, 110, 1386–1434 1386

N,N-dialkylhydrazones in Organic Synthesis. From Simple N,N-dimethylhydrazones to Supported Chiral Auxiliaries

Reaction of 2-phenylacetaldehyde with the Me3Si ether of diphenyl-prolinol, with removal of H2O, gives a crystalline enamine (1). The HBF4 salts of the MePh2Si ether of diphenyl-prolinol and of 2-(tert-butyl)-3-methyl- and 5-benzyl-2,2,3-trimethyl-1,3-imidazolidin-4-one react with cinnamaldehyde to give crystalline iminium salts 2, 3, and 4. Single crystals of the enamine and of two iminium salts, 2 and 3, were subjected to X-ray structure analysis (Figs. 1, 2, and 6), and a 2D-NMR spectrum of the third iminium salt was recorded (Fig. 7). The crystal and NMR structures confirm the commonly accepted, general structures of the two types of reactive intermediates in organocatalysis with the five-membered heterocycles, i.e., D, E (Scheme 2). Fine details of the crystal structures are discussed in view of the observed stereoselectivities of the corresponding reactions with electrophiles and nucleophiles. The structures 1 and 2 are compared with those of other diphenyl-prolinol derivatives (from the Cambridge File CSD; Table 1) and discussed in connection with other reagents and ligands, containing geminal diaryl groups and being used in enantioselective synthesis (Fig. 4). The iminium ions 3 and 4 are compared with N-acylated imidazolidinones F and G (Figs. 9, 12, and 13, and Table 3), and common structural aspects such as minimalization of 1,5-repulsion (the ‘A1,3-effect’), are discussed. The crystal structures of the simple diphenyl-prolinol⋅HBF4 salt (Fig. 3) and of Boc- and benzoyl-(tert-butyl)methyl-imidazolidinone (Boc-BMI and Bz-BMI, resp.; Figs. 10 and 11) are also reported. Finally, the crystal structures are compared with previously published theoretical structures, which were obtained from high-level-of-theory DFT calculations (Figs. 5 and 8, and Table 2). Delicate details including pyramidalization of trigonal N-atoms, distortions around iminium CN bonds, shielding of diastereotopic faces, and the π-interaction between a benzene ring and a Me group match so well with, and were actually predicting the experimental results that the question may seem appropriate, whether one will soon start considering to carry out such calculations before going to the laboratory for experimental optimizations.

Isolation and X-Ray Structures of Reactive Intermediates of Organocatalysis with Diphenylprolinol Ethers and with Imidazolidinones

Aldehyde N,N-Dialkylhydrazones as Neutral Acyl Anion Equivalents: Umpolung of the Imine Reactivity

The nucleophilic 1,2-addition of formaldehyde N,N-dialkylhydrazones 1, 2, and 7−10 to trifluoromethyl ketones 3a−e takes place in the absence of any catalyst or promoter to afford a series of α-hydroxy-α-trifluoromethylhydrazones (4, 5, and 11−14) in good-to-excellent yields. From the several reagents studied, optimal results were achieved using 1-(methyleneamino)pyrrolidine (2) for the synthesis of racemic adducts and (S)-1-(methyleneamino)-2-[1-(methoxy)diphenyl-methyl]-pyrrolidine (10) for the asymmetric version of the reaction. The resolving properties of the chiral auxiliary carried by 10 allowed an easy chromatographic (flash) separation of any obtained diastereomeric mixture. Thus, a single operation rendered moderate-to-good amounts (42−75%) of optically pure adducts (S,S)-14 (de ≥ 98%) by combining excellent chemical (82−92%) and moderate optical (51−81%) yields. Hydrazones 5 and (S,S)-14 were protected by benzylation [→ 16 and (S,S)-18] and then transformed into benzyl-protected α-trifluoromethy...

Stereoselective Synthesis of Trifluoromethylated Compounds: Nucleophilic Addition of Formaldehyde N,N-Dialkylhydrazones to Trifluoromethyl Ketones

Formaldehyde dialkylhydrazones behave as neutral d1 synthons in their uncatalyzed reaction with trifluoromethyl ketones (see reaction). Both racemic and optically pure 1,2-adducts were obtained in good yields. Efficient deprotection of the hydrazone moiety afforded interesting fluorinated quaternary compounds such as 1 and 2.

Synthesis of Enantiopure α‐Alkoxy‐α‐Trifluoromethyl Aldehydes and Carboxylic Acids from Trifluoromethyl Ketones

The spontaneous 1,2-addition of formaldehyde N,N-dialkylhydrazones to carbohydrate-derived α-alkoxyaldehydes takes place under neutral conditions and in the absence of catalysts or promoters to afford the corresponding α-hydroxyhydrazones in good to excellent yields and with highly anti diastereoselectivities. Subsequent transformations of the hydrazono group into aldehydes and nitriles following known procedures provide a new entry into the homologation of carbohydrates and the synthesis of cyanohydrins, respectively. Additionally, reaction of methyleneaminopyrrolidine with N-Boc-protected α-aminoaldehydes from natural amino acids efficiently affords the corresponding adducts under the same conditions. From these adducts, a variety of biologically interesting α-hydroxy-β-aminocarbonyl compounds can be accessed upon manipulation of the hydrazone moiety.

Carmen Pareja

Papers

Stereoselective Synthesis of Trifluoromethylated Compounds: Nucleophilic Addition of Formaldehyde N,N-Dialkylhydrazones to Trifluoromethyl Ketones

Synthesis of Enantiopure α‐Alkoxy‐α‐Trifluoromethyl Aldehydes and Carboxylic Acids from Trifluoromethyl Ketones

Stereoselective Nucleophilic Formylation and Cyanation of α-Alkoxy- and α-Aminoaldehydes

Direct synthesis of dithioketals from N,N-dialkylhydrazones

Stereospecific addition of formaldehyde dialkylhydrazones to sugar aldehydes. Synthesis of cyanohydrins and α-hydroxy aldehydes