Ti-catalyzed reformatsky-type coupling between alpha-halo ketones and aldehydes

We describe the first Ti-catalyzed Reformatsky-type coupling between alpha-halo ketones and aldehydes. The reaction affords beta-hydroxy ketones under mild, neutral conditions compatible with ketones and other electrophiles. The catalytic cycle possibly proceeds via bis(cyclopentadienyl)titanium enolates.     

Reformatsky-type reaction of chiral nonracemic alpha-bromo-alpha'-sulfinyl ketones with aldehydes. Synthesis of enantiomerically pure 2-methyl-1,3-diol moieties

Chiral nonracemic alpha-bromo-alpha'-sulfinyl ketones were shown to react with aldehydes in the presence of SmI(2) in a Reformatsky-type reaction to give the corresponding adduct with excellent syn diastereoselectivity. Further reduction of the Reformatsky adducts furnished anti- and syn-2-methyl-1,3-diol moieties in excellent yields and diastereoselectivities.     

Reactive barium-promoted Reformatsky-type reaction of alpha-chloroketones with aldehydes

A Reformatsky-type aldol reaction of alpha-chloroketones with aldehydes has been achieved using reactive barium as a low-valent metal in THF; this one-pot process is more effective for obtaining the desired beta-hydroxy ketones in high yields than the stepwise process in which barium enolates are prepared prior to the reaction with aldehydes.     

Visible-light-induced transition metal and photosensitizer free decarbonylative addition of amino-arylaldehydes to ketones

The decarbonylative-coupling reaction is generally promoted by transition metals (via organometallic complexes) or peroxides (via radical intermediates), often at high temperatures to facilitate the CO release. Herein, a visible-light-induced, transition metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes at room temperature is reported. Tertiary/secondary alcohols were obtained in moderate to excellent yields promoted by using CsF under mild conditions. The detailed mechanistic investigation showed that the reaction proceeded through photoexcitation–decarbonylation of the aldehyde to generate an aromatic anion, followed by its addition to ketones/aldehydes. The reaction mechanism was verified by the density functional theory (DFT) calculations.

A visible-light-induced, transition-metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes via anion intermediates at room temperature is developed.     

Reductive aldol-type reaction of α,β-unsaturated esters with aldehydes or ketones in the presence of Rh catalyst and Et2Zn

The reaction of RhCl(PPh₃)₃ with Et₂Zn easily generated a rhodium–hydride complex (Rh−H) that added to α,β-unsaturated esters to form rhodium enolate complexes by formal 1,4-reduction. These rhodium enolates gave the corresponding Reformatsky-type reagents through transmetalation, and they reacted with various aldehydes and ketones to give reductive aldol-type products in good to excellent yields.     

Versatility of the Biginelli reaction: Synthesis of new biphenyl dihydropyrimidin-2-thiones using different ketones as building blocks

A multi-component synthesis of biphenyl dihydropyrimidin-2-thiones from 1-phenylthiourea, aldehydes and ketones or di-ketones has been demonstrated. The reaction proceeded well for aldehydes with electron donor or acceptor substituents under mild conditions.     

Reformatsky-type addition of esters of α-halogeno carboxylic acids to aldehydes and ketones in the presence of Fe(CO)5

Reformatsky-type addition of esters of α-halogeno carboxylic acids to aldehydes and ketones in the presence of Fe(CO)₅ and an activating agent (CBrCl₃ or I₂) afforded the corresponding esters of β-hydroxy acids in good yields. Possible reaction mechanisms are discussed. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1132–1138, June, 1999.     

Copper‐Catalyzed Dehydrogenative Cross‐Coupling Reaction between Allylic CH Bonds and α‐CH Bonds of Ketones or Aldehydes

A dehydrogenative cross‐coupling reaction between allylic C?H bonds and the α‐C?H bond of ketones or aldehydes was developed using Cu(OTf)₂ as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ‐unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)₂ as a Lewis acid catalyst was also proposed (DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Tf=trifluoromethanesulfonate).     

Stereoselective dimerization of chiral α-bromoamides promoted by Fe(CO)5

Organic -bromocarboxylates react with aldehydes and ketones in the presence of Fe(CO)₅ (the Reformatsky-type reactions). Unlike them, N-oxazolidinone derivatives of the same acids undergo diastereoselective reductive dimerization to give (2S,3S)-dimers, regardless of the configuration of the -chiral center in the starting reagent.     

1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride in combination with triethylamine: an improved catalytic system for hydroacylation/reduction of activated ketones

A rapid, economic, and high yielding methodology has been developed for hydroacylation/reduction of activated ketones by using 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride as a catalyst in combination with triethylamine. The reaction proceeded at an ambient temperature via generating N-heterocyclic carbene in situ that interacted with the (hetero)aryl aldehyde employed. While the reduction of ketones takes place in MeOH, the hydroacylation process was found to be effective in THF for both electron rich and deficient aldehydes.     

Designer chiral quaternary ammonium bifluorides as an efficient catalyst for asymmetric nitroaldol reaction of silyl nitronates with aromatic aldehydes

Designer chiral quaternary ammonium bifluoride 1 has been prepared, and both its catalytic and its chiral efficiency have been clearly demonstrated by achieving the first catalytic asymmetric nitroaldol reaction of silyl nitronate with aldehydes. For instance, the reaction of trimethylsilyl nitronate 2 (R(1) = Me) with benzaldehyde (R(2) = Ph) in THF in the presence of (S,S)-1 (2 mol %) proceeded smoothly at -78 degrees C, giving the corresponding nitroaldol adduct 3 (R(1) = Me, R(2) = Ph) in 92% isolated yield (anti/syn = 92:8) with 95% ee (anti isomer). The method was found to be successfully applicable to other aromatic aldehydes and silyl nitronates, and a high level of anti selectivity and enantiomeric excess was constantly observed. This finding should lead to the further development of fluoride ion-catalyzed asymmetric carbon-carbon bond-forming reactions.     

Reactions of aliphatic ketones R2CO (R=Me, Et, iPr and tBu) with the MCI4/Li(Hg) system (M=U or Ti): mechanistic analogies between the McMurry, Wittig, and Clemmensen reactions

Analysis of the products of the reactions of ketones R2CO (R = Me, Et, iPr, tBu) with the MCl4/Li(Hg) system (M = U, Ti) at 20 degrees C revealed significant differences. For R = Me, the reaction proceeded exclusively (M = U) or preferentially (M = Ti) via a metallopinacol intermediate resulting from dimerization of ketyl radicals. Pinacol was liberated by hydrolysis, and tetramethylethylene was obtained after further reduction at 65 degrees C. For R=iPr, formation of iPr2C=CiPr2 as the only coupling product, the nonproduction of this alkene by reduction of the uranium pinacolate [U]-OCR2CR2O-[U] (R= iPr) at 20 degrees C, and the instability of the corresponding titanium pinacolate towards rupture of the pinacolic C-C bond indicated that reductive coupling of iPr2CO did not proceed by dimerization of ketyl radicals. Formation of 2,4-dimethyl-2-pentene was in favor of a carbenoid intermediate resulting from deoxygenative reduction of the ketyl. These results revealed that for sterically hindered ketones, McMurry reactions can be viewed as Wittig-like olefination reactions. For R=tBu, no coupling product was obtained and the alkane tBu2CH2 was the major product. The involvement of the carbenoid species [M]=CtBu2 was confirmed by its trapping with H2O, leading to tBu2CH2, and with the aldehydes RCHO, giving the cross-coupling products tBu2C=C(R)H (R = Me, tBu). Therefore, in the case of severely congested ketones, McMurry reactions present strong similarities to the Clemmensen reduction of ketones, owing to the involvement in both reactions of carbenoid species which exhibit similar reactivity.     

P-hydrogen-substituted 1,3,2-diazaphospholenes: molecular hydrides

P-Hydrogen-substituted 1,3,2-diazaphospholenes 1 were prepared by an improved procedure from diazadienes and were characterized by spectroscopy and in one case by X-ray diffraction. A unique hydride-type reactivity of the P-H bonds was documented by extensive reactivity studies. Aldehydes and ketones were readily reduced to diazaphospholene derivatives of the corresponding alcohols, with alkyl-substituted ketones being converted at much lower rates than aldehydes or diaryl ketones. Reactions with the tetrachlorides of group 14 elements proceeded via hydride/chloride metathesis to give either partially chlorinated derivatives EH(n)Cl(4-n) (n = 0-3 for E = C, Si) or HCl and phosphenium salts 16c[ECl3] (for E = Ge, Sn) which were characterized by spectroscopic and X-ray diffraction studies. Tin dichloride was readily reduced to the element. Reactions of 1c with the P-chloro-diazaphospholene 3c and the salt 16c[OTf] allowed the first experimental detection of intermolecular exchange of a hydride, rather than a proton, between phosphine derivatives. Computational studies indicated that the hydride transfer between 1c and the cation 16c involves a transient H-bridged species with bonding properties similar to those of B2H7-. The preference for the formation of these bridged intermediates over P-P bonded phosphenium-phosphine adducts is attributed to the low electrophilicity of the diazaphospholenium cations and characterizes a novel reaction mode for phosphenium ions.     

Catalytic Oxidation of Alcohols to Corresponding Aldehydes or Ketones with TEMPO-Mediated Iodosobenzene in Water in the Presence of a Surfactant

An efficient, facile, and rapid oxidation of alcohols to the corresponding aldehydes or ketones with a stoichiometric amount of iodosobenzene (PhIO) in the presence of catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxyl free radical (TEMPO), KBr, and a surfactant, such as SDS (sodium dodecylsulfate), was reported. The oxidation proceeded in water at room temperature to afford aldehydes or ketones in excellent yields and high selectivity without overoxidation to carboxylic acids. Selective oxidation of primary alcohols in the presence of secondary alcohols was also achieved with the catalytic system of PhIO/TEMPO/KBr/SDS. A possible mechanism for the oxidation was supposed.     

Pyrrolidine as an efficient organocatalyst for direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with ketones

Pyrrolidine-catalyzed aldol reaction of trifluoroacetaldehyde ethyl hemiacetal (1) with ketones or aldehydes was described. In the presence of 20 mol % of pyrrolidine, the reaction proceeded smoothly at room temperature to afford the aldol products in good to excellent yields (up to 95%). Pyrrolidine showed a much higher catalytic activity than piperidine in the reaction with less reactive ketones. GC analysis clearly indicated that the catalyst and the enamine intermediates were kept at extremely low concentration during the reaction. Based on these observations, we suggested that formation of the enamine would be a rate-determining step for the catalytic aldol reaction. In addition, the asymmetric aldol reaction of 1 with cyclohexanone catalyzed by l-proline derivatives was also discussed.     

Nucleophilic additions of arylzinc compounds to aldehydes mediated by CrCl(3): efficient and facile synthesis of functionalized benzhydrols, 1(3H)-isobenzofuranones, benzyl alcohols, or diaryl ketones

In the presence of a stoichiometric amount of CrCl(3) and trimethylchlorosilane (TMSCl), nucleophilic addition of arylzinc compounds 1c-h to arylaldehydes 2a,b,g smoothly proceeded at room temperature to yield corresponding benzhydrols 4a-f in good yields. From arylzinc compounds 1a,b, 3-aryl-1(3H)-isobenzofuranones 3a-f were given by the CrCl(3)-mediated reaction with arylaldehydes 2a-f. Diaryl ketones 5a-e were obtained in good yields by the addition of excess amount of benzaldehyde as an oxidant to the resulting solution after the CrCl(3)-mediated reaction between arylzinc compounds 1c-g and arylaldehydes 2b,g was completed. In the nucleophilic additions of arylzinc compounds 1a,d,f to alkyladehydes 6b-f, the treatment of arylzinc compounds with CrCl(3) was required prior to the addition of the aldehydes in order to prevent the fast protodezincation of arylzinc compounds by the enolizable aldehydes. In these CrCl(3)-mediated nucleophilic additions of arylzinc compounds to aldehydes, arylchromium(III) species are probably reactive intermediates.     

Synthesis of α-fluoro-β-hydroxy esters by an enantioselective Reformatsky-type reaction

The first enantioselective Reformatsky-type reaction of ethyl iodofluoroacetate has been accomplished with alkyl aryl ketones. High diastereoselectivities and excellent enantioselectivities for the major diastereomer (93-95% ee) were achieved with large alkyl groups. For smaller alkyl groups the diastereoselectivities were moderate, but excellent enantioselectivities were obtained for both diastereomers (79-94% ee).     

Polysubstituted oxygen heterocycles by a Reformatsky-type reaction/reductive cyclization approach from enantiopure beta-ketosulfoxides

The stereoselective synthesis of tetrasubstituted tetrahydrofurans and trisubstituted tetrahydropyrans bearing a sulfoxide was achieved by reductive cyclization (Et3SiH/TMSOTf) from the corresponding enantiopure hydroxy ketones protected as a dioxolane. These derivatives are easily accessible from a Reformatsky-type reaction between alpha-bromo-alpha'-sulfinyl ketones and protected alpha- or beta-ketoaldehydes, followed by diastereoselective reduction of the resulting beta-ketosulfoxide.     

Room-temperature Ru(II)-catalyzed transfer hydrogenation of ketones and aldehydes in air

Transfer hydrogenation (TH) of ketones and aldehydes was efficiently carried out in 2-propanol at room temperature by means of a ruthenium(II) complex catalyst bearing a 2-(benzoimidazol-2-yl)-6-(pyrazol-1-yl)pyridine ligand. TH of the ketone substrates proceeded in air, reaching final TOFs of up to 59,400 h⁻¹, and the reduction of aldehydes proceeded under a nitrogen atmosphere to achieve final TOFs of up to 5940 h⁻¹.     

Reactions of substituted (1,3-butadiene-1,4-diyl)magnesium, 1,4-bis(bromomagnesio)butadienes and 1,4-dilithiobutadienes with ketones, aldehydes and PhNO to yield cyclopentadiene derivatives and N-Ph pyrroles by cyclodialkenylation

1,4-Dilithiobutadiene derivatives 1, 1,4-bis(bromomagnesio)butadiene derivatives 2 and metallacyclic (1,3-butadiene-1,4-diyl)magnesium reagents 3 were prepared and their reactions with ketones, aldehydes, and PhNO were investigated. Multiply substituted cyclopentadienes and N-Ph pyrroles were formed by unprecedented reaction conditions. The carbonyl group of aldehydes and ketones was deoxygenated during the reaction and behaved formally as a one-carbon unit; the N==O moiety of PhNO was cleaved to afford N-Ph pyrrole derivatives. Furthermore, different reactivities among these three types of reagents 1, 2 and 3 were revealed. The 1,4-dilithium reagents 1 readily reacted with both aldehydes and ketones; the 1,4-dimagnesium reagents 2 reacted with aldehydes, but not ketones; the metallacyclopentadiene reagents of magnesium 3 showed higher reactivity and did react with ketones.