Asymmetric Mannich Reaction of Aryl Methyl Ketones with Cyclic Imines Benzo[e][1,2,3]oxathiazine 2,2‐Dioxides Catalyzed by Cinchona Alkaloid‐based Primary Amines

Aryl ketones represent problematic substrates for asymmetric Mannich reactions due to a large steric hindrance exhibited by such compound species. A highly enantioselective direct Mannich reaction of aryl methyl ketones with cyclic imine benzo[e][1,2,3]oxathiazine 2,2‐dioxides could be successfully carried out utilizing a combination of cinchona alkaloid‐derived primary amines with trifluoroacetic acid (TFA); the primary amines feature a superior catalytic efficacy over secondary amines with a variety of sterically hindered carbonyl compounds as substrates. The reaction proceeded well with various cyclic imines in 89–97 % ee and with various aryl methyl ketones in 85–98 % ee. Moreover, the aryl carbonyl of a Mannich product could be transformed to ketoxime, which further undergoes a Beckmann rearrangement to produce an amide compound while maintaining enantioselectivity.     

Ag-catalyzed asymmetric mannich reactions of enol ethers with aryl, alkyl, alkenyl, and alkynyl imines

An efficient catalytic and enantioselective method (up to >98% ee) for Mannich reactions between trimethylsilyl enol ethers derived from acetone and acetophenone and aryl, alkenyl, alkynyl, and alkyl imines is disclosed. A large variety of beta-amino ketones can be synthesized in the presence of 1-5 mol % AgOAc and an inexpensive and readily available amino acid-derived phosphine. All Ag-catalyzed asymmetric Mannich reactions can be run in undistilled THF and air. The o-anisyl activating groups of product amines can be removed in >70% isolated yield through a single vessel operation. The synthetic utility of the catalytic asymmetric method is illustrated by a four-pot synthesis of optically pure alkaloid (-)-sedamine.     

The proline-catalyzed direct asymmetric three-component Mannich reaction: scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols

We have developed proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines. Several of the studied reactions provide beta-amino carbonyl compounds (Mannich products) in excellent enantio-, diastereo-, regio-, and chemoselectivities. The scope of each of the three components and the influence of the catalyst structure on the reaction are described. Reaction conditions have been optimized, and the mechanism and source of asymmetric induction are discussed. We further present application of our reaction to the highly enantioselective synthesis of 1,2-amino alcohols.     

Carbonylation of Difluoroalkyl Bromides Catalyzed by Palladium

Although important progress has been made in the fluoroalkylation reactions, the transition‐metal‐catalyzed carbonylative fluoroalkylation reaction remains challenging so far. Herein, we report the first example of a Pd‐catalyzed carbonylation of difluoroalkyl bromides with (hetero)arylboronic acids under one atmosphere pressure of CO. The reaction can also be extended to the aryl potassium trifluoroborate salts. The advantages of this protocol are synthetic simplicity, broad substrate scope, and excellent functional group compatibility. The resulting difluoroalkyl ketones can serve as versatile building blocks for the synthesis of various useful fluorinated compounds.     

Preparation and NMR studies of cobalt-containing diphosphine ligand chelated W, Ru, Au and Pd complexes: Suzuki cross-coupling reactions and carbonylation catalyzed by the Pd complex

Treatment of a cobalt-containing diphosphine ligand, [[mu-P,P-PPh2CH2PPh2]Co2(CO)4[mu-PPh2C[triple bond]CPPh2]] 1 with metal complexes W(CO)6, Ru3(CO)12, AuCl(tht)(tht = tetrahydrothiophene) and (COD)PdCl2(COD = 1,5-cycloctadiene) gave 1-chelated metal complexes [(1)W(CO)4], [(mu-1)Ru3(CO)10] 4, [(1)(AuCl)2] 5 and [(1)PdCl2] 6, respectively. All these compounds were characterized by spectroscopic means whereas 3, 4 and 6 were also studied by X-ray diffraction. These compounds display chelating and bridging modes of metal-phosphine complexation. Variable-temperature 1H and 31P NMR experiments were carried out for 3-6 and revealed that the fluxional behavior of each individual bridging dppm fragment was affected greatly by the bite angle of 1 in each metal complex. Suzuki cross-coupling reactions were satisfactorily catalyzed by under mild conditions. The reactions of aryl halides or iodothiophenes with chloroform and alkali in biphasic solution utilizing a catalytic amount of result into the formation of benzoic and thiophenic acids, respectively.     

Pd(OAc)2/P(cC6H11)3-catalyzed allylation of aryl halides with homoallyl alcohols via retro-allylation

Allylations of aryl halides take place upon treatment of tertiary homoallyl alcohols with aryl halides in the presence of cesium carbonate and a palladium catalyst. The allylation reaction would consist of the following steps: (1) oxidative addition of aryl halide to palladium, (2) ligand exchange between the halide and the homoallyl alcohol affording aryl(homoallyloxy)palladium, (3) retro-allylation of the palladium alkoxide to generate sigma-allyl(aryl)palladium with concomitant liberation of the relevant ketone, and (4) productive reductive elimination. Since the retro-allylation step proceeds in a concerted fashion via a conformationally regulated six-membered cyclic transition state, the allylation reactions are highly regio- and stereospecific when homoallyl alcohols having a substituted allyl group are used. Whereas triarylphosphine is known to serve as a ligand for the palladium-catalyzed allyl transfer reactions, tricyclohexylphosphine proves to significantly expand the scopes of aryl halides to electron-rich aryl chlorides and of homoallyl alcohols to cyclic homoallyl alcohols. The new arylative ring-opening reactions of cyclic homoallyl alcohols allow for the synthesis of ketones having a branched or linear allylarene moiety at the remote terminus in regio- and stereospecific manners.     

Catalytic cross-coupling reaction of esters with organoboron compounds and decarbonylative reduction of esters with HCOONH4: a new route to acyl transition metal complexes through the cleavage of acyl-oxygen bonds in esters

The Ru3(CO)12-catalyed cross-coupling reaction of esters with organoboron compounds leading to ketones is described. A wide variety of functional groups can be tolerated under the reaction conditions. Aromatic boronates function as a coupling partner to give aryl ketones. Acyl-alkyl coupling to dialkyl ketones is also achieved by the use of 9-alkyl-9-BBN in place of boronates. The Ru3(CO)12-catalyzed decarbonylative reduction of esters with ammonium formate (HCOONH4) leading to hydrocarbons is also described. No expected aldehydes are produced, and controlled experiments indicate that aldehydes are not intermediate for the transformation. A hydrosilane can also be used as a reducing reagent in place of HCOONH4. A wide variety of functional groups are compatible for both reactions. The key step for both catalytic reactions is the directing group-promoted cleavage of an acyl carbon-oxygen bond in esters, leading to the generation of acyl transition metal alkoxo complexes.     

An extremely efficient three-component reaction of aldehydes/ketones, amines, and phosphites (Kabachnik-Fields reaction) for the synthesis of alpha-aminophosphonates catalyzed by magnesium perchlorate

Commercially available magnesium perchlorate is reported as an extremely efficient catalyst for the synthesis of alpha-aminophosphonates. A three-component reaction (3-CR) of an amine, an aldehyde or a ketone, and a di-/trialkyl phosphite (Kabachnik-Fields reaction) took place in one pot under solvent-free conditions to afford the corresponding alpha-aminophosphonates in high yields and short times. The use of solvent retards the rate of the reaction and requires a much longer reaction time than that for neat conditions. The reactions involving an aldehyde, an aromatic amine without any electron-withdrawing substituent, and a phosphite are carried out at rt. The reactions involving cyclic ketones, aromatic amines with an electron-withdrawing substituent, and aryl alkyl ketone (e.g., acetophenone) require longer reaction times at rt or heating. Magnesium perchlorate was found to be superior to other metal perchlorates and metal triflates during the reaction of 4-methoxybenzaldehyde, 2,4-dinitroaniline, and dimethyl phosphite. The catalytic activity of various magnesium compounds was influenced by the counteranion, and magnesium perchlorate was found to be the most effective. The reaction was found to be general with di-/trialkyl phosphites and diaryl phosphite. The Mg(ClO4)2-catalyzed alpha-aminophosphonate synthesis in the present study perhaps represents a true three-component reaction as no intermediate formation of either an imine or alpha-hydroxy phosphonate was observed that indicated the simultaneous involvement of the carbonyl compound, the amine, and the phosphite in the transition state.     

Metal-free sp3 C-H bond dual-(het)arylation: I2-promoted domino process to construct 2,2-bisindolyl-1-arylethanones

A molecular I(2)-promoted sp(3) C-H bond dual-(het)arylation protocol was developed for the synthesis of 2,2-bisindolyl-1-arylethanones. Through a logical design, three mechanism-different reactions (iodination, Kornblum oxidation, and Friedel-Crafts reaction) were assembled in a single reactor. A variety of 2,2-bisindolyl-1-aryl ethanones were synthesized from simple and readily available aryl methyl ketones and indoles. In the reaction, metal, base, and ligand were all avoidable.     

Metal enolates of alpha-CF3 ketones: theoretical guideline, direct generation, and synthetic use

The difficulty as well as the significance of the direct generation of metal enolates of alpha-CF(3) ketones cannot be easily understood by chemists unfamiliar with F. In sharp contrast to the sunny side of non-F, hydrocarbon chemistry, F chemistry has long been overshadowed. Metal enolates of carbonyl compounds are synthetically important in C-C bond-forming reactions. However, the metal enolates of fluorinated carbonyl compounds have been severely limited to alpha-F metal enolates. Alpha-CF(3) metal enolates have generally been recognized as unstable and difficult to prepare because of the facile beta-M-F elimination. However, we have developed a direct generation and synthetic application of alpha-CF(3) metal enolates. Therefore, the present results regarding the direct generation and synthetic use of metal enolates of alpha-CF(3) ketones might be recognized as a real breakthrough for the general use of metal enolates in F chemistry.     

Direct catalytic diastereoselective Mannich reactions: the synthesis of protected α-hydroxy-β-aminoketones

The combination of Mg(ClO₄)₂, 2,2′-bipyridine and N-methylmorpholine generates an effective catalyst system for the direct addition of α-carbonate-substituted ketones to aryl N-Ts imines. Methyl-carbonate-substituted ketones deliver acyclic α-hydroxy-β-aminoketone derivates, while ketones substituted with α-iso-propenyl-carbonates furnish cyclic carbamate adducts. In both cases the anti-configured Mannich products dominate.     

Direct organocatalytic enantioselective α-aminomethylation of ketones

The scope and limitations of the direct organocatalytic asymmetric α-aminomethylation of ketones are disclosed. The proline-catalyzed classical Mannich reactions between unmodified ketones, aqueous formaldehyde and aromatic amines furnished the desired Mannich bases in high yield with up to >99% ee. Moreover, methyl alkyl ketones were regioselectively α-aminomethylated at the methylene carbon affording the corresponding Mannich products with up to >99% ee. In addition, the proline-catalyzed one-pot three-component reaction between p-anisidine, aqueous formaldehyde and 4,4-dimethyl-2-cycloxehen-1-one furnished the corresponding bicyclic aza-Diels–Alder adduct with >99% ee.     

Synthesis of N1-Substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyra-zolethiocarboxamide as Novel Small Molecule Inhibitors of Cysteine Protease of T.cruzi

It has been reported that the pyrazoline scaffold has activity against a broad range of therapeutic targets (e.g antibacterial、antiviral、anti-inflammatary )1,2. In our previous studies of the small molecule inhibitors of cysteine protease of T.cruzi (cruzain), the compounds, 1-(3-bromopropiophenone)-4-subsituted-thiosemicarbazonesVII, have been designed and tested both in vitro as potential antitrypanosomal agents and in the cell culture assay against T. cruzi (the causative agent of Chag…     

Acyclic chiral amines and amino acids as inexpensive and readily tunable catalysts for the direct asymmetric three-component Mannich reaction

The direct three-component asymmetric Mannich reaction catalyzed by acyclic chiral amines or amino acids is presented. Simple acyclic chiral amines and amino acids--such as alanine-tetrazole (9), alanine, valine, and serine-catalyzed the three-component asymmetric Mannich reactions between unmodified ketones, p-anisidine, and aldehydes with high chemo- and stereoselectivity, furnishing the corresponding Mannich bases with up to >99 % ee. This study demonstrates that the whole range of amino acids in nature, as well as nonproteogenic amino acid derivatives, can be considered in the design and tuning of novel, inexpensive organocatalysts for the direct asymmetric Mannich reaction.     

Ba-catalyzed direct Mannich-type reactions of a beta,gamma-unsaturated ester providing beta-methyl aza-Morita-Baylis-Hillman-type products

Barium-catalyzed direct Mannich-type reactions of a beta,gamma-unsaturated ester are described. The Ba-catalyst not only promoted the Mannich-type reactions, but also isomerized Mannich adducts to afford beta-methyl aza-Morita-Baylis-Hillman-type products in 61-88% yield from various aryl, heteroaryl, and alkyl imines. Preliminary trials on enantioselective variants with a chiral biaryldiol ligand gave products in up to 80% ee.     

Catalyst-free alkanoylation of aromatic rings via arylstannanes. Scope and limitations

The reaction of alkanoyl chlorides with arylstannanes in 1,2-dichlorobenzene (180 °C) is a simple and direct route for the catalyst-free and regioselective synthesis of tertiary alkyl aryl ketones in good to excellent isolated yields (55-77%). Nevertheless, under similar conditions, reactions carried out with alkanoyl chlorides bearing α-hydrogens render only the product of protodestannylation.     

Ruthenium-catalyzed functionalization of aryl carbon-oxygen bonds in aromatic ethers with organoboron compounds

The ruthenium-catalyzed reaction of aryl ethers having a carbonyl group at the ortho position to the ether group with organoboronates (R-B(OCH2CMe2CH2O), R = aryl, alkenyl, and alkyl) resulted in site-selective C-C bond formation. Among the transition metal complexes screened, the RuH2(CO)(PPh3)3 complex showed the highest activity. Several aromatic ketones having methoxy or phenoxy groups at the ortho position can also be used in this coupling reaction. A variety of arylboronates containing electron-donating (NMe2, OMe, methyl, and vinyl) and -withdrawing (F and CF3) groups reacted with methoxy ketones to give the corresponding coupling products in high yields.     

Origins of opposite absolute stereoselectivities in proline-catalyzed direct Mannich and aldol reactions

[structure: see text] The first computational studies to elucidate the stereoselectivity of the proline-catalyzed direct Mannich reaction have been performed using density functional theory (B3LYP/6-31G*). The transition states for the proline-catalyzed direct Mannich reaction of the proline enamine of acetone with the N-phenyl imine of acetaldehyde are reported here. The computed transition states provide a general model that explains the origin of the opposite stereoselectivities of proline-catalyzed Mannich and aldol reactions.     

Direct asymmetric aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral BINOL-derived zincate catalyst

Direct asymmetric aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral metal complex is reported for the first time herein. Two novel semicrown chiral ligands 1a and 1b were synthesized from (S)- and (R)-BINOL, respectively, and then employed to catalyze the direct asymmetric aldol addition of aryl ketones to aryl aldehydes. Introduced with 2.0 equiv of diethylzinc, 1b had higher enantioselectivity than 1a. Up to 97% yield and up to 80% enantioselectivity were achieved.     

3-Aryl- or 3-(trans-4-alkylcyclohexyl)- 6-arylcyclohex-2-enones: synthesis, transformations and mesomorphic properties

The synthesis and chemical transformations of 3-aryl- or 3-(trans-4-alkylcyclohexyl)- 6-arylcyclohex-2-enones into liquid crystalline compounds are discussed. These 3,6-disubstituted cyclohex-2-enones were prepared by the condensation of appropriate Mannich salts or trans-4-alkylcyclohexyl 2-bromoethyl ketones with 4-substituted benzyl methyl ketones.