L-Prolinamide Catalyzed Aqueous Direct Aldol Reaction： an Environment-friendly Method for the Synthesis of β- Hydroxyl keto nes

An environment-friendly L-prolinamide catalyzed aldol reaction has been developed. The reaction exhibited broad substrate generality, and high yields with good diastereoselectivity were obtained for cyclic ketones.The simplicity of product isolation, usage of water as environmentally benign reaction medium, and the usage of cheap, readily available and recyclable catalyst make this process promising to be developed for large-scale preparation of β-hydroxyl ketones.     

ZnCl2‐Promoted Asymmetric Hydrogenation of β‐Secondary‐Amino Ketones Catalyzed by a P‐Chiral Rh–Bisphosphine Complex

A new catalytic system has been developed for the asymmetric hydrogenation of β‐secondary‐amino ketones using a highly efficient P‐chiral bisphosphine–rhodium complex in combination with ZnCl₂ as the activator of the catalyst. The chiral γ‐secondary‐amino alcohols were obtained in 90–94 % yields, 90–99 % enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C=substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl₂ on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)‐duloxetine, (R)‐fluoxetine, and (R)‐atomoxetine, in high yields and with excellent enantioselectivities.     

Ketones from Nickel‐Catalyzed Decarboxylative,Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Synthesis of the C?C bonds of ketones relies upon one high‐availability reagent (carboxylic acids) and one low‐availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N‐hydroxyphthalimide esters and S‐2‐pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron‐poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl₂ to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α‐heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20‐mer peptide fragment analog of Exendin(9–39) on solid support.     

Ketones from Nickel‐Catalyzed Decarboxylative,Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Synthesis of the C?C bonds of ketones relies upon one high‐availability reagent (carboxylic acids) and one low‐availability reagent (organometallic reagents or alkyl iodides). We demonstrate here a ketone synthesis that couples two different carboxylic acid esters, N‐hydroxyphthalimide esters and S‐2‐pyridyl thioesters, to form aryl alkyl and dialkyl ketones in high yields. The keys to this approach are the use of a nickel catalyst with an electron‐poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl₂ to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary/tertiary ketones with strained rings and ketones with α‐heteroatoms. The conditions can be employed in the coupling of complex fragments, including a 20‐mer peptide fragment analog of Exendin(9–39) on solid support.     

Asymmetric Radical–Radical Cross‐Coupling through Visible‐Light‐Activated Iridium Catalysis

Combining single electron transfer between a donor substrate and a catalyst‐activated acceptor substrate with a stereocontrolled radical–radical recombination enables the visible‐light‐driven catalytic enantio‐ and diastereoselective synthesis of 1,2‐amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99 % ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C? C bond formation mediated by single electron transfer.     

Kinetic Resolution of β‐Sulfonyl Ketones through Enantioselective β‐Elimination using a Cation‐Binding Polyether Catalyst

Reported herein is the first enantioselective β‐elimination reaction catalyzed by a chiral cation‐binding polyether. By using this catalytic protocol, a wide range of β‐sulfonyl ketones could be effectively resolved with high stereoselectivity (S up to >300). Key to the success of this process is the favorable secondary interactions of the catalyst with the Lewis basic groups on the sulfone substrate. The enone product of this process can be easily converted into the racemic starting material, and allows an effective recycling and overall synthesis of chiral β‐sulfonyl ketones in high yield and excellent enantioselectivity.     

多相 MnOx氮掺杂碳材料催化氮杂环侧链 Csp3-H的氧化反应

sp3杂化的碳氢键氧化成酮是有机合成中一个重要方法.相应的酮产物被广泛应用在医药和天然产物合成中.目前已经开发出多种衍生于含 N杂环酮的药物化合物和具有生物活性的天然产物,例如阿普米定、苯吡胺、氯苯吡胺、曲普利啶、多西拉敏等.传统的含 N杂环侧链氧化生成酮的方法使用化学计量的强氧化剂(如高锰酸钾),不可避免地产生众多的副产物.近年来,均相的过渡金属催化剂被广泛应用于含 N杂环侧链氧化生成酮的反应中.但是 N杂环和过渡金属配位导致催化剂失活,选择性降低.金属的残留也使后处理过程变得繁琐.均相催化剂还存在难以回收利用的缺点.使用多相催化剂可以解决上述问题,因而具有重大的研究意义.目前为止,还很少有文献报道多相催化剂催化含 N杂环侧链氧化生成酮的方法.本文使用硝酸锰和菲啰啉的络合物在氮气氛围中高温焙烧,制备了一系列新型 MnOx-N@C材料.首次应用于 C–H氧化成酮的领域中.以2-苄基吡啶为模板底物,使用叔丁基过氧化氢为氧化剂,我们研究了 MnOx-N@C材料的催化活性.研究发现,在600oC焙烧得到的 MnOx-N@C材料具有最高的催化活性.实验得到最佳的反应条件：0.5 mmol底物,3当量的叔丁基过氧化氢,1 mg MnOx-N@C (600oC)材料. ICP结果表明,1 mg MnOx-N@C (600oC)材料中含有的锰相对于0.5 mmol底物的摩尔分数为0.79 mol%,说明该材料具有很高的催化活性.我们进一步研究了 MnOx-N@C (600oC)材料适用的底物范围,发现它可以催化2,3-环戊烯并吡啶类化合物、苄基吡啶类化合物发生氧化反应生成相应的酮;当反应底物中存在其他可以被氧化的碳氢键时,该材料表现出很高的选择性,可见其具有广泛的底物范围和优异的选择性.对于克级以上规模的底物量, MnOx-N@C仍能表现出很高的催化活性,表明其在有机合成中具有很好的实用性;连续使用6次后,该催化剂依然表现出很高的催化活性.表征结果表明, MnOx-N@C (600oC)材料中 MnOx粒子大小为1.71–6.56 nm;样品中存在 C–N, C=N和吡咯型的 N; Mn的化学态有+2,+3和+4.     

Lutidine‐Based Chiral Pincer Manganese Catalysts for Enantioselective Hydrogenation of Ketones

A series of Mn^I complexes containing lutidine‐based chiral pincer ligands with modular and tunable structures has been developed. The complex shows unprecedentedly high activities (up to 9800 TON; TON=turnover number), broad substrate scope (81 examples), good functional‐group tolerance, and excellent enantioselectivities (85–98 % ee) in the hydrogenation of various ketones. These aspects are rare in earth‐abundant metal catalyzed hydrogenations. The utility of the protocol have been demonstrated in the asymmetric synthesis of a variety of key intermediates for chiral drugs. Preliminary mechanistic investigations indicate that an outer‐sphere mode of substrate–catalyst interactions probably dominates the catalysis.     

Gold‐Catalyzed Synthesis of Functionalized Pyridines by Using 2H‐Azirines as Synthetic Equivalents of Alkenyl Nitrenes

2H‐Azirines are easily synthesized from the corresponding ketones and, despite possessing a C?N bond embedded in a strained three‐membered cycle, they are sufficiently stable to be isolated, stored, and manipulated. 2H‐Azirines can be regarded as valuable synthetic equivalents of alkenyl nitrenes, however, reactions capitalizing on the cyclic strain of the heterocyclic motif and involving the cleavage of the C? N single bond remain surprisingly limited. A gold‐catalyzed reaction that allows the formation of polysubstituted functionalized pyridines from easily accessible 2‐propargyl 2H‐azirine derivatives was developed. This transformation, which corresponds to an unprecedented intramolecular transfer of an alkenyl nitrene to an alkyne, proceeds with low catalyst loading, is efficient, and exhibits a high functional‐group tolerance and a wide substrate scope.     

Facile One‐Pot Multicomponent Synthesis of β‐Acetamido Ketones with Amberlyst‐15 as Heterogeneous Catalyst

The one‐pot multicomponent coupling of an aromatic aldehyde, an enolizable ketone or keto ester, acetonitrile, and acetyl chloride at room temperature in the presence of Amberlyst‐15 as catalyst affords β‐acetamido ketones in high yields. The inexpensive catalyst works under heterogeneous conditions and can be readily reused.     

Palladium‐Catalyzed α‐Arylation of Arylketones at Low Catalyst Loadings

A general catalytic protocol for the α‐arylation of aryl ketones has been developed. It involves the use of a preformed, bench‐stable Pd–N‐heterocyclic carbene pre‐catalyst bearing IHept as an ancillary ligand, and allows the coupling of various functionalized coupling partners at very low catalyst loading. Careful choice of the solvent/base system was crucial to obtain optimum catalyst performance. The pre‐catalyst was also successfully tested in the synthesis of an industrially relevant compound.     

手性Ru复合物催化剂的固载化及其不对称氢转移反应催化应用

Chiral Ru-BsDPEN, (1R,2R)-N-p-benzenesulfonyl-1,2-diphenylethylenediamine, catalyst has been immobilized on a mesoporous molecular sieve of MCM-41 type successfully. A hybrid mesoporous molecular sieve was synthesized using a precursor bearing benzene group, which in organosilica were sulfonylated and reacted with (1R,2R)-l,2-diphenylethylenediamine and [RuC1E(p-cymene)]2 successively to afford immobilized catalyst. The Brunauer-Emmett-Teller (BET) surface area and Barrett-Joyner-Halenda (BJH) pore size decreased after immobilization of catalyst onto the mesoporous material. Enantioselective transfer hydrogenation of ketones catalyzed by immobilized catalyst showed the highest yield of 22.36% and e.e. value of 31.47% by using acetophenone as substrate when reaction time was 48 and 16 h respectively.     

Facile Access to Chiral Alcohols with Pharmaceutical Relevance Using a Ketoreductase Newly Mined from Pichia guilliermondii

Chiral secondary alcohols with additional functional groups are frequently required as important and valuable synthons for pharmaceuticals, agricultural and other fine chemicals. With the advantages of environmentally benign reaction conditions, broad reaction scope, and high stereoselectivity, biocatalytic reduction of prochiral ketones offers significant potential in the synthesis of optically active alcohols. A CmCR homologous carbonyl reductase from Pichia guilliermondii NRRL Y‐324 was successfully overexpressed. Substrate profile characterization revealed its broad substrate specificity, covering aryl ketones, aliphatic ketones and ketoesters. Furthermore, a variety of ketone substrates were asymmetrically reduced by the purified enzyme with an additionally NADPH regeneration system. The reduction system exhibited excellent enantioselectivity (>99% ee) in the reduction of all the aromatic ketones and ketoesters, except for 2‐bromoacetophenone (93.5% ee). Semi‐preparative reduction of six ketones was achieved with high enantioselectivity (>99% ee) and isolation yields (>80%) within 12 h. This study provides a useful guidance for further application of this enzyme in the asymmetric synthesis of chiral alcohol enantiomers.     

Chemo‐ and Stereoselective Iron‐Catalyzed Hydrosilylation of Ketones

The reduction of ketones with polymethylhydrosiloxane (PMHS) gives the corresponding alcohols in good to excellent yield applying iron‐based catalyst systems. In the case of prochiral ketones, the use of Fe(OAc)₂/(S,S)‐Me‐DuPhos leads to high enantioselectivity up to 99 % ee. The reaction proceeds in the presence of several functional groups such as esters, halides as well as conjugated double bonds, with high chemoselectivity. The advantage of this protocol is that the reaction requires no activating agents or additives.     

Chiral Silver Phosphate Catalyzed Transformation of ortho‐Alkynylaryl Ketones into 1H‐Isochromene Derivatives through an Intramolecular‐Cyclization/Enantioselective‐Reduction Sequence

The transformation of ortho‐alkynylaryl ketones through a cyclization/enantioselective‐reduction sequence in the presence of a chiral silver phosphate catalyst afforded 1H‐isochromene derivatives in high yield with fairly good to high enantioselectivity. An asymmetric synthesis of the 9‐oxabicyclo[3.3.1]nona‐2,6‐diene framework, which has been found in some biologically active molecules, is presented as a demonstration of the synthetic utility of this method.     

An Environmentally Benign Process for the Hydrogenation of Ketones with Homogeneous Iron Catalysts

Iron complexes generated in situ catalyze homogeneously the transfer hydrogenation of aliphatic and aromatic ketones by utilizing 2‐propanol as a hydrogen donor in the presence of base. The influence of different reaction parameters on the catalytic activity is investigated in detail by applying a three‐component catalyst system composed of an iron salt, 2,2′:6′,2′′‐terpyridine, and PPh₃. The scope and limitations of the described catalyst is shown in the reduction of 11 different ketones. In most cases, high conversion and excellent chemoselectivity are obtained. Mechanistic studies indicate a monohydride reaction pathway for the homogeneous iron catalyst.     

Transfer Hydrogenation of Ketones Catalyzed by Surface‐Active Ruthenium and Rhodium Complexes in Water

An improved, high‐yield, one‐pot synthetic procedure for water‐soluble ligands functionalized with trialkyl ammonium side groups H₂N(CH₂)₂NHSO₂‐p‐C₆H₄CH₂[NMe₂(C_nH_2n+1)]⁺ ( [HL ⁿ ]⁺ ; n=8, 16) was developed. The corresponding new surface‐active complexes [(p‐cymene)RuCl( L ⁿ )] and [Cp*RhCl( L ⁿ )] (Cp*=η⁵‐C₅Me₅) were prepared and characterized. For n=16 micelles are formed in water at concentrations as low as 0.6 mM , as demonstrated by surface‐tension measurements. The complexes were used for catalytic transfer hydrogenation of ketones with formate in water. Highly active catalyst systems were obtained in the case of complexes bearing C₁₆ tails due to their ability to be adsorbed at the water/substrate interface. The scope of these catalyst systems in aqueous solutions was extended from partially water soluble aryl alkyl ketones (acetophenone, butyrophenone) to hydrophobic dialkyl ketones (2‐dodecanone).     

Expeditious synthesis of 2,3-dihydroquinazolin-4(1H)-ones in aqueous medium using thiamine hydrochloride (VB1) as a mild,efficient, and reusable organocatalyst

A simple and straightforward synthesis of 2,3-dihydroquinazolin-4(1H)-ones is developed by reacting anthranilamide with various aldehydes or ketones under mild reaction conditions, using thiamine hydrochloride as a cost-effective, readily available, and green catalyst in water. Simple purification process, high yields within short reaction time, wide substrate scope, operational simplicity, and reusability of the catalyst up to three cycles enrich the applicability of the protocol.     

2,2,2‐Trifluoroacetophenone as an Organocatalyst for the Oxidation of Tertiary Amines and Azines to N‐Oxides

A cheap, mild and environmentally friendly oxidation of tertiary amines and azines to the corresponding N‐oxides is reported by using polyfluoroalkyl ketones as efficient organocatalysts. 2,2,2‐Trifluoroacetophenone was identified as the optimum catalyst for the oxidation of aliphatic tertiary amines and azines. This oxidation is chemoselective and proceeds in high‐to‐quantitative yields utilizing 10 mol % of the catalyst and H₂O₂ as the oxidant.     

Polystyrene‐supported Pd(II) complex‐catalysed carboacylation of 2‐arylpyridines with alcohols via C─H bond activation under solvent‐free conditions

Polystyrene‐supported N ,N ‐dimethylethylenediamine Pd(II) complex C was used as an efficient catalyst for the synthesis of aromatic ketones via ortho ‐acylation of sp² C─H bonds of 2‐arylpyridines with alcohols as effective coupling partners. The alcohols were oxidized with tert ‐butyl hydroperoxide to their corresponding aldehydes in situ and efficiently coupled with 2‐arylpyridines to form aryl ketones under solvent‐free conditions. Furthermore, catalyst C could be easily recovered by simple filtration and reused for five cycles without any significant decrease in its activity.