PdI2-catalyzed coupling-cyclization reactions involving two different 2,3-allenols: an efficient synthesis of 4-(1',3'-dien-2'-yl)-2,5-dihydrofuran derivatives

Transition-metal-catalyzed dimeric coupling-cyclization reactions of two different 2,3-allenols afforded 4-(1',3'-dien-2'-yl)-2,5-dihydrofuran derivatives 3. 2-Substituted 2,3-allenols 1 cyclized to form the 2,5-dihydrofuran ring, whereas the 2-unsubstituted 2,3-allenols 2 provided the 1,3-diene unit at the 4-position. The reaction is proposed to proceed through an oxypalladation, insertion, and beta-hydroxide elimination process. The C=C double bond was formed with high E stereoselectivity by beta-hydroxide elimination.     

Efficient preparation of highly optically active (S)-(-)-2,3-allenols and (R)-(+)-2,3-allenyl acetates by a clean novozym-435-catalyzed enzymatic separation of racemic 2,3-allenols

Novozym-435 has been found to be an effective biocatalyst for the kinetic resolution of a series of racemic 2,3-allenols, affording highly optically active (S)-(-)-2,3-allenols and (R)-(+)-2,3-allenyl acetates in high yields and with excellent ee values. The reaction of 3-(n-butyl)-3,4-pentadien-2-ol (1 a) was successfully performed on a 10 g scale to afford the corresponding (S)-(-)-2,3-allenol (1 a) and (R)-(+)-2,3-allenyl acetate (2 a) in synthetically useful amounts and with high ee values. The advantages of this reaction are the ready availability of the starting materials, high stereoselectivities for both (-)-2,3-allenols and (+)-2,3-allenyl acetates, the use of a relatively high substrate concentration, and a lower catalyst loading. The resulting (S)-(-)-2,3-allenol 1 a can be converted into the corresponding chiral 2,5-dihydrofuran and the vinylic epoxide.     

2,3-联烯醇及其衍生物的反应

2,3-联烯醇是一类含1,2-二烯官能团和羟基的化合物, 具有很高的反应活性, 它及其衍生物是一类重要的联烯化合物. 概述了2,3-联烯醇及其衍生物的反应, 包括2,3-联烯醇在过渡金属催化下的自身异构环化反应、钯催化的偶联反应、钌催化的环羰基化反应、不同条件下不同方式的扩环反应、亲电试剂参与的反应、分子内环加成反应、自由基反应等和2,3-联烯醇衍生物在零价钯催化下基于亚甲基-π-烯丙基钯中间体生成联烯或1,3-共轭二烯的区域选择性反应, S_N2'类型的加成-消除反应, 二价钯催化下的分子内环化反应以及重排反应等.     

Palladium-catalyzed coupling reaction of propargylic oxiranes with arylboronic acids in aqueous media

A novel type of coupling reaction has been developed by the palladium-catalyzed reaction of propargylic oxiranes with arylboronic acids, in which anti-substituted 4-aryl-2,3-allenols were produced in a highly diastereoselective manner. A chiral-substituted allene has been synthesized from the reaction of a chiral propargylic oxirane without loss of the chirality.     

Construction of Chiral 2,3-Allenols through a Copper(I)-Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

Chiral 2,3-allenols were constructed through copper(I)-catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)-DTBM-SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but-2-yn-1-ol as the substrates and (R,R)-Ph-BPE as the ligand were found to be crucial to get good to high regio- and diastereoselectivity. The produced chiral 2,3-allenols are easily transformed into synthetically useful 2-furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.     

Novozym 435-catalyzed kinetic resolution of β-allenols. A facile route for the preparation of optically active β-allenols or allenyl acetates

A variety of optically active β-allenols and β-allenyl acetates were synthesized via the Novozym 435-mediated kinetic resolution of racemic β-allenols. A dramatic solvent effect was observed for the stereoselectivity. The scope of the substrates and the effect of the concentration and temperature on the reaction were also investigated.     

The reactions of 5-aryl-2,3-dimethylisoxazolium salts with aromatic aldehydes

The reactions of the 3-methyl group in 5-aryl-2,3-dimethylisoxazolium tetrafluoroborates with aromatic aldehydes, in the presence of piperidine were studied. Isoxazolium salt reactivity is independent of the phenyl group substituent at C-5 on the isoxazolium salt ring. However, it does depend on the aldehyde structure.     

Carbonyl-yne reactions of 3,3,3-trifluoropyruvates

An efficient synthesis of trifluoromethyl-containing 2,3-allenols via carbonyl-yne reaction of 3,3,3-trifluoropyruvates with acetylenes is described. In the presence of MgBr₂·Et₂O the reaction of methyl trifluoropyruvate with hex-1-yne proceeds diastereoselectively. Trifluoromethyl-substituted 2,3-allenols can be stereoselectively transformed into trifluoromethyl-substituted 2,5-dihydrofurans on treatment with AgNO₃.     

Enantioenriched 1-aryl-2-fluoroethylamines. Efficient lipase-catalysed resolution and limitations to the Mitsunobu inversion protocol

Both enantiomers of eight 1-aryl-2-fluoroethylamines have been synthesised starting with 1-aryl-2-fluoroethanones. Kinetic resolution of the amines using lipase B from Candida antarctica with ethyl methoxyacetate as the acyl donor gave the (R)-amines in 96-99% ee and the (S)-methoxyacetamides in >99.5% ee. The resolution was robust with respect to variation in reaction temperature, acyl donor concentration, water activity and substrate structure. Nine other lipase preparations failed to catalyse the reaction or gave a low enantioselectivity. Secondly, a Mitsunobu inversion protocol starting with enantioenriched 1-aryl-2-fluoroethanols using phthalimide as nucleophile was employed in the synthesis of the (S)-1-aryl-2-fluoroethylamines. Both the inversion efficiency and yield depended on the aromatic substituents. For six of the substrates, clean inversion of the stereochemistry was observed. However, racemisation and low yields were the result when electron-donating substituents were present at the aromatic ring. When substituted with a cyano or a nitro group, an unexpected fluorine elimination occurred, limiting the yield for these transformations. The absolute configuration of the 1-aryl-2-fluoroethylamines was determined using circular dichroism.     

Development of palladium-catalyzed transformations using propargylic compounds

It is known that propargylic compounds having an ester and a halide at the propargylic positions react with palladium complexes leading to π-propargylpalladium and allenylpalladium complexes, which cause various transformations in the presence of the reactants. The aim of the present study was to develop novel palladium-catalyzed transformations using propargylic compounds. As diastereoselective reactions of propargylic compounds with bis-nucleophiles, we have developed palladium-catalyzed reactions of propargylic carbonates with 2-substituted cyclohexane-1,3-diones, 2-(2-hydroxyphenyl)acetates and 2-oxocyclohex-3-enecarboxylates. These processes produce highly substituted cyclic compounds in a highly stereoselective manner. Through our studies on the construction of substituted 2,3-allenols by the reactions of propargylic oxiranes, it has been made clear that palladium-catalyzed coupling reactions occur in the presence of arylboronic acids and terminal alkynes. The processes can be carried out in mild conditions to yield substituted 4-aryl-2,3-allenols in a diastereoselective manner. In our attempt to develop CO2-recycling reactions, we developed a methodology for the synthesis of cyclic carbonates by palladium-catalyzed reactions of propargylic carbonates with phenols. Our findings suggested that the process proceeds through a pathway involving decarboxylation-followed fixation of the liberated CO2. Diastereoselective, enantioselective, and enantiospecific construction of cyclic carbonates have been achieved by the application of this methodology.     

Enzymatic resolution of (+/-)-5-acetoxy-4-aryl-(2E)-pentenoate derivatives

Enzymatic resolution of six (+/-)-5-acetoxy-4-aryl-(2E)-pentenoate derivatives, compounds 9, 11, 13, 15, 17, and 19 bearing a different aromatic substitution pattern, using lipase OF-360 from Candida rugosa was carried out. The absolute configurations of all hydrolyzed products and all unchanged acetates were found to be S and R, respectively. Moreover, the enantiomeric excess of the enzymatic resolution products from 9, 11, and 13 with the ortho-methoxyl group in the aromatic ring was higher than that of the substrates with no methoxyl group at the ortho-position in the aromatic ring.     

2D NMR analysis of highly restricted internal rotation in 2-methylthio-3H-4-p-bromophenyl)-7-[(ortho- and para-substituted)-phenylthio]-1, 5-benzodiazepines

The complete assignments of twelve 4-aryl-7-thioaryl-1,5-benzodiazepines 1H and 13C spectra, performed with the use of high resolution variable solvent and temperature 1D and 2D techniques (e.g. HOMOCOSY, NOESY, HMQC and HMBC), lead to the determination of conformational equilibria between two rotamers having the aromatic ring of the thioaryl oriented in a perpendicular or helical orientation toward the benzodiazepine ring. The restricted rotation was evaluated from the population of these conformers.     

An ionic liquid mediated one-pot synthesis of substituted thiazolidinones and benzimidazoles

An expeditious one-pot synthesis of 2,3-diaryl/2-aryl-3-heteroaryl-1,3-thiazolidin-4-ones and 1-aryl-1H,3H-thiazolo[3,4-a]benzimidazoles have been accomplished by condensing hetero/aromatic amine, 2-mercaptoacetic acid, aromatic aldehyde and 1,2-phenylenediamine, 2-mercaptoacetic acid and aromatic aldehyde, respectively, in ionic liquids, viz, 1-butyl-3-methyl-imidazolium tetrafluoroborate and 1-methoxyethyl-3-methylimidazolium trifluoroacetate.     

One-pot construction of aza- or oxa-bridged benzocycloheptanes from readily available 2,3-allenyl malonates or 2,3-allenols and o-iodobenzaldehyde or imine

A Pd(OAc)(2)-catalyzed reaction of 2,3-alkadienyl malonates or 2,3-allenols with o-iodobenzaldehyde or its N-tosyl imine occurred smoothly in MeCN at 80 °C to form the oxa- or aza-bridged benzocycloheptane derivatives with important biological potential. With the optically active 2,3-allenols, the absolute configurations of all the three chiral centers have been conveniently established.     

Reformatsky reaction of methyl 1-bromocycloalkane-1-carboxylates with phenyl-and benzoylhydrazones derived from aromatic aldehydes

Reformatsky reagents obtained from methyl 1-bromocyclohexane-and 1-bromocyclopentane-1-carboxylates reacted with aromatic aldehyde phenyl-and benzoylhydrazones to give 3-aryl-2-phenylamino-2-azaspiro[3.5]nonan-, 3-aryl-2-phenylamino-2-azaspiro[3.4]octan-, 3-aryl-2-benzoylamino-2-azaspiro[3.5]-nonan-, and 3-aryl-2-benzoylamino-2-azaspiro[3.4]octan-1-ones, respectively. The reaction of furan-2-carbaldehyde phenylhydrazone with methyl 1-bromocyclohexane-1-carboxylate and zinc led to the formation of 4-(2-furyl)-2-phenyl-2,3-diazaspiro[4.5]decan-1-one.     

Synthesis of unsymmetrical arylthiophenes and bithienyls via oxidative cyclization of 1,3-butadiene-1-thiols

Oxidative cyclization of 2-mercapto-5-aryl-2,4-pentadienoic acids with iodine produced the respective 5-aryl-2-thenoic acids. The method was also suitable for the synthesis of unsymmetrical substituted 2,2′-bithienyls, and 2,3′-bithienyls. The synthesis of 5-carboxy-2′-bromo-5′-phenyl-2,3′-bithienyl from benzal-acetone demonstrated that oxidative cyclization of 1,3-butadiene-1-thiols is a useful procedure for preparing 5′-aryl-2,3′-bithienyls from simple carbonyl compounds. Preferential ring bromination of 2-phenyl-4-methyl-thiophene with N-bromosuccinimide and a radical catalyst was also observed.     

Synthesis of 5-Amino-1-aryl-4-(4-aryl-1,3-thiazol-2-yl)- 2,3-dihydro-1H-pyrrol-3-ones*

Reactions of 2-(4-aryl-1,3-thiazol-2-yl)-3-oxo-4-chlorobutyronitriles with primary aromatic amines result in nucleophilic substitution of the chlorine atom by amino group, followed by intramolecular addition of the secondary amino group to the cyano group. The products are 5-amino-1-aryl-4-(4-aryl-1,3-thiazol-2-yl)- 2,3-dihydro-1H-pyrrol-3-ones which are structurally related to the known antiischemic drugs.     

Lewis Acid-Mediated Ring Contraction of 2,4-Diaryl-2,3-dihydro-1H-1,5-benzodiazepines: Access to 2-Aryl-1-styrylbenzimidazoles

2,4-Diaryl-2,3-dihydro-1H-1,5-benzodiazepines readily undergo a ring contraction to generate 2-aryl-1-styrylbenzimidazoles in the presence of some Lewis acids. Copper acetate shows high efficiency compared with other Lewis acids. The ring contraction includes Lewis acid-catalyzed intramolecular addition, ammonium-induced ring-opening of the generated four-membered azetidine ring, deprotonation, and amine-promoted nucleophilic styryl 1,2-shift and elimination. Copper acetate serves as Lewis acid, base, and oxidant. The current reaction provides an efficient method for the convenient synthesis of 2-aryl-1-styrylbenzimidazole derivatives from readily available 2,4-diaryl-2,3-dihydro-1H-1,5-benzodiazepines.     

Straightforward methodology for the enantioselective synthesis of benzo[a]- and indolo[2,3-a]quinolizidines

An enantioselective two-step route to substituted benzo[a]- and indolo[2,3-a]quinolizidines has been developed. It consists of (i) a stereoselective cyclocondensation of a racemic or prochiral delta-oxo(di)ester with either (S)-(3,4-dimethoxyphenyl)alaninol or (S)-tryptophanol in a process involving a dynamic kinetic resolution and/or the differentiation of enantiotopic or diastereotopic ester groups, and (ii) a subsequent stereocontrolled cyclization on the aromatic ring taking advantage of the masked N-acyl iminium ion present in the resulting oxazolopiperidone lactams.     

Synthesis and antifungal activity of novel 14-membered benzomacrolides, as galbonolide analogues

Asymmetric total synthesis of benzene analogues of galbonolide, a 14-membered antifungal macrolide, possessing a benzene ring instead of a conjugated diene structure, was achieved starting from chiral 1-aryl-1-propanol obtained by enzyme-catalyzed kinetic resolution with high enantioselectivity. Representatively, a method for the introduction of a methylthio and chloride function at the vinyl position was also established. The resulting analogues unfortunately exhibited very little antifungal potency in comparison with galbonolide A.