Highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides from 1-bromo-1-fluoroalkenes via palladium-catalyzed carbonylation reactions

The highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides is described. 1-Bromo-1-fluoroalkenes (E/Z approximately 1:1), which are readily available starting materials, have been found to isomerize to high E/Z ratios after storage at -20 degrees C for 1 week or by photolysis at 254 nm. Since the (E)-isomers have been found to react faster than the corresponding (Z)-isomers at room temperature in Pd(0)-catalyzed reactions, the palladium-catalyzed carboalkoxylation of high E/Z 1-bromo-1-fluoroalkenes lead to a high Z/E (Z/E >/= 98:2) ratio of the alpha-fluoro-alpha,beta-unsaturated esters. When 1-bromo-1-fluoroalkenes (E/Z approximately 1:1) were reacted with HCOOH/NBu(3)/Pd(II)/DMF, the (E)-isomer was selectively reduced, and the remaining (Z)-1-bromo-1-fluoroalkenes were recovered in essentially pure isomeric form. The resulting mixture of (Z)-1-bromo-1-fluoroalkenes and the reduced products underwent similar palladium-catalyzed carboalkoxylation reactions at 70 degrees C, and the (E)-alpha-fluoro-alpha,beta-unsaturated esters were stereospecifically obtained. This methodology was also successfully applied for the stereospecific synthesis of (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides: the palladium-catalyzed carboamidation reaction of high E/Z and (Z)-1-bromo-1-fluoroalkenes lead to pure (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides, respectively.     

Studies on Pd(II)-catalyzed synthesis of (Z)-alpha-haloalkylidene-beta-lactones from cyclocarbonylation of 2-alkynols and the subsequent coupling reactions

[reaction: see text] A good regio- and stereoselectivity was observed for the PdCl2-catalyzed cyclocarbonylation of 2-alkynols with CuCl2 affording (Z)-alpha-chloroalkylidene-beta-lactones. The highly optically active (Z)-alpha-chloroalkylidene-beta-lactones could be easily prepared from the readily available optically active propargylic alcohols. The Pd(II)-catalyzed cyclocarbonylation of 2-alkynols with CuBr2 was also studied. Although the yields of (Z)-alpha-bromoalkylidene-beta-lactones were low, due to the relatively higher activity of the C-Br bond, the coupling reactions of (Z)-alpha-bromoalkylidene-beta-lactones were quite smooth to afford the corresponding products in high yields. A rationale for this reaction is discussed.     

Operationally simple and highly (E)-styrenyl-selective Heck reactions of electronically nonbiased olefins

Simple, mild, and efficient conditions are reported for a Pd(0)-catalyzed Heck reaction that delivers high yields and selectivity for (E)-styrenyl products using electronically nonbiased olefin substrates bearing a range of useful functionality. Preliminary mechanistic studies demonstrate that the σ-donating DMA solvent is crucial for high selectivity. Further studies suggest that the catalyst distinguishes between β-hydrogens on the basis of their relative hydridic character, in contrast to previously reported Pd(II)-catalyzed oxidative reaction conditions.     

Mechanistic analysis of iridium(III) catalyzed direct C-H arylations: a DFT study

In a recent experimental work the Ir complex [Ir(cod)(py)(PCy(3))](PF(6)) (that is, Crabtree's catalyst) has been shown to catalyze the C-H arylation of electron-rich heteroarenes with iodoarenes using Ag(2)CO(3) as base. For this process, an electrophilic metalation mechanism, (S(E)Ar) has been proposed as operative mechanism rather than the concerted metalation-deprotonation (CMD) mechanism, widely implicated in Pd-catalyzed arylation reactions. Herein we have investigated the C-H activation step for several (hetero)arenes catalyzed by a Ir(III) catalyst and compared the data obtained with the results for the Pd(II)-catalyzed C-H bond activation. The calculations demonstrate that, similar to Pd(II)-catalyzed reactions, the Ir(III)-catalyzed direct C-H arylation occurs through the CMD pathway which accounts for the experimentally observed regioselectivity. The transition states for Ir(III)-catalyzed direct C-H arylation feature stronger metal-C((arene)) interactions than those for Pd(II)-catalyzed C-H arylation. The calculations also demonstrate that ligands with low trans effect may decrease the activation barrier of the C-H bond cleavage.     

Total synthesis and biological evaluation of (-)-apicularen A and its analogues

The total synthesis of (-)-apicularen A (1), a highly cytostatic 12-membered macrolide, and its analogues is described. The convergent and distinct approach not only provides 1, but also opens the opportunity to synthesize C10-C11 functional analogues of 1. The key steps of the total synthesis include assembling of iodoalkene 12 and aldehyde 13by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. The (17E,20Z,22Z)-heptadienoylenamine moiety in the side chain is installed by an efficient Cu(I)-mediated coupling to complete the synthesis. Analogues of C11-epi-, C11-deoxy-C10-α-hydroxy-, and C10-C11 dehydrated apicularen A 3-5 were also prepared. Cytostatic activities of (-)-apicularen A and the three analogues for three different cancer cell lines are described.     

Conjugate Addition vs Heck Reaction: A Theoretical Study on Competitive Coupling Catalyzed by Isoelectronic Metal (Pd(II) and Rh(I))

Density functional theory studies have been carried out to investigate the mechanism of the Pd(II)(bpy)- and Rh(I)(bpy)-catalyzed conjugate additions and their competitive Heck reactions involving α,β-unsaturated carbonyl compounds. The critical steps of the mechanism are insertion and termination. The insertion step favors 1,2-addition of the vinyl-coordinated species to generate a stable C-bound enolate intermediate, which then may isomerize to either an oxa-π-allyl species or an O-bound enolate. The termination step involves a competition between β-hydride elimination, leading to a Heck reaction product, and protonolysis reaction that gives a conjugate addition product. These two pathways are competitive in the Pd(II)-catalyzed reaction, while a preference for protonolysis has been found in the Rh(I)-catalyzed reaction. The calculations are in good agreement with the experimental observations. The potential energy surface and the rate-determining step of the β-hydride elimination are similar for both Pd(II)- and Rh(I)-catalyzed processes. The rate-determining steps of the Pd(II)- and Rh(I)-catalyzed protonolysis are different. Introduction of an N- or P-ligand significantly stabilizes the protonolysis transition state via the O-bound enolate or oxa-π-allyl complex intermediate, resulting in a reduced free energy of activation. However, the barrier of the β-hydride elimination is less sensitive to ligands. For the Rh(I)-catalyzed reaction, protonolysis is calculated to be more favorable than the β-hydride elimination for all investigated N and P ligands due to the significant ligand stabilization to the protonolysis transition state. For the Pd(II)-catalyzed reaction, the complex with monodentate pyridine ligands prefers the Heck-type product through β-hydride elimination, while the complex with bidentate N and P ligands favors the protonolysis. The theoretical finding suggests the possibility to control the selectivity between the conjugate addition and the Heck reaction by using proper ligands.     

Allylsulfones through Palladium-Catalyzed Allylic C−H Sulfonylation of Terminal Alkenes

Two previously unknown protocols for Pd-catalyzed allylic C−H sulfonylation of terminal alkenes have been developed. While the former consists of a direct Pd(II)-catalyzed oxidative C−H allylic sulfonylation in the presence of sulfinate anions, the latter involves a sequential one-pot Pd(II)-catalyzed C−H allylic acetoxylation followed by a Pd(0)-catalyzed sulfonylation. The scope of both protocols was studied on 25 examples.     

Transannular macrocyclization via intramolecular B-alkyl Suzuki reaction

[reaction: see text]Transannular macrocyclizations via intramolecular B-alkyl Suzuki reactions are described. Regioselective terminal olefin hydroboration with 9-BBN followed by Pd(0)-catalyzed Suzuki reaction in the presence of a base such as TlOEt at high dilution generates macrocycles with a high degree of control over olefin geometry with isomerically pure E or Z vinyl iodide substrates. These reactions are complementary to ring closing metathesis (RCM) macrocyclizations and may prove superior in cases where control of olefin geometry is required.     

Convergent approach to pumiliotoxin alkaloids. Asymmetric total synthesis of (+)-pumiliotoxins A,B, and 225F

A versatile convergent approach for preparing the pumiliotoxin alkaloids has been developed employing Pd(0)-catalyzed cross-coupling reactions between homoallylic organozincs and vinyl iodides. The (Z)-iodoalkylidene indolizidine 34, which served as a common key intermediate, was synthesized through highly stereoselective addition of the chiral silylallene 19 to (S)-acetylpyrrolidine followed by a palladium-catalyzed intramolecular carbonylation[bond]cyclization sequence. This synthetic process allowed the first total synthesis of (+)-pumiliotoxin 225F. The intermediate (Z)-iodoalkylidene indolizidine 34 obtained was converted to a homoallylzinc chloride derivative and subjected to homoallyl-vinyl cross-coupling with the (E)-vinyl iodide 42 using Pd(PPh(3))(4) catalyst to give the cross-coupled product 47 with a 1,5-diene side chain. Subsequent deprotection provided (+)-pumiliotoxin A. On the other hand, the (Z)-iodoalkylidene indolizidine 34 was transformed into the homoallyl-tert-butyl zinc derivative, which underwent palladium-catalyzed cross-coupling with the (E)-vinyl iodide 50 and subsequent deprotection to afford (+)-pumiliotoxin B.     

Pd(OAc)2-catalyzed cyclization of 2,3-allenoic acids in the presence of terminal alpha,beta-unsaturated alkynones: a one-pot highly stereoselective synthesis of 4-(3'-oxo-1'(E)-alkenyl)-2(5H)-furanones

The Pd(OAc) 2-catalyzed cyclization reaction of 2,3-allenoic acids in the presence of terminal alpha,beta-unsaturated alkynones afforded an E/ Z mixture of 4-(3'-oxo-1'-alkenyl)-2(5 H)-furanones. A subsequent complete isomerization of the Z-isomer to E-isomer was observed in DMSO at 90 degrees C, which led to a highly stereoselective synthesis of 4-(3'-oxo-1'( E)-alkenyl)-2(5 H)-furanones. A possible mechanism is proposed.     

Regioselective Mercury(I)/Palladium(II)-Catalyzed Single-Step Approach for the Synthesis of Imines and 2-Substituted Indoles

An efficient synthesis of ketimines was achieved through a regioselective Hg(I)-catalyzed hydroamination of terminal acetylenes in the presence of anilines. The Pd(II)-catalyzed cyclization of these imines into the 2-substituted indoles was satisfactorily carried out by a C-H activation. In a single-step approach, a variety of 2-substituted indoles were also generated via a Hg(I)/Pd(II)-catalyzed, one-pot, two-step process, starting from anilines and terminal acetylenes. The arylacetylenes proved to be more effective than the alkyl derivatives.     

Stereodivergent approach to beta-hydroxy alpha-amino acids from C(2)-symmetrical alk-2-yne-1,4-diols

[reaction: see text] A new stereodivergent route to erythro- and threo-beta-substituted serines from a common C(2)-symmetrical alk-2-yne-1,4-diol is described. Stereocontrol in such an acyclic system is achieved by taking advantage of symmetry. Stereoselective alkyne reduction to either (Z)- or (E)-olefin allows selection of the stereochemistry of alpha-carbon in the final amino acid by using a Pd(0)-catalyzed process. This strategy has been applied to the synthesis of (2S,3S)-3-hydroxyleucine.     

Phosphine/palladium-catalyzed syntheses of alkylidene phthalans, 3-deoxyisoochracinic acid, isoochracinic acid, and isoochracinol

In this study we used sequential catalysis-PPh(3)--catalyzed nucleophilic addition followed by Pd(0)-catalyzed Heck cyclization--to construct complex functionalized alkylidene phthalans rapidly, in high yields, and with good stereoselectivities (E/Z ratios of up to 1:22). The scope of this Michael-Heck reaction includes substrates bearing various substituents around the alkylidene phthalan backbone. Applying this efficient sequential catalysis, we accomplished concise total syntheses of 3-deoxyisoochacinic acid, isoochracinic acid, and isoochracinol.     

Pd(0)/Au(I) redox incompatibilities as revealed by Pd-catalyzed homo-coupling of arylgold(I)-complexes

A Pd(II)-catalyzed homo-coupling of Au(I)-aryls is reported. The reaction is driven by a Pd(0)/Au(I) redox reaction that generates a gold mirror and Pd(II), and illustrates one of the challenges for developing dual catalytic Au-Pd systems.     

Snapshot of the palladium(II)-catalyzed oxidative biaryl bond formation by X-ray analysis of the intermediate diaryl palladium(II) complex

Pd(II) caught in the act: The diaryl Pd(II) intermediate of a Pd(II)-catalyzed oxidative biaryl bond formation proceeding via a double C-H bond activation has been isolated and fully characterized, including an X-ray crystal structure analysis. Stabilization due to chelation by adjacent pivaloyloxy and acetyl groups has allowed the isolation of this long-sought crucial intermediate. On gentle warming, the complex is transformed into a carbazole product, and the catalytically active Pd(II) species is regenerated by oxidation with Cu(II).     

Facile Synthesis of (Z,E)-9,11-Hexadecadienal,the Major Sex Pheromone Component of the Sugarcane Borer Diatraea saccharalis: An Efficient Strategy for Synthesis of (Z,E)-Dienic Pheromones

Practical and improved procedures for the synthesis of 7-bromo-(Z,E)-4,6-heptadienal by Pd(II)-catalyzed coupling reaction were developed. Based on the improved method, an efficient and stereoselective synthesis of (Z,E)-9,11-hexadecadienal, the main pheromone component of the sugarcane borer, Diatraea saccharalis, was achieved in 38% overall yield, which more desirable then previously reported methods. The stereochemistry relied on cross-coupling between Grignard reagent and protected 7-bromo-(Z,E)-4,6-heptadienal. The concise and facile synthetic strategy described herein provided a generally synthetic approach to other (Z,E)-dienic compounds.     

New reactivity of oxaziridine: Pd(II)-catalyzed aromatic C-H ethoxycarbonylation via C-C bond cleavage

A novel Pd(II)-catalyzed aromatic C-H ethoxycarbonylation with oxaziridine involving C-C bond cleavage is described. Various aromatic 2-phenylpyridines and related compounds as well as aryl ureas can be effectively ethoxycarbonylated. A catalytic cycle involving Pd(II) and Pd(IV) is proposed.     

Sequential reactions of trimethylstannyl anions with vinyl chlorides and dichlorides by the SRN1 mechanism followed by palladium-catalyzed cross-coupling processes

The reactions of trimethylstannyl ions (Me(3)Sn(-)) with vinyl chlorides in liquid ammonia give good yields of vinylstannanes. Some of them react in the dark, and others need light stimulation to react. The fact that these reactions are inhibited by radical and radical anion traps shows that they occur by the S(RN)1 mechanism. When the reaction takes place with 1,1-dichloro-1-alkenes, monosubstitution reduced products are formed in an E/Z mixture. The efficient synthesis of triarylolefins by Pd(0)-catalyzed cross-coupling reactions of vinylstannanes with several iodoarenes is reported. Similar yields were obtained in one-pot-type reactions.     

Palladium-catalyzed reactions of N-allylbenzotriazoles with amines and sulfonamides: A facile route to functionalized allylamines and N-allylsulfonamides

A variety of functionalized N-allylamines and N-allylsulfonamides are synthesized by Pd(II)-catalyzed intermolecular amination of the corresponding N-allylbenzotriazoles.     

Pd(II)-catalyzed annulation of N-benzyl-N-aroylmethyl-2-alkynamides with arylboronic acids: an efficient synthesis of highly substituted α-alkylidene-β-hydroxy-γ-lactams

A simple palladium(II)-catalyzed intramolecular addition of vinylpalladium species to ketones initiated by the carbopalladation of alkynamides under mild conditions without a Pd(II)/Pd(0) redox system was developed. This cascade reaction provides a new approach for the synthesis of highly substituted α-alkylidene-β-hydroxy-γ-lactams.