Sequential hydrocarbon functionalization: allylic C-H oxidation/vinylic C-H arylation

A Pd(II)/sulfoxide-catalyzed sequential allylic C-H oxidation/vinylic C-H arylation of alpha-olefins to furnish E-arylated allylic esters in high regio- and E:Z selectivities (>20:1) is reported. The broad scope of this method with respect to the alpha-olefin, carboxylic acid, and aryl boronic acid enables the rapid assembly of densely functionalized fragments for complex molecule synthesis from cheap, abundant hydrocarbon starting materials. The Pd(II)/sulfoxide-catalyzed vinylic C-H arylation of electronically unbiased olefins with aryl boronic acids proceeds under oxidative, acidic conditions and mild temperatures (room temperature to 45 degrees C).     

Highly (E)-selective Wadsworth-Emmons reactions promoted by methylmagnesium bromide

An experimentally simple protocol for the very highly (E)-selective Wadsworth-Emmons reaction [(E):(Z) selectivities in excess of 180:1 in some cases] of a range of straight-chain and branched aliphatic, substituted aromatic, and base-sensitive aldehydes via reaction with an alkyl diethylphosphonoacetate and MeMgBr is reported.     

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.     

Transmetallation versus β-hydride elimination: the role of 1,4-benzoquinone in chelation-controlled arylation reactions with arylboronic acids

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4-benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron-deficient alkene opens up a low-energy reaction pathway from the post-insertion σ-alkyl complex. The association of BQ lowers the free-energy barrier for transmetallation of the σ-alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ-mediated reductive elimination and leads to the saturated diarylated product.     

A versatile catalyst for Heck reactions of aryl chlorides and aryl bromides under mild conditions.

In the presence of Cy2NMe, Pd/P(t-Bu)3 serves as an exceptionally mild and versatile catalyst for Heck reactions of aryl chlorides and bromides. A sterically and electronically diverse array of aryl bromides, as well as activated aryl chlorides, couple with a range of mono- and disubstituted olefins at room temperature, furnishing the arylated product with high E/Z stereoselection. The corresponding reactions of a broad spectrum of electron-neutral and electron-rich aryl chlorides proceed at elevated temperature, also with high selectivity. In terms of scope and mildness, Pd/P(t-Bu)3/Cy2NMe represents an advance over previously reported catalysts for these Heck coupling processes.     

Transmetallation Versus β‐Hydride Elimination: The Role of 1,4‐Benzoquinone in Chelation‐Controlled Arylation Reactions with Arylboronic Acids

The formation of an atypical, saturated, diarylated, Heck/Suzuki, domino product produced under oxidative Heck reaction conditions, employing arylboronic acids and a chelating vinyl ether, has been investigated by DFT calculations. The calculations highlight the crucial role of 1,4‐benzoquinone (BQ) in the reaction. In addition to its role as an oxidant of palladium, which is necessary to complete the catalytic cycle, this electron‐deficient alkene opens up a low‐energy reaction pathway from the post‐insertion σ‐alkyl complex. The association of BQ lowers the free‐energy barrier for transmetallation of the σ‐alkyl complex to create a pathway that is energetically lower than the oxidative Heck reaction pathway. Furthermore, the calculations showed that the reaction is made viable by BQ‐mediated reductive elimination and leads to the saturated diarylated product.     

Highly selective palladium-catalyzed Heck reactions of aryl bromides with cycloalkenes

[reaction: see text] The influence of palladium catalysts and reaction conditions on the selectivity of Heck reactions of aryl bromides with cyclohexene and cyclopentene has been investigated. It is shown that the addition of DMSO as a cosolvent leads to improved selectivities of nonconjugated aryl olefins. On the other hand, high selectivities for conjugated arylcyclopentenes have been obtained with the catalytic system DMA/Na2CO3/Pd2(dba)3 x dba/PCy3.     

Solvent-dependent stereoselectivity in a Still-Wittig rearrangement: an experimental and ab initio study

[see reaction]. The Still-Wittig rearrangement gave opposite selectivities for (Z:E)-alkenes in THF (3:1) vs toluene (1:3) in the synthesis of serine-proline dipeptide amide isosteres. Four transition states leading to (Z)-and (E)-alkenes with THF and without (representing toluene) were identified by ab initio calculations at the 3-21G* level. The calculated (Z:E)-ratios with THF (4.7:1) and without THF (1:3.2) suggested that the transition state geometries and energies were well-represented by the calculations.     

Intramolecularly sensitized precipitons: a model system for application to metal sequestration

We have investigated light-triggered or catalytically activated precipitation agents and have proposed the name "precipiton" for such molecules or molecular fragments. A phase separation is induced when the precipiton isomerizes to a low-solubility form. In this paper we describe the first intramolecularly activated precipitons. The isomerization process is induced by intramolecular triplet energy transfer from a covalently attached metal complex. As expected, intramolecular sensitization leads to a more rapid isomerization than can be achieved by intermolecular sensitization at accessible concentrations. Two isomeric bichromophoric precipiton species, each containing [Ru(bpy)(3)](2+) and 1,2-bis(biphenyl)ethene units covalently linked together by an ether tether, have been synthesized and characterized, and their photochemical properties have been investigated. The rates of photoisomerization of these complexes, [((Z)-1,2-bis(biphenyl)ethene-bpy)Ru(bpy)(2)](PF(6))(2) (2Z) and [((E)-1,2-bis(biphenyl)ethene-bpy)Ru(bpy)(2)](PF(6))(2) (2E), were compared to those of their untethered analogues, (Z)-1,2-bis(biphenyl)ethene-OTBS (1Z) and (E)-1,2-bis(biphenyl)ethene-OTBS (1E), where ruthenium sensitization occurred through an intermolecular pathway. Upon irradiation with visible light (lambda > or = 400 nm) in degassed solution, 2Z/E and 1Z/E obeyed reversible first-order rate kinetics. The intramolecularly sensitized precipiton 2Z isomerized 250 times faster (k(2Z-->2E) = 1.0 x 10(-3) s(-1) with a 51% neutral density filter) than the intermolecular case 1Z (k(1Z-->1E) = 0.80 x 10(-5) s(-1)). For 1E and 2E, the isomerization rates were k(1E-->1Z) = 11.0 x 10(-5) s(-1) and k(2E-->2Z) = 1.6 x 10(-3) s(-1), respectively. The average Z/E mole ratio at the photostationary state was 62/38 for 2Z/E and 93/7 for 1Z/E. The impetus for this study was our desire to evaluate the possibility of using metal-binding precipitons that would precipitate only upon metal-to-precipiton binding and would be inert to visible light in the absence of metals.     

Alkyne Aminopalladation/Heck and Suzuki Cascades: An Approach to Tetrasubstituted Enamines

Alkyne aminopalladation reactions starting from tosylamides are reported. The emerging vinylic Pd species are converted either in an intramolecular Heck reaction with olefinic units or in an intermolecular Suzuki reaction by using boronic acids exhibiting broad functional group tolerance. Tetra(hetero)substituted tosylated enamines are obtained in a simple one-pot process.     

Stereoselective synthesis of 3-alkylideneoxindoles via palladium-catalyzed domino reactions

We have developed efficient catalytic methods for the stereoselective and diversity synthesis of various (E)-, (Z)-, and disubstituted 3-alkylideneoxindoles and 3-alkylidenebenzofuran-2-ones via palladium-catalyzed Heck/Suzuki-Miyaura, Heck/Heck, and Heck/carbonylation/Suzuki-Miyaura domino reactions.     

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.     

3-bromozinc propenyl esters: an experimental and theoretical study of the unique stereocrossover observed in their addition to aromatic and aliphatic aldehydes

We report the results of a combined experimental and theoretical study on the reaction of 3-bromopropenyl acetate in the presence of zinc with three different aldehydes (i.e., benzaldehyde, 2-methylpropanal, and cyclohexanecarboxaldehyde). A 80% de in favor of the anti product has been experimentally observed with both saturated aldehydes, while for benzaldehyde, a 1:1 syn/anti ratio has been found. DFT computations show the existence of three eta1-allylic organozinc complexes [gamma-(Z)-5a, gamma-(E)-5a, and alpha-5a], very close in energy. Only gamma-(Z)-5a and gamma-(E)-5a lead to the observed product. The computational investigation of the reaction of these allylic organozinc complexes with benzaldehyde and 2-methylpropanal demonstrates in both cases the existence of two competitive reaction paths leading to the syn and anti adducts, respectively. An anti preference has been found for 2-methylpropanal with both gamma-(Z)-5a and gamma-(E)-5a species (a diastereoselectivity larger than 80% is predicted), in agreement with the experiment. With benzaldehyde, while the reaction of gamma-(Z)-5a retains an anti-stereopreference (de = 70%), that involving gamma-(E)-5a is characterized by two degenerate transition states. In this case, the agreement between computations and experiments would be satisfactory under the assumption that the initial oxidative addition affords the gamma-(E)-5a zinc complex only. Additional MP2 computations have demonstrated that pi-stacking interactions can play a significant role in determining the relative energy of the transition states leading to the syn and anti products.     

Enantioselective Difunctionalization of Alkenes by a Palladium-Catalyzed Heck/Sonogashira Sequence

Sonogashira-type cross-couplings are one of the most significant alkynylations in organic chemistry. One of the first palladium-catalyzed intramolecular Heck/Sonogashira reactions of alkenes with terminal alkynes is now reported. With this method, a variety of uniquely substituted chiral benzene-fused heterocycles bearing a propargyl-substituted all-carbon quaternary stereocenter were obtained in a straightforward, high-yielding, and highly stereoselective manner under mild conditions. Salient features of this process include the use of readily available substrates, high selectivities, a broad substrate scope as well as versatile product functionalizations.     

Nickel‐Catalyzed Mizoroki–Heck Reaction of Aryl Sulfonates and Chlorides with Electronically Unbiased Terminal Olefins: High Selectivity for Branched Products

Achieving high selectivity in the Heck reaction of electronically unbiased alkenes has been a longstanding challenge. Using a nickel‐catalyzed cationic Heck reaction, we were able to achieve excellent selectivity for branched products (≥19:1 in all cases) over a wide range of aryl electrophiles and aliphatic olefins. A bidentate ligand with a suitable bite angle and steric profile was key to obtaining high branched/linear selectivity, whereas the appropriate base suppressed alkene isomerization of the product. Although aryl triflates are traditionally used to access the cationic Heck pathway, we have shown that, by using triethylsilyl trifluoromethanesulfonate, we can effect a counterion exchange of the catalytic nickel complex, such that cheaper and more stable aryl chlorides, mesylates, tosylates, and sulfamates can be used to yield the same branched products with high selectivity.     

Oxidative dimerization of (E)- and (Z)-2-propenylsesamol with O2 in the presence and absence of laccases and other catalysts: selective formation of carpanones and benzopyrans under different reaction conditions

The oxidative dimerization of 2-propenylsesamol to carpanone with O(2) as the oxidant, which probably proceeds as a domino phenol oxidation/anti-β,β-radical coupling/intramolecular hetero Diels-Alder reaction, can be efficiently catalyzed by laccases. Experiments with laccases and other catalysts like a Co(salen) type catalyst and PdCl(2) clearly demonstrate that the diastereoselectivity of the carpanone formation does not depend on the catalyst but on the double-bond geometry of the substrate. With (E)-2-propenylsesamol as the substrate, carpanone and a so far unknown carpanone diastereoisomer are formed in a 9:1 ratio. When (Z)-2-propenylsesamol is used as starting material, carpanone is accompanied by two carpanone diastereoisomers unknown so far in a 5:1:4 ratio. All three carpanone diastereoisomers have been separated by HPLC, and their structures have been elucidated unambiguously by NMR spectroscopy, DFT calculations, and spin work analysis. When the oxidation of 2-propenylsesamol with O(2) is performed in the absence of any catalyst two diastereoisomeric benzopyrans are formed, probably as the result of a domino oxidation/intermolecular hetero Diels-Alder reaction. Under these conditions, carpanone is formed in trace amounts only.     

A palladium-catalyzed regio- and stereoselective four-component coupling reaction

Pd(PPh(3))(4) catalytically assembles sulfenamide, alkyne, carbon monoxide, and diphenyl diselenide regio- and stereoselectively in a one-pot four-component coupling reaction to yield (Z)-beta-selenyl acrylamides. The reaction proceeds in good to excellent yields (60-95%) and is tolerant of a range of functional groups on both the nitrogen of the sulfenamide and the alkyne. Moderate selectivities ranging from 4:1 to 7:1 beta-selenyl to beta-sulfenyl acrylamide have been observed despite the initial concentration of 2:1 selenium to sulfur in the reaction. The chalcogeno selectivity was found to depend directly on CO pressure; increased pressure decreased selectivity for selenium over sulfur.     

Heck‐Type Reactions of Imine Derivatives: A DFT Study

The mechanism of a recently discovered intramolecular Heck‐type coupling of oximes with aryl halides (Angew. Chem. Int. Ed. 2007 , 46, 6325) was systematically studied by using density functional methods enhanced with a polarized continuum solvation model. The overall catalytic cycle of the reaction was found to consist of four steps: oxidative addition, migratory insertion, β‐H elimination, and catalyst regeneration, whereas an alternative base‐promoted C? H activation pathway was determined to be less favorable. Migratory insertion was found to be the rate determining step in the catalytic cycle. The apparent activation barrier of migratory insertion of the (E)‐oxime was +20.5 kcal mol^?1, whereas the barrier of (Z)‐oxime was as high as +32.7 kcal mol^?1. However, (Z)‐oxime could isomerize to form the more active (E)‐oxime with the assistance of K₂CO₃, so that both the (E)‐ and (Z)‐oxime substrates could be transformed to the desired product. Our calculations also indicated that the Z product was predominant in the equilibrium of the isomerization of the imine double bond, which constituted the reason for the good Z‐selectivity observed for the reaction. Furthermore, we examined the difference between the intermolecular Heck‐type reactions of imines and of olefins. It was found that in the intermolecular Heck‐type coupling of imines, the apparent activation barrier of migratory insertion was as high as +35 kcal mol^?1, which should be the main obstacle of the reaction. The analysis also revealed the main problem for the intermolecular Heck‐type reactions of imines, which was that the breaking of a C?N π bond was much more difficult than the breaking of a C?C π bond. After systematic examination of a series of substituted imines, (Z)‐N‐amino imine and N‐acetyl imine were found to have relatively low barriers of migratory insertion, so that they might be possible substrates for intermolecular Heck‐type coupling.     

Enantioselective and Regiodivergent Addition of Purines to Terminal Allenes: Synthesis of Abacavir

The rhodium‐catalyzed atom‐economic asymmetric N‐selective intermolecular addition of purine derivatives to terminal allenes is reported. Branched allylic purines were obtained in high yields, regioselectivity and outstanding enantioselectivity utilizing a Rh/Josiphos catalyst. Conversely, linear selective allylation of purines could be realized in good to excellent regio‐ and E/Z‐selectivity with a Pd/dppf catalyst system. Furthermore, the new methodology was applied to a straightforward asymmetric synthesis of carbocyclic nucleoside abacavir.     

Pd-catalyzed alkyl to aryl migration and cyclization: an efficient synthesis of fused polycycles via multiple C-H activation

A novel palladium migration methodology for the synthesis of complex fused polycycles has been developed. This process involves 1,4-palladium alkyl to aryl migrations via through-space C-H activation, followed by intramolecular arylation or an intermolecular Heck reaction providing a very efficient way to synthesize fused ring systems.