127 research outputs found
Palladium-catalyzed annulation of internal alkynes
A variety of aromatic and vinylic hetero- and carbocycles have been prepared in good yields by treating halogen- or triflate-containing substrates with internal alkynes in the presence of a palladium catalyst. Synthetically, the methodology provides a convenient, regioselective route to indenones, isocoumarins, [alpha]-pyrones, benzofurans, isochromenes, phenanthrenes, and other miscellaneous hetero- and carbocycles containing aryl, silyl, ester, and tert-alkyl groups. The regiochemistry of the process is generally controlled sterically and the reaction yields usually range from 50-80%
Controlling the Ambiphilic nature of sigma-arylpalladium intermediates in intramolecular cyclization reactions
The reactivity of main group organometallics, such as organolithium compounds (RLi) and Grignard reagents (RMgX), is quite straightforward. In these species the R group usually exhibits nucleophilic reactivity without any possibility of inducing electrophilic character. In contrast, in organopalladium complexes, researchers can switch the reactivity from electrophilic to nucleophilic relatively simply. Although σ-aryl and σ-vinylpalladium complexes are commonly used as electrophiles in C-C bond-forming reactions, recent research has demonstrated that they can also react with carbon-heteroatom multiple bonds in a nucleophilic manner. Nevertheless, researchers have completely ignored the issue of controlling the ambiphilic nature of such species. This Account describes our efforts toward selectively promoting the same starting materials toward either electrophilic α-arylation or nucleophilic addition reactions to different carbonyl groups. We could tune the properties of the σ-arylpalladium intermediates derived from amino-tethered aryl halides and carbonyl compounds to achieve chemoselective transformations. Therefore, chemists can control the ambiphilic nature of such intermediates and, consequently, the competition between the alternative reaction pathways by the adequate selection of the reaction conditions and additives (base, presence/absence of phenol, bidentate phosphines). The nature of the carbonyl group (aldehydes, ketones, esters, and amides) and the length of the tether connecting it to the aniline moiety also play an important role in the outcome of these processes. Our joint computational and experimental efforts to elucidate the reaction mechanism of these palladium-catalyzed transformations suggest that beyond the formation of the four-membered azapalladacycle, two major factors help to control the dual character of the palladium(II) intermediates derived from 2-haloanilines. First, their high nucleophilicity strongly modifies the interaction of the metal center with the carbonyl group. Second, the additive phenol exchanges the iodide ligand to give an arylpalladium(II) phenoxide complex, which has a beneficial effect on the arylation. The formation of this transient intermediate not only stabilizes the arylpalladium moiety, thus preventing the nucleophilic attack at the carbonyl group, but also assists the enolization reaction, which takes place in a more favorable intramolecular manner. The azapalladacycle intermediate is, in the words of J. R. R. Tolkien, "the one ring to bring them all and in the darkness to bind them." With this intermediate, we can easily achieve the synthesis of a variety of heterocyclic systems by selectively promoting electrophilic α-arylation or nucleophilic addition reactions from the same precursors
Palladium-Catalyzed Chemoselective Protodecarboxylation of Polyenoic Acids
Conditions for the first palladium-catalyzed chemoselective protodecarboxylation of polyenoic acids to give the desired polyenes in good yields are presented. The reactions proceed under mild conditions using either a Pd(0) or Pd(II) catalyst and tolerate a variety of aryl and aliphatic substitutions. Unique aspects of the reaction include the requirement of phosphines, water, and a polyene adjacent to the carboxylic acid
Synthesis of tetrasubstituted olefins and aryl ketones via carbopalladation of alkynes and nitriles
Palladium-catalyzed reactions are versatile methods for carbon-carbon bond formation due to their generality and ability to tolerate a wide range of important organic functional groups. Developing novel Palladium-catalyzed reactions has therefore been of great interest to synthetic chemists for years;The regio- and stereoselective synthesis of tetrasubstituted olefins is a long-pursuing challenge for synthetic chemists. A multi-component reaction route is ideal to generate various tetrasubstituted olefins in a very concise manner and should be highly desirable for applications in combinatorial chemistry. A highly efficient, regio- and stereoselective route to tetrasubstituted olefins has been developed by the Pd-catalyzed three-component reaction of aryl iodides, internal alkynes, and arylboronic acids as described in Chapter 1. By applying the synthetic protocol we have developed, tamoxifen and its derivatives have been successfully prepared in one step with excellent regio- and stereochemical control, employing readily available starting materials;A novel Pd-catalyzed reaction between arylboronic acids and internal alkynes for the synthesis of tetrasubstituted olefins has been successfully developed as described in Chapter 2. Molecular O2 is used as an oxidant and no base is needed for this reaction. A wide variety of tetrasubstituted olefins have been successfully synthesized under our simple and very mild reaction conditions;The activation of nitrile functionality by organopalladium compounds is rather rare and a challenge in Pd chemistry. Using a highly cationic Pd(II) catalyst, a new route to aryl ketones or ketimines has been successfully developed by a novel reaction between arenes and nitriles as described in Chapter 3. A novel reaction between an arylboronic acid and a nitrile has also been successfully developed as a convenient route to aryl ketones;Chromone is an abundant key structure in many natural products. An efficient route to iodochromones has been successfully developed via ICl-induced cyclization as described in Chapter 4. The chemistry is run under very mild conditions and tolerates a wide variety of functional groups. The iodochromones products can be easily transformed to other substituted chromones or polycyclic compounds using organopalladium chemistry
Carbocycle synthesis via novel organopalladium addition to nitriles
Rarely observed carbopalladation of the cyano group has been investigated. Synthetic methodology for 2,3-diarylindenones by the palladium-catalyzed annulation of alkynes with 2-iodoarenenitriles has been developed. This methodology has also been adapted to the annulation of bicyclic olefins. The reaction affords 2,3-diarylindenones and polycyclic aromatic ketones in very good to excellent yields and tolerates a number of functional groups, making it an efficient synthetic route to these compounds. The reaction is believed to proceed via (1) oxidative addition of the aryl iodide to Pd(0), (2) arylpalladium addition to the carbon-carbon multiple bond, (3) addition of the resulting vinylic or alkylpalladium species across the triple bond of the cyano group to produce an iminopalladium moiety, and (4) hydrolysis of the imine intermediate. A model accounting for the electronic effects of substituents on the aromatic ring of the nitrile has also been proposed.;The palladium-catalyzed annulation of alkynes with iodoarenes containing a cyano group has been extended to the synthesis of 3,4-disubstituted 2-aminonaphthalenes. (2-Iodophenyl)-acetonitrile reacts with a variety of internal alkynes to afford 2-aminonaphthalenes in high yields. In many cases, the regioselectivity of this reaction is excellent. The scope and limitations of this process, which proceeds via a mechanism similar to the reaction between 2-iodoarenenitriles and alkynes, have been studied. When introduced into the reaction, certain hindered propargylic alcohols have been found to afford 1,3-benzoxazine derivatives rather than the expected 2-aminonaphthalenes. The involvement of trialkylamine bases in the formation of these heterocyclic compounds has been established and a mechanism for this transformation has been proposed.;A general and efficient procedure for the synthesis of 2,2-disubstituted indanones by the palladium-catalyzed cyclization of 3-(2-iodoaryl)propanenitriles has been developed. This process is also based on intramolecular carbopalladation of the cyano group. A variety of indanones have been prepared in high yields from readily available starting materials containing various functional groups that are compatible with the reaction conditions. The reaction is not limited to the synthesis of indanones as other benzocyclic ketones, as well as a number of substituted cyclopentenones, have been synthesized by this methodology
Palladium-catalyzed approaches to carbo- and heterocyclic compounds
The palladium-catalyzed annulation of alkenes, 1,3-dienes, and alkynes has been further extended to include the synthesis of alpha-alkylidene-gamma-butyrolactones, indanones, 2-cyclopentenones, and quinolines. In addition, the scope and limitations of a palladium(II)-catalyzed process are presented in which alpha,beta-unsaturated ketones are formed from the corresponding enol silyl ethers.;Chapter 1 is a publication that describes the synthesis of alpha-alkylidene-gamma-butyrolactones via the palladium-catalyzed heteroannulation of acyclic and cyclic 1,3-dienes by alpha-iodo and alpha-bromo acrylic acids. This process has proven to be highly regio- and stereoselective. Annulation predominately occurs on the less hindered end of the diene, and with acyclic dienes the E-isomer is the major product. The success of this process is dependent upon the use of the sterically hindered, electron-rich phosphine ligand D tBPF.;Chapter 2 presents the synthesis of indanones and 2-cyclopentenones by the palladium-catalyzed carbonylative cyclization of unsaturated aryl iodides and dienyl triflates, iodides, and bromides. This cyclization is particularly effective on substrates that contain a terminal olefin. It is likely that this palladium transformation is forming an indenone intermediate, which is coordinated to a palladium hydride species. This palladium hydride can add back across the carbon-carbon double bond to form a palladium enolate, which is protonated by H2O.;Chapter 3 examines the synthesis of quinolines through a palladium-catalyzed iminoannulation of internal alkynes. In order to achieve quinoline product, this annulation process needs to proceed through a 6-endo ring closure. However, this process is in competition with the more favorable 5-exo ring closure, which leads to an isoindole system. While the yields and generality for the synthesis of quinolines are only moderate, the optimization results have proven to be interesting from a mechanistic point of view.;Chapter 4 concerns the synthesis of alpha,beta-unsaturated ketones from the corresponding enol silyl ethers using a catalytic palladium(II) strategy. This palladium(II) procedure is performed using catalytic amounts of Pd(OAc) 2 in DMSO at room temperature and uses O2 as an efficient reoxidant
Synthesis of heterocycles via palladium-catalyzed carbonylative annulation of internal and terminal alkynes
The subject of this dissertation is the study of palladium-catalyzed reactions of internal and terminal alkynes with ortho-substituted aryl iodides such as, o-iodophenols and N-substituted o-iodoanilines, in the presence of carbon monoxide (carbonylative annulation). The exploration of these reactions have led to the development of efficient syntheses of the important heterocycles coumarins and 2-quinolones.;3,4-Disubstituted coumarins are efficiently synthesized by the palladium-catalyzed annulation of internal alkynes by o-iodophenols in the presence of just one atmosphere of carbon monoxide. The use of a sterically unhindered pyridine base is essential to achieve high yields. The reaction accommodates a number of organic functional groups both on the alkyne and the o-iodophenol, thus affording a wide variety of coumarins in moderate to good yields. The main disadvantage of the process is formation of mixtures of regioisomers in reactions employing unsymmetrical alkynes.;The use of N-substituted o-iodoanilines as annulating agents provides an efficient synthesis of 3,4-disubstituted 2-quinolones. In this process, the selection of the nitrogen protecting group is crucial for the success of the reaction. The best results are obtained utilizing alkyl carbamates, tosylamides and trifluoroacetamides. The major features of this process are similar to those of the coumarin synthesis.;These annulation processes are the first examples of the insertion of an alkyne into the arylpalladium bond occurring in preference to the insertion of CO. We have shown that the unusual order of insertion arises from the low reactivity of the initially formed acylpalladium complex towards internal alkynes.;Utilizing the reaction conditions developed for the carbonylative annulation of internal alkynes we have been able to affect the carbonylative annulation of terminal alkynes by o-iodophenols or o-iodoaniline derivatives to afford coumarins or 2-quinolones, respectively, in modest yields. The formation of coumarins and 2-quinolones in this process is in stark contrast with all previously described palladium-catalyzed carbonylative annulations of terminal alkynes, which have afforded chromones and 4-quinolones. Moreover, under our reaction conditions terminal alkynes insert into the carbon-palladium bond instead of undergoing a Sonogashira-type coupling. This reaction pathway is confirmed by an isotope labeling experiment
Palladium-catalyzed synthesis of heterocycles and highly functionalized polycyclics
Palladium catalyzes the regio- and stereoselective annulation of allenes by vinylic halides bearing tertiary alcohol and p-toluenesulfonamide groups to produce a variety of 5- and 6-membered ring heterocycles containing a 1,3-diene moiety. In addition, the palladium-catalyzed reaction of N-(2-iodo-2-alkenyl)-p-toluenesulfonamides with diphenylacetylene or 4,4-dimethyl-2-pentyne affords pyrolidine derivatives containing a 1,3-diene moiety, or unexpected 2-alkenyl substituted [alpha],[beta]-unsaturated aldehydes. These synthetically useful intermediates are difficult to prepare or inaccessible by other existing methodology;A number of 3,4,6-tri- and 3,4,5,6-tetrasubstituted [alpha]-pyrones have been prepared in good yields by the reaction of vinylic iodides or triflates bearing ester functionality with internal alkynes in the presence of a palladium catalyst. The methodology provides an especially simple, convenient, and regioselective route to [alpha]-pyrones containing aryl, silyl, tert,-alkyl and other hindered groups. This methodology is important due to the fact that [alpha]-pyrones occur as structural subunits in numerous natural products that exhibit a wide range of biological activity, and very recently, low molecular weight [alpha]-pyrones have been shown to be potent HIV-1 protease inhibitors;2,5-Cyclohexadienyl-substituted aryl and vinylic iodides have been reacted with carbon nucleophiles (diethyl malonate, 2-methyl-1,3-cyclohexanedione), nitrogen nucleophiles (morpholine, potassium phthalimide, N-benzyl tosylamide, di-tert,-butyl iminodicarboxylate, lithium azide and anilines), a sulfur nucleophile (sodium benzenesulfinate), and oxygen nucleophiles (lithium acetate and phenols) in the presence of a palladium catalyst to afford products of cyclization and subsequent cross-coupling in good to excellent yields. In most cases, this process is highly diastereoselective and the products are formed as single diastereoisomers. The structures of the representative compounds have been determined by 1H NMR, 13C NMR, COSY, HMQC, and NOESY spectroscopy. This methodology has potential applications in natural product synthesis, and may provide quick access to a library of compounds with different skeletons and functionality
- …