John P. Wolfe

An Ammonia Equivalent for the Palladium-Catalyzed Amination of Aryl Halides and Triflates

Abstract Commercially available benzophenone imine serves as a convenient ammonia equivalent in the palladium-catalyzed amination of aryl halides and triflates. The benzophenone imine adducts can be cleaved directly to the corresponding primary anilines by catalytic hydrogenation or treatment with hydroxylamine hydrochloride or a catalytic amount of HCl in wet THF.

INTRAMOLECULAR PALLADIUM-CATALYZED ARYL AMINATION AND ARYL AMIDATION

Abstract Upon treatment with a palladium catalyst and a suitable base, aromatic halides undergo intramolecular substitution to form five, six, and seven-membered rings. In a similar fashion aryl halides with pendant amides or sulfonamides are cyclized to form five and six-membered rings.

Asymmetric Palladium-Catalyzed Carboamination Reactions for the Synthesis of Enantiomerically Enriched 2-(Arylmethyl)- and 2-(Alkenylmethyl)pyrrolidines

The enantioselective synthesis of 2-(arylmethyl)- and 2-(alkenylmethyl)pyrrolidine derivatives via Pd-catalyzed alkene carboamination reactions is described. These transformations generate enantiomerically enriched products with up to 94% ee from readily available alkenyl or aryl bromides and N-boc-pent-4-enylamines. The application of this method to a concise asymmetric synthesis of (-)-tylophorine is also discussed.

Improved Functional Group Compatibility in the Palladium-Catalyzed Amination of Aryl Bromides

Abstract Aryl bromides are coupled with amines in the presence of a palladium catalyst and a stoichiometric amount of cesium carbonate. Using these conditions base-sensitive functional groups, which were incompatible with our previously reported catalytic-amination reaction conditions, are well tolerated.

Intramolecular Alkene Aminopalladation Reactions of (dppf)Pd(Ar)[N(Ar1)(CH2)3CH═CH2] Complexes. Insertion of Unactivated Alkenes into Pd−N Bonds

The synthesis of (dppf)Pd(C(6)H(4)-p-F)[N(Ar(1))(CH(2))(3)CH horizontal lineCH(2)] complexes (3), which are thought to be intermediates in Pd-catalyzed alkene carboamination reactions, is described. These complexes undergo syn-migratory insertion of the alkene into the Pd-N bond to yield observable (dppf)palladium(aryl)(pyrrolidin-2-yl-methyl) complexes 6. Reductive elimination from 6 provides 2-benzylpyrrolidine derivatives 4. The rates of conversion of 3 to 6 (k(1)) and 6 to 4 (k(2)) were measured and are within 1 order of magnitude of each other. The syn-migratory insertion stereochemistry was confirmed through a deuterium labeling experiment. These are the first examples of syn-migratory insertions of unactivated alkenes into Pd-N bonds of well-defined complexes.

Synthesis of enantiomerically enriched imidazolidin-2-ones through asymmetric palladium-catalyzed alkene carboamination reactions

Positive water effect: A catalyst composed of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and (S)-Siphos-PE is effective for the enantioselective coupling of N-allyl ureas with aryl bromides to afford 4-substituted imidazolidin-2-ones. Added water leads to significantly improved enantioselectivities with electron-poor aryl halide substrates. It is suggested that the C-C bond-forming reductive elimination is the enantiodetermining step in these reactions.

Intramolecular Alkoxycyanation and Alkoxyacylation Reactions: New Types of Alkene Difunctionalizations for the Construction of Oxygen Heterocycles

Saturated oxygen heterocycles, such as tetrahydrofurans and dihydrobenzofurans, are important motifs in a myriad of biologically active compounds, including natural products and pharmaceutical targets. Therefore, there has been considerable interest in the development of new synthetic methods for the construction of these important structures. Many traditional approaches to the generation of these compounds involve ring formation through intramolecular SN2 reactions and related strategies. However, these approaches typically lead to the formation of only one bond during ring closure and often require somewhat complicated substrates. Late transition metal catalyzed alkene carboalkoxylations are a subclass of alkene difunctionalization reactions that have considerable utility for the construction of tetrahydrofurans, dihydrobenzofurans, and related oxygen heterocycles. These reactions effect formation of a C O bond during ring closure along with a C C bond adjacent to the ring and up to two stereocenters (Scheme 1). In most instances these transformations involve the coupling of an alcohol that bears

New strategy for the synthesis of substituted morpholines

A four-step synthesis of cis-3,5-disubstituted morpholines from enantiomerically pure amino alcohols is described. The key step in the synthesis is a Pd-catalyzed carboamination reaction between a substituted ethanolamine derivative and an aryl or alkenyl bromide. The morpholine products are generated as single stereoisomers in moderate to good yield. This strategy also provides access to fused bicyclic morpholines as well as 2,3- and 2,5-disubstituted products.

Stereoselective synthesis of cis- or trans-3,5-disubstituted pyrazolidines via Pd-catalyzed carboamination reactions: use of allylic strain to control product stereochemistry through N-substituent manipulation.

The stereoselective synthesis of either trans- or cis-3,5-disubstituted pyrazolidines is accomplished via Pd-catalyzed carboamination reactions of unsaturated hydrazine derivatives. The products are obtained in good yield with up to >20:1 diastereoselectivity. Stereocontrol is achieved by modulating the degree of allylic strain in the transition state for syn-aminopalladation through a simple modification of the substrate N(2)-substituent. The pyrazolidine products can be further transformed to 3,5-disubstituted pyrazolines via deprotection/oxidation, or to substituted 1,3-diamines via N-N bond cleavage.

Influence of Hydroxylamine Conformation on Stereocontrol in Pd-Catalyzed Isoxazolidine-Forming Reactions

Palladium-catalyzed carboamination reactions between N-Boc-O-(but-3-enyl)hydroxylamine derivatives and aryl or alkenyl bromides afford cis-3,5- and trans-4,5-disubstituted isoxazolidines in good yield with up to >20:1 dr. The diastereoselectivity observed in the formation of cis-3,5-disubstituted isoxazolidines is superior to selectivities typically obtained in other transformations, such as 1,3-dipolar cycloaddition reactions, that provide these products. In addition, the stereocontrol in the C-N bond-forming Pd-catalyzed carboamination reactions of N-Boc-O-(but-3-enyl)hydroxylamines is significantly higher than that of related C-O bond-forming carboetherification reactions of N-benzyl-N-(but-3-enyl)hydroxylamine derivatives. This is likely due to a stereoelectronic preference for cyclization via transition states in which the Boc group is placed in a perpendicular orientation relative to the plane of the developing ring, which derives from the conformational equilibria of substituted hydroxylamines.