DFT calculations have been performed on the palladium-catalyzed carboiodination reaction. The reaction involves oxidative addition, alkyne insertion, C−N bond cleavage, and reductive elimination. For the alkylpalladium iodide intermediate, LiOtBu stabilizes the intermediate in non-polar solvents, thus promoting reductive elimination and preventing β-hydride elimination. The C−N bond cleavage process was explored and the computations show that PPh₃ is not bound to the Pd center during this step. Experimentally, it was demonstrated that LiOtBu is not necessary for the oxidative addition, alkyne insertion, or C−N bond cleavage steps, lending support to the conclusions from the DFT calculations. The turnover-limiting steps were found to be C−N bond cleavage and reductive elimination, whereas oxidative addition, alkyne insertion, and formation of the indole ring provide the driving force for the reaction.

Palladium-catalyzed allylic substitution reactions are among the most efficient methods to construct C−C bonds between sp³-hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a “soft”-nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with “hard” nucleophiles, which attack the metal before C−C bond formation. Introduced herein is a rare nickel-based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft-nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising.

The first two highly enantioselective palladium-catalyzed allylic alkylations with benzylic nucleophiles, activated with Cr(CO)₃, have been developed. These methods enable the enantioselective synthesis of α-2-propenyl benzyl motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99 % ee and 92 % yield). This approach was employed to prepare a nonsteroidal anti-inflammatory drug analogue.

A unique chemo- and regioselective α- and γ-arylation of palladium azapentadienyl intermediates is presented. Two distinct catalysts and sets of conditions successfully controlled the regioselectivity of the arylation. These methods provide the first umpolung C−H functionalization of azapentadienyl palladium intermediates and enable the divergent synthesis of allylic amine and enamine derivatives, which are of significant interest in the pharmaceutical industry.

Palladium-catalyzed allylic substitution reactions are among the most efficient methods to construct C−C bonds between sp³-hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a “soft”-nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with “hard” nucleophiles, which attack the metal before C−C bond formation. Introduced herein is a rare nickel-based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft-nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising.

The first two highly enantioselective palladium-catalyzed allylic alkylations with benzylic nucleophiles, activated with Cr(CO)₃, have been developed. These methods enable the enantioselective synthesis of α-2-propenyl benzyl motifs, which are important scaffolds in natural products and pharmaceuticals. A variety of cyclic and acyclic allylic carbonates are competent electrophilic partners furnishing the products in excellent enantioselectivity (up to 99 % ee and 92 % yield). This approach was employed to prepare a nonsteroidal anti-inflammatory drug analogue.

A unique chemo- and regioselective α- and γ-arylation of palladium azapentadienyl intermediates is presented. Two distinct catalysts and sets of conditions successfully controlled the regioselectivity of the arylation. These methods provide the first umpolung C−H functionalization of azapentadienyl palladium intermediates and enable the divergent synthesis of allylic amine and enamine derivatives, which are of significant interest in the pharmaceutical industry.

Diarylmethylamines are key intermediates and products in the pharmaceutical industry. Herein we disclose a novel method toward the synthesis of these important compounds via CH functionalization. Presented is a reversible deprotonation of N-Boc benzylalkylamines at the benzylic CH with in situ arylation by a NiXantPhos-based palladium catalyst (50–93 % yield, 29 examples). The method is also successful with N-Boc-tetrahydroisoquinolines. The advantages of this method are it avoids strong bases, low temperatures, and the need to transmetallate to main group metals for the coupling.

A formidable challenge at the forefront of organic synthesis is the control of chemoselectivity to enable the selective formation of diverse structural motifs from a readily available substrate class. Presented herein is a detailed study of chemoselectivity with palladium-based phosphane catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts, and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki–Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity. Studies on the chemoselectivity of Pd catalysts in their reactivity with boron-bearing allylic acetate derivatives led to the development of diverse and practical reactions with potential utility in synthetic organic chemistry.

A novel approach to produce diaryl sulfoxides from aryl benzyl sulfoxides is reported. Optimization of the reaction conditions was performed using high-throughput experimentation techniques. The [Pd(dba)₂]/NiXantPhos catalyst system successfully promotes a triple relay process involving sulfoxide α-arylation, CS bond cleavage, and CS bond formation. The byproduct benzophenone is formed by an additional palladium-catalyzed process. It is noteworthy that palladium-catalyzed benzylative CS bond cleavage of sulfoxides is unprecedented. A wide range of aryl benzyl sulfoxides, as well as alkyl benzyl sulfoxides with various (hetero)aryl bromides were employed in the triple relay process in good to excellent yields (85–99 %). Moreover, aryl methyl sulfoxides, dibenzyl sulfoxides, and dimethylsulfoxide could be utilized to generate diaryl sulfoxides involving multiple catalytic cycles by a single catalyst.

Sulfenate anions are known to act as highly reactive species in the organic arena. Now they premiere as organocatalysts. Proof of concept is offered by the sulfoxide/sulfenate-catalyzed (1–10 mol %) coupling of benzyl halides in the presence of base to generate trans-stilbenes in good to excellent yields (up to 99 %). Mechanistic studies support the intermediacy of sulfenate anions, and the deprotonated sulfoxide was determined to be the resting state of the catalyst.

By using a novel, simple, and convenient synthetic route, enantiopure 6-ethynyl-BINOL (BINOL=1,1-binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper-catalyzed alkyne–azide cycloaddition (CuAAC) reaction. The polystyrene (PS)-supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert-butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson–Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co₂(CO)₈/N-methyl morpholine N-oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.

The combination of aryl bromides, allylbenzene, base and a palladium catalyst usually results in a Heck reaction. Herein we combine these same reagents, but override the Heck pathway by employing a strong base. In the presence of LiN(SiMe₃)₂, allylbenzene derivatives undergo reversible deprotonation. Transmetalation of the resulting allyllithium intermediate to LPdAr(Br) and reductive elimination provide the 1,1-diarylprop-2-enes, which are not accessible by the Heck reaction. The regioselectivity in this deprotonative cross-coupling process is catalyst-controlled and very high.

Sulfenate anions are known to act as highly reactive species in the organic arena. Now they premiere as organocatalysts. Proof of concept is offered by the sulfoxide/sulfenate-catalyzed (1–10 mol %) coupling of benzyl halides in the presence of base to generate trans-stilbenes in good to excellent yields (up to 99 %). Mechanistic studies support the intermediacy of sulfenate anions, and the deprotonated sulfoxide was determined to be the resting state of the catalyst.

A novel approach to produce diaryl sulfoxides from aryl benzyl sulfoxides is reported. Optimization of the reaction conditions was performed using high-throughput experimentation techniques. The [Pd(dba)₂]/NiXantPhos catalyst system successfully promotes a triple relay process involving sulfoxide α-arylation, CS bond cleavage, and CS bond formation. The byproduct benzophenone is formed by an additional palladium-catalyzed process. It is noteworthy that palladium-catalyzed benzylative CS bond cleavage of sulfoxides is unprecedented. A wide range of aryl benzyl sulfoxides, as well as alkyl benzyl sulfoxides with various (hetero)aryl bromides were employed in the triple relay process in good to excellent yields (85–99 %). Moreover, aryl methyl sulfoxides, dibenzyl sulfoxides, and dimethylsulfoxide could be utilized to generate diaryl sulfoxides involving multiple catalytic cycles by a single catalyst.

The combination of aryl bromides, allylbenzene, base and a palladium catalyst usually results in a Heck reaction. Herein we combine these same reagents, but override the Heck pathway by employing a strong base. In the presence of LiN(SiMe₃)₂, allylbenzene derivatives undergo reversible deprotonation. Transmetalation of the resulting allyllithium intermediate to LPdAr(Br) and reductive elimination provide the 1,1-diarylprop-2-enes, which are not accessible by the Heck reaction. The regioselectivity in this deprotonative cross-coupling process is catalyst-controlled and very high.

α-Halogenated aldimines have emerged as an important class of synthetic intermediates. The stability and reactivity of α-halo aldimines can vary greatly depending on the nitrogen protecting group. A general synthesis of stable, chiral α-halo-N-sulfonyl and N-phosphinoyl aldimine precursors is presented (42–96% yield). The corresponding α-halo aldimines can be isolated upon treatment with a mild base. Enantioenriched α-chloro aldehydes can be employed to afford aldimine precursors with no erosion of optical purity. Both the enantioenriched aldimine precursor and the isolated aldimine can react with an alkynyllithium nucleophile to give trans-β-chloroamine products with excellent dr. Ring closure affords the enantioenriched trans-aziridine, demonstrating the potential for this approach in complex molecule synthesis.

Reaction of p-benzoquinone (BQ) with a series of rare-earth metal/alkali metal/1,1′-BINOLate (REMB) complexes (RE: La, Ce, Pr, Nd; M: Li) results in the largest recorded shift in reduction potential observed for BQ upon complexation. In the case of cerium, the formation of a 2:1 Ce/BQ complex shifts the two-electron reduction of BQ by greater than or equal to 1.6 V to a more favorable potential. Reactivity investigations were extended to other RE^III (RE=La, Pr, Nd) complexes where the resulting highly electron-deficient quinone ligands afforded isolation of the first lanthanide quinhydrone-type charge-transfer complexes. The large reduction-potential shift associated with the formation of 2:1 Ce/BQ complexes illustrate the potential of Ce complexes to function both as a Lewis acid and an electron source in redox chemistry and organic-substrate activation.

The prevalence of cyclopropanes in biologically active compounds has fueled many investigations into their preparation. Despite significant advances, more efficient methods for their catalytic enantioselective synthesis remain in demand. Previously, we reported a novel tandem approach to diastereo- and enantioenriched cyclopropyl alcohols. Our method involved an initial asymmetric C–C bond formation by addition of organozinc reagents to aldehydes catalyzed by a (−)-MIB-based catalyst. The resulting allylic zinc alkoxides were then subject to directed cyclopropanations. Although this approach provided cyclopropyl alcohols with very high enantio- and diastereoselectivity, it was successful with only aliphatic aldehydes. Aryl aldehyde substrates, on the other hand, exhibited low conversion and variable diastereomeric ratios. The present study is aimed at raising the stereoselectivity and yield of the aforementioned tandem reaction with aryl aldehyde substrates to make the method synthetically useful. Herein, we report the successful optimization of aryl aldehyde substrates in our one-pot tandem approach leading to cyclopropyl alcohols with high yields and enantio- and diastereoselectivities. Copyright © 2012 John Wiley & Sons, Ltd.