Palladium-catalyzed intramolecular C-O bond formation.

A number of oxygen heterocycles were synthesized using the palladium-catalyzed intramolecular etherification of aryl halides by employing di-tert-butylphosphinobiaryl ligands. The reaction proceeds under mild conditions using weak bases such as Cs(2)CO(3) or K(3)PO(4). A variety of functional groups are tolerated in the reaction, and enantioenriched alcohols can be coupled without erosion of optical purity. The mildness of the reaction conditions allows for the use of polyfunctionalized substrates. This method was used as the key step in the synthesis of MKC-242, an antidepressant currently in clinical trials. The synthesis of MKC-242 was achieved in 40% overall yield from commercially available sesamol and acrylonitrile.

Synthesis of N-aryl hydrazides by copper-catalyzed coupling of hydrazides with aryl iodides.

[reaction--see text] A convenient method for intermolecular N-arylation of hydrazides with substituted aryl iodides in the presence of a copper catalyst and Cs(2)CO(3) is reported. The C-N coupling of N-Boc hydrazine with para- and meta-substituted aryl iodides afforded the N-arylated products A, regioselectively. A reversal in regioselectivity is observed for the arylation of benzoic hydrazide with ortho-substituted aryl iodides, providing the N'-arylated products B.

New ammonia equivalents for the Pd-catalyzed amination of aryl halides.

[reaction: see text]. LiN(SiMe3)2, Ph3SiNH2, and LiNH2 can be be used as ammonia equivalents for the Pd-catalyzed coupling of aryl halides. Using these amine derivatives, simple anilines, including ortho-substituted ones, as well as di- and triarylamines can be readily prepared.

Palladium-catalyzed alpha-arylation of esters.

A new and simple one-pot procedure for the palladium-catalyzed intermolecular alpha-arylation of esters is described. A number of esters can be functionalized with a wide range of aryl bromides using Pd(OAc)(2) or Pd(2)(dba)(3) and bulky electron-rich o-biphenyl phosphines 1-3. Under the reaction conditions, using LiHMDS as base, alpha-arylation proceeds at room temperature or at 80 degrees C with very good yields and high selectivities for monoarylation. Important nonsteroidal antiinflammatory drug derivatives such as (+/-)-naproxen tert-butyl ester and (+/-)-flurbiprofen tert-butyl ester can be prepared in 79% and 86% yield, respectively. The catalyst system based on the di-tert-butylphosphine (2) is also active for the alpha-arylation of esters using aryl chlorides. Furthermore, using (3) the alpha-arylation of trisubstituted ester enolates can be accomplished to provide compounds that have quaternary centers.

Copper-catalyzed coupling of arylboronic acids and amines.

[reaction: see text] A general catalytic coupling of arylboronic acids and amines is reported. This room-temperature coupling was realized through the use of catalytic copper(II) acetate, 2,6-lutidine as base, and myristic acid as an additive. Functionalized aniline substrates provided the diarylamine coupling products in good yield (58-91%). A variety of alkylamines were also successfully coupled to give N-alkyl anilines in moderate yield (50-64%).

Catalytic asymmetric vinylation of ketone enolates.

[see reaction]. A protocol for the catalytic asymmetric vinylation of ketone enolates has been developed. Key to the success of this process was the development of new electron-rich chiral monodentate ligands.

One-pot synthesis of enantiomerically enriched 2,3-disubstituted cyclopentanones via copper-catalyzed 1,4-reduction and alkylation.

[reaction: see text]. Enantiomerically enriched 2,3-disubstituted cyclopentanones were prepared via copper-catalyzed 1,4-reduction of 3-substituted cyclopentenones followed by alkylation of the resulting silyl enol ether. Using this procedure, trans-2,3-disubstituted cyclopentanones were produced in moderate to good overall yields (42-67%) and with excellent enantiomeric and diastereomeric excesses. The reduction and alkylation were performed in a single reaction vessel.

Use of polymer-supported dialkylphosphinobiphenyl ligands for palladium-catalyzed amination and Suzuki reactions.

The preparations of polymer-supported dialkylphosphinobiphenyl ligands (3) are reported. A palladium catalyst based on ligand 3a is active for amination and Suzuki reactions using unactivated aryl iodides, bromides, or chlorides. Filtration of the catalyst from the reaction mixture allows for simplified product isolation via an aqueous workup. The resin-bound catalyst can be recycled without additional palladium in both the amination and Suzuki reactions.

An improved method for the palladium-catalyzed amination of aryl iodides.

Aryl iodides are coupled with amines to give the corresponding arylamines in high yield in the presence of palladium, a suitable ligand, and NaOt-Bu. Functionalized aryl iodides give good yields of the corresponding arylamines when Cs(2)CO(3) is substituted as the base.

One-pot synthesis of unsymmetrical triarylamines from aniline precursors.

The "one-pot" synthesis of triarylamines from an aniline and two different aryl halides is described. A catalytic system composed of Pd2(dba)3/P(t-Bu)2-o-biphenyl (1) is used to prepare a variety of triarylamines in a single flask by the coupling of an aniline with an aryl bromide and aryl chloride. The synthesis of triarylamines containing a heterocyclic aryl group is also described by employing a one-flask, two-step method. These methods can be used to synthesize both discrete triarylamines and a triarylamine library.

An improved synthesis of functionalized biphenyl-based phosphine ligands.

Functionalized dicyclohexyl- and di-tert-butylphosphinobiphenyl ligands are prepared by the reaction of arylmagnesium halides with benzyne, followed by the addition of a chlorodialkylphosphine. This one-pot procedure is considerably less expensive and time-consuming than the method used previously to prepare such ligands. The cost of introducing the dicyclohexylphosphine group can be decreased by preparing chlorodicyclohexylphosphine from PCl3 and cyclohexylmagnesium chloride, and using the reagent without further purification. The new method is significant, as a variety of ligands can be produced in useful amounts by a procedure that is simple, with starting materials that are relatively inexpensive, and, in most cases, without chromatographic purification.

Pd(PhCN)(2)Cl(2)/P(t-Bu)(3): a versatile catalyst for Sonogashira reactions of aryl bromides at room temperature.

[reaction: see text] Pd(PhCN)(2)Cl(2)/P(t-Bu)(3) serves as an efficient and a versatile catalyst for room-temperature Sonogashira reactions of aryl bromides.

A method for the asymmetric hydrosilylation of N-aryl imines.

[reaction: see text] The asymmetric reduction of N-aryl imines to yield chiral amines with enantiomeric excesses above 90% was achieved. Ethylenebis(eta5-tetrahydroindenyl)titanium difluoride ((EBTHI)TiF2, 1) was employed as the precatalyst with polymethylhydrosiloxane (PMHS) as the stoichiometric reducing agent. A variety of N-aryl imines derived from nonaromatic ketones were reduced with high ee.

Efficient palladium-catalyzed N-arylation of indoles.

[equation--see text] The N-arylation of indoles, including a variety of substituted ones, has been carried out using bulky, electron-rich phosphines as the supporting ligand in combination with Pd(2)(dba)(3). Using this catalyst system, the efficient coupling of indole and a variety of substituted indoles with aryl iodides, bromides, chlorides, and triflates can be achieved.

Palladium-catalyzed intermolecular coupling of aryl halides and amides.

[formula: see text] The first general intermolecular C-N bond-forming reactions between aryl halides and amides were realized using a palladium catalyst with Xantphos as the ligand. Aryl triflates, carbamates, and sulfonamides are also viable substrates for the amidations, which proceed at 45-110 degrees C with 1-4 mol% of Pd catalyst in 66-99% yields and exhibit good functional group compatibility.

Kinetic resolution and isomerization of 2,5-disubstituted pyrrolines.

The efficient kinetic resolution of 2,5-disubstituted pyrrolines was accomplished by employing hydrosilylation with a chiral catalyst, (EBTHI)TiF2 (EBTHI = ethylenebis(tetrahydroindenyl)). An interesting isomerization reaction of the cyclic imines catalyzed by the same chiral catalyst was also discovered.

Efficient kinetic resolution in the asymmetric hydrosilylation of imines of 3-substituted indanones and 4-substituted tetralones.

Kinetic resolution of the N-methyl imines of 3-substituted indanones and 4-substituted tetralones could be accomplished by hydrosilylation with a chiral titanocene catalyst. N-Methyl imines of 4-substituted tetralones were resolved to yield, after hydrolysis of the unreacted starting materials, ketones with high ee's and the amine products with high diastereomeric and enantiomeric purity. The utility of this process was demonstrated in the synthesis of sertraline.