Palladium‐Catalyzed Methoxycarbonylation of 1,3‐Butadiene: Catalysis and Mechanistic Studies

The palladium‐catalyzed methoxycarbonylation of 1,3‐butadiene to methyl 3‐pentenoate has been studied. Intermediates of the proposed catalytic cycle were synthesized and the elementary steps of the reaction have been investigated in detail. It is shown that the first step of the catalytic cycle, the formation of crotylpalladium complexes from 1,3‐butadiene, proceeds even at room temperature. Examination of the influence of different reaction parameters on product yield and selectivity demonstrate the importance of chelating phosphine ligands and benzoic acids as additive in order to get good results.     

Oxygen‐Involved Oxidative Deacetylation of α‐Substituted β‐Acetyl Amides – Synthesis of α‐Keto Amides

α‐Substituted β‐acetyl amides could undergo C C bond cleavage to form α‐keto amides when treated with copper(II) chloride (CuCl₂) and boron trifluoride diethyl etherate (BF₃⋅OEt₂) under an oxygen atmosphere. The yield can be increased by the addition of tert‐butyl hydroperoxide which alone can also effect the reaction. The reaction provides a new protocol for the synthesis of α‐keto amides.

     

Palladium‐Catalyzed Suzuki Carbonylative Reaction of α‐Halomethyl Oxime Ethers: A Regioselective Route to Unsymmetrical 1,3‐Oxyiminoketones

The three‐component reaction of α‐halomethyl oxime ethers, boronic acids and carbon monoxide at atmospheric pressure catalyzed by tetrakis(triphenylphosphine)palladium(0) gives efficiently unsymmetrical β‐alkoxyimino carbonyl compounds with total control of the regioselectivity, in high yield and atomic economy. Simple commercially available starting materials are used in this synthetic procedure. The three components assembly takes place preferentially versus the competing direct coupling or other possible side reactions. The mechanism of the transformation was investigated by NMR and intermediate palladium(II) complexes were detected.

     

Palladium‐Catalyzed Carbonylation of Diols to Cyclic Carbonates

The catalytic alkoxycarbonylation of 1,2‐diols by (neocuproine)palladium(II) acetate (neocuproine=2,9‐dimethyl‐1,10‐phenanthroline) or palladium(II) acetate/(−)‐sparteine using N‐chlorosuccinimide as the oxidant affords cyclic carbonates. The oxidative carbonylation of diols proceeds under mild conditions, requiring only 1 atm of carbon monoxide, and produces cyclic carbonates in moderate to good yields. Both 1,2‐ and 1,3‐diols can be carbonylated using (neocuproine)Pd(OAc)₂ and sodium dichloroisocyanuric acid, which serves as a competent oxidant and base for this system, to yield 5‐ and 6‐membered cyclic carbonates.     

A General and Practical Palladium‐Catalyzed Direct α‐Arylation of Amides with Aryl Halides

An efficient system for the direct catalytic intermolecular α‐arylation of acetamide derivatives with aryl bromides and chlorides is presented. The palladium catalyst is supported by Kwong’s indole‐based phosphine ligand and provides monoarylated amides in up to 95% yield. Excellent chemoselectivities (>10:1) in the mono‐ and diarylation with aryl bromides were achieved by careful selection of bases, solvents, and stoichiometry. Under the coupling conditions, the weakly acidic α‐protons of amides (pK_a up to 35) were reversibly depotonated by lithium tert‐butoxide (LiO‐t‐Bu), sodium tert‐butoxide (NaO‐t‐Bu) or sodium bis(trimethylsilyl)amide [NaN(SiMe₃)₂].

     

Palladium‐Catalyzed N‐Arylations of 1,4,7‐Triazacyclononanes

Various 1,4,7‐triazacyclononanes have been N‐arylated by palladium catalysis. Using optimized Buchwald–Hartwig protocols the corresponding products have been obtained in high yields.     

A Microfluidic Approach to the Rapid Screening of Palladium‐Catalysed Aminocarbonylation Reactions

The evaluation and selection of the most appropriate catalyst for a chemical transformation is an important process in many areas of synthetic chemistry. Conventional catalyst screening involving batch reactor systems can be both time‐consuming and expensive, resulting in a large number of individual chemical reactions. Continuous flow microfluidic reactors are increasingly viewed as a powerful alternative format for reacting and processing larger numbers of small‐scale reactions in a rapid, more controlled and safer fashion. In this study we demonstrate the use of a planar glass microfluidic reactor for performing the three‐component palladium‐catalysed aminocarbonylation reaction of iodobenzene, benzylamine and carbon monoxide to form N‐benzylbenzamide, and screen a series of palladium catalysts over a range of temperatures. N‐Benzylbenzamide product yields for this reaction were found to be highly dependent on the nature of the catalyst and reaction temperature. The majority of catalysts gave good to high yields under typical flow conditions at high temperatures (150 °C), however the palladium(II) chloride‐Xantphos complex [PdCl₂(Xantphos)] proved to be far superior as a catalyst at lower temperatures (75–120 °C). The utilised method was found to be an efficent and reliable way for screening a large number of palladium‐catalysed carbonylation reactions and may prove useful in screening other gas/liquid phase reactions.     

Facile Palladium‐Catalyzed Synthesis of 3‐Arylpyrazolo[1,5‐a]pyrimidines

An efficient palladium‐catalyzed synthesis of 3‐arylpyrazolo[1,5‐a]pyrimidines has been investigated. The key step in the synthesis is a Suzuki biaryl coupling of 3‐bromo‐2,5‐dimethyl‐7‐aminopyrazolo[1,5‐a]pyrimidines with arylboronic acids to provide 3‐arylpyrazolo[1,5‐a]pyrimidines in moderate to good yield. The synthetic utility of this methodology has been demonstrated by a concise and convergent synthesis of R121920, a potent CRHR₁ antagonist recently undergoing clinical evaluations.     

Palladium‐Catalyzed Carbonylative Synthesis of 2,3‐Disubstituted Chromones

An unexpected palladium‐catalyzed carbonylative synthesis of 2,3‐disubstituted chromones has been developed. Starting from 2‐bromofluorobenzenes and ketones, the corresponding chromones were produced in good yields. By control experiments, this transformation was found to proceed through a sequential carbonylation/Claisen–Hasse rearrangement/intramolecular nucleophilic aromatic substitution approach (S_NAr). More specifically, the reaction sequence started with a palladium‐catalyzed carbonylation of the ketone with o‐bromofluorobenzene to give the vinyl benzoates, which subsequently transformed into 1,3‐diketones via a Claisen–Hasse rearrangement. The final products were produced after an intramolecular S_NAr reaction of the in situ formed 1,3‐diketone.

     

Optically Active 2,3‐Allenoates via Palladium‐Catalyzed Carbonylation of Enantioenriched Propargylic Mesylates

Under mild conditions, optically active 2,3‐allenoates were synthesized from enantioenriched propargylic mesylates with moderate to excellent yields and high efficiency of chirality transfer by using palladium(0) bis(dibenzylideneacetone) (3 mol%) with (S)‐(−)‐5,5′‐bis(diphenylphosphino)‐4,4′‐bi‐1,3‐benzodioxole [(S)‐SEGPHOS] (3 mol%) as the catalyst and diammonium hydrogen phosphate (1.1 equiv .) as the base.     

Suzuki Coupling of Amides via Palladium‐Catalyzed C–N Cleavage of N‐Acylsaccharins

A palladium‐catalyzed cross‐coupling of activated amides with arylboronic acids has been developed via C–N bond cleavage. This approach demonstrated high tolerance to a variety of alkyl, aryl, heterocyclic and vinyl substituents. Unsymmetrical ketones could be achieved in excellent yield under mild conditions with 1% catalyst loadings.

     

Palladium‐Catalyzed Intermolecular Asymmetric Hydroamination with 4,4′‐Disubstituted BINAP and SEGPHOS

A family of tunable precatalysts [Pd((S)‐L*)(NCMe)₂](OTf)₂, where L* is 4,4′‐disubstituted BINAP or SEGPHOS, was synthesized and used for the asymmetric intermolecular hydroamination of aniline to vinylarenes with ee values of up to 85 %, and it is believed that the bulky groups on the 4,4′‐positions and the narrower dihedral angle of the biaryl moiety are responsible for the ee enhancement in these reactions.     

Mild and Functional Group Tolerant Method for Tandem Palladium‐Catalyzed Carbocyclization–Coupling of ε‐Acetylenic β‐Ketoesters with Aryl Bromides and Chlorides

We report a new protocol for the annulative difunctionalization of acetylenes via tandem carbocyclization–coupling of ε‐acetylenic β‐ketoesters with aryl and heteroaryl bromides and chlorides catalyzed by the palladium species derived from an air‐ and moisture‐stable palladacyclic precatalyst. In the tandem process, the palladium complex combines appropriate carbophilic Lewis acidity and redox activity to catalyze two mechanistically distinct reactions ‐ nucleophilic addition of the enolate to unactivated alkyne, followed by C C coupling. We found that a broad range of electronically varied aryl and heteroaryl bromides and chlorides underwent this reaction with various ε‐acetylenic β‐ketoesters, providing corresponding substituted vinylidenecyclopentanes in high yield with excellent functional group tolerance.

     

Palladium‐Catalyzed Acylation of 2‐Aryl‐1,2,3‐triazoles with Aldehydes

The palladium‐catalyzed acylation of 2‐aryl‐1,2,3‐triazoles with aldehydes via C H bond activation is described. A wide variety of products was isolated in good to excellent yields. This finding provides a new and useful strategy for the synthesis of aromatic ketones.

     

Poly(1,3‐disila‐1,3‐diphenyl‐2‐oxaindane)– poly(dimethylsiloxane) block copolymers

The hydrolytic condensation of 1,3‐dichloro‐1,3‐disila‐1,3‐diphenyl‐2‐oxaindane under neutral conditions produced α'ω‐dihydroxy‐1,3‐disila‐1,3‐diphenyl‐2‐oxaindane (polymerization degree ≈ 4). The homofunctional condensation of α'ω‐dihydroxy‐1,3‐disila‐1,3‐diphenyl‐2‐oxaindane in a toluene solution and in the presence of activated carbon was performed, and dihydroxy‐containing oligomers with various degrees of condensation were obtained. Through the heterofunctional condensation of dihydroxy‐containing oligomers with α'ω‐dichlorodimethylsiloxanes in the presence of amines, corresponding block copolymers were obtained. Gel permeation chromatography, differential scanning calorimetry, thermomechanical analysis, thermogravimetry, and wide‐angle roentgenography investigations were carried out. Differential scanning calorimetry and roentgenography studies of the block copolymers showed that their properties were determined by the ratio of the lengths of the flexible and linear poly(dimethylsiloxane) and rigid poly(1,3‐disila‐1,3‐diphenyl‐2‐oxaindane) fragments in the macromolecular chain. At definite values of the lengths of the flexible and rigid fragments, a microheterogeneous structure was observed in the synthesized block copolymers. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 1409–1417, 2002; DOI 10.1002/app.10335     

Synthesis of Fused Cyclopentenones through Palladium‐Catalyzed Cyclization of 2‐Iodoaryl Allenols

A versatile strategy for the synthesis of fused cyclopentenones, key structural motifs in biologically relevant compounds such as indenones and indole alkaloids, has been established successfully through regioselective palladium‐catalyzed cyclization of 2‐iodoaryl allenols.

     

New Palladium‐Catalyzed Domino Reaction with Intramolecular Ring Closure of an N‐(2‐Chloro‐3‐heteroaryl)arylamide: First Synthesis of Oxazolo[4,5‐b]pyrazines

The synthesis of novel planar heterocycles is at the heart of basic research as such scaffolds constitute key building blocks in important diverse areas of research: drug discovery, material sciences, and pesticides. The well‐known benzoxazole is often contained in drug candidates but tweaking its lipophilicity and target interaction points are often desired. In this respect, the oxazolo[4,5‐b]pyrazine is an attractive heterocyclic scaffold as it possesses increased water solubility as well as two additional hydrogen bonding acceptors. We here report a new Pd(II)‐catalyzed domino reaction comprising the first Pd(II)‐assisted intramolecular cyclization of an N‐(2‐chloro‐3‐heteroaryl)arylamide and validate its value by application to the first synthesis of 2‐substituted oxazolo[4,5‐b]pyrazines. We demonstrate that a bidentate phosphorus ligand as well as the presence of an aromatic nitrogen atom is required for the domino reaction to proceed. The robustness of the methodology is confirmed by the synthesis of 23 2‐substituted oxazolo[4,5‐b]pyrazine analogues in good‐to‐high yields and containing both electron‐withdrawing as well as electron‐donating substituents on the reacting arylamide.

     

Selective Aryl α‐Diimine/Palladium‐Catalyzed Bis‐Alkoxy‐ carbonylation of Olefins for the Synthesis of Substituted Succinic Diesters

Aryl α‐diimine derivatives have been used, for the first time, as efficient new ligands for the palladium‐catalyzed oxidative bis‐alkoxycarbonylation reaction of olefins. The most active catalyst was formed in situ from bis(9‐anthryl)‐2,3‐dimethyl‐1,4‐diazabutadiene and palladium(II) trifluoroacetate [Pd(TFA)₂]. This catalytic system was able to selectively convert olefins into succinic diesters in good yields (up to 97%) and low catalyst loading (up to 0.5 mol%) under mild reaction conditions [4 bar of carbon monoxide (CO) at 20 °C in the presence of p‐toluenesulphonic acid as additive and p‐benzoquinone as oxidant]. The optimized conditions could be successfully applied to both aromatic and aliphatic olefins, by using methanol, benzyl alcohol or isopropyl alcohol as nucleophiles.

     

Modification of Chiral Monodentate Phosphine Ligands (MOP) for Palladium‐Catalyzed Asymmetric Hydrosilylation of Cyclic 1,3‐Dienes

Several MOP ligands 5 containing aryl groups at 2′ position of (R)‐2‐(diphenylphosphino)‐1,1′‐binaphthyl skeleton were prepared and used for palladium‐catalyzed asymmetric hydrosilylation of cyclic 1,3‐dienes 6 with trichlorosilane. Highest enantioselectivity was observed in the reaction of 1,3‐cyclopentadiene ( 6a ) catalyzed by a palladium complex (0.25 mol %) coordinated with (R)‐2‐(diphenylphosphino)‐2′‐(3,5‐dimethyl‐4‐methoxyphenyl)‐1,1′‐binaphthyl ( 5f ), which gave (S)‐3‐(trichlorosilyl)cyclopentene of 90% ee.