Negishi cross-coupling reaction catalyzed by an aliphatic, phosphine based pincer complex of palladium. biaryl formation via cationic pincer-type Pd(IV) intermediates

The aliphatic, phosphine-based pincer complex [(C(10)H(13)-1,3-(CH(2)P(Cy(2))(2))Pd(Cl)] (1) is a highly active Negishi catalyst, enable to quantitatively couple various electronically activated, non-activated, deactivated, sterically hindered and functionalized aryl bromides with various diarylzinc reagents within short reaction times and low catalyst loadings. Experimental observations strongly indicate that a molecular mechanism is operative with initial chloride dissociation of 1 and formation of the cationic T-shaped 14e(-) complex [(C(10)H(13)-1,3-(CH(2)P(C(6)H(11))(2))(2))Pd](+) (B), which undergoes oxidative addition of an aryl bromide (Ar'Br) to yield the cationic, penta-coordinated aryl bromide pincer complexes of type [(C(10)H(13)-1,3-(CH(2)P(Cy(2))(2))Pd(Br)(aryl')](+) (C) with the metal center in the oxidation state of +IV and the aryl unit in cis position relative to the aliphatic pincer core. Subsequent transmetalation with Zn(aryl)(2) result in the cationic diaryl pincer complexes of type [(C(10)H(13)-1,3-(CH(2)P(Cy(2))(2))Pd(aryl)(aryl')](+) (D), which reductively eliminate the coupling products, thereby regenerating the catalyst. The neutral square planar aryl pincer complex--a possible key intermediate in the catalytic cycle--was found to be reversibly formed in the reaction mixture but is not involved in the catalytic mechanism. Similarly, palladium nanoparticles as the catalytically active form of 1 could have been excluded.     

Structure, formation and catalytic studies of a meso-palladioporphyrin intermediate in a Heck reaction

A meso-palladioporphyrin intermediate was isolated from a Heck reaction between an iodoporphyrin and a non-activated olefin using a Pd(PPh3)2Cl2/Et3N system; its structure was characterized by NMR, MS and X-ray crystallography. Studies on its formation indicate that the Pd(II) catalyst was reduced in situ by Et3N with the assistance of water. The catalytic activity of the intermediate was confirmed by stoichiometric and catalytic reactions using a more reactive olefin, ethyl acrylate.     

Enantioselective fluorination of tert-butoxycarbonyl lactones and lactams catalyzed by chiral Pd(II)-bisphosphine complexes

An efficient catalytic enantioselective fluorination of tert-butoxycarbonyl lactones and lactams is reported. Reactions of the lactone substrates proceeded smoothly in an alcoholic solvent with a catalytic amount of chiral Pd(II) complex. In the case of the less acidic lactam substrates, concurrent use of the Pd complex and 2,6-lutidine as a cocatalyst was effective. Under the reaction conditions, the fluorinated lactones and lactams were obtained in good yield with excellent enantioselectivity (94-99% ee).     

Direct C-4 arylation of crotonaldehyde with arenediazonium tetrafluoroborates

Arenediazonium tetrafluoroborates react with crotonaldehyde (2-butenal) in methanol in the presence of catalytic amounts of Pd(OAc)₂ to yield mainly 4,4-dimethoxy-1-butenylarenes. In most of the examples studied, small amounts of an isomeric byproduct were formed, presumably 3,3-dimethoxy-1-methylenepropylarenes. Because crotonaldehyde and arenediazonium salts are cheap and readily available, this reaction is a convenient access to protected 4-arylbutenals.     

Oxidative Pd(II)-catalyzed C-H bond amination to carbazole at ambient temperature

We report a new Pd(II)-catalyzed C-H bond amination reaction to form carbazoles, an important motif that is prevalent in a range of systems. The catalytic amination process operates under extremely mild conditions and produces carbazole products in good to excellent yields. Carbazoles possessing complex molecular architecture can also be formed using this reaction, highlighting its potential in natural product synthesis applications. Preliminary mechanistic investigations reveal the reaction proceeds through a Pd(II)/Pd(IV) manifold and that reductive elimination from a high oxidation state Pd(IV) complex facilitates the mild conditions of this transformation.     

Acid-base catalysis of chiral Pd complexes: development of novel catalytic asymmetric reactions and their application to synthesis of drug candidates

Using the unique character of the chiral Pd complexes 1 and 2, highly efficient catalytic asymmetric reactions have been developed. In contrast to conventional Pd(0)-catalyzed reactions, these complexes function as an acid-base catalyst. Thus active methine and methylene compounds were activated to form chiral palladium enolates, which underwent enantioselective carbon-carbon bond-forming reactions such as Michael reaction and Mannich-type reaction with up to 99% ee. Interestingly, these palladium enolates acted cooperatively with a strong protic acid, formed concomitantly during the formation of the enolates to activate electrophiles, thereby promoting the C-C bond-forming reaction. This palladium enolate chemistry was also applicable to electrophilic enantioselective fluorination reactions, and various carbonyl compounds including beta-ketoesters, beta-ketophosphonates, tert-butoxycarbonyl lactone/lactams, cyanoesters, and oxindole derivatives could be fluorinated in a highly enantioselective manner (up to 99% ee). Using this method, the catalytic enantioselective synthesis of BMS-204352, a promising anti-stroke agent, was achieved. In addition, the direct enantioselective conjugate addition of aromatic and aliphatic amines to alpha,beta-unsaturated carbonyl compound was successfully demonstrated. In this reaction, combined use of the Pd complex 2 having basic character and the amine salt was the key to success, allowing controlled generation of the nucleophilic free amine. This aza-Michael reaction was successfully applied to asymmetric synthesis of the CETP inhibitor torcetrapib.     

Enantioselective synthesis of (-)-cis-clavicipitic acid

An enantioselective synthetic method for (-)-cis-clavicipitic acid (1) was reported. 1 was obtained in 10 steps (99% ee and 20% overall yield) from 1H-indole-3-carboxylic acid methyl ester (9) via asymmetric phase-transfer catalytic alkylation and diastereoselective Pd(II)-catalyzed intramolecular aminocyclization as key steps.     

Palladium(II)-catalyzed asymmetric cyclization of (Z)-4'-acetoxy-2'-butenyl 2-alkynoates. Role of nitrogen-containing ligands in palladium(II)-mediated reactions.

Pd(OAc)(2) combined with nitrogen-containing ligands (e.g., 2,2'-bipyridine) catalyzed the cyclization of (Z)-4'-acetoxy-2'-butenyl 2-alkynoates (1) in acetic acid to afford the alpha-(Z)-acetoxyalkylidene-beta-vinyl-gamma-butyrolactones (2) with high efficiency and high stereoselectivity. The nitrogen-containing ligands, like halides, served to favor beta-heteroatom elimination over beta-hydride elimination in Pd(II)-mediated reactions. The generality of this ligand effect was probed in both stoichiometric and catalytic reactions. With these results in hand, the catalytic asymmetric protocol was achieved with high enantioselectivity (up to 92% ee) when pymox (pyridyl monooxazoline) or bisoxazoline was used. The absolute configuration of the products and the synthetic utility of this asymmetric transformation were established through the convenient synthesis of (3S)-(+)-A-factor.     

Total synthesis of (+/-)-stemodinone via an efficient ring-exchange strategy

A total synthesis of (+/-)-stemodinone, a tetracyclic stemodane diterpene, from the known tricyclic methyl olefin 11 is described. The key steps involve an efficient ring-exchange reaction and palladium(0)-catalyzed lactone migration. The ring-exchange strategy for controlling the stereochemistry was based on an initial Diels-Alder reaction to form a new ring followed by cleavage of the original ring. Cleavage of the original ring of the Diels-Alder adduct 9 was achieved by an initial regio- and chemoselective Baeyer-Villiger oxidation followed by the Pd(0)-catalyzed lactone-migration reaction reported by us.     

Enantioselective total synthesis of a natural iridoid

The first total synthesis of 6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1(3H)-one has been accomplished. A key feature of the synthesis includes facile construction of the bicyclic lactone intermediate via intramolecular Pd(0)-catalyzed allylic alkylation and the efficient transformation of this intermediate into the iridoid skeleton employing silicon tethered radical cyclization.     

Influence of the reaction parameters on the Pd—HCl catalysed synthesis of phenylacetic acid derivatives via reduction of mandelic acid derivatives with carbon monoxide

The catalytic system Pd/C—HCl is highly active in the reduction of mandelic acid derivatives to phenylacetic acid derivatives with carbon monoxide when the aromatic ring is para-substituted with a hydroxy group. Typical reaction conditions are: 70–110 °C, 20–100 atm of carbon monoxide, benzene—ethanol as reaction medium, substrate/Pd=10²–10⁴/1, HCl/substrate=0.3–0.8/1. [Pd] = 10⁻² −10⁻⁴ M. When the catalytic system is used in combination with PPh₃ a slightly higher activity is observed. Comparable results are observed when using a Pd(II) catalyst precursor such as PdX₂, in combination with PPh₃, or PdX₂(PPh₃)₂ (XCl, AcO). When operating at 110 °C, decomposition to metallic palladium occurs. Pd(II) complexes with diphosphine ligands, such as diphenylphosphinemethane, -ethane, -propane or -butane, do not show any catalytic activity and are recovered unchanged. These observations suggest that Pd(0) complexes play a key role in the catalytic cycle. The proposed catalytic cycle proceeds as follows: the chloride ArCHClCOOR, formed in situ upon reaction of ArCHOHCOOR with hydrochloric acid, oxidatively adds to a Pd(0) species with formation of a catalytic intermediate having a Pd—[CH(Ar)COOR] moiety, which inserts a CO molecule, yielding an acyl intermediate of the type Pd—[COCH(Ar)COOR]. The nucleophilic attack of H₂O on the carbon atom of the carbonyl ligand gives back the Pd(0) complex to the catalytic cycle and yields a phenylmalonic acid derivative, which produces the final product, ArCH₂COOR, upon CO₂ evolution. Alternatively, protonolysis of the intermediate having a Pd—[CH(Ar)COOR] moiety yields directly the final product and a Pd(II) species, which is then reduced by CO to Pd(0). Moreover, no catalytic activity is observed when the Pd/C—HCl system is used in combination with any one of the above diphosphine ligands, probably because these ligands block the sites on the catalyst able to promote the catalytic cycle or because they prevent the reduction of Pd(II) to Pd(0). The influence of the following reaction parameters has been studied: concentration of HCl, PPh₃, palladium and substrate, pressure of carbon monoxide, the temperature, reaction time and solvent. The results are compared with those obtained in the carbonylation of aromatic aldehydes to phenylacetic acid derivatives catalyzed by the same system, for which it has been proposed that the catalysis occurs via carbonylation of the aldehyde to a mandelic acid derivative as an intermediate, which is further reduced with CO to yield the final product.     

Concise Approach to the “Higher Sugar” Core of the Nucleoside Antibiotic Hikizimycin

A highly productive synthesis of phenylthio glycoside 33 is described which constitutes a fully functional surrogate for the hikosamine core of hikizimycin 1 , a complex nucleoside antibiotic endowed with promising anthelmintic properties. The chosen approach to this undecose derivative starts from mannofuranose 7 which was one‐carbon homologated to alkyne 8 in one step on treatment with lithio (trimethylsilyl)diazomethane. Alkynyl iodide 12 derived from 8 was combined with the tartrate‐derived aldehyde 17 by a Nozaki–Hiyama–Kishi reaction that can either be performed using overstoichiometric amounts of CrCl₂ or by means of a catalytic manifold based on the turnover of a cat. CrCl₂/chlorosilane/manganese redox couple. Semi‐hydrogenation of the resulting alkyne 18 to (Z)‐olefin 19 required the use of Pd/C as the catalyst, whereas conventional Lindlar reduction was unsatisfactory. Attempted cis‐dihydroxylation of alkene 22 (formed from 19 by a Mitsunobu reaction with phthalimide) by using catalytic amounts of OsO₄ and NMO as the stoichiometric oxidant essentially failed, whereas a stoichiometric osmylation afforded the stable osmate ester 26 a as a single diastereomer. Since the use of OsO₄ in stoichiometric amounts deemed inappropriate for a total synthesis project, recourse was taken to catalytic “Blitz dihydroxylation” with RuO₄ in the presence of FeCl₂ ? 4 H₂O as co‐catalyst. Application of these conditions to alkene 30 bearing a free aldehyde function at the terminus of the “higher sugar” chain furnished pyranose 32 in good yield and excellent diastereoselectivity, which was converted into the targeted thioglycoside 33 on treatment with PhSSPh/Et₃P. It is particularly noteworthy that the conformational constraints of the acyclic substrate 30 enforce the dihydroxylation to violate Kishi's empirical rule for transformations of this type.     

Palladium(II)-catalyzed oxidative transformation of allylic alcohols and vinyl ethers into 2-alkoxytetrahydrofurans: catechol as an activator of catalyst

[chemical reaction: see text]. A highly effective synthesis of 2-alkoxytetrahydrofurans from allylic alcohols and vinyl ethers was achieved by using catalytic amounts of Pd(OAc)2, Cu(OAc)2, and catechol (1:1:2) under O2. The use of catechol as an activator of Pd(II)-Cu(II) catalyst has been unprecedented. The 2-alkoxytetrahydrofurans are formed via oxypalladation of allylic alcohols toward vinyl ethers followed by 5-exo cyclization of the resulting oxypalladation intermediate and subsequent beta-Pd-H elimination. No 6-endo cyclization of the oxypalladation intermediate occurs.     

负载型Cu-Pd双金属纳米氧化物催化剂催化合成碳酸二乙酯：Cu（I）作为活性中心

催化反应活性与催化剂活性组分的存在价态密切相关,所以探讨催化剂在反应过程中的活性中心及其价态变化,对于催化反应机理和催化剂的研究都显得十分重要.目前对于氧化羰基合成碳酸二甲酯催化剂的机理的探讨很多,主要存在的争议是Cu+还是Cu2+作为活性中心,以及铜物种的配位状态.大多体系都是以分子筛为载体的铜基催化剂,其活性中心的研究存在铜离子在分子筛中的定位问题,而且催化活性也会受到分子筛结构的影响.采用这种方法研究活性中心的影响因素较多,存在一定的局限性.因此,直接制备纳米级的铜基氧化物用于本催化体系,有利于更直观简单地探索其活性中心.纳米级金属氧化物材料是一种新型的功能性材料,而纳米铜基氧化物(CuO和Cu2O)因其独特的物化性质和结构而引起广泛关注.我们采用水热法制备纳米CuO及其它氧化物,研究了NaOH浓度对催化剂的催化性能的影响;葡萄糖是一种还原性较强的还原剂,其用量必定会对所制备的氧化物的物种有所影响.为了探究Cu0和Cu+在本体系中的作用,采用不同葡萄糖用量制备了具有不同Cu2O含量的PdCl2/Cu-Cu2O催化剂.在上述研究基础上,我们采用X射线衍射、场发射扫描电子显微镜、热重分析、等离子体原子发射光谱等表征手段研究了负载型纳米铜基氧化物催化剂在合成碳酸二乙酯反应中催化性能差异的原因,旨在直接考察活性中心主要是Cu+还是Cu2+,避免分子筛等体系中载体结构的影响,研究结果更具参考性.结果发现, NaOH浓度为5 mol/L时制备的PdCl2/CuO和PdCl2/Cu-Cu2O催化剂的性能优于其他浓度下制备的催化剂,这可能是由于不同浓度的碱溶液会对铜离子的沉淀过程产生不同的影响;相同NaOH浓度下制备的催化剂中, PdCl2/Cu-Cu2O催化剂的催化性能明显优于PdCl2/CuO催化剂,这可能是由于PdCl2/Cu-Cu2O催化剂更有利于反应过程中电子的传递,从而表现出更好的催化性能,我们推测Cu0和Cu+可能更有利催化乙醇氧化羰基合成DEC;表征分析发现PdCl2/CuO和PdCl2/Cu-Cu2O均具有很好的热稳定性,两种催化剂中PdCl2负载量几乎相同,因此,主要影响催化性能的因素是载体CuO和Cu-Cu2O中铜的价态.采用不同葡萄糖用量制备了含有不同Cu2O含量的PdCl2/Cu-Cu2O催化剂,其中, PdCl2/Cu-Cu2O-2催化剂中含有更多的Cu2O,在反应中乙醇转化率达到了7.2%, DEC的选择性为97.9%, DEC的时空收率可达到151.9 mg·g–1·h–1.由此可见在乙醇气相氧化羰基合成DEC体系中, Cu+是主要的活性中心.     

Palladium(II)-catalyzed tandem intramolecular aminopalladation of alkynylanilines and conjugate addition for synthesis of 2,3-disubstituted indole derivatives

An efficient method for the synthesis of 2,3-disubstituted indoles with high selectivity from 2-ethynylaniline derivatives and α,β-unsaturated carbonyl compounds was developed. This Pd(II)-catalyzed reaction involves tandem intramolecular aminopalladation, olefin insertion and protonolysis of the carbon-palladium bond with the regeneration of Pd(II) species in the presence of halide ions.     

Palladium(II) and platinum(II) complexes of bidentate 2-pyridyl-1,2,3-triazole “click” ligands: Synthesis,properties and X-ray structures

The synthesis and characterization of palladium(II) and platinum(II) complexes of isomeric bidentate 2-pyridyl-1,2,3-triazole “click” ligands is reported. The complexes have been fully characterized by elemental analysis, HRESI-MS, IR, UV–Vis, ¹H and ¹³C NMR spectroscopy. Additionally, the molecular structures of the Pd(II) and Pt(II) complexes of the 2-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]pyridine ligand are confirmed by X-ray crystallography. Solution studies indicate the 2-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine ligand forms more stable complexes with Pd(II) and Pt(II) than the isomeric 2-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]pyridine ligand.     

Nanosized Pd37(CO)28{P(p-Tolyl)3}12 containing geometrically unprecedented central 23-atom interpenetrating tri-icosahedral palladium kernel of double icosahedral units: its postulated metal-core evolution and resulting stereochemical implications

Pd37(CO)28{P(p-Tolyl)3}12 (1) was obtained in approximately 50% yield by the short-time thermolysis of Pd10(CO)12{P(p-Tolyl)3}6 in THF solution followed by crystallization via layering with hexane under N2. The low-temperature (100 K) CCD X-ray diffraction study of 1 revealed an unusual non-spheroidal Pd37-atom polyhedron, which may be readily envisioned to originate via the initial formation of a heretofore non-isolated central Pd23 kernel composed of three interpenetrating trigonal-planar double icosahedra (DI) that are oriented along the three bonding edges of its interior Pd3 triangle. This central Pd23 kernel is augmented by face condensations with two additional phosphorus-free and 12 tri(p-C6H4Me)phosphine-ligated Pd atoms, which lower the pseudo-symmetry of the resulting 37-atom metal core from D(3h) to C2. The 12 P atoms and 28 bridging CO connectivities preserve the pseudo-C2 symmetry. The central Pd23 kernel in 1 provides the only crystallographic example of the 23-atom member of the double icosahedral family of "twinned" interpenetrating icosahedra (II), which includes the 19-atom two II (1 DI), the 23-atom three II (3 DI), the 26-atom four II (6 DI), and the 29-atom five II (9 DI). The n-atoms of these DI models coincide exactly with prominent atom-peak maxima of 19, 23, 26, and 29, respectively, in the mass spectrum of charged argon clusters formed in a low-temperature free-jet expansion. The only previous crystallographically proven 26- and 29-atom DI members are the central pseudo-T(d) tetrahedral Pd26 kernel (4 II, 6 DI) in the PMe3-ligated Pd29Ni3(CO)22(PMe3)13 (2) and the central pseudo-D(3h) trigonal-bipyramidal Pd29 kernel (5 II, 9 DI) in the PMe3-ligated Pd35(CO)23(PMe3)15 (3). Two highly important major stereochemical implications are noted: (1) The formation of geometrically identical idealized architectures for these three II palladium kernels with corresponding DI models constructed for the charged argon clusters provides compelling evidence that the nature of delocalized Pd-Pd bonding in these II (and presumably other nanosized) Pd clusters, in which each zerovalent Pd atom individually has a closed-subshell 4d (10) ground state, may likewise (as in argon clusters) be viewed primarily in terms of (considerably stronger) attractive dispersion interactions. (2) The existence of the 23-atom II Pd23 kernel in 1 provides an essential heretofore "missing" geometrical link as an intermediate in the same sequential growth pathway to give the 26- and 29-atom II Pd(n) kernels found in 2 and 3, respectively. Accommodation of the 12 bulky P(p-Tolyl)3 ligands around the entire 37-atom palladium core necessitates an extended metal surface that originates from the pseudo-2D trigonal-planar Pd23 kernel found in 1. The much smaller PMe3 ligands in 2 and 3 would sterically allow further sequential transformations of an initially formed 23-atom II intermediate palladium kernel into the 26-atom spheroidal II palladium kernel in 2 or further into the 29-atom semi-spheroidal II palladium kernel in 3, but with smaller total metal-atom nuclearities of 32 and 35, respectively.     

Highly stereoselective total synthesis of fully hydroxy-protected mycolactones A and B and their stereoisomerization upon deprotection

Unprecedentedly efficient and highly (≥98 %) stereoselective syntheses of mycolactones A and B side chains relied heavily on Pd‐catalyzed alkenylation (Negishi version) and were completed in 11 longest linear steps from ethyl (S)‐3‐hydroxybutyrate in 12 % and 11 % overall yield, respectively, roughly corresponding to an average of 82 % yield per step. The synthesis of mycolactone core was realized by using Pd‐catalyzed alkenyl? allyl coupling and an epoxide‐opening reaction with a trialkylalkenylaluminate as key steps. Fully hydroxy‐protected mycolactones A and B of ≥98 % isomeric purity were synthesized successfully for the first time. However, unexpected 4:3–5:4 inseparable mixtures of mycolactones A and B were obtained upon deprotection.     

Stable N-heterocyclic carbene (NHC)-palladium(0) complexes as active catalysts for olefin cyclopropanation reactions with ethyl diazoacetate

The Pd(0) complexes [(NHC)PdL(n)] (NHC=N-heterocyclic carbene ligand; L=styrene for n=2 or PR(3) for n=1) efficiently catalyse olefin cyclopropanation by using ethyl diazoacetate (EDA) as the carbene source with activities that improve on previously described catalytic systems based on this metal. Mechanistic studies have shown that all of these catalyst precursors deliver the same catalytic species in solution, that is, [(IPr)Pd(sty)], a 14e(-) unsaturated intermediate that further reacts with EDA to afford [(IPr)Pd(=CHCO(2)Et)(sty)], from which the cyclopropane is formed.     

Divergent synthetic strategy leading to structurally diverse pyrrolidines and piperidines from common gamma-aminoalkyl butenolide and aldehyde precursors

Condensation between aldehydes and the secondary amino function of 5-(aminoalkyl)furan-2(5H)-ones, obtained by the silyloxyfuran dienolate addition to imine-type derivatives, produces either aminoalkylbenzotriazoles or 1,2,3,4-tetrahydropyridines. The former can be reduced with SmI2 to generate alpha-aminoalkyl radicals that are trapped by the alpha,beta-unsaturated lactone moiety yielding substituted pyrrolidines diastereoselectively, while catalytic hydrogenation of the latter affords isomeric piperidine analogues. Alternatively, SmI2-promoted reduction of tetrahydropyridines in the presence of acid also leads to intermediate alpha-aminoalkyl radicals that participate in inter- or intramolecular olefin addition reactions. Further manipulation of the lactone functionality in various ways gives access to a number of interesting derivatives based upon either a pyrrolidine or a piperidine structural motif. As a result, a high degree of structural diversity is obtained in a few steps starting from a common set of simple materials.