Highly efficient Heck reactions of aryl bromides with n-butyl acrylate mediated by a palladium/phosphine-imidazolium salt system

[reaction: see text] A new phosphine-imidazolium salt, L.HBr (1, L = (1-ethylenediphenylphosphino-3-(mesityl))imidazol-2-ylidene), has been prepared. A combination of 0.5 mol % of Pd(dba)(2) and 0.5 mol % of L.HBr in the presence of 2 equiv of Cs(2)CO(3) as base has proven to be highly efficient in the Heck coupling reactions of aryl bromides (from electron-deficient to electron-rich aryl bromides) with n-butyl acrylate.     

Synthesis of seven-membered ring diazepin-2-ones via palladium-catalyzed highly regioselective cyclization of 2-vinylpyrrolidines with aryl isocyanates

The first palladium-catalyzed ring-expansion reaction of 2-vinylpyrrolidines with aryl isocyanates to form seven-membered ring heterocycles is described. This regioselective reaction requires 5 mol % of Pd(2)(dba)(3).CHCl(3) and 10 mol % of dppp at 40-60 degrees C in THF and results in the formation of 1,3-diazepin-2-ones in good isolated yields. When Pd(OAc)(2) and PPh(3) were utilized in the reaction, an intramolecular hydrogen migration occurs resulting in the formation of conjugated diene derivatives of urea.     

Stereoselective palladium-catalyzed carbocyclization of allenic allylic carboxylates

Palladium(0)-catalyzed reaction of allene-substituted allylic carboxylates 3-8 employing 2-5 mol % of Pd(dba)(2) in refluxing toluene leads to the carbocyclization and elimination of carboxylic acid to give bicyclo[4.3.0]nonadiene and bicyclo[5.3.0]decadiene derivatives (12-17). The carbon-carbon bond formation is stereospecific, occurring syn with respect to the leaving group. Addition of maleic anhydride as a ligand to the above-mentioned procedures changed the outcome of the reaction, and under these conditions 3-5 afforded cycloisomerized products 21-23. The experimental results are consistent with a mechanism involving oxidative addition of the allylic carboxylate to Pd(0) to give an electron-deficient (pi-allyl)palladium intermediate, followed by nucleophilic attack by the allene on the face of the pi-allyl opposite to that of the palladium atom. Furthermore, it was found that the Pd(dba)(2)-catalyzed cyclization of the trans-cycloheptene derivative (trans-8) can be directed to give either the trans-fused (trans-17) or the cis-fused (cis-17) ring system by altering the solvent. The former reaction proceeds via a nucleophilic trans-allene attack on the (pi-allyl)palladium intermediate, whereas the latter involves a syn-allene insertion into the allyl-Pd bond of the same intermediate. The products from the carbocylization undergo stereoselective Diels-Alder reactions to give stereodefined polycyclic systems in high yields.     

Synthesis of allyl cyanamides and N-cyanoindoles via the palladium-catalyzed three-component coupling reaction

The palladium-catalyzed three-component coupling reaction (TCCR) of aryl isocyanides, allyl methyl carbonate, and trimethylsilyl azide was conducted in the presence of Pd(2)(dba)(3).CHCl(3) (2.5 mol %) and dppe (1,2-bis(diphenylphosphino)ethane) (10 mol %). Allyl aryl cyanamides with a wide variety of functional groups were obtained in excellent yields. This palladium-catalyzed TCCR was further utilized for the synthesis of N-cyanoindoles. The reaction of 2-alkynylisocyanobenzenes, allyl methyl carbonate, and trimethylsilyl azide in the presence of Pd(2)(dba)(3).CHCl(3) (2.5 mol %) and tri(2-furyl)phosphine (10 mol %) at higher temperatures afforded N-cyanoindoles in good to allowable yields. (eta(3)-Allyl)(eta(3)-cyanamido)palladium complex, an analogue of the bis-pi-allylpalladium complex, is a key intermediate in the TCCR, and a pi-allylpalladium mimic of the Curtius rearrangement is involved to generate the (eta(3)-allyl)(eta(3)-cyanamido)palladium intermediate.     

钯催化芳基溴代物和氨基乙醛缩二乙醇的偶联反应研究

以Pd2（dba）3／XantPhos为原位生成的催化剂,研究了以芳基溴代物与氨基乙醛缩二乙醇之间的偶联反应合成N-（2,2-二乙氧基乙基）芳胺的反应,考察了催化剂前体、配体以及催化剂前体与配体的用量对该反应的影响．实验结果表明,当以2．5％Pd2（dba）3作为催化剂前体,3．75％XantPhos作为配体,吸电子取代和给电子取代的芳基溴代物均可与氨基乙醛缩二乙醇发生C—N交叉偶联反应,高选择性的得到产物N-（2,2-二乙氧基乙基）芳胺,分离收率为73％-96％．     

Novel synthesis of carbapenam by intramolecular attack of lactam nitrogen toward eta1-allenyl and eta3-propargylpalladium complex

When a THF solution of beta-lactam having propargyl phosphate was warmed in the presence of 5 mol % of Pd(2)(dba)(3) x CHCl(3), 20 mol % of a bidentate ligand, and sodium acetate (1.5 equiv) at 40 degrees C for 22 h, carbapenam was produced in high yield. In this reaction, the lactam nitrogen attacked the central carbon of a eta(3)-propargylpalladium complex, which was formed from propargyl phosphate and Pd(0).     

Palladium-catalyzed aminoallylation of activated olefins with allylic halides and phthalimide

The three-component aminoallylation reaction of the activated olefins 2 with the phthalimide 1a and allyl chloride proceeded very smoothly in the presence of Pd(2)dba(3).CHCl(3) (5 mol %)/P(4-FC(6)H(4))(3) (40 mol %) and Cs(2)CO(3) (3 equiv against 2) in dichloromethane at room temperature to give the corresponding aminoallylated products, N-pent-4-enylphthalimides 3, in 58-99% yields. The reaction of oxazolidinone 1b also proceeded very smoothly to give N-(2,2-dicyano-1-phenylpent-4-enyl)oxazolidinone in a quantitative yield; however, the Tsuji-Trost-type allylation products 4 were obtained in the case of dibenzylamine, N-tosylaniline, and pyrrolidin-2-one. Further, 2 underwent cycloaddition with N-tosylvinylaziridine 9a in the presence of Pd(2)dba(3).CHCl(3) (5 mol %)/P(4-FC(6)H(4))(3) (40 mol %) in THF at room temperature, giving the corresponding pyrrolidines 11 in 69-99% yields.     

Efficient synthesis of N-aryl-aza-crown ethers via palladium-catalyzed amination

N-Aryl-aza-crown ethers were efficiently prepared by reaction of an aza-crown ether with an aryl bromide via a palladium-catalyzed amination. The combination of Pd(2)(dba)(3) and a biphenyl-based electron-rich bulky monophosphine is effective for catalyzing the coupling of 1-aza-15-crown-5 with both electron-deficient and electron-rich aryl bromides under mild conditions. N-Aryl-aza-crown ethers were produced in 75-91% yields. N-Aryl-aza-crown ethers with o-aryl substituents can also be synthesized using this catalyst system, albeit in lower yields ( approximately 40%).     

Palladium-catalyzed cyclization reactions of 2-vinylthiiranes with heterocumulenes. Regioselective and enantioselective formation of thiazolidine, oxathiolane, and dithiolane derivatives

The first palladium-catalyzed ring-expansion reaction of 2-vinylthiiranes with heterocumulenes to form sulfur-containing five-membered-ring heterocycles is described. This regioselective reaction requires 5 mol % of Pd(2)(dba)(3).CHCl(3) and 10 mol % of bidendate phosphine ligand (dppp, BINAP), at 50-80 degrees C, in THF. The reaction of 2-vinylthiiranes with carbodiimides, isocyanates, and ketenimines affords 1,3-thiazolidine derivatives, whereas the reaction with diphenylketene or isothiocyanates results in the formation of 1,3-oxathiolane or 1,3-dithiolane compounds in good to excellent isolated yields and in up to 78% ee.     

Unusual palladium-catalyzed silaboration of allenes using organic iodides as initiators: mechanism and application

A highly regio- and stereoselective method for the synthesis of various 2-silylallylboronates 7 from allenes 1 and 2-(dimethylphenylsilanyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (5) catalyzed by palladium complexes and initiated by organic iodides is described. Treatment of monosubstituted aryl and alkylallenes RCH=C=CH(2) (1a-m) and 1,1-dimethylallene (1n) with borylsilane 5 in the presence of Pd(dba)(2) (5 mol %) and organic iodide 3a (10 mol %) afforded the corresponding silaboration products 7a-n in moderate to excellent yields. This catalytic silaboration is totally regioselective with the silyl group of 5adding to the central carbon and the boryl group to the unsubstituted terminal carbon of allene. Furthermore, the reactions show very high E stereoselectivity with the Z/E ratios lying in the range from 1/99 to 7/93. In the absence of an organic iodide, silaboration of 1 with 5 still proceeds, but gives products having completely different regiochemistry as that of 7. The silaboration chemistry can be applied to the synthesis of homoallylic alcohols. Treatment of allenes (1) with borylsilane 5 and aldehydes 14 in the presence of Pd(dba)(2) (5 mol %) and 3a (10 mol %) at 80 degrees C in ethyl acetate for 5 h afforded homoallylic alcohols 15a-p in one pot in good to excellent yields, with exceedingly high syn selectivity (>93%). Mechanistic pathways involving an unusual palladium-catalyzed three-component assembling reaction of dimethylphenylsilyl iodide, allene 1, and borylsilane 5 were proposed to account for these catalytic reactions.     

Synthesis of heterocyclic allenes via palladium-catalyzed hydride-transfer reaction of propargylic amines

[reaction: see text] Propargylic diisopropylamines containing heterocycles, which were prepared readily from heterocyclic bromides and propargyldiisopropylamine by the Sonogashira coupling reaction, underwent the allene transformation reaction in the presence of Pd(2)(dba)(3).CHCl(3) catalyst (2.5 mol %) and 1,2-bis[bis(pentafluorophenyl)phosphino]ethane (10 mol %) at 100 degrees C in CHCl(3), giving the corresponding heterocyclic allenes in good to high yields via the palladium-catalyzed hydride-transfer reaction.     

A bimetallic catalyst and dual role catalyst: synthesis of N-(alkoxycarbonyl)indoles from 2-(alkynyl)phenylisocyanates

3-allyl-N-(alkoxycarbonyl)indoles are synthesized via the reaction of 2-(alkynyl)phenylisocyanates and allyl carbonates in the presence of Pd(PPh(3))(4) (1 mol %) and CuCl (4 mol %) bimetallic catalyst. It is most probable that Pd(0) acts as a catalyst for the formation of a pi-allylpalladium alkoxide intermediate and Cu(I) behaves as a Lewis acid to activate the isocyanate, and the cyclization step proceeds with a cooperative catalytic activity of Pd and Cu. On the other hand, N-(alkoxycarbonyl)indoles are produced via the reaction of 2-(alkynyl)phenylisocyanates and alcohols under a catalytic amount of Na(2)PdCl(4) (5 mol %) or PtCl(2) (5 mol %). Pd(II) or Pt(II) catalyst exhibits dual roles; it acts as a Lewis acid to accelerate the addition of alcohols to isocyanates and as a typical transition-metal catalyst to activate the alkyne for the subsequent cyclization.     

1,2-Bis(diphenylphosphino)carborane as a dual mode ligand for both the Sonogashira coupling and hydride-transfer steps in palladium-catalyzed one-pot synthesis of allenes from aryl iodides

[reaction: see text] One-pot allene synthesis from aryl iodides 1 and propargyldicyclohexylamine 2 proceeded in the presence of Pd(2)(dba)(3).CHCl(3) catalyst (2.5 mol %), 1,2-bis(diphenylphosphino)carborane 5 (10 mol %), CuI (15 mol %), and Et(3)N (150 mol %) to give the corresponding allenes 4 in good to high yields. Electron-deficient bidentate phosphines, such as 1,2-bis(diphenylphosphino)carborane 5 and (C(6)F(5))(2)PC(2)H(4)P(C(6)F(5))(2), play the role of a dual mode ligand for both the Sonogashira coupling and hydride-transfer reactions.     

Formation of a quaternary carbon center through the Pd(0)/PhCOOH-catalyzed allylation of cyclic beta-keto esters and 1,3-diketones with alkynes

Formation of a quaternary carbon center through the allylation of beta-keto esters and 1,3-diketones with alkynes is accomplished by the use of Pd(0)/benzoic acid catalyst. Reactions of various cyclic beta-keto esters and 1,3-diketones with alkynes in the presence of Pd(2)dba(3).CHCl(3) (5 mol %), PPh(3) (40 mol %), and PhCOOH (10 mol %) proceeded at 100 degrees C in toluene (5 M) to give the corresponding allylation products in high yields in a regio- and stereoselective manner. The possibility of asymmetric allylation is also discussed.     

Palladium-catalyzed selective synthesis of 2-allyltetrazoles

The palladium-catalyzed three-component coupling (TCC) reaction of cyano compounds, allyl methyl carbonate, and trimethylsilyl azide under a catalytic amount of Pd2(dba)3.CHCl3 (2.5 mol %) and tri(2-furyl)phosphine (10 mol %) gave various kinds of 2-allyltetrazoles in good to excellent yields. A pi-allylpalladium azide complex is proposed as a key intermediate in the TCC reaction.     

Novel synthesis of conjugated dienes attached to a quaternary carbon center via Pd(0)-catalyzed deconjugative allylation of alkenylidenemalonates

Palladium(0)-catalyzed deconjugative allylation of alkenylidenemalonates and alkylidenemalonates was achieved for the first time. Reactions of dimethyl 2-((E)-but-2-enylidene)malonate with various allylic acetates using LHMDS as a base in DMF in the presence of Pd(2)dba(3) (2.5 mol %) and PPh(3) (10 mol %) proceeded at room temperature to give the corresponding alpha-allylation products in good yields in a regio- and stereoselective manner. This reaction can also be used for allylation of dimethyl ethylidenemalonate or dimethyl 2-((E)-pent-2-enylidene)malonate and give the desired alpha-allylation products in good yields.     

Palladium-catalyzed synthesis of 1-alkylphosphonium salts from 1-alkenes

A palladium(0) complex catalyzes the addition reaction of a triarylphosphine and a protic acid to a 1-alkene, giving a 1-alkylphosphonium salt. The treatment of atmospheric ethylene, triphenylphosphine, and (CF3SO2)2NH in the presence of Pd2(dba)3.CHCl3 (dba = dibenzylideneacetone) (0.1 mol %) in chlorobenzene at 65 degrees C for 5 h gave ethylphosphonium salt in 98% isolated yield. The anti-Markovnikov adduct 1-propylphosphonium salt was obtained by the reaction of atmospheric propene in 95% yield. 1-Butene was converted to 1-butylphosphonium salt in 92% yield in the presence of 1 mol % catalyst. This reaction competed with olefin isomerization, and a mixture of 2-butene and 1-butene (>20:1) was recovered. The reactions of 1-pentene and 1-hexene with triphenylphosphine gave modest yields of the products. The less reactive 1-alkenes, however, reacted effectively with tris(p-chlorophenyl)phosphine. The inner olefins, 2- and 3-pentene also gave a 1-pentylphosphonium salt in high yields via rapid olefin migration.     

Highly efficient syntheses of [methyl-11C]thymidine and its analogue 4'-[methyl-11C]thiothymidine as nucleoside PET probes for cancer cell proliferation by Pd(0)-mediated rapid C-[11C]methylation

Pd(0)-mediated rapid couplings of CH(3)I (and then [(11)C]CH(3)I) with excess 5-tributylstannyl-2'-deoxyuridine and -4'-thio-2'-deoxyuridine were investigated for the syntheses of [methyl-(11)C]thymidine and its stable analogue, 4'-[methyl-(11)C]thiothymidine as PET probes for cancer diagnosis. The previously reported conditions were attempted using Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3) (1?:?4 in molar ratio) at 130 °C for 5 min in DMF, giving desired products only in 32 and 30% yields. Therefore, we adapted the current reaction conditions developed in our laboratory for heteroaromatic compounds. The reaction using CH(3)I/stannane/Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3)/CuCl/K(2)CO(3) (1?:?25?:?1?:?32?:?2?:?5) at 80 °C gave thymidine in 85% yield. Whereas, CH(3)I/stannane/Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3)/CuBr/CsF (1?:?25?:?1?:?32?:?2?:?5) including another CuBr/CsF system promoted the reaction at a milder temperature (60 °C), giving thymidine in 100% yield. Chemo-response of thiothymidine-precursor was different from thymidine system. Thus, the above optimized conditions including CuBr/CsF system gave 4'-thiothymidine only in 40% yield. The reaction using 5-fold amount of CuBr/CsF at 80 °C gave much higher yield (83%), but unexpectedly, the reaction was accompanied by a considerable amount of undesired destannylated product. Such destannylation was greatly suppressed by changing to a CuCl/K(2)CO(3) system using CH(3)I/stannane/Pd(2)(dba)(3)/P(o-CH(3)C(6)H(4))(3)/CuCl/K(2)CO(3) (1?:?25?:?1?:?32?:?2?:?5) at 80 °C, giving the 4'-thiothymidine in 98% yield. The each optimized conditions were successfully applied to the syntheses of the corresponding PET probes in 87 and 93% HPLC analytical yields. [(11)C]Compounds were isolated by preparative HPLC after the reaction conducted under slightly improved conditions, exhibiting sufficient radioactivity of 3.7-3.8 GBq and specific radioactivity of 89-200 GBq μmol(-1) with radiochemical purity of ≥99.5% for animal and human PET studies.     

Palladium(0)-catalyzed intramolecular [2+2+2] alkyne cyclotrimerizations with electron-deficient diynes and triynes

In the presence of 2.5 mol % of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and 5 mol % of PPh(3), nearly equimolar amounts of dimethyl nona-2,7-diyne-1,9-dioate derivatives (diyne diesters) and dialkyl acetylenedicarboxylates were allowed to react in toluene at 110 degrees C to afford [2+2+2] cycloadducts in moderate-to-good yields. Similarly, dimethyl trideca-2,7,12-triyne-1,13-dioate derivatives (triyne diesters) were catalytically transformed into phthalic acid ester analogues in excellent yields. To gain insight into the mechanism of these intramolecular alkyne cyclotrimerizations, stoichiometric reactions of [Pd(2)(dba)(3)] with a diyne diester and a triyne diester bearing ether tethers were conducted in acetone at room temperature to furnish an oligomeric bicyclopalladacyclopentadiene and a Pd(0) triyne complex, respectively. The structures of these novel complexes were unequivocally determined by Xray structure analysis. The isolated triyne complex was heated at 50 degrees C or treated with PPh(3) in acetone at room temperature to afford the arene product. Furthermore, the same complex catalyzed the triyne cyclization with or without PPh(3).     

Palladium-catalyzed Stille cross-couplings of sulfonyl chlorides and organostannanes

Arene and phenylmethanesulfonyl chlorides can be cross-coupled with aryl, heteroaryl, and alkenylstannanes with desulfitation in the presence of 10 mol % CuBr.Me2S, 1.5 mol % Pd2dba3, and 5 mol % tri-2-furylphosphine in tetrahydrofuran or toluene under reflux. This extension of the Stille cross-coupling reaction realizes a new and economical method for the generation of C-C bonds. The palladium-catalyzed carbonylative Stille cross-coupling reactions of arenesulfonyl chlorides and organostannanes in the presence of CO (60 bar) at 110 degrees C in toluene generate the corresponding ketones. Arenesulfonyl chlorides are more reactive than aryl chlorides and aryl bromides in their Stille cross-coupling with organostannanes but less reactive than aryl iodides. The new methods disclosed for the generation of C-C bonds open new possibilities for medicinal chemistry and material sciences.