Palladium-catalyzed reactions of hypophosphorous compounds with allenes, dienes, and allylic electrophiles: methodology for the synthesis of allylic h-phosphinates

Hypophosphorous compounds (MOP(O)H(2), M = H, R(3)NH) effectively participate in metal-catalyzed C-P bond-forming reactions with allenes, dienes, and activated allylic electrophiles under mild conditions. The catalytic system Pd(2)dba(3)/xantphos is crucial to avoid or minimize the competitive reductive transfer-hydrogenation pathway available to hypophosphorous acid derivatives. Further investigation into the allylation mechanism provided access to the analogy allylic acetate-allylic phosphinate, which then led to the development of a Pd-catalyzed rearrangement of preformed allylic phosphinates esters and, ultimately, to a catalytic dehydrative allylation of hypophosphorous acid with allylic alcohols. The reactions disclosed herein constitute efficient synthetic approaches, not only to prepare allylic H-phosphinic acids but also their esters via one-pot tandem processes. In addition, the potential of H-phosphinates as useful synthons for the preparation of other organophosphorus compounds is demonstrated.     

Synthesis of isoquinolines and pyridines by the palladium-catalyzed iminoannulation of internal alkynes.

A wide variety of substituted isoquinoline, tetrahydroisoquinoline, 5,6-dihydrobenz[f]isoquinoline, pyrindine, and pyridine heterocycles have been prepared in good to excellent yields via annulation of internal acetylenes with the tert-butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals in the presence of a palladium catalyst. The best results are obtained by employing 5 mol % of Pd(OAc)(2), an excess of the alkyne, 1 equiv of Na(2)CO(3) as a base, and 10 mol % of PPh(3) in DMF as the solvent. This annulation methodology is particularly effective for aryl- or alkenyl-substituted alkynes. When electron-rich imines are employed, this chemistry can be extended to alkyl-substituted alkynes. Trimethylsilyl-substituted alkynes also undergo this annulation process to afford monosubstituted heterocyclic products absent the silyl group.     

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.     

Recent advances in phosphorus-carbon bond formation: synthesis of H-phosphinic acid derivatives from hypophosphorous compounds

This account summarizes the research conducted in our laboratory over the past five years. New methodologies were devised for the formation of P-C bonds with a focus on the reactions of hypophosphorous acid derivatives. Three types of reactions have been developed: palladium-catalyzed cross-coupling, room-temperature radical addition, and palladium-catalyzed addition. Our results are summarized in each of these areas and include some of our most recent data. (1) Our palladium-catalyzed cross-coupling has been extended to the direct coupling of alkyl phosphinates with a variety of aryl, heteroaryl, and even alkenyl electrophiles. (2) The addition of sodium hypophosphite under radical conditions is extended from alkenes to alkynes. (3) The catalytic addition of hypophosphorous compounds using palladium catalysts (hydrophosphinylation) is also discussed.     

Environmentally benign synthesis of h-phosphinic acids using a water-tolerant, recyclable polymer-supported catalyst

[reaction: see text] A reusable polymer-supported hydrophosphinylation catalyst is described for the preparation of H-phosphinic acids. The polystyrene-based ligand is prepared in one step from commercially available compounds. The polymeric catalyst generally gives good yields for a variety of substrates and is water- and air-tolerant, although the scope of alkenes and alkynes which can be employed is somewhat narrower than with our original xantphos/Pd(2)dba(3) catalyst.     

Synthesis of N-(2-pyridyl)indoles via Pd(II)-catalyzed oxidative coupling

Readily available Pd(II) chloride catalysts can catalyze selective and efficient oxidative coupling between N-aryl-2-aminopyridines and internal alkynes to yield N-(2-pyridyl)indoles. This process involves the ortho C-H activation of N-aryl-2-aminopyridines, and CuCl(2) was used as an oxidant. Compared to our previously reported Rh(III)-catalyzed synthesis of this class of product, this method is advantageous with a wider scope of alkynes and cost-effective Pd(II) catalysts. Molecular oxygen can be used as a terminal oxidant.     

A new strategy for the synthesis of chiral β-alkynyl esters via sequential palladium and copper catalysis

A new strategy for the synthesis of chiral β-alkynyl esters which relies on sequential Pd and Cu catalysis is reported. Terminal alkynes bearing aryl, alkyl, and silyl groups can be employed without prior activation yielding a wide range of important chiral building blocks. The reaction sequence utilizes a robust Pd(II)-catalyzed hydroalkynylation of ynoates with terminal alkynes providing geometrically pure ynenoates which are readily reduced by CuH. In contrast to previous reports, where additions to ynenoates proceed with marginal preference for the 1,6-pathway, this conjugate reduction occurs with high 1,4-selectivity yielding β-alkynyl esters with excellent levels of enantioselectivity. Importantly, the method tolerates a wide range of functionality, including allylic carbonates and carbamates, and thus allows for rapid elaboration of the β-alkynyl esters into a variety of chiral, substituted heterocycles.     

Facile synthesis of 2-alkynyl buta-1,3-dienes via Sonogashira cross-coupling methodology

2-alkynyl buta-1,3-dienes 4 can be synthesized in moderate to high yields by the reactions of the corresponding diiodides 1 derived from methylenecyclopropanes with substituted alkynes 2 via Sonogashira cross-coupling in the catalysis of Pd(PPh3)4/CuI.     

Palladium-catalyzed carbonylative annulation of internal alkynes: synthesis of 3,4-disubstituted coumarins

The palladium-catalyzed annulation of internal alkynes by o-iodophenols in the presence of CO results in exclusive formation of coumarins. No isomeric chromones have been observed. The best reaction conditions utilize the 2-iodophenol, 5 equiv of alkyne, 1 atm of CO, 5 mol % Pd(OAc)2, 2 equiv of pyridine, and 1 equiv of n-Bu4NCl in DMF at 120 degrees C. The use of a sterically unhindered pyridine base is essential to achieve high yields. A wide variety of 3,4-disubstituted coumarins containing alkyl, aryl, silyl, alkoxy, acyl, and ester groups have been prepared in moderate to good yields. Mixtures of regioisomers have been obtained when unsymmetrical alkynes are employed. 2-iodophenols with electron-withdrawing and electron-donating substituents and 3-iodo-2-pyridone are effective in this annulation process. The reaction is believed to proceed via (1) oxidative addition of the 2-iodophenol to Pd(0), (2) insertion of the alkyne triple bond into the aryl-palladium bond, (3) CO insertion into the resulting vinylic carbon-palladium bond, and (4) nucleophilic attack of the phenolic oxygen on the carbonyl carbon of the acylpalladium complex with simultaneous regeneration of the Pd(0) catalyst. This annulation process is the first example of intermolecular insertion of an alkyne occurring in preference to CO insertion.     

Ruthenium-catalyzed oxidative cleavage of alkynes to carboxylic acids

We describe an efficient method for the oxidative cleavage of alkynes to carboxylic acids using a combination of RuO(2)/Oxone/NaHCO(3) in a CH(3)CN/H(2)O/EtOAc solvent system. Both internal and terminal alkynes, regardless of their electron density, can be oxidized to carboxylic acids in excellent yield (up to 99%). (1)H NMR spectroscopy and ESI-MS experiments provided evidence for alpha-diketones and anhydrides as possible intermediates in these oxidation reactions.     

Efficient palladium-catalyzed homocoupling reaction and Sonogashira cross-coupling reaction of terminal alkynes under aerobic conditions

An efficient method for palladium-catalyzed homocoupling reaction of terminal alkynes in the synthesis of symmetric diynes is presented. The results showed that both Pd(OAc)(2) and CuI played crucial roles in the reaction. In the presence of 2 mol % Pd(OAc)(2), 2 mol % CuI, 3 equiv of Dabco, and air, homocoupling of various terminal alkynes afforded the corresponding symmetrical diynes in moderate to excellent yields, whereas low yields were obtained without either Pd(OAc)(2) or CuI. Moreover, high TONs (turnover numbers; up to 940 000 for the reaction of phenylacetylene) for the homocoupling reaction were observed. Under similar reaction conditions, cross-coupling of 1-iodo-4-nitrobenzene with phenylacetylene was also carried out smoothly in quantitative yield. However, the presence of CuI disfavored the palladium-catalyzed Sonogashira cross-coupling reactions of the less active aryl iodides and bromides. In the presence of 0.01-2 mol % Pd(OAc)(2), a number of aryl iodides and bromides were coupled with terminal alkynes in good to excellent yields. It is noteworthy that this protocol employs mild, efficient, aerobic, copper-free, and ligand-free conditions.     

Investigation of an efficient palladium-catalyzed C(sp)-C(sp) cross-coupling reaction using phosphine-olefin ligand: application and mechanistic aspects

A pi-acceptor phosphine-electron-deficient olefin ligand was found effective in promoting Pd-catalyzed C(sp)-C(sp) cross-coupling reactions. The new protocol realized the cross-coupling of a broad scope of terminal alkynes and haloalkynes in good to excellent yields with high selectivities. Electron-rich alkynes, which are normally difficult substrates in Glaser couplings, could be employed as either nucleophiles or electrophiles. Alkynes bearing similar substituents, such as n-C5H11CCBr and n-C4H9CCH, which usually suffer from homocoupling side reactions under Cadiot-Chodkiewicz conditions, were successfully cross-coupled in the system. Preliminary kinetic studies revealed that the reaction rate was zero-order in the concentrations of both haloalkynes and terminal alkynes and first order in the loading of Pd(dba)2 and exhibited no obvious dependence on the loading of the copper salt. Control experiments with other phosphines such as PPh3 and DPPF as the ligand were carried out. All the kinetic evidence indicated that the phosphine-olefin ligand facilitated the reductive elimination in the catalytic cycle.     

Regio- and stereoselective dimerization of terminal alkynes to enynes catalyzed by a palladium/imidazolium system.

A Palladium/imidazolium chloride system has been used to mediate the dimerization of terminal alkynes to enynes. The combination of 1 mol % Pd(OAc)(2) and 2 mol % IMes.HCl in the presence of Cs(2)CO(3) as base shows high activity and high regio- and steroselectivity for the dimerization of aryl and aliphatic terminal alkynes to enynes.     

Efficient P,O chelate palladium(II)/AgNO3 cocatalyzed homocoupling of aromatic terminal alkynes in aqueous media under ambient atmosphere

A new and efficient protocol for the P, O chelate Pd(II)/AgNO₃ cocatalyzed oxidative homocoupling reaction of aromatic terminal alkynes in the synthesis of symmetrical 1,4-disubstituted-1,3-diynes was described in aqueous media under ambient atmosphere. The results showed that both NEt₃ and THF/H₂O (in 4:1 proportion) played crucial roles in the reaction. In contrast, this protocol employs a low palladium(II) complex loading and AgNO₃ as cocatalyst to obtain the homocoupled products in moderate to good yields.     

Enynylation of 2-iodo-4-(phenylchalcogenyl)-1-butenes via intramolecular chelation: approach to the synthesis of conjugated dienynes or trienynes

[reaction: see text] 2-Iodo-4-(phenylchalcogenyl)-1-butenes 3 and 4, which are derived from methylenecyclopropanes 1, can be enynylated with alkynes catalyzed by Pd(OAc)(2) to give conjugated dienynes 5 and 6 in the absence of any phosphine ligand and copper salt, and trienyne 9a can be obtained by oxidation of compound 5a. A plausible reaction mechanism has been proposed.     

Nanomorphology of polymer frameworks and their role as templates for generating size-controlled metal nanoclusters

The microporous (gel-type) functional resin co-poly-N,N-dimethylacrylamide (DMAA) (88 % mol)/methacrylic acid (MAA) (8 % mol)/N,N'-methylenebisacrylamide (MBAA) (4 % mol) (MPIF(H)) is employed as the hosting framework for the production of resin-supported Pd(0) nanoclusters. The obtained composite MPIF(-)Na(+)/Pd(0) is prepared upon reducing, in ethanol, MPIF(-)Pd(2+) (0.5), obtained upon previous homogeneous dispersion of "Pd(2+)" inside the resin particles (XRMA control) through ion-exchange. Metal nanoclusters appear to be size-controlled (2.0+/-0.2 nm) and are seen to reasonably fit the predominant resin "nanopores" diameter, determined in ethanol (3.2 nm) by means of inverse steric exclusion chromatography (ISEC).     

Heteropolynuclear palladium complexes with pyrazolate and its 3-tert-butyl derivatives: the effect of heterometal ions on the rate of isomerization

The heteropolynuclear complexes [Pd(2)M'(2)(mu-pz)(6)] (M'=Ag (1), Au (2); pzH=pyrazole), HT-[Pd(2)M'(2)(mu-3-tBupz)(6)] (M'=Ag (3 a), Au (4 a); 3-tBupzH=3-tert-butylpyrazole), and HH-[Pd(2)Au(2)(mu-3-tBupz)(6)] (4 b) have been prepared and some of them were structurally characterized. When 3-tert-butylpyrazolate was employed as a bridging ligand, two linkage isomers (head-to-tail (HT) and head-to-head (HH)) arise from the difference in orientation of the substituent groups on the pyrazolate bridges between the two Pd atoms. (1)H NMR spectroscopy has been used to identify and to follow the reversible stereochemical rearrangement of the HH isomer of [Pd(2)Ag(2)(mu-3-tBupz)(6)] (3 b) to form the HT isomer 3 a in CDCl(3) and the HT isomer of [Pd(2)Au(2)(mu-3-tBupz)(6)] (4 a) to form the HH isomer 4 b in C(6)D(6). Kinetic studies of the reaction have established the rate law to be -d(HH)/dt=d(HT)/dt=k(2)[HH]-k(1)[HT] for 3 b and -d(HT)/dt=d(HH)/dt=k(1)[HT]-k(2)[HH] for 4 a, where k(1) and k(2) denote the rate of isomerization from the HT to the HH isomer and that from the HH to the HT isomer, respectively. For typical runs at 50 degrees C in C(6)D(6), k(1)=13.8x10(-5) s(-1), k(2)=18.6x10(-5) s(-1), and K(eq)=k(2)/k(1)=1.24 for 3 b, and k(1)=1.26x10(-5) s(-1), k(2)=3.52x10(-5) s(-1), and K(eq)=k(1)/k(2)=0.36 for 4 a. Temperature-dependent rate measurements reveal DeltaH(not equal) and DeltaS(not equal) to be 100(1) kJ mol(-1) and 0(3) J mol(-1) K(-1) for 3 b and 112(5) kJ mol(-1) and 20(17) J mol(-1) K(-1) for 4 a, respectively. The rate of isomerization is essentially unaffected by the concentration of the complex or by the presence of neutral bridging ligands. These data and observations imply that the isomerization involves an intramolecular exchange process.     

A facile regiocontrol in the palladium-catalyzed annulation of fluorine-containing internal alkynes with variously substituted 2-iodoanilines: a new regioselective synthesis of 2- or 3-fluoroalkylated indole derivatives

Treatment of various types of fluoroalkylated alkynes with o-iodoaniline in the presence of Pd(PPh(3))(4) in DMF at 80 degrees C for 8 h mainly gave 2-fluoroalkylated indoles in high yields. The use of P(o-Tol)(3) instead of PPh(3) as a ligand led to the preferential formation of 3-fluoroalkylated indoles in high yields. Interestingly, the reaction of trifluoromethylated alkynes bearing a benzylic substituent afforded 2- or 3-trifluoroethylated indole derivatives in good yields.     

Remarkable ligand effect in Ni- and Pd-catalyzed bisthiolation and bisselenation of terminal alkynes: solving the problem of stereoselective dialkyldichalcogenide addition to the C triple chemical bond C Bond

We have developed two new catalytic systems based on Ni and Pd complexes to solve the challenging problem of dialkyldichalcogenide (Alk2E2; E=S, Se) addition to alkynes. A comparative study of two catalytic systems-Ni/PMe2Ph and Pd/PCy2Ph-has revealed that the Ni catalyst is superior with respect to high catalytic activity and more general scope relative to the Pd system. A novel synthetic methodology was developed for the preparation of (Z)-bis(alkylthio)alkenes and (Z)-bis(alkylseleno)alkenes from terminal alkynes with excellent stereoselectivity and high yields.     

钯催化下(Z)-3-碘-3-三氟甲基-1-芳基烯丙醇与末端炔 烃的偶联反应

在Pd(PPh~3)~4/CuI催化下和使用1mol的NEt~3作碱和THF作溶剂,(Z)-3-碘-3-三氟甲基-1-芳基烯丙醇(1)与末端炔烃(3)反应得到正常的偶联产物5。当以NEt~3作碱和溶剂,Pd(PPh~3)~4/CuI催化1与3的交叉偶联反应生成化合物4。4为正常偶联化合物5在NEt~3存在下双键发生重排反应的产物。