Selective and catalytic arylation of N-phenylpyrrolidine: sp3 C-H bond functionalization in the absence of a directing group

We herein describe our studies on arylation of N-phenylpyrrolidine, which led to the development of a new transformation for the direct and selective arylation of sp3 C-H bonds in the absence of a directing group. In this method, Ru(H)2(CO)(PCy3)3 4 was used as the catalyst, and preliminary mechanistic studies suggested that Ru(Ph)(I)(CO)(PCy3)2 5 is the key intermediate of the catalytic cycle. A large kinetic isotope effect (kH/kD = 5.4) was observed, which supports the proposal that C-H bond metalation is the slow step. Preliminary examination of the substrate scope showed that in addition to N-phenylpyrrolidine, N-methyl- and N-benzylpyrrolidine, as well as N-benzoylpyrrolidine, were arylated under the reaction conditions.     

Palladium-catalyzed rearrangement/arylation of 2-allyloxypyridine leading to the synthesis of N-substituted 2-pyridones

[reaction: see text] The Pd-catalyzed one-pot rearrangement/arylation of 2-allyloxypyridine is described. The catalyst/base combination of Pd[P(t-Bu)(3)](2)/Ag(2)CO(3) was found to be optimal for this one-pot rearrangement/arylation. The initial rearrangement of 2-allyloxypyridine was found to be catalyzed by both Pd(0) and Pd(II) complexes with different mechanisms.     

Steric control over the formation of cis and trans bis-chelated palladium(II) complexes using a new series of flexible N,P pyridyl-phosphine ligands

The deprotection of phosphonium chloride salts [PR2(CH2OH)2]+Cl- and subsequent condensation reaction with N-methyl-2-aminopyridine has been carried out to give a series of ligands of the form PR2CH2N(CH3)C5H4N (R=Ph , Cy , t-Bu ) which have been fully characterised either as the pure ligand () or the air stable borane adducts (R=Cy , t-Bu ). The 1:1 reactions of , and with PdCl2(COD) gave the N,P chelate complexes [Pd{PR2CH2N(CH3)C5H4N}Cl2]; the Cy () and t-Bu () complexes were characterised by X-ray crystallography. The bisligated species [Pd{PCy2CH2N(CH3)C5H4N}2Cl2] () was obtained when the reaction was carried out at higher temperatures and the ligands were found to be coordinated to the metal in a trans configuration through the phosphorus donors. Abstraction of the chlorides from the bis-ligated species , using silver salts, resulted in the coordination of the pyridine ring forming the bis-chelate complex [Pd{PCy2CH2N(CH3)C5H4N}2]2+. In comparison, the palladium bis-chelate complex of ligand [Pd{PPh2CH2N(CH3)C5H4N}2]2+ () was shown to form in a cis configuration and was fully characterised by X-ray crystallography.     

A versatile catalyst for Heck reactions of aryl chlorides and aryl bromides under mild conditions.

In the presence of Cy2NMe, Pd/P(t-Bu)3 serves as an exceptionally mild and versatile catalyst for Heck reactions of aryl chlorides and bromides. A sterically and electronically diverse array of aryl bromides, as well as activated aryl chlorides, couple with a range of mono- and disubstituted olefins at room temperature, furnishing the arylated product with high E/Z stereoselection. The corresponding reactions of a broad spectrum of electron-neutral and electron-rich aryl chlorides proceed at elevated temperature, also with high selectivity. In terms of scope and mildness, Pd/P(t-Bu)3/Cy2NMe represents an advance over previously reported catalysts for these Heck coupling processes.     

Palladium-catalyzed cascade reaction of alpha,beta-unsaturated sulfones with aryl iodides

Unlike traditionally used acyclic 1,2-disubstituted alkenes, the reaction of alpha,beta-unsaturated phenyl sulfones with aryl iodides under Heck reaction conditions (Pd(OAc)(2) as catalyst, Ag(2)CO(3) as base in DMF at 120 (0)C) takes place mainly by a cascade process, involving one unit of the alkene and three units of the aryl iodide, to afford a substituted 9-phenylsulfonyl-9,10-dihydrophenanthrene. The dominant formation of this 3:1 coupling product, instead of the Heck trisubstituted olefin, shows that aromatic C-H bond activation processes can compete with the usually fast syn beta-hydrogen elimination step in the Heck arylation of an acyclic olefin. The structural scope of this palladium-catalyzed cascade arylation of alpha,beta-unsaturated sulfones has proved to be wide with regard to substitution at the beta-position (alkyl, aryl, or alkenyl substitution), substitution at the sulfone unit (alkyl or phenyl sulfones), and configuration at the CdoublebondC bond (trans or cis). Moreover, although less favored than in the case of the arylation of alpha,beta-unsaturated sulfones, similarly substituted 9,10-dihydrophenanthrenes have also been obtained in the case of alpha,beta-unsaturated phosphine oxides and alpha,beta-unsaturated phosphonate esters. A Pd(0)-Pd(II)-Pd(IV) mechanistic pathway involving the successive formation of highly electrophilic sigma-alkylpalladium intermediates and palladacycles is proposed for this multicomponent arylation.     

Diastereoselective palladium-catalyzed alpha-arylation of 4-substituted cyclohexyl esters

A diastereoselective palladium-catalyzed arylation of 4-substituted cyclohexyl esters has been developed. The reaction proceeds at room temperature in the presence of [(t-Bu3P)PdBr]2 providing products in up to 37:1 dr.     

The synthesis of non‐symmetrical stilbene analogs of trans‐resveratrol using the same Pd catalyst in a sequential double‐Heck arylation of ethylene

We have developed a sequential and selective Pd‐catalyzed double‐Heck arylation of ethylene that results in non‐symmetrical nitro‐stilbene analogs of trans‐resveratrol at excellent yields. A catalytic system consisting of Pd(OAc)₂ and P(o‐tolyl)₃ permitted us to carry out the two consecutive Heck arylations without losing activity from the first to the second Heck reaction. After the first Heck arylation of ethylene, no isolation or additional catalyst loading is required for the second Heck arylation reaction. This protocol was applied to the synthesis of methylated trans‐resveratrol, which was obtained at a 65% overall yield. Copyright © 2011 John Wiley & Sons, Ltd.     

Gold(I) phosphido complexes: synthesis, structure, and reactivity

Deprotonation of the phosphine complexes Au(PHR(2))Cl with aqueous ammonia gave the gold(I) phosphido complexes [Au(PR(2))](n)() (PR(2) = PMes(2) (1), PCy(2) (2), P(t-Bu)(2) (3), PIs(2) (4), PPhMes (5), PHMes (6); Mes = 2,4,6-Me(3)C(6)H(2), Is = 2,4,6-(i-Pr)(3)C(6)H(2), Mes = 2,4,6-(t-Bu)(3)C(6)H(2), Cy = cyclo-C(6)H(11)). (31)P NMR spectroscopy showed that these complexes exist in solution as mixtures, presumably oligomeric rings of different sizes. X-ray crystallographic structure determinations on single oligomers of 1-4 revealed rings of varying size (n = 4, 6, 6, and 3, respectively) and conformation. Reactions of 1-3 and 5 with PPN[AuCl(2)] gave PPN[(AuCl)(2)(micro-PR(2))] (9-12, PPN = (PPh(3))(2)N(+)). Treatment of 3 with the reagents HI, I(2), ArSH, LiP(t-Bu)(2), and [PH(2)(t-Bu)(2)]BF(4) gave respectively Au(PH(t-Bu)(2))(I) (14), Au(PI(t-Bu)(2))(I) (15), Au(PH(t-Bu)(2))(SAr) (16, Ar = p-t-BuC(6)H(4)), Li[Au(P(t-Bu)(2))(2)] (17), and [Au(PH(t-Bu)(2))(2)]BF(4) (19).     

A guide to Sonogashira cross-coupling reactions: the influence of substituents in aryl bromides, acetylenes, and phosphines

The conversion-time data for 168 different Pd/Cu-catalyzed Sonogashira cross-coupling reactions of five arylacetylenes (phenylacetylene; 1-ethynyl-2-ethylbenzene; 1-ethynyl-2,4,6-R(3)-benzene (R = Me, Et, i-Pr)) and Me(3)SiCCH with seven aryl bromides (three 2-R-bromobenzenes (R = Me, Et, i-Pr); 2,6-Me(2)-bromobenzene and three 2,4,6-R(3)-bromobenzenes (R = Me, Et, i-Pr)) with four different phosphines (P-t-Bu(3), t-Bu(2)PCy, t-BuPCy(2), PCy(3)) were determined using quantitative gas chromatography. The stereoelectronic properties of the substituents in the aryl bromides, acetylenes, and phosphines were correlated with the performance in Sonogashira reactions. It was found that the nature of the most active Pd/PR(3) complex for a Sonogashira transformation is primarily determined by the steric bulk of the acetylene; ideal catalysts are: Pd/P-t-Bu(3) or Pd/t-Bu(2)PCy for sterically undemanding phenylacetylene, Pd/t-BuPCy(2) for 2- and 2,6-substituted arylacetylenes or Me(3)SiCCH and Pd/PCy(3) for extremely bulky acetylenes and aryl bromides. Electron-rich and sterically demanding aryl bromides with substituents in the 2- or the 2,6-position require larger amounts of catalyst than 4-substituted aryl bromides. The synthesis of tolanes with bulky groups at one of the two aryl rings is best done by placing the steric bulk at the arylacetylene, which is also the best place for electron-withdrawing substituents.     

Selective terminal heck arylation of vinyl ethers with aryl chlorides: a combined experimental-computational approach including synthesis of betaxolol

Reaction conditions have been developed for palladium-catalyzed terminal (beta-) arylation of acyclic vinyl ethers with high regioselectivity using inexpensive aryl chlorides as starting materials and the P(t-Bu)3 releasing preligand [(t-Bu3)PH]BF4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to minimize handling and processing times and uses aqueous DMF or environmentally friendly PEG-200 as the reaction medium. The selectivity for linear beta-product in PEG-200 is slightly higher than in aqueous DMF. DFT calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of bulky P(t-Bu)3 ligand provides improved beta-selectivity in the essential insertion step also with electron-rich aryl chlorides. A tentative computational rationalization of the improved selectivity in non-methylated PEG is discussed. Finally the synthetic methodology was used to provide efficient access to linear p-[2-(cyclopropylmethoxy)ethyl] phenol from p-nitrophenyl chloride, a key intermediate in the synthesis of the beta-adrenergic blocking agent Betaxolol.     

Studies on the Heck reaction with alkenyl phosphates: can the 1,2-migration be controlled? Scope and limitations

A catalyst system was identified which promotes the Heck coupling of nonactivated vinyl phosphates with electron deficient alkenes providing a new entry to diene products from simple and readily accessible starting materials. In contrast to our earlier work exploiting P(t-Bu)3 as the ligand in the presence of PdCl2(COD), the application of Buchwald's dialkylbiarylphosphines, X-Phos, effectively promoted the vinylic substitution with a wide range of alkenyl phosphates in the presence of 10 equiv of lithium chloride. Importantly, these reaction conditions suppressed 1,2-migration of the alkenyl palladium(II) intermediate. Further studies are also reported with the catalytic system which encourages isomerization in order to determine the range of vinyl phosphates that may participate in these coupling reactions. The extent of the 1,2-migration was dependent on the C1-substituent where best results were noted for substrates possessing a C1-alkyl quaternary carbon. Hence, with certain members of this class of alkenyl phosphates either the migrated or nonmigrated Heck products may be preferentially synthesized by selection of the phosphine ligand. Finally, competition experiments between an unactivated aryl chloride and a vinyl phosphate with a palladium catalyst possessing either X-Phos or P(t-Bu)3 as ligand demonstrated the ability to carry out Heck coupling reactions selectively with the aryl halide. Oxidative addition of the metal catalyst into the aryl chloride bond rather than the C-O bond of the alkenyl phosphate is therefore preferred.     

Dynamics of a cis-dihydrogen/hydride complex of iridium

Insertion of CS2 into one of the Ir-H bonds of [Ir(H)5(PCy3)2] takes place to afford the dihydrido dithioformate complex cis-[Ir(H)2(eta2-S2CH)(PCy3)2] accompanied by the elimination of H2. Protonation of the dithioformate complex using HBF4.Et2O gives cis-[Ir(H)(eta2-H2)(eta2-S2CH)(PCy3)2][BF4] wherein the H atom undergoes site exchange between the dihydrogen and the hydride ligands. The dynamics was found to be so extremely rapid with respect to the NMR time scale that the barrier to exchange could not be measured. Partial deuteration of the hydride ligands resulted in a J(H,D) of 6.5 and 7.7 Hz for the H2D and the HD2 isotopomers of cis-[Ir(H)(eta2-H2)(eta2-S2CH)(PCy3)2][BF4], respectively. The H-H distance (d(HH)) for this complex has been calculated to be 1.05 A, which can be categorized under the class of elongated dihydrogen complexes. The cis-[Ir(H)(eta2-H2)(eta2-S2CH)(PCy3)2][BF4] complex undergoes substitution of the bound H2 moiety with CH(3)CN and CO resulting in new hydride derivatives, cis-[Ir(H)(L)(eta2-S2CH)(PCy3)2][BF4] (L = CH3CN, CO). Reaction of cis-[Ir(H)2(eta2-S2CH)(PCy3)2] with electrophilic reagents such as MeOTf and Me3SiOTf afforded a new hydride aquo complex cis-[Ir(H)(H2O)(eta2-S2CH)(PCy3)2][OTf] via the elimination of CH4 and Me3SiH, respectively, followed by the binding of a water molecule (present in trace quantities in the solvent) to the iridium center. The X-ray crystal structures of cis-[Ir(H)2(eta2-S2CH)(PCy3)2] and cis-[Ir(H)(H2O)(eta2-S2CH)(PCy3)2][OTf] have been determined.     

Preparation and characterization of ruthenium(II) monophosphaferrocene complexes. Reactivity, dynamic solution behavior, and X-ray structure of [RuH(2)(eta(2)-H(2))(PCy(3))2(2-phenyl-3,4-dimethylphosphaferrocene)

The bis(dihydrogen) complex RuH(2)(H(2))(2)(PCy(3))(2) (1) reacts with 2-phenyl-3,4-dimethylphosphaferrocene (L(1)) to give RuH(2)(H(2))(PCy(3))(2)(L(1)) (2). This dihydride-dihydrogen complex has been characterized by X-ray crystallography and variable-temperature (1)H and (31)P NMR spectroscopy. The exchange between the dihydrogen ligand and the two hydrides is characterized by a DeltaG() of 46.2 kJ/mol at 263 K. H/D exchange is readily observed when heating a C(7)D(8) solution of 2 (J(H-D) = 30 Hz). The H(2) ligand in 2 can be displaced by ethylene or carbon monoxide leading to the corresponding ethylene or carbonyl complexes. The reaction of 1 with 2 equiv of 3,4-dimethylphosphaferrocene (L(2)) yields the dihydride complex RuH(2)(PCy(3))(2)(L(2))(2) (5).     

Mechanistic origin of ligand-controlled regioselectivity in Pd-catalyzed C-H activation/arylation of thiophenes

The use of ligands to control regioselectivity in transition-metal-catalyzed C-H activation/functionalization is a highly desirable but challenging task. Recently, Itami et al. reported an important finding relating to Pd-catalyzed ligand-controlled α/β-selective C-H arylation of thiophenes. Specifically, the use of the 2,2'-bipyridyl ligand resulted in α-arylation, whereas the use of the bulky fluorinated phosphine ligand P[OCH(CF(3))(2)](3) resulted in β-arylation. Understanding of this surprising ligand-controlled α/β-selectivity could provide important insights into the development of more efficient catalyst systems for selective C-H arylation, and so we carried out a detailed computational study on the problem with use of density functional theory methods. Three mechanistic possibilities--S(E)Ar and migration, metalation/deprotonation, and Heck-type arylation mechanisms--were examined. The results showed that the S(E)Ar and migration mechanism might not be plausible, because the key Wheland intermediates could not be obtained. On the other hand, our study indicated that the metalation/deprotonation and Heck-type arylation mechanisms were both involved in Itami's reactions. In the metalation/deprotonation pathway the α-selective product (C5-product) was preferred, whereas in the Heck-type arylation mechanism the β-selective product (C4-product) was favored. The ligands played crucial roles in tuning the relative barriers of the two different pathways. In the 2,2'-bipyridyl-assisted system, the metalation/deprotonation pathway was energetically advantageous, leading to α-selectivity. In the P[OCH(CF(3))(2)](3)-assisted system, on the other hand, the Heck-type arylation mechanism was kinetically favored, leading to β-selectivity. An interesting finding was that P[OCH(CF(3))(2)](3) could produce a C-H···O hydrogen bond in the catalyst system, which was crucial for stabilization of the Heck-type transition state. In comparison, this C-H···O hydrogen bond was absent with the other phosphine ligands [i.e., P(OMe)(3), PPh(3), PCy(3)] and these phosphine ligands therefore favored the metalation/deprotonation pathway leading to α-selectivity. Furthermore, in this study we have provided theoretical evidence showing that the Heck-type arylation reaction could proceed through an anti-β-hydride elimination process.     

Highly selective palladium-catalyzed Heck reactions of aryl bromides with cycloalkenes

[reaction: see text] The influence of palladium catalysts and reaction conditions on the selectivity of Heck reactions of aryl bromides with cyclohexene and cyclopentene has been investigated. It is shown that the addition of DMSO as a cosolvent leads to improved selectivities of nonconjugated aryl olefins. On the other hand, high selectivities for conjugated arylcyclopentenes have been obtained with the catalytic system DMA/Na2CO3/Pd2(dba)3 x dba/PCy3.     

Pd-catalyzed cross-coupling of aryl carboxylic acids with propiophenones through a combination of decarboxylation and dehydrogenation

A Heck of a reaction: With a PCy(3)-supported Pd catalyst, aryl carboxylic acids cross-couple to saturated propiophenones through a combination of decarboxylation and dehydrogenation to give chalcones bearing a variety of functional groups in generally good yields (see scheme). Furthermore, a one-pot procedure, involving this reaction and a subsequent selective hydrogenative cyclization process, has been developed for the facile synthesis of quinoline derivatives from 2-nitrobenzoic acids.     

Efficient synthesis of alpha-aryl esters by room-temperature palladium-catalyzed coupling of aryl halides with ester enolates

A catalytic amount of Pd(dba)(2) ligated by either carbene precursor N,N'-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium (1) or P(t-Bu)(3) mediated the coupling of aryl halides and ester enolates to produce alpha-aryl esters in high yields at room temperature. The reaction was highly tolerant of functionalities and substitution patterns on the aryl halide. Improved protocols for the selective monoarylation of tert-butyl acetate and the efficient arylation of alpha,alpha-disubstituted esters were developed with LiNCy(2) as base and P(t-Bu)(3) as ligand. In addition, tert-butyl esters, such as those of Naproxen and Flurbiprofen, were prepared from tert-butyl propionate and aryl bromides in high yields in the presence of Pd(dba)(2) and the hindered, saturated heterocyclic carbene ligand precursor.     

Air-stable Pd(R-allyl)LCl (L= Q-Phos, P(t-Bu)3, etc.) systems for C-C/N couplings: insight into the structure-activity relationship and catalyst activation pathway

A series of Pd(R-allyl)LCl complexes [R = H, 1-Me, 1-Ph, 1-gem-Me(2), 2-Me; L = Q-Phos, P(t-Bu)(3), P(t-Bu)(2)(p-NMe(2)C(6)H(4)), P(t-Bu)(2)Np] have been synthesized and evaluated in the Buchwald-Hartwig aminations in detail, in addition to the preliminary studies on Suzuki coupling and α-arylation reactions. Pd(crotyl)Q-PhosCl (9) was found to be a superior catalyst to the other Q-Phos-based catalysts, and the reported in situ systems, in model coupling reactions involving 4-bromoanisole substrate with either N-methylaniline or 4-tert-butylbenzeneboronic acid. Precatalyst 9 also performed better than the catalysts bearing P(t-Bu)(2)(p-NMe(2)C(6)H(4)) ligand; however, it is comparable to the new crotyl catalysts bearing P(t-Bu)(3) or P(t-Bu)(2)Np ligands. In α-arylation of a biologically important model substrate, 1-tetralone, Pd(allyl)P(t-Bu)(2)(p-NMe(2)C(6)H(4))Cl (15) was found to be the best catalyst. The reason for the relatively higher activity of the crotyl complexes in comparison to the allyl derivatives in C-N bond formation reactions was investigated using X-ray crystallography in conjunction with NMR spectroscopic studies.     

Ligand substitution reactions of W6S8L6 with tricyclohexylphosphine (L = 4-tert-butylpyridine or n-butylamine): 31P NMR and structural studies of W6S8(PCy3)n(4-tert-butylpyridine)6-n (0 < n < or = 6) complexes

The substitution reactions by bulky tricyclohexylphosphine (PCy3) ligands on W6S8L6 (L = 4-tert-butylpyridine or n-butylamine) clusters were investigated to prepare clusters with mixed axial ligands for low-dimensional cluster linking. When 4-6 equiv of PCy3 are used to react with W6S8(4-tert-butylpyridine)6 (4) in THF, cis-W6S8(PCy3)4(4-tert-butylpyridine)2 (1) is preferentially formed. But when starting with W6S8(n-butylamine)6 (2), only W6S8(PCy3)6 (3) is produced with 6 equiv of PCy3. Other conditions with fewer equivalents of PCy3 led to mixtures of partially substituted complexes in the W6S8L6-n(PCy3)n (0 < or = n < or = 6, L = 4-tert-butylpyridine or n-butylamine) series. A significantly distorted structure for 1 helps to explain its preferential formation. 1H NMR spectra were collected for clusters 1 and 2 and 31P NMR spectra for 1 and W6S8(4-tert-butylpyridine)6-n(PCy3)n complexes. P-P coupling through P-W-W-P is reported for the first time in octahedral metal clusters and shown to be very useful in identifying nearly all the W6S8L6-n(PR3)n complexes and their stereoisomers in the mixtures even before individual species are isolated.     

Highly active,air-stable palladium catalysts for the C-C and C-S bond-forming reactions of vinyl and aryl chlorides: use of commercially available [(t-Bu)(2)P(OH)](2)PdCl(2), [(t-Bu)(2)P(OH)PdCl(2)](2), and [[(t-Bu)(2)PO...H...OP(t-Bu)(2)]PdCl](2) as catalysts

Air-stable palladium complexes [(t-Bu)(2)P(OH)](2)PdCl(2), [(t-Bu)(2)P(OH)PdCl(2)](2), and [[(t-Bu)(2)PO...H...OP((t-Bu)(2)]PdCl](2) serve as efficient catalysts for a variety of cross-coupling reactions of vinyl and aryl chlorides with arylboronic acids, arylzinc reagents, and thiols to yield the corresponding styrene derivatives, biaryls, and thioethers. (31)P NMR and mechanistic studies argue that the phosphinous acid ligands in the complexes can be deprotonated in the presence of a base to yield an electron-rich anionic species, which is likely a catalyst intermediate, and dimeric [[(t-Bu)(2)PO...H...OP((t-Bu)(2)]PdCl](2) was isolated and cystallographically characterized. These anionic complexes are anticipated not only to accelerate the rate-determining oxidative addition of aryl chlorides but also to stabilize the palladium complexes in the catalytic cycle.