Iridium-catalyzed borylation of thiophenes: versatile, synthetic elaboration founded on selective C-H functionalization

Iridium-catalyzed borylation has been applied to various substituted thiophenes to synthesize poly-functionalized thiophenes in good to excellent yields. Apart from common functionalities compatible with iridium-catalyzed borylations, additional functional group tolerance to acyl (COMe) and trimethylsilyl (TMS) groups was also observed. High regioselectivities were observed in borylation of 3- and 2,5-di-substituted thiophenes. Electrophilic aromatic C-H/C-Si bromination on thiophene boronate esters is shown to take place without breaking the C-B bond, and one-pot C-H borylation/Suzuki-Miyaura cross-coupling has been accomplished on 2- and 3-borylated thiophenes.     

Sodium halides as the source of electrophilic halogens in green synthesis of 3-halo- and 3,n-dihalobenzo[b]thiophenes

A convenient methodology for the synthesis of mono- and di-halogenated benzo[b]thiophenes is described herein, which utilizes copper(II) sulfate pentahydrate and various sodium halides in the presence of substituted 2-alkynylthioanisoles. The proposed method is facile, uses ethanol as a green solvent, and results in uniquely substituted benzo[b]thiophene structures with isolated yields up to 96%. The most useful component of this methodology is the selective introduction of bromine atoms at every available position (2–7) around the benzo[b]thiophene ring, while keeping position 3 occupied by a specific halogen atom such as Cl, Br or I. Aromatic halogens are useful reactive handles; therefore, the selective introduction of halogens at specific positions would be valuable in the targeted synthesis of bioactive molecules and complex organic materials via metal-catalyzed cross coupling reactions. This work is a novel approach towards the synthesis of dihalo substituted benzo[b]thiophene core structures, which provides a superior alternative to the current methods discussed herein.     

Iridium‐Catalyzed Annulation Reactions of Thiophenes with Carboxylic Acids: Direct Evidence for a Heck‐type Pathway

The functionalization of thiophenes is a fundamental and important reaction. Herein, we disclose iridium‐catalyzed one‐pot annulation reactions of (benzo)thiophenes with (hetero)aromatic or α,β‐unsaturated carboxylic acids, which afford thiophene‐fused coumarin‐type frameworks. Dearomatization reactions of 2‐substituted thiophenes with α,β‐unsaturated carboxylic acids deliver various thiophene‐containing spirocyclic products. The occurrence of two interconnected reactions provides direct evidence for a Heck‐type pathway. The mechanistic scenario described herein is distinctly different from the S_EAr and concerted metalation–protodemetalation (CMD) pathways encountered in the well‐described oxidative C?H/C?H cross‐coupling reactions of thiophenes with other heteroarenes.     

C-H activation motivated by N,N'-diisopropylcarbodiimide within a lutetium complex stabilized by an amino-phosphine ligand

A lutetium bis(alkyl) complex stabilized by a flexible amino-phosphine ligand LLu(CH(2)Si(CH(3))(3))(2)(THF) (L = (2,6-C(6)H(3)(CH(3))(2))NCH(C(6)H(5))CH(2)P(C(6)H(5))(2)) was prepared which upon insertion of N,N'-diisopropylcarbodiimide led to C-H activation via metalation of the ligand aryl methyl followed by reduction of the C[double bond, length as m-dash]N double bond.     

Preparation of five- and six-coordinate aryl(hydrido) iridium(III) complexes from benzene and functionalized arenes by C-H activation

The reaction of the in situ generated cyclooctene iridium(I) derivative trans-[IrCl(C8H14)(PiPr3)2] with benzene at 80 degrees C gave a mixture of the five-coordinate dihydrido and hydrido(phenyl) iridium(III) complexes [IrH2(Cl)(PiPr3)2] 2 and [IrH(C6H5)(Cl)(PiPr3)2] 3 in the ratio of about 1 : 2. The chloro- and fluoro-substituted arenes C6H5X (X = Cl, F), C6H4F2 and C6H4F(CH3) reacted also by C-H activation to afford the corresponding aryl(hydrido) iridium(III) derivatives [IrH(C6H4X)(Cl)(PiPr3)2] 7, 8, [IrH(C6H3F2)(Cl)(PiPr3)2] 9-11 and [IrH[C6H3F(CH3)](Cl)(PiPr3)2] 12, 13, respectively. The formation of isomeric mixtures had been detected by 1H, 13C, 19F and 31P NMR spectroscopy. Treatment of 3 and 7-13 with CO gave the octahedral carbonyl iridium(III) complexes [IrH(C6H3XX')(Cl)(CO)(PiPr3)2] 5, 14-20 without the elimination of the arene. The reactions of trans-[IrCl(C8H14)(PiPr3)2] with aryl ketones C6H5C(O)R (R = Me, Ph), aryl ketoximes C6H5C(NOH)R (R = Me, Ph) and benzaloxime C6H5C(NOH)H resulted in the formation of six-coordinate aryl(hydrido) iridium(III) compounds 21-25 with the aryl ligand coordinated in a bidentate kappa2-C,O or kappa2-C,N fashion. With C6H5C(O)NH2 as the substrate, the two isomers [IrH[kappa2-N,O-NHC(O)C6H5](Cl)(PiPr3)2] 26 and [IrH[kappa2-C,O-C6H4C(O)NH2](Cl)(PiPr3)2] 27 were prepared stepwise. Treatment of trans-[IrCl(C8H14)(PiPr3)2] with benzoic acid gave the benzoato(hydrido) complex [IrH[kappa2-O,O-O2CC6H5](Cl)(PiPr3)2] 29 which did not rearrange to the kappa2-C,O isomer.     

Effect of trimethylsilyl substitution on the chemical properties of triarylphosphines and their corresponding metal-complexes: solubilising effect in supercritical carbon dioxide

The donor strengths of the following triarylphosphine ligands P(Ar)(2)(Ar')(Ar = Ar'= 4-Me(3)SiC(6)H(4), 1b; 4-Me(3)CC(6)H(4), 1d; 4-F(3)CC(6)H(4), 1e; Ar = C(6)H(5), Ar'= 4-Me(3)SiC(6)H(4), 1c) have been evaluated experimentally and theoretically. The measurements of the J(P-Se) coupling constants of the corresponding synthesised selenides Se=P(Ar)(2)(Ar'), 2b,c and the DFT calculation of the energies of the phosphine lone-pair (HOMO) reveal insignificant influence on the electronic properties of the substituted phosphines when the trimethylsilyl group is attached to the aryl ring, in marked contrast to the strong electronic effect of the trifluoromethyl group. These triarylphosphine ligands P(Ar)(2)(Ar') reacted with (eta5-C(5)H(5))Co(CO)(2), (eta5-C(5)H(5))Co(CO)I(2) or PdCl(2) to yield the new compounds (eta5-C(5)H(5))Co(CO)[P(Ar)(2)(Ar')], 3b,d; (eta5-C(5)H(5))CoI(2)[P(Ar)(2)(Ar')], 4b-e; and PdCl(2)[P(Ar)(2)(Ar')](2), 5b,c respectively. These complexes have been characterized and their spectroscopic properties compared with those reported for the known triphenylphosphine complexes. Again, the contrast of the (31)P NMR and (13)C NMR chemical shifts or C-O or M-Cl stretching frequencies, when applied, does not show an important electronic effect on the metal complex of the trimethylsilyl substituted phosphines with respect to P(C(6)H(5))(3) derivatives. Solubility measurements of complexes 3a and 3b in scCO(2) were performed. We conclude that Me(3)Si groups on the triarylphosphine improve the solubility of the corresponding metal complex in scCO(2).     

Modular Synthesis of Phenanthro[9,10‐c]thiophenes by a Sequence of CH Activation,Suzuki Cross‐Coupling and Photocyclization Reactions

A total number of 15 different 3,4‐diarylthiophenes were synthesized, which bear a chlorine atom in ortho‐position of one of the aryl substituents. One aryl group was introduced by an oxidative cross‐coupling reaction, involving a C?H activation at C4(3) of the thiophene core. The other aryl group was in most cases introduced by a Suzuki cross‐coupling reaction, which succeeded the oxidative cross‐coupling step. Photocyclization reactions of the 3,4‐diarylthiophenes were performed in a solvent mixture of benzene and acetonitrile (50:50 v/v) at λ=254 nm and proceeded to the title compounds in yields of 60–82 %. The selectivity of the photocyclization was determined at the ortho‐chloro‐substituted aryl ring by the position of the chlorine substituent. At the other ring, a single regioisomer was observed for phenyl and para‐substituted phenyl groups. For 2‐naphthyl and ortho‐substituted phenyl rings a clear preference was observed in favor of a major regioisomer, while meta‐substitution in the phenyl ring led to a about 1:1 mixture of 5‐ and 7‐substituted phenanthro[9,10‐c]thiophenes. Mechanistically, the photocyclization is likely to occur as a photochemically allowed, conrotatory [(4n+2)π] process accompanied by elimination of HCl. It was shown for two phenanthro[9,10‐c]thiophene products that they can be readily brominated in positions C1 and C3 (74–77 %), which in turn allows for further functionalization at these positions, for example, in the course of halogen–metal exchange and polymerization reactions.     

EPR studies on the thiophenodithiazolyl radical, C4H2S3N

Selective chlorination of thiophene-2,3-dithiol with SO(2)Cl(2) generates the corresponding sulfenyl chloride, 2,3-C(4)H(2)S(SCl)(2). Subsequent condensation with Me(3)SiN(3) yields the thiophenodithiazolylium salt [C(4)H(2)S(3)N]Cl, [TDTA]Cl. The structure of the cation, TDTA+, was established by X-ray diffraction as both its AsF(6)(-) and HSO(4)(-) salts. Reduction of [TDTA]Cl with Ag powder yields the radical TDTA* which was characterised by X- and Q-band (9 and 34 GHz) EPR and ENDOR studies. The spin density distributions estimated from the EPR/ENDOR measurements were found to be in very good agreement with those determined by DFT (B3LYP/6-31G*) indicating that ca 10% of the spin density is delocalised onto the thiophene ring. Comparison of the spin density distributions in TDTA* and the isoelectronic trithiatriazapentalenyl radical C(2)S(3)N(3), TTTA*, indicates that replacement of N by C-H leads to a localisation of the spin density on the dithiazolyl ring.     

Tandem palladium-catalyzed borylation and Suzuki coupling (BSC) to thienocarbazole precursors

Substituted 2-methyl-2′-nitro diaryl compounds in the benzo[b]thiophene series were prepared by palladium-catalyzed, two-step, one-pot borylation/Suzuki coupling (BSC) reaction in good to high yields. The borylation reaction was performed on methylated 6-bromobenzo[b]thiophenes using pinacolborane and was followed by in situ Suzuki coupling with substituted (CF₃, OMe) 2-bromonitrobenzenes. The compounds obtained were cyclized to the corresponding ring A substituted thienocarbazoles which can have biological activity or/and be used as biomarkers due to their fluorescence properties and possible DNA intercalation.     

Condensed thiophenes and selenophenes: thionyl chloride and selenium oxychloride as sulfur and selenium transfer reagents

3,4-Cyanomethyl substituted thiophenes reacted with thionyl chloride in the presence of base to give dicyano substituted thieno(3,4-c)thiophenes. The use of selenium oxychloride furnished the corresponding cyano substituted seleno(3,4-c)thiophene. 1,2-Phenylenediacetonitriles gave the corresponding cyano substituted benzo(c)thiophenes and benzo(c)selenenophenes, respectively, upon reaction with thionyl chloride and selenium oxychloride in the presence of base.     

Synthesis, characterization, and structure of cyclopenta[c]thiophenes and their manganese complexes

1,3-Diaryl-4H-cyclopenta[c]thiophenes are efficiently prepared from 1,2-diaroylcyclopentadienes by use of Lawesson's reagent. eta5-Cyclopenta[c]thienyl complexes, [Mn(eta5-SC7H3-1,3-R2)(CO)3] (R = Me, Ph), are prepared in high yield by ligand substitution reactions of [MnBr(CO)5] with [SnMe3(SC7H3-1,3-R2)]. Alternatively, thiation with P4S10/NaHCO3 converts [Mn{eta5-1,2-C5H3(COR)2)(CO)3] to [Mn(eta5-SC7H3-1,3-R2)(CO)3] (R = Ph, 4-tolyl, 4-MeOC6H4, benzo[2,3-b]thienyl). The molecular structures of complexes with R = Me, Ph show planar eta5-cyclopenta[c]thienyl ligands, with the manganese atom slightly displaced away from the ring-fusion bond.     

Synthesis of polycyclic heterocycles via a one-pot ortho alkylation/direct heteroarylation sequence

[reaction: see text] Polycyclic thiophenes and furans were synthesized using a one-pot ortho alkylation/direct heteroarylation reaction sequence. Under the optimized reaction conditions, aryl iodides were coupled with 3-(bromoalkyl)thiophenes or -furans, affording six- and seven-membered annulated ring products via formation of two C-C bonds from two aryl C-H bonds.     

Direct 2-Arylation of Thiophene Using Low Loading of a Phosphine-Free Palladium Catalyst

The direct coupling of aryl halides with thiophene would be a considerable advantage for sustainable development because of only HBr associated with a base as by-product is formed and the number of steps to prepare these compounds is less than in more classical coupling reactions. We observed that through the use of only 0.2 mol% Pd(OAc)₂ as the catalyst, a range of aryl bromides undergoes coupling via a C-H bond activation/functionalization reaction with thiophene to give 2-arylated thiophenes in good yields. In most cases, only traces of polyarylated thiophenes were detected when a large excess of thiophene was employed. This air-stable catalyst can be used with a wide variety of aryl bromides.      

Synthetic and structural studies of monocyclopentadienyl cyclometalated aryl tantalum(V) compounds

Cyclometalated aryl tetra- or trichlorido cyclopentadienyl tantalum complexes [TaXCl(3){C(6)H(4)(2-CH(2)NMe(2))-κ(2)C,N}] (X = Cl 1, η(5)-C(5)H(5)2, η(5)-C(5)H(4)(SiMe(3)) 3, η(5)-C(5)Me(5)4) containing a five-membered TaC(3)N chelate ring were synthesized by reaction of the TaXCl(4) (X = Cl, η(5)-C(5)H(5), η(5)-C(5)H(4)(SiMe(3)), η(5)-C(5)Me(5)) with the appropriate lithium aryl reagent [Li{C(6)H(4)(2-CH(2)NMe(2))}]. The reported complexes were studied by IR and NMR spectroscopy and the X-ray molecular structures of compounds 2, 3 and 4 were determined by diffraction methods. These compounds were theoretically analyzed by the DFT method and their structures were rationalized. The preferential coordination of the 2-{(dimethylamino)methyl}phenyl ligand was justified by an analysis of the molecular orbitals of the Ta(η(5)-C(5)H(5))Cl(3) and C(6)H(4)(2-CH(2)NMe(2)) fragments. In addition, the exchange pathways that account for the NMR equivalency of the Me(2)N- methyl groups and -CH(2)- hydrogen atoms of the coordinated C(6)H(4)(2-CH(2)NMe(2))-κ(2)C,N ligand were theoretically studied.     

Diversity‐Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero‐Fused Analogues through Palladium‐Catalyzed Oxidative CH Functionalization/Intramolecular Arylthiolation

An efficient, high yielding route to multisubstituted benzo[b]thiophenes has been developed through palladium‐catalyzed intramolecular oxidative C?H functionalization–arylthiolation of enethiolate salts of α‐aryl‐β‐(het)aryl/alkyl‐β‐mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one‐pot, two‐step process in which enethiolate salts [generated in situ through base‐mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular C?H functionalization–arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N,N‐dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[b]thiophenes were better in a two‐step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc)₂ (or PdCl₂) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2‐ and 3‐positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno‐fused heterocycles such as thieno[2,3‐b]thiophenes, thieno[2,3‐b]indoles, thieno[3,2‐c]pyrazole, and thieno[2,3‐b]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd‐S adduct or palladacycle intermediate has been proposed on the basis of experimental studies.     

Palladium-catalyzed amination and cyclization to heteroannellated indoles and carbazoles

New ortho-bromodiarylamines in the benzo[b]thiophene series were prepared by palladium-catalyzed amination, either in the benzene or in the thiophene ring. These were submitted to palladium-catalyzed cyclization, under different required conditions, to give several differently substituted thieno[3,2-c] or [2,3-b]carbazoles and indolo[3,2-b]benzo[b]thiophenes. This constitutes a novel synthetic route to both tetracyclic systems.     

Application of directed metalation in synthesis. Part 4: Expedient synthesis of substituted benzo[b]thiophene and naphthothiophene

A short, simple and inexpensive synthesis of several diversely substituted benzo[b]thiophenes and one naphthothiophene is described. The method involves introduction of methylsulfanyl group ortho- to the amide function of readily available N,N-diethylamides of aryl carboxylic acid by directed metalation. Thioindoxyls, obtained in high yields through side-chain deprotonation and cyclisation in one pot, are reduced to benzo[b]thiophene or napthothiophene.     

Comparative reactivity of TpRu(L)(NCMe)Ph (L = CO or PMe3): impact of ancillary ligand l on activation of carbon-hydrogen bonds including catalytic hydroarylation and hydrovinylation/oligomerization of ethylene

Complexes of the type TpRu(L)(NCMe)R [L = CO or PMe3; R = Ph or Me; Tp = hydridotris(pyrazolyl)borate] initiate C-H activation of benzene. Kinetic studies, isotopic labeling, and other experimental evidence suggest that the mechanism of benzene C-H activation involves reversible dissociation of acetonitrile, reversible benzene coordination, and rate-determining C-H activation of coordinated benzene. TpRu(PMe3)(NCMe)Ph initiates C-D activation of C6D6 at rates that are approximately 2-3 times more rapid than that for TpRu(CO)(NCMe)Ph (depending on substrate concentration); however, the catalytic hydrophenylation of ethylene using TpRu(PMe3)(NCMe)Ph is substantially less efficient than catalysis with TpRu(CO)(NCMe)Ph. For TpRu(PMe3)(NCMe)Ph, C-H activation of ethylene, to ultimately produce TpRu(PMe3)(eta3-C4H7), is found to kinetically compete with catalytic ethylene hydrophenylation. In THF solutions containing ethylene, TpRu(PMe3)(NCMe)Ph and TpRu(CO)(NCMe)Ph separately convert to TpRu(L)(eta3-C4H7) (L = PMe3 or CO, respectively) via initial Ru-mediated ethylene C-H activation. Heating mesitylene solutions of TpRu(L)(eta3-C4H7) under ethylene pressure results in the catalytic production of butenes (i.e., ethylene hydrovinylation) and hexenes.     

Thiophene chemistry—XXII : Some reactions of benzo[b]thiophene-2(3H)one

Benzo[b]thiophene-2(3H)one has been prepared from 2-t-butoxybenzo[b]thiophene by dealkylation. Alkylation of sodium, thallium and tetrabutylammonium salts of benzo[b]thiophene-2(3H)one produces both C- and O-alkylation along with products due to ring-opening. At elevated temperatures benzo[b]thiophene-2(3H)one reacts with HMPA (hexamethylphosphorictriamide) to give 2-dimethylaminobenzo[b]thiophene. Other 2-aminobenzo[b]thiophenes are produced by refluxing benzo[b]thiophene-2(3H)one in HMPA in the presence of excess of the corresponding amine.     

C?H Bond Activation/Borylation of Furans and Thiophenes Catalyzed by a Half‐Sandwich Iron N‐Heterocyclic Carbene Complex

A coordinatively unsaturated iron‐methyl complex having an N‐heterocyclic carbene ligand, [Cp*Fe(L^Me)Me] ( 1 ; Cp*=η⁵‐C₅Me₅, L^Me=1,3,4,5‐tetramethyl‐imidazol‐2‐ylidene), is synthesized from the reaction of [Cp*Fe(TMEDA)Cl] (TMEDA=N,N,N′,N′‐tetramethylethylenediamine) with methyllithium and L^Me. Complex 1 is found to activate the C? H bonds of furan, thiophene, and benzene, giving rise to aryl complexes, [Cp*Fe(L^Me)(aryl)] (aryl=2‐furyl ( 2 ), 2‐thienyl ( 3 ), phenyl ( 4 )). The C? H bond cleavage reactions are applied to the dehydrogenative coupling of furans or thiophenes with pinacolborane (HBpin) in the presence of tert‐butylethylene and a catalytic amount of 1 (10 mol % to HBpin). The borylation of the furan/thiophene or 2‐substituted furans/thiophenes occurs exclusively at the 2‐ or 5‐positions, respectively, whereas that of 3‐substituted furans/thiophenes takes place mainly at the 5‐position and gives a mixture of regioisomers. Treatment of 2 with 2 equiv of HBpin results in the quantitative formation of 2‐boryl‐furan and the borohydride complex [Cp*Fe(L^Me)(H₂Bpin)] ( 5 ). Heating a solution of 5 in the presence of tert‐butylethylene led to the formation of an alkyl complex [Cp*Fe(L^Me)CH₂CH₂tBu] ( 6 ), which was found to cleave the C? H bond of furan to produce 2 . On the basis of these results, a possible catalytic cycle is proposed.