Site-selective Suzuki-Miyaura reactions of 2,3-dibromo-1H-inden-1-one

The first transition metal-catalyzed cross-coupling reactions of 2,3-dibromo-1H-inden-1-one are reported. The Suzuki-Miyaura reaction of 2,3-dibromo-1H-inden-1-one with 2 equiv of arylboronic acid gave 2,3-diaryl-1H-inden-1-ones. The reaction with 1 equiv of arylboronic acid gave 2-bromo-3-aryl-1H-inden-1-ones with very good site-selectivity. The one-pot reaction of 2,3-dibromo-1H-inden-1-one with two different arylboronic acids afforded 2,3-diaryl-1H-inden-1-ones containing two different terminal aryl groups.     

Lewis acid catalyzed asymmetric halohydrin reactions of chiral α,β-unsaturated carboxylic acid derivatives with N-halosuccinimide (NXS) as the halogen source

Lewis acid catalyzed asymmetric halohydrin reactions—(halohydroxylation as well as halomethoxylation) of chiral α,β-unsaturated carboxylic acid derivatives were performed using N-halosuccinimide (NXS; X = Br, I) as the halogen source. Regio- and anti-selectivity of 100% and moderate to good diastereoselectivity with good yields were observed when Oppolzer’s sultam was used as the chiral auxiliary. Among the Lewis acids, Yb(OTf)₃ was found to be the best catalyst. Alkenoyl and cinnamoyl substrates smoothly underwent bromohydrin reactions and the more electron-rich cinnamoyl substrates preferred to undergo iodohydrin reactions. However, electron-deficient cinnamoyl substrates did not respond to this Lewis acid catalyzed halohydrin reaction with NXS (X = Cl, Br, I).     

Selective enhancement effects of silver salts on the transition metal-catalyzed synthesis of gem-difluorinated heterocyclics using 2,2-difluorohomopropargyl amides

The addition of silver salts had an effect on the catalyst activity in the Pd(0)-catalyzed cyclization-coupling tandem reaction, as well as in the Rh(I)-catalyzed Pauson-Khand reaction. The cationic palladium complex generated from Pd(PPh₃)₄ (2.5 mol%) with AgSbF₆ (1.5 equiv.) activates the triple bond of 2,2-difluoropropargylic amides to give the 4,5-disubstituted 3,3-difluoro-γ-lactams, through a sequential 5-endo-dig cyclization and cross-coupling reaction. The γ-lactam was transformed into ring-opened monofluorovinylic compounds after silica-gel chromatography. Pauson-Khand reaction of fluorinated 1,7-enyne amides using catalytic amounts of [Rh(COD)₂]₂ (5 mol%) and AgOTf (20 mol%) gave the corresponding gem-difluorinated bicyclic lactam.     

Efficient solid-phase synthesis of cyclic RGD peptides under controlled microwave heating

Cyclic RGD peptides are potent antagonists for the α_vβ₃ integrin receptor. In this Letter, microwave-assisted solid-phase synthesis of cyclic RGD peptides is described. In a coupling reaction between Fmoc-Arg(Pbf)-OH and high-loading H-Gly-Trt(2-Cl) resin, multiple coupling reactions were required for completion under the conventional HBTU activation. We found that the use of COMU, a new coupling reagent, under microwave heating to 50 °C accelerated the reaction even inside the resin. This method was applicable to the synthesis of linear pentapeptides, H-Asp(OtBu)-Xxx-Yyy-Arg(Pbf)-Gly-OH (Xxx = d-Phe(p-Br) or d-Tyr, Yyy = Lys(Boc) or MeVal). Cyclization of these peptides followed by deprotection gave the desired cyclic RGD peptides with high purity.     

Thermal hydrosilylation of olefin with hydrosilane. Preparative and mechanistic aspects

The reaction of trichlorosilane (1a) at 250 °C with cycloalkenes, such as cyclopentene (2a), cyclohexene (2b), cycloheptene (2c), and cyclooctene (2d), gave cycloalkyltrichlorosilanes [C_nH_2n−1SiCl₃: n = 5 (3a), 6 (3b), 7 (3c), 8 (3d)] within 6 h in excellent yields (97-98%), but the similar reactions using methyldichlorosilane (1b) instead of 1a required a longer reaction time of 40 h and afforded cycloalkyl(methyl)dichlorosilanes [C_nH_2n−1SiMeCl₂: n = 5 (3e), 6 (3f), 7 (3g), 8 (3h)] in 88-92% yields with 4-8% recovery of reactant 2. In large (2, 0.29 mol)-scale preparations, the reactions of 2a and 2b with 1a (0.58 mol) under the same condition gave 3a and 3b in 95% and 94% isolated yields, respectively. The relative reactivity of four hydrosilanes [HSiCl_3−mMe_m: m = 0-3] in the reaction with 2a indicates that as the number of chlorine-substituent(s) on the silicon increases the rate of the reaction decreases in the following order: n = 3 > 2 > 1 ? 0. In the reaction with 1a, the relative reactivity of four cycloalkenes (ring size = 5-8) decreases in the following order: 2d > 2a > 2c > 2b. Meanwhile linear alkenes like 1-hexene undergo two reactions of self-isomerization and hydrosilylation with hydrosilane to give a mixture of the three isomers (1-, 2-, and 3-silylated hexanes). In this reaction, the reactivity of the terminal 1-hexene is higher than the internal 2- and 3-hexene. The redistribution of hydrosilane 1 and the polymerization of olefin 2 occurred rarely under the thermal reaction condition.     

Palladium-catalyzed cross-coupling of trimethoxysilylbenzene with aryl bromides and chlorides using phosphite ligands

Phosphites were employed as ligands in palladium-catalyzed Hiyama coupling reactions. The optimized reaction conditions were equimolar amounts (5 mol % each) of Pd(acac)₂ and phosphite 1 in p-xylene at 80 °C with TBAF as an additive. This catalyst system exhibited high activities in the reactions with trimethoxysilylbenzene and aryl bromides that have electron-donating or electron-withdrawing groups. In the case of aryl chlorides, substrates possessing electron-withdrawing groups gave the coupled products in high yields.     

Reaction studies on some functionalized alkyl transition metal compounds and the crystal structure of [Cp(CO)3W{(CH2)3NO2}]

The reactions of the halogenoalkyl compounds [Cp(CO)₃W{(CH₂)_nX}] (Cp = η⁵-C₅H₅; n = 3-5; X = Br, I) and [Cp(CO)₂(PPhMe₂)Mo{(CH₂)₃Br}] with the nucleophiles Z = CN⁻ and gave compounds of the type [Cp(CO)₃W{(CH₂)_nZ}] for the tungsten compounds, whilst cyclic carbene compounds were obtained from the reactions of the molybdenum compound. The reactions of [Cp(CO)₃W{(CH₂)_nBr}] (n = 3, 4) and [Cp(CO)₂(PPhMe₂)Mo{(CH₂)₃Br}] with gave [Cp(CO)₃W{(CH₂)_nONO₂}] and [Cp(CO)₂(PPhMe₂)Mo{(CH₂)₃ONO₂}], respectively. The reaction of [Cp(CO)₃W{(CH₂)_nBr}] with AgNO₂ gave [Cp(CO)₃W{(CH₂)_nNO₂}]. In the solid state the complex [Cp(CO)₃W{(CH₂)₃NO₂}] crystallizes in a distorted square pyramidal geometry. In this molecule the nitropropyl chain deviates from the ideal, all-trans geometry as a result of short, non-hydrogen intermolecular N-O?O-N contacts. The reactions of the heterobimetallic compounds [Cp(CO)₃W{(CH₂)₃}ML_y] {ML_y = Mo(CO)₃Cp, Mo(CO)₃Cp^∗ and Mo(CO)₂(PMe₃)Cp; Cp^∗ = η⁵-C₅(CH₃)₅} with PPh₃ and CO were found to be totally metalloselective, with the ligand always attacking the metal site predicted by the reactions of the corresponding monometallic analogues above with nucleophiles. Thus the compounds [Cp(CO)₃W{(CH₂)₃}C(O)ML_z] {ML_z = Mo(CO)₂YCp, Mo(CO)₂YCp^∗ and Mo(CO)Y(PMe₃)Cp; Y = PPh₃ or CO} were obtained. Similarly, the reaction of [Cp(CO)₂Fe{(CH₂)₃}Mo(CO)₂(PMe₃)Cp] with CO gave only [Cp(CO)₂Fe{(CH₂)₃C(O)}Mo(CO)₂(PMe₃)Cp]. Hydrolysis of the bimetallic compound, [Cp(CO)₃W(CH₂)₃C(O)Mo(CO)(PPh₃)(PMe₃)Cp], gave the carboxypropyl compound [Cp(CO)₃W{(CH₂)₃COOH}]. Thermolysis of the compound [Cp(CO)₂Fe(CH₂)₃Mo(CO)₃(PMe₃)Cp] gave cyclopropane and propene, indicating that β-elimination and reductive processes had taken place.     

Theoretical study on the substitution and insertion reactions of silylenoid H2SiLiF with CH3XHn−1 (X = F, Cl, Br, O, N; n = 1, 1, 1, 2, 3)

The substitution and insertion reactions of H₂SiLiF (A) with CH₃XH_n−1 (X = F, Cl, Br, O, N; n = 1, 1, 1, 2, 3) have been studied using density functional theory. The results indicate that the substitution reactions of A with CH₃XH_n−1 proceed via two reaction paths, I and II, forming the same product H₂SiFCH₃. The insertion reactions of A with CH₃XH_n−1 form H₂SiXH_n−1CH₃. The following conclusions emerge from this work. (i) The substitution reactions of A with CH₃XH_n−1 occur in a concerted manner. The substitution barriers of A with CH₃XH_n−1 for both pathways decrease with the increase of the atomic number of the element X for the same family systems or for the same row systems. Path I is more favorable than path II. (ii) A inserts into a C-X bond via a concerted manner, and the reaction barriers increase for the same-row element X from right to left in the periodic table, whereas change very little for the systems of the same-family element X. (iii) The substitution reactions occur more readily than the insertion reactions for A with CH₃XH_n−1 systems. (iv) All substitution and insertion reactions of A with CH₃XH_n−1 are exothermic. (v) In solvents, the substitution reaction process of A with CH₃XH_n−1 is similar to that in vacuum. The barrier heights in solvents increase in the order CH₃F < CH₃Cl < CH₃Br < CH₃OH < CH₃NH₂. The solvent polarity has little effects on the substitution barriers. The calculations are in agreement with experiments.     

Reverse atom transfer radical polymerisation (RATRP) of methacrylates using copper(I)/pyridinimine catalysts in conjunction with AIBN

N-n-Propyl-2-pyridylmethanimine, 1, N-n-octyl-2-pyridylmethanimine, 2, N-n-lauryl-2-pyridylmethanimine, 3, and N-n-octadecyl-2-pyridylmethanimine, 4 have been used in conjunction with copper(II) bromide and azo initiators for the reverse atom transfer radical polymerisation of a range of methacrylates. AIBN to Cu^IIBr₂ ratios of 0.5:1, 0.75:1 and 1:1 give PMMA with M_n 11 500 g mol⁻¹ (PDi = 1.24) (at 22% conversion), 12 500 g mol⁻¹ (PDi = 1.06) (at 83% conversion) and 10 900 g mol⁻¹ (PDi = 1.11) (at 84% conversion), respectively. A Cu^IIBr₂ complex is demonstrated to be needed at the start of the reaction for good control over molecular weight and polydispersity as reactions using Cu(I)Br as catalyst yielded PMMA of M_n 31 000 g mol⁻¹ (PDi = 2.90), reactions with no copper yield PMMA of M_n 33 000 g mol⁻¹ (PDi = 2.95). The RATRP of styrene was carried out using Cu^IIBr₂ as catalyst. AIBN to Cu^IIBr₂ ratio of 0.5:1, 0.75:1 and 1:1 gave PS with M_n = 12 400 g mol⁻¹ (PDi = 1.27) at low conversion, M_n = 15 500 g mol⁻¹ (PDi = 1.11) and 12 400 g mol⁻¹ (PDi = 1.38), respectively at ∼85% conversion. A series of block copolymers of MMA with BMA, BzMA and DMEAMA (15 600 g mol⁻¹ (PDi = 1.18), 13 300 g mol⁻¹ (PDi = 1.14) 15 300 g mol⁻¹ (PDi) = 1.16), using a PMMA macroinitiator were prepared. Emulsion polymerisation of MMA using [initiator]:[Cu^(II)Br₂] ratio = 0.5:1 with Brij surfactant gave a linear increase of M_n with respect to conversion, final M_n = 112 800 g mol⁻¹ (PDi = 1.42). Further reactions were carried out with [initiator]:[Cu^(II)Br₂] ratio = 0.75:1 and 1:1. Both giving PMMA with M_n ∼ 32 000 g mol⁻¹ (PDi ∼ 2.4). These reactions exhibit no control, this is because the azo initiator is present in excess and all of the monomer is consumed by a free radical polymerisation as opposed to a controlled reaction. Particle size analysis (DLS) showed the particle size between 160 and170 nm in all cases.     

Ruthenium-catalyzed cyclization of 3-en-1-ynyl imines with nucleophiles via tandem 5-exo-dig cyclization and nucleophilic addition

Treatment of 3-en-1-ynyl imines with TpRuPPh₃(CH₃CN)₂PF₆ catalyst (1 mol %) in DCE (50 °C, 6 h) effected catalytic cyclization with suitable nucleophiles and gave functionalized pyrroles in good yields. The reaction mechanism is proposed to proceed via (2-pyrrolyl)carbenoid intermediates derived from 5-exo-dig cyclization. This catalytic reaction works well with various nucleophiles, including water, alcohols and anilines.     

Kinetic study of the oxidative addition reaction between methyl iodide and [Rh(FcCOCHCOCF3)(CO)(PPh3)]: Structure of [Rh(FcCOCHCOCF3)(CO)(PPh3)(CH3)(I)]

The kinetics of oxidative addition of CH₃I to [Rh(FcCOCHCOCF₃)(CO)(PPh₃)], where Fc = ferrocenyl and (FcCOCHCOCF₃)⁻ = fctfa = ferrocenoylacetonato, have been studied utilizing UV/Vis, IR, ¹H and ³¹P NMR techniques. Three definite sets of reactions involving isomers of at least two distinctly different classes of Rh^III-alkyl and two different classes of Rh^III-acyl species were observed. Rate constants for this reaction in CHCl₃ at 25 °C, applicable to the reaction sequence below, were determined as k₁ = 0.00611(1) dm³ mol⁻¹ s⁻¹, k₋₁ = 0.0005(1) s⁻¹, k₃ = 0.00017(2) s⁻¹ and k₄ = 0.0000044(1) s⁻¹ while k₋₃ ? k₃ and k₋₄ ? k₄ but both ≠0. The indeterminable equilibrium K₂ was fast enough to be maintained during Rh^I depletion in the first set of reactions and during the Rh^IIIalkyl2 formation in the second set of reactions. From a ¹H and ³¹P NMR study in CDCl₃, K_c1 was found to be 0.68, K_c2 = 2.57, K_c3 = 1.00, K_c4 = 4.56 and K_c5 = 1.65.     

Conjugate addition of aromatic amines to ethenetricarboxylates

The conjugate addition of amines is considered to be a useful reaction in synthetic organic chemistry. The reaction of reactive electrophilic olefins, ethenetricarboxylates, and aromatic amines with and without catalytic Lewis acids such as ZnCl₂ and ZnBr₂ at room temperature gave amine adducts in high yields. The products were converted to α-amino acid, dl-aspartic acid derivatives. Using Lewis acids such as Sc(OTf)₃ and Zn(OTf)₂ at higher temperature (40-80 °C), the reaction of ethenetricarboxylates and N-methylaniline gave an aromatic substitution product. A catalytic enantioselective conjugate addition using a chiral Lewis acid was also investigated. For example, the reaction of 1,1-diethyl 2-tert-butyl ethenetricarboxylate with N-methylaniline in the presence of chiral bisoxazoline-Cu(II) complex in THF at −20 °C for 17 h gave an amine adduct in 91% yield and 78% ee. On the other hand, the reaction with aniline and primary aniline derivatives gave adducts with almost no ee%.     

DAST promotes the synthesis of new 5-(trifluoromethyl)-3-(1,1-difluoroethan-2-yl)-1H-pyrazoles

This study describes, firstly, the synthesis of a new precursor, 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one (1), from the trifluoroacetylation reaction of 1,1,3,3-tetramethoxybutane, in 65% yields. Afterwards, the reaction of 1 with two hydrazines (NH₂NHR, where R = 2-furanoyl, C₆F₅) led to a new series of 4,5-dihydro-1H-pyrazoles, containing an acetal-protected aldehyde function as substituent, in 90-97% yields. In a subsequent step, the dehydration reactions of these 4,5-dihydro-1H-pyrazoles gave the respective aromatic 1H-pyrazoles. Finally, we report the results of the deprotection reactions of the acetals to obtain the respective aldehyde function, as well as, the subsequent fluorination reaction using DAST, leading to new difluorinated derivatives in 55-60% yields.     

Platinum-catalyzed double silylations of alkynes with bis(dichlorosilyl)methanes

Bis(dichlorosilyl)methanes 1 undergo the two kind reactions of a double hydrosilylation and a dehydrogenative double silylation with alkynes 2 such as acetylene and activated phenyl-substituted acetylenes in the presence of Speier’s catalyst to give 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 and 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-enes 4 as cyclic products, respectively, depending upon the molecular structures of both bis(dichlorosilyl)methanes (1) and alkynes (2). Simple bis(dichlorosilyl)methane (1a) reacted with alkynes [R¹-CC-R²: R¹ = H, R² = H (2a), Ph (2b); R¹ = R² = Ph (2c)] at 80 °C to afford 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 as the double hydrosilylation products in fair to good yields (33-84%). Among these reactions, the reaction with 2c gave a trans-4,5-diphenyl-1,1,3,3-tetrachloro-1,3-disilacyclopentane 3ac in the highest yield (84%). When a variety of bis(dichlorosilyl)(silyl)methanes [(Me_nCl_3 − nSi)CH(SiHCl₂)₂: n = 0 (1b), 1 (1c), 2 (1d), 3 (1e)] were applied in the reaction with alkyne (2c) under the same reaction conditions. The double hydrosilylation products, 2-silyl-1,1,3,3-tetrachloro-1,3-disilacyclopentanes (3), were obtained in fair to excellent yields (38-98%). The yields of compound 3 deceased as follows: n = 1 > 2 > 3 > 0. The reaction of alkynes (2a-c) with 1c under the same conditions gave one of two type products of 1,1,3,3-tetrachloro-1,3-disilacyclopentanes 3 and 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-enes (4): simple alkyne 2a and terminal 2b gave the latter products 4ca and 4cb in 91% and 57% yields, respectively, while internal alkyne 2c afforded the former cyclic products 3cc with trans form between two phenyl groups at the 3- and 4-carbon atoms in 98% yield, respectively. Among platinum compounds such as Speier’s catalyst, PtCl₂(PEt₃)₂, Pt(PPh₃)₂(C₂H₄), Pt(PPh₃)₄, Pt[ViMeSiO]₄, and Pt/C, Speier’s catalyst was the best catalyst for such silylation reactions.     

Synthesis of platinum-iodo-alkyl/aryl complexes in ligand-exchange reactions: Determination of the structure of Pt{(S,S)-bdpp}(X)I complexes (X = Me, I) by X-ray crystallography

Pt{(S,S)-bdpp}(R)I (bdpp = 2,4-bis(diphenylphosphino)pentane; R = Me, Ph, Bz, 2-Tioph) complexes were formed in alkyl/aryl ligand - iodide ligand-exchange reactions by reacting the corresponding Pt{(S,S)-bdpp}R₂ complexes with methyl iodide. The Pt{(S,S)-bdpp}(Me)I complex was isolated and fully characterised. The influence of the X ligand on the platinum-bdpp chelate conformation was investigated in Pt{(S,S)-bdpp}(X)I (X = I, SnCl₃, Me) complex series by means of X-ray crystallography.     

Synthesis of dihydropyrano[3,2-e]indoles as rotationally restricted phenolic analogs of 5-hydroxyindole—thermal Claisen approach versus gold catalysis

The Claisen rearrangement/cyclization of 5-propargyloxyindoles (2) to afford dihydropyrano[3,2-e]indoles (3) as direct precursors to tetrahydropyrano[3,2-e]indoles (1, a rotationally restricted phenolic analog of 5-hydroxyindole) was examined using either refluxing bromobenzene (156 °C) or Au⁺¹ catalysis in refluxing dioxane (101 °C). This transformation was best effected using Au⁺¹ catalysis (i.e., tris[triphenylphosphinegold(I)] oxonium tetrafluoroborate) because this method required a lower reaction temperature and gave better yields when compared to the simple thermal reaction conditions (156 °C).     

Regio- and stereo-specific addition of organotellurium trihalides to ferrocenylacetylene: Molecular and crystal structure of (Z)-halovinyl organotellurium dihalides

Organotellurium(IV) trihalides RTeX₃ (X = Br, I) reacts readily with ferrocenylacetylene to give (Z)-products of electrophilic addition to C-C triple bond: (Z)-FcXC = CTeX₂R (R = Ph, X = Br (1) or I (2); R = trans-8-ethoxy-4-cyclooctenyl, X = Br (3)). In case of PhTeX₃ (X = Br or I) the room temperature reaction is spontaneous and the structure of the product does not depends on the polarity of the solvent used; this is in contrast to the reaction of aryl-acetylenes with RTeBr₃ which were reported to afford (E)-bromovinyl aryltellurium dibromides in methanol and its (Z)-isomer in benzene. Molecular and crystal structures of new compounds and effect of bulky and electron-rich ferrocenyl substituent on the reactivity of acetylene moiety are discussed in this paper.     

Rhodium-catalyzed alkylthio exchange reaction of thioester and disulfide

The Wilkinson complex RhCl(PPh₃)₃ catalyzes equilibrating alkylthio exchange reaction of thioesters with disulfides. The treatment of a thioester and a dialkyl disulfide in refluxing diethyl ketone in the presence of RhCl(PPh₃)₃ (2.5 mol %) for 1.5 h gave an alkylthio exchanged thioester. The reaction of S-methyl ester was conducted shifting the equilibrium by removing volatile dimethyl disulfide.     

Pd(OAc)2-catalyzed cross-coupling of polyfluoroarenes with simple aromatics in imidazolium ionic liquids (ILs) without oxidant and additive and with recycling/reuse of the IL

Polyfluoroarenes can be cross-coupled with simple aromatics (benzene, toluene, and anisole), in good isolated yields, by using Pd(OAc)₂ dissolved in imidazolium ILs [(bmim)PF₆ and (bmim)BF₄] as solvent, without the need for an oxidant and an additive. The reaction is catalyzed by HOAc and it is subject to a primary isotope effect (K_H/K_D = 4.87). Competitive cross-coupling reactions of 1,2,4,5-tetrafluorobenzene with benzene/toluene, benzene/anisole, and anisole/toluene gave K_B/K_T = 5.1, K_B/K_A = 5.7, and K_A/K_T = 5.0, respectively, indicative of a remote substituent effect on Pd insertion into the phenyl C-H bond. Mild reaction conditions, simple product isolation and recycling/reuse of the IL are additional advantages of this method.     

Asymmetric reduction of perfluoroalkyl ketones with chiral lithium alkoxides

Reduction of perfluoroalkyl ketones with chiral lithium alkoxides gave chiral α-perfluoroalkyl alcohols in high enantiomeric excesses. Interestingly, reaction of 2,2,2-trifluoroacetophenone (1) with lithium (S)-1-phenylethoxide (2) gave (S)-2,2,2-trifluoro-1-phenylethanol (3), while the same reaction of perfluorooctan-1-one (7) with 2 gave (R)-1H-1-phenylperfluorooctanol (8). Based on the speculation of mechanism, the order of steric effects on this reaction is estimated as C₇F₁₅ > substituted phenyl > CF₃.