New coupling reaction of secondary amines, aldehydes, and alkynes catalyzed by an iridium complex

A new reductive coupling reaction of secondary amines, aldehydes, and alkynes using an iridium complex as catalyst has been developed. For example, dibutylamine was allowed to react with butyraldehyde and 1-octyne in 1,4-dioxane at 50 degrees C under the influence of a catalytic amount of [IrCl(cod)](2) to give the corresponding allylamines such as N,N-dibutyl-2-butylideneoctylamine and N,N-2-tributyl-2-octenylamine in excellent yields. [reaction: see text]     

Mechanistic investigation of the iridium-catalysed alkylation of amines with alcohols

The [Cp*IrCl(2)](2)-catalysed alkylation of amines with alcohols was investigated using a combination of experimental and theoretical methods. A Hammett study involving a series of para-substituted benzyl alcohols resulted in a line with a negative slope. This clearly documents that a positive charge is built up in the transition state, which in combination with the measurement of a significant kinetic isotope effect determines hydride abstraction as being the selectivity-determining step under these conditions. A complementary Hammett study using para-substituted anilines was also carried out. Again, a line with a negative slope was obtained suggesting that nucleophilic attack on the aldehyde is selectivity-determining. A computational investigation of the entire catalytic cycle with full-sized ligands and substrates was performed using density functional theory. The results suggest a catalytic cycle where the intermediate aldehyde stays coordinated to the iridium catalyst and reacts with the amine to give a hemiaminal which is also bound to the catalyst. Dehydration to the imine and reduction to the product amine also takes place without breaking the coordination to the catalyst. The fact that the entire catalytic cycle takes place with all the intermediates bound to the catalyst is important for the further development of this synthetic transformation.     

Microwave-assisted solventless reaction of iridium-catalyzed alkylation of amines with alcohols in the absence of base

Microwave-assisted iridium catalyzed alkylation of amines with alcohols was undertaken under solvent-free and base-free conditions. Such alkylation reactions are green, atom-economic, and effective for mono-, di-, and triaklyation of amines. Good isolated yields were obtained for mono- and dialkylated amines using stoichiometric amounts of amines and alcohols, in the presence of 1 mol % [Cp*IrCl(2)](2). Reasonable yields of trialkylated products were obtained using 4 equiv of alcohols.     

Enantioselective iridium-catalyzed carbonyl allylation from the alcohol or aldehyde oxidation level using allyl acetate as an allyl metal surrogate

Protocols for highly enantioselective carbonyl allylation from the alcohol or aldehyde oxidation level are described based upon transfer hydrogenative C-C coupling. Exposure of allyl acetate to benzylic alcohols 1a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (R)-BINAP delivers products of C-allylation 2a-i. Employing isopropanol as terminal reductant, exposure of allyl acetate to aryl aldehydes 3a-i in the presence of an iridium catalyst derived from [IrCl(cod)]2 and (-)-TMBTP delivers identical products of C-allylation 2a-i. In all cases examined, exception levels of enantioselectivity are observed. Thus, enantioselective carbonyl allylation is achieved from the alcohol or aldehyde oxidation level in the absence of any preformed allylmetal reagents. These studies define a departure from preformed organometallic reagents in carbonyl additions that transcend the boundaries of oxidation level.     

Discovery of Novel Catalysts for Allylic Alkylation with a Visual Colorimetric Assay

The first non-phosphane iridium catalyst, made from [{IrCl(cod)}(2)] and iPr-pybox (shown schematically; cod=1,5-cyclooctadiene), for allylic alkylation in neutral medium was discovered by a simple, rapid, and inexpensive screening assay. The red coloration upon treatment of the reaction mixtures with Fast Red (see the 96-well plate) indicates the presence of 1-naphthol and thus the occurrence of allylic alkylation.     

Iridium-catalyzed coupling of simple primary or secondary amines, aldehydes and trimethylsilylacetylene: preparation of propargylic amines

The coupling of amines, aldehydes and trimethylsilylacetylene was found to be promoted in the presence of a catalytic amount of [IrCl(cod)]2; 1 : 1 : 1 or 1 : 2 : 2 coupling products were obtained by allowing primary amine to react with aldehyde and trimethylsilylacetylene.     

The preparation and characterisation of bimetallic iridium(II) complexes containing derivatised bridging naphthalene-1,8-disulfur or 4,5-dithiolato acephenanthrylene ligands

Oxidative addition of the disulfide compounds naphtho[1,8-cd][1,2]dithiole, 2-tert-butylnaptho[1,8-cd][1,2]dithiole, 2,7-di-tert-butylnaphtho[1,8-cd][1,2]dithiole, 4,5-dithiaacephenanthrylene and the thio/sulfinyl and thio/sulfonyl compounds naphtho[1,8-cd][1,2]dithiole 1-oxide, and naphtho[1,8-cd][1,2]dithiole 1,1-dioxide respectively to [[Ir(mu-Cl)(cod)](2)] give dinuclear Ir-Ir bonded Ir(II) compounds [[IrCl(cod)](2)(mu(2)-1,8-S(2)-nap)] 1, [[IrCl(cod)](2)(mu(2)-1,8-S(2)-2-(t)Bu-nap)] 2, [[IrCl(cod)](2)(mu(2)-1,8-S(2)-2,7-di-(t)Bu-nap)]] 3, [[IrCl(cod)](2)(mu(2)-4,5-S(2)-phenan)] 4, [[IrCl(cod)](2)(mu(2)-1-S,8-[S(O)]-nap)] 5 and [[IrCl(cod)](2)(mu(2)-1-S,8-[S(O)(2)]-nap)] 6 where the di-sulfur ligands act as bridges between the two Ir(II) metal centres. The compounds were obtained in moderate to good yields as orange or deep red powders or crystalline solids. Five of the new complexes have been structurally characterised and were found to have Ir-Ir bond lengths in the range 2.7630(8) to 2.8113(11) A.     

Effective reductive amination of carbonyl compounds with hydrogen catalyzed by iridium complex in organic solvent and in ionic liquid

The direct reductive amination (DRA) of carbonyl compounds with amines has been achieved using homogenous iridium catalyst and gaseous hydrogen. It appeared that the cationic iridium catalyst, [Ir(cod)₂]BF₄, without any other ligands was sufficient for the reaction. For the DRA of the ketone substrates, an ionic liquid, [Bmim]BF₄, was found to be superior to the other organic solvent used. Especially, the counter anion of the ionic liquid has a significant influence on the selectivity, and at the same time, a high reaction temperature was found to be crucial for the excellent selectivity.     

Synthesis of aromatic compounds by catalytic C-C bond activation of biphenylene or angular [3]phenylene

Substituted phenanthrenes and picenes were easily prepared by reaction of biphenylene or angular [3]phenylene with various alkynes in the presence of a catalytic amount of [IrCl(cod)](2) /dppe (cod=1,5-cyclooctadiene, dppe=1,2-bis(diphenylphosphino)ethane). The reaction is based on C-C bond activation of the cyclobutane ring. The reaction tolerates the presence of bulky groups on the alkyne, such as the ferrocene moiety. In addition, a catalytic system based on [RhCl(cod)](2)/dppe enabled the, hitherto unreported, reaction of biphenylene with nitriles to provide phenanthridines.     

B(C6F5)3: an efficient catalyst for reductive alkylation of alkoxy benzenes and for synthesis of triarylmethanes using aldehydes

Tris(pentafluorophenyl)borane [B(C₆F₅)₃] has been used as an efficient catalyst for reductive alkylation of alkoxy benzenes using aldehydes as an alkylating agent in the presence of polymethylhydrosiloxane (PMHS). Various alkylated trimethoxybenzene derivatives have been prepared in good to high yields. In addition, B(C₆F₅)₃ was also used as a catalyst for the reaction of electron-rich arenes with aldehydes to obtain triarylmethanes. The use of reductive alkylation protocol for the synthesis of an isochroman and tetrahydroisoquinoline derivatives has also been demonstrated.     

Highly chemoselective reductive amination of carbonyl compounds promoted by InCl3/Et3SiH/MeOH system

A new strategy has been developed for reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH system, which is a nontoxic system with highly chemoselective and nonwater sensitive properties. The methodology can be applied to a variety of cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are found to be stable under our conditions. The reaction shows a first-order kinetics profile with respect to both InCl3 and Et3SiH. Spectroscopic techniques such as NMR and ESI-MS have been employed to probe the active and resulting species arising from InCl3 and Et3SiH in MeOH, which are important in deriving a mechanistic proposal. In the ESI-MS studies, we have first discovered the existence of stable methanol-coordinated indium(III) species which are presumably responsible for the gentle generation of indium hydride at room temperature. The solvent attribution was crucial in tuning the reactivity of [In-H] species, leading to the establishment of mild reaction conditions. The system is superior in flexible tuning of hydride reactivity, resulting in the system being highly chemoselective.     

Mechanistic insight into hydrosilylation reactions catalyzed by high valent ReX (X = O, NAr, or N) complexes: the silane (Si-H) does not add across the metal-ligand multiple bond

Treatment of oxo and imido-rhenium(V) complexes Re(X)Cl3(PR3)2 (X = O, NAr, and R = Ph or Cy) (1-2) with Et3SiH affords Re(X)Cl2(H)(PR3)2 in high yields. Cycloaddition of silane across the ReX multiple bonds is not observed. Two rhenium(V) hydrides (X = O and R = Ph, 4a; X = NMes and R = Ph, 5a) have been structurally characterized by X-ray diffraction. The kinetics of the reaction of Re(O)Cl3(PPh3)2 (1a) with Et3SiH is characterized by phosphine inhibition and saturation in [Et3SiH]. Hence, formation of Re(O)Cl2(H)(PPh3)2 (4a) proceeds via a sigma-adduct followed by heterolytic cleavage of the Si-H bond and transfer of silylium (Et3Si+) to chloride. Oxo and imido complexes of rhenium(V) (1-2) as well as their nitrido analogues, Re(N)Cl2(PR3)2 (3), catalyze the hydrosilylation of PhCHO under ambient conditions, with the reactivity order imido > oxo > nitrido. The isolable oxorhenium(V) hydride 4a reacts with PhCHO to afford the alkoxide Re(O)Cl2(OCH2Ph)(PPh3)2 (6a) with kinetic dependencies that are consistent with aldehyde coordination followed by aldehyde insertion into the Re-H bond. The latter (6a) regenerates the rhenium hydride upon reaction with Et3SiH. These stoichiometric reactions furnish a possible catalytic cycle. However, quantitative kinetic analysis of the individual stoichiometric steps and their comparison to steady-state kinetics of the catalytic reaction reveal that the observed intermediates do not account for the predominant catalytic pathway. Furthermore, for Re(O)Cl2(H)(PCy3)2 and Re(NMes)Cl2(H)(PPh3)2 aldehyde insertion into the Re-H bond is not observed. Therefore, based on the kinetic dependencies under catalytic conditions, a consensus catalytic pathway is put forth in which silane is activated via sigma-adduct formation cis to the ReX bond followed by heterolytic cleavage at the electrophilic rhenium center. The findings presented here demonstrate the so-called Halpern axiom, the observation of "likely" intermediates in a catalytic cycle, generally, signals a nonproductive pathway.     

Quasi-octahedral complexes of pentamethylcyclopentadienyliridium(III) bearing bis(diphenylphosphinomethyl)phenylphosphine (dpmp)

Reaction of [Cp*IrCl2]2 (1) with dpmp in the presence of KPF6 afforded a binuclear complex [Cp*IrCl(dpmp-P1,P2;P3)IrCl2Cp*](PF6) (2) (dpmp =(Ph2PCH2)2PPh). The mononuclear complex [Cp*IrCl(dpmp-P1,P2)](PF6) (4) was generated by the reaction of [Cp*IrCl2(BDMPP)](BDMPP =PPh[2,6-(MeO)2C6H3]2) with dpmp in the presence of KPF6. These mono- and binuclear complexes have four-membered ring structures with a terminal and a central P atom of the dpmp ligand coordinated to an iridium atom as a bidentate ligand. Since there are two chiral centers at the Ir atom and a central P2 atom, there are two diastereomers that were characterized by spectrometry. Complexes anti-4 and syn-4 reacted with [Cp*RhCl2]2 or [(C6Me6)RuCl2]2, giving the corresponding mixed-metal complexes, anti- and syn- [Cp*IrCl(dppm-P1,P2;P3)MCl2L](PF6) (6: M = Rh, L = Cp*; 7: M = Ru, L = C6Me6). Treatment with AuCl(SC4H8) gave tetranuclear complexes, anti- and syn-8 [[Cp*IrCl(dppm-P1,P2;P3)AuCl]2](PF6)2 bearing an Au-Au bond. Reaction of anti- with PtCl2(cod) generated the trinuclear complex anti-9, anti-[[Cp*IrCl(dppm-P1,P2;P3)]2PtCl2](PF6)2. These reactions proceeded stereospecifically. The P,O-chelated complex syn-[Cp*IrCl(BDMPP-P,O)] (syn-10)(BDMPP-P,O = PPh[2,6-(MeO)2C6H3][2-O-6-(MeO)C6H3]2) reacted with dpmp in the presence of KPF6, generating the corresponding anti-complex as a main product as well as a small amount of syn-complex, [Cp*Ir(BDMPP-P,O)(dppm-P1)](PF6) (11). The reaction proceeded preferentially with inversion. The reaction processes were investigated by PM3 calculation. anti- was treated with MCl2(cod), giving anti-[Cp*Ir(BDMPP-P,O)(dppm-P1;P2,P3)MCl2](PF6)(14: M = Pt; 15: M = Pd), in which the MCl2 moiety coordinated to the two free P atoms of anti-11. The X-ray analyses of syn-2, anti-2, anti-4, anti-8 and anti-11 were performed.     

Development and mechanistic investigation of a highly efficient iridium(V) silyl complex for the reduction of tertiary amides to amines

The cationic Ir(III) acetone complex (POCOP)Ir(H)(2)(acetone)(+) (POCOP = 2,6-bis(di-tert-butylphosphinito)phenyl) was shown to catalyze the reduction of a variety of tertiary amides to amines using diethylsilane as reductant. Mechanistic studies established that a minor species generated in the reaction, the neutral silyl trihydride Ir(V) complex (POCOP)IrH(3)(SiEt(2)H), was the catalytically active species. High concentrations of this species could be conveniently generated by treatment of readily available (POCOP)IrHCl with tert-butoxide in the presence of Et(2)SiH(2) under H(2). Thus, using this mixture in the presence of a trialkylammonium salt, a wide array of tertiary amides, including extremely bulky substrates, are rapidly and quantitatively reduced to tertiary amines under mild conditions with low catalyst loading. A detailed mechanistic study has been carried out and intermediates identified. In brief, (POCOP)IrH(3)(SiEt(2)H) reduces the amide to the hemiaminal silyl ether that, in the presence of a trialkylammonium salt, is ionized to the iminium ion, which is then reduced to the tertiary amine by Et(2)SiH(2). Good functional group compatibility is demonstrated, and a high catalyst stability has provided turnover numbers as high as 10,000.     

Anilines as C‐Nucleophiles in Ir‐Catalyzed Intramolecular Asymmetric Allylic Substitution Reactions

Anilines generally act as N‐nucleophiles in transition‐metal‐catalyzed allylic substitution reactions. In this paper, a highly enantioselective intramolecular Friedel–Crafts‐type allylic alkylation of aniline derivatives was realized by using an iridium catalyst derived from [Ir(cod)Cl]₂ and (R _a)‐BHPphos. Various tetrahydroisoquinilin‐5‐amines were obtained in moderate to good yields, excellent enantioselectivity and regioselectivity under mild reaction conditions. BHPphos=N ‐benzhydryl‐N ‐phenyldinaphthophosphoramidite.     

The ruthenium-catalyzed reduction and reductive N-alkylation of secondary amides with hydrosilanes: practical synthesis of secondary and tertiary amines by judicious choice of hydrosilanes

A triruthenium cluster, (mu3,eta2,eta3,eta5-acenaphthylene)Ru3(CO)7 (1) catalyzes the reaction of secondary amides with hydrosilanes, yielding a mixture of secondary amines, tertiary amines, and silyl enamines. Production of secondary amines with complete selectivity is achieved by the use of higher concentration of the catalyst (3 mol %) and the use of bifunctional hydrosilanes such as 1,1,3,3-tetramethyldisiloxane. Acidic workup of the reaction mixture affords the corresponding ammonium salts, which can be treated with a base, providing a facile method for isolation of secondary amines with high purity. In contrast, tertiary amines are formed with high selectivity by using lower concentration of the catalyst (1 mol %) and polymeric hydrosiloxanes (PMHS) as reducing agent. Reduction with PMHS encapsulates the ruthenium catalyst and organic byproducts to the insoluble silicone resin. The two reaction manifolds are applicable to various secondary amides and are practical in that the procedures provide the desired secondary or tertiary amine as a single product. The product contaminated with only minimal amounts of ruthenium and silicon residues. On the basis of the products and observed side products as well as NMR studies a mechanistic scenario for the reaction is also described.     

Additive effects of amines on asymmetric hydrogenation of quinoxalines catalyzed by chiral iridium complexes

The additive effects of amines were realized in the asymmetric hydrogenation of 2-phenylquinoxaline, and its derivatives, catalyzed by chiral cationic dinuclear triply halide-bridged iridium complexes [{Ir(H)[diphosphine]}(2) (μ-X)(3) ]X (diphosphine=(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [(S)-BINAP], (S)-5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole [(S)-SEGPHOS], (S)-5,5'-bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-1,3-benzodioxole [(S)-DIFLUORPHOS]; X=Cl, Br, I) to produce the corresponding 2-aryl-1,2,3,4-tetrahydroquinoxalines. The additive effects of amines were investigated by solution dynamics studies of iridium complexes in the presence of N-methyl-p-anisidine (MPA), which was determined to be the best amine additive for achievement of a high enantioselectivity of (S)-2-phenyl-1,2,3,4-tetrahydroquinoxaline, and by labeling experiments, which revealed a plausible mechanism comprised of two cycles. One catalytic cycle was less active and less enantioselective; it involved the substrate-coordinated mononuclear complex [IrHCl(2) (2-phenylquinoxaline){(S)-BINAP}], which afforded half-reduced product 3-phenyl-1,2-dihydroquinoxaline. A poorly enantioselective disproportionation of this half-reduced product afforded (S)-2-phenyl-1,2,3,4-tetrahydroquinoxaline. The other cycle involved a more active hydride-amide catalyst, derived from amine-coordinated mononuclear complex [IrCl(2) H(MPA){(S)-BINAP}], which functioned to reduce 2-phenylquinoxaline to (S)-2-phenyl-1,2,3,4-tetrahydroquinoxaline with high enantioselectivity. Based on the proposed mechanism, an Ir(I) -JOSIPHOS (JOSIPHOS=(R)-1-[(S(p) )-2-(dicyclohexylphosphino)ferrocenylethyl]diphenylphosphine) catalyst in the presence of amine additive resulted in the highest enantioselectivity for the asymmetric hydrogenation of 2-phenylquinoxaline. Interestingly, the reaction rate and enantioselectivity were gradually increased during the reaction by a positive-feedback effect from the product amines.     

Catalytic Asymmetric Hydrogenation of Pyrimidines

The asymmetric hydrogenation of pyrimidines proceeded with high enantioselectivity (up to 99 % ee) using an iridium catalyst composed of [IrCl(cod)]₂, a ferrocene‐containing chiral diphosphine ligand (Josiphos), iodine, and Yb(OTf)₃ (cod=1,5‐cyclooctadiene). The chiral catalyst converted various 4‐substituted pyrimidines into chiral 1,4,5,6‐tetrahydropyrimidines in high yield. The lanthanide triflate is crucial for achieving the high enantioselectivity as well as for activating the heteroarene substrate.     

Deoxygenation of tertiary and secondary benzylic alcohols into alkanes with triethylsilane catalyzed by solid acid tin(IV) ion-exchanged montmorillonite

We discovered an efficient protocol for the conversion of tertiary and secondary benzylic alcohols into the corresponding alkanes in good to quantitative yields by employing tin(IV) ion-exchanged montmorillonite (Sn-Mont) as a solid acid catalyst and Et3SiH as the hydride source. The reaction is likely to proceed via the S_N1-type reaction mechanism, that is, the formation of carbenium ions, followed by the addition of a hydride from the silane. The work-up of the reaction only requires simple filtration of the solid acid without any neutralization of the acid catalyst.     

Coordination versatility of pyridine-functionalized N-heterocyclic carbenes: a detailed study of the different activation procedures. Characterization of new Rh and Ir compounds and study of their catalytic activity

Three different reaction procedures for the coordination of N-n-butyl-N'-(2-pyridylmethyl)imidazolium salt have produced new N-heterocyclic complexes of Rh and Ir. The direct reaction of the imidazolium salt with [IrCl(cod)](2) provides a NHC-Ir(III)-H complex, while transmetalation from a silver-NHC complex and deprotonation with NEt(3) give new NHC complexes of M(I) and M(III) when reacting with [MCl(cod)](2) or [MCl(coe)(2)](2) (M = Rh, Ir). The crystal structures of the biscarbene Rh(III) and Ir(III) complexes are described. The catalytic properties of the compounds obtained have been tested in the hydrosilylation of acetylenes, the cyclization of acetylenic carboxylic acids, and hydrogen transfer to ketones.