Catalytic, enantioselective alpha-additions of isocyanides: Lewis base catalyzed Passerini-type reactions

[reaction: see text] The generality of catalytic, enantioselective alpha-additions of isocyanides to aldehydes has been demonstrated (Passerini-type reactions). The catalytic system of silicon tetrachloride and a chiral bisphosphoramide (R,R)-1b provided high yields and good to excellent enantioselectivities for the addition of tert-butyl isocyanide to a wide range of aldehydes (aromatic, heteroaromatic, olefinic, acetylenic, aliphatic). Aqueous workup afforded the alpha-hydroxy tert-butyl amides whereas a low-temperature methanol quench followed by basic workup afforded the alpha-hydroxy methyl esters. The reaction is also successful for other isocyanides, albeit with reduced enantioselectivity. Reaction conditions, particularly the rate of addition of the isocyanide was found to be crucial for good yields and high selectivities.     

Synthesis of novel heterocyclic structures via reaction of isocyanides with S-trans-enones

The reaction of enone 1, bearing an internal nucleophilic moiety, i.e., furan or pyrrole (X = O, NR'), with isocyanides is presented. The formation of products resulting from the reaction of the zwitterionic intermediate 2 with a second equivalent of isocyanide prior to cyclization to give 3, as well as the direct formation of 4 from 2, is described.     

Insertion reactions of isocyanides with platinumcarbon σ-bonded complexes

[Pt(C₁₀H₁₂OCH₃)(PPh₃)Cl] reacts readily with isocyanides by displacement of the coordinated olefinic end of the organic moiety followed by insertion of the isocyanide into the metalcarbon σ-bond. The reaction between the methoxydienyl complex [Pt(C₁₀H₁₂OCH₃)Cl]₂ and cyclohexyl isocyanide involves chloride bridge-splitting to give [Pt(C₁₀H₁₂OCH₃)(C₆H₁₁NC)Cl], followed by olefin displacement and finally isocyanide insertion. The imino derivative produced in this latter reaction has a trans-isocyanide configuration.The chemical properties of these new isocyanide complexes are discussed in terms of relative trans influences, coordinating abilities, and electrophilic characters in comparison with the CO analogues.     

The first catalytic,asymmetric alpha-additions of isocyanides. Lewis-base-catalyzed,enantioselective Passerini-type reactions

The first, catalytic, enantioselective alpha-additions of isocyanides to aldehydes have been demonstrated (Passerini-type reactions). The catalytic system of silicon tetrachloride and a chiral bisphosphoramide 5a provided high yields and good to excellent enantioselectivities for the addition of tert-butyl isocyanide to a wide range of aldehydes (aromatic, olefinic, acetylenic, aliphatic). Aqueous workup afforded the alpha-hydroxy tert-butyl amides, whereas methanolic quench followed by basic workup afforded the alpha-hydroxy methyl esters.     

Rare-earth silylamide-catalyzed monocoupling reaction of isocyanides with terminal alkynes

[reaction: see text] Rare-earth silylamides, Ln[N(SiMe3)2]3 (Ln = Y, La, Sm, Yb), serve as good catalysts for monoinsertion of isocyanides into terminal alkynes in the presence of amine additives, leading to 1-aza-1,3-enyens in excellent yields. The reaction is applicable to a diverse set of terminal alkynes with various functionalities such as ethers, acetals, and amino groups. Larger metals (La and Sm) give a better performance than smaller ones (Y and Yb). Using less hindered primary amines and, in contrast, bulky isocyanides is crucial for the coupling reaction; otherwise, competitive oligomerization of the isocyanides occurs predominantly. In the mechanistic study, the rate-determining step of the reaction seems to be the first insertion of the isocyanides into rare-earth alkynides, which is followed by spontaneous protonation with the amine additives.     

Isocyanide ligands adsorbed on metal surfaces: applications in catalysis, nanochemistry, and molecular electronics

Knowledge of the coordination chemistry and reactivity of isocyanide ligands in transition-metal complexes forms the basis for understanding the adsorption and reactions of isocyanides on metal surfaces. In this overview, we explore reactions (often catalytic) of isocyanides adsorbed on metal surfaces that reflect their patterns of reactivity in metal complexes. We also examine applications of isocyanide adsorption to the stabilization of metal nanoparticles, the functionalization of metal electrodes, and the creation of conducting organic-metal junctions in molecule-scale electronic devices.     

Studies on vinyl isocyanides

The vinyl Isocyanides 2,4,6-(CH₃)₃C₆H₂CHCHNC and (CH₃)₃CCHCHNC and the new 1,3-dienyl isocyanide CH₃CHCH(CH₃)-CHCHNC have been prepared from the corresponding aldehydes and methyl isocyanide using a method first developed by Schöllkopf, Stafforst, and Jentsch. ⁵ The new vinyl isocyanides (CH₃)₂CCHNC and CH₃CHC(CH₃)NC have been prepared by the Cu₂O-catalyzed isomerization of the corresponding allyl isocyanides The liquid vinyl isocyanides may be characterized by the formation of solid cis-(RNC)₂Mo(CO)₄ derivatives through reaction with norbornadienetetracarbonylmolybdenum in hexane solution at ambient temperature. Examination of these molybdenum carbonyl complexes by proton and carbon-13 NMR spectroscopy Indicates that the isocyanide carbon atom but not the carbon-carbon double bond of the vinyl 1socyanide ligands is bonded to the molybdenum atom. The proton-decoupled carbon-13 NMR spectra of the vinyl isocyanides, but not their molybdenum carbonyl complexes, indicate coupling of the isocyanide nitrogen to both the isocyanide carbon (¹J(C-N)6 Hz. ) and the vinyl carbon bearing the isocyanide group (¹J(C-N)11-13 Hz. ) leading to 1:1:1 triplets for these resonances. These vinyl carbonyl resonances are used to estimate the cis-trans isomer ratios in vinyl isocyanides of the type RCHCHNC. Such studies suggest that the formation of vinyl isocyanides by the copper(I) catalyzed isomerization of the corresponding allylic isocyanides is more nearly stereospecific than the formation of vinyl isocyanides by the elimination reaction of the Schollkopf/Stafforst/Jentsch synthetic method.     

Screw-sense-selective polymerization of aryl isocyanides initiated by a Pd-Pt mu-ethynediyl dinuclear complex: a novel method for the synthesis of single-handed helical poly(isocyanide)s with the block copolymerization technique

Living polymerization of chiral aryl isocyanides, such as m- and p-menthoxycarbonylphenyl isocyanides 2 and 5, initiated by the Pd-Pt mu-ethynediyl dinuclear complex 1, proceeds with a high screw-sense selectivity to give the poly(isocyanide)s 3 and 6, which exhibit a large specific rotation and an intense CD band at lambda = 364 nm as a consequence of a helical chirality. The molar optical rotation and molar circular dichroism of the resulting polymers 3 and 6 reach a constant value at a degree of polymerization (Pn) of more than 30. Screw-sense-selective polymerization of achiral aryl isocyanides that bear very bulky substituents, such as 3,5-di(propoxycarbonyl)phenyl isocyanide (11), 3,5-di(butoxycarbonyl)phenyl isocyanide (13), and 3,5-di(cyclohexyloxycarbonyl)phenyl isocyanide (15), is achieved by the use of chiral oligomer complexes 3(30) and 6(30), prepared from the reaction of 1 with 30 equivalents of 2 or 5, as an initiator to give predominantly single-handed helical polymers. In contrast, smaller aryl isocyanides are also polymerized by 3(30) and 6(30) with screw-sense selectivity in the initial stage of the reaction, but the single-handed helix is not preserved up to high molecular weight. Kinetic studies of the polymerization of (L)- and (D)-2, or (L)- and (D)-5 with chiral oligomer complexes (L)-3(50) or (L)-6(100) suggests that the screw sense of the polymer backbone is not controlled kinetically, but rather that the thermodynamically stable screw sense is produced.     

The reactions of alkyltrimethylphosphinenickel complexes with isocyanides and alkynes

t-Butylisocyanide reacts with NiRCl(PMe₃)₂ (R  CH₃, Ia; R  CH₂SiMe₃, Ib) to give, successively, the products of mono- and di-insertion into the nickelcarbon bonds; with more than two equivalents of isocyanide, trimethylphosphine ligands are displaced. In contrast to related palladium reactions, cyclohexyl isocyanide gives mono-insertion products only, while benzyl isocyanide is polymerised. The reactions of diphenylacetylene with Ia and Ib in methanol give (Z) vinylnickel complexes, trans-Ni{C(Ph)C(Ph)R}Cl(PMe₃)₂, while from reaction in diethyl ether a precursor complex [NiMeCl(PMe₃)₂ · (PhCCPh)_0.5] can be isolated. On heating the (Z)-vinyl complexes come into thermodynamic equilibrium with their (E)-isomers. The vinyl complexes are stereochemically rigid and resistant to further insertion.     

Gold carbene complexes as intermediates in the α-addition of amines to isocyanides

The reaction of amines and isocyanides with tetrachloroaurate(III) yields carbene complexes of the type Au {C(NHR)NR′R″}₂⁺. Under thermal decomposition or treatment with added ligands (cyanide ion or methyl isocyanide) the carbene ligands are liberated to yield formamidines.     

Base Metal Catalyzed Isocyanide Insertions

Isocyanides are diverse C₁ building blocks considering their potential to react with nucleophiles, electrophiles, and radicals. Therefore, perhaps not surprisingly, isocyanides are highly valuable as inputs for multicomponent reactions (MCRs) and other one‐pot cascade processes. In the field of organometallic chemistry, isocyanides typically serve as ligands for transition metals. The coordination of isocyanides to metal centers alters the electronic distribution of the isocyano moiety, and reaction pathways can therefore be accessed that are not possible in the absence of the metal. The tunable reactivity of the isocyanide functional group by transition metals has evolved into numerous useful applications. Especially palladium‐catalyzed isocyanide insertion processes have emerged as powerful reactions in the past decade. However, reports on the use of earth‐abundant and cheap base metals in these types of transformations are scarce and have received far less attention. In this Minireview, we focus on these emerging base metal catalyzed reactions and highlight their potential in synthetic organic chemistry. Although mechanistic studies are still scarce, we discuss distinct proposed catalytic cycles and categorize the literature according to 1) the (hetero)atom bound to and 2) the type of bonding with the transition metal in which the (formal) insertion occurs.     

Mechanisms of nucleophilic and electrophilic attack on carbon bonded palladium(II) and platinum(II) complexes

A systematic mechanistic study is reported for the formation of palladium(II) carbene complexes by nucleophilic attack of aromatic amines on isocyanide derivatives. The most prominent step of the reaction involves direct attack of the amine nitroge on the isocyanide carbon to give an intermediate which then is converted to the final carbene species by the agency of the entering amine itself which behaves as a bifunctional catalyst. The rate of the primary step is affected by the donor ability of the entering amine, by the electrophilic character of the isocyanide carbon, and by steric crowdiness around the reacting centers, with the solvent also playing an important role. The reaction system displays a high versatility through a proper choice of the substituents on the amine and isocyanide aromatic rings and of the ancillary ligands in the metal complex.A mechanistic study is also described of the cleavage of the platinum-carbon σ-bond by electrophilic attack by the proton on organoplatinum(II) complexes. The particular mechanism which is operative, viz. direct electrophilic attack at the metalcarbon bond or oxidative addition/reductive elimination, appears to be the result of many factors. These include electronic and steric properties of the cleaved group and of ancillary ligands, steric configuration of the substrate, nature of the electrophile and solvating ability of the medium.     

Cyanides and isocyanides of first-row transition metals: molecular structure, bonding, and isomerization barriers

Cyanides and isocyanides of first-row transition metal M(CN) (M=Sc-Zn) are investigated with quantum chemistry techniques, providing predictions for their molecular properties. A careful analysis of the competition between cyanide and isocyanide isomers along the transition series has been carried out. In agreement with the experimental observations, late transition metals (Co-Zn) clearly prefer a cyanide arrangement. On the other hand, early transition metals (Sc-Fe), with the only exception of the Cr(CN) system, favor the isocyanide isomer. The theoretical calculations predict the following unknown isocyanides, ScNC(3Delta), TiNC(4Phi), VNC(5Delta), and MnNC(7Sigma+), and agree with the experimental observation of FeNC(6Delta) and the CrCN(6Sigma+) cyanide. First-row transition metal cyanides and isocyanides are predicted to have relatively large dissociation energies with values within the range 80-101 kcal mol(-1), except Zn(CN), which has a dissociation energy around 50-55 kcal mol(-1), and low isomerization barriers. A detailed analysis of the bonding has been carried out employing the topological analysis of the charge density and an energy decomposition analysis. The role of the covalent and electrostatic contributions to the metal-ligand bonding, as well as the importance of pi bonding, are discussed.     

Palladium-catalyzed denitrogenation reaction of 1,2,3-benzotriazin-4(3H)-ones incorporating isocyanides

1,2,3-Benzotriazin-4(3H)-ones and 1,2,3,4-benzothiatriazine 1,1(2H)-dioxide reacted with isocyanides in the presence of a palladium catalyst to give 3-(imino)isoindolin-1-ones and 3-(imino)thiaisoindoline 1,1-dioxides, respectively, in high yield. An intermediate azapalladacycle was generated through denitrogenation of the triazine moiety, and an isocyanide was incorporated therein.     

Highly selective double chalcogenation of isocyanides with disulfide-diselenide mixed systems

A highly selective method for introducing thio and seleno groups into a variety of isocyanides has been developed based on the elucidation of the relative reactivities of organic dichalcogenides and chalcogen-centered free radicals. When the reactions of aromatic isocyanides (ArNC) with organic disulfides (R'SSR') and diselenides (R'SeSeR') are conducted upon irradiation with a tungsten lamp through Pyrex (hnu>300 nm), simultaneous introduction of both thio and seleno groups into the isocyanides takes place to provide the corresponding thioselenation products (R'S-C(=NAr)-SeR') in good yields with excellent selectivity. In the cases of aliphatic isocyanides (RCN), a novel diselenide-assisted bisthiolation of RNC with diaryl disulfides (Ar'SSAr') proceeds successfully to give the corresponding bisthiolation products (Ar'S-C(=NR)-SAr'), although the same photoirradiated reaction of RNC with diaryl disulfides does not occur in the absence of diselenide. These double chalcogenation reactions are assumed to proceed via the formation of imidoyl radical intermediates by the reaction of isocyanides with relatively reactive thio radicals (compared with seleno radicals). The obtained thioselenation products can be employed as useful precursors for the construction of beta-lactam framework by the formal [2+2] cyclization with ketene equivalents.     

Template synthesis of benzannulated N-heterocyclic carbene ligands

The reaction of 2-azidophenyl isocyanide (7) with [M(CO)(5)(thf)] (M=Cr, W) yields the isocyanide complexes [M(CO)(5)(7)] (M=Cr 8, M=W 9). Complexes 8 and 9 react with tertiary phosphines such as triphenylphosphane at the azido function of the isocyanide ligand to give the 2-triphenylphosphiniminophenyl isocyanide complexes 10 (M=Cr) and 11 (M=W). The polar triphenylphosphiniminophenyl function in complexes 10 and 11 can be hydrolyzed with H(2)O/HBr to afford triphenylphosphane oxide and the complexes containing the unstable 2-aminophenyl isocyanide ligand. This ligand spontaneously cyclizes by intramolecular nucleophilic attack of the primary amine at the isocyanide carbon atom to yield the 2,3-dihydro-1H-benzimidazol-2-ylidene complexes 12 (M=Cr) and 13 (M=W). Double deprotonation of the cyclic NH,NH-carbene ligands in 12 and 13 with KOtBu and reaction with two equivalents of allyl bromide yields the N,N'-dialkylated benzannulated N-heterocyclic carbene complexes 14 (M=Cr) and 15 (M=W). The molecular structures of complexes 9 and 11-15 were confirmed by X-ray diffraction studies.     

Luminescence and mesogenic properties in crown-ether-isocyanide or carbene gold(I) complexes: luminescence in solution, in the solid, in the mesophase, and in the isotropic liquid state

A crown ether isocyanide CNR (R = benzo-15-crown-5) has been synthesized by dehydration of the corresponding formamide. Substitution reactions with the appropriate gold(I) precursors afford the luminescent mononuclear derivatives [AuX(CNR)] (X = Cl, C 6F 5, Br, I), [Au(C 6F 4OCH 2C 6H 4OC nH 2 n+1 - p)(CNR)] ( n = 4, 8, 10, 12), and [Au(C 6F 4OCH 2C 6H 2-3,4,5-(OC n H 2 n+1 ) 3(CNR)] ( n = 4, 8, 12). X-ray diffraction studies of [AuCl(CNR)] show the molecules associated in a tetranuclear manner with an antiparallel orientation and gold-gold distances of 3.420 and 3.427 A (Au...Au...Au angles are 121.2 degrees ). These tetranuclear units generate infinite zigzag chains through longer Au...Au distances of 3.746 A and weak C-H...O nonclassic interactions. Nucleophilic attack to the coordinated isocyanide in [AuCl(CNR)] by methanol or a primary amine produces the carbene derivatives [AuCl{C((NHR)(OMe)}] and [AuCl{C(NHR')(NHR)}] (R' = Me, n-Bu). The ether crown in these complexes is able to coordinate sodium from NaClO 4, affording the corresponding bimetallic complexes (Na/Au = 1:1). The derivatives containing one alkoxy chain are liquid crystals, displaying a smectic C mesophase (for n > 4), whereas the trialkoxy derivatives display unidentified or smectic C mesophases, depending on the alkyl chain length. After complexation of sodium salts, the mesogenic behavior is lost. All of the derivatives are luminescent at room temperature in the solid state with emission maxima in the range 405-550 nm; they emit at 77 K from 410 to 572 nm. Only the ligand and the fluoroaryl complexes emit in solution at room temperature, but all of the compounds are luminescent at 77 K. Very interestingly, some fluoroaryl derivatives with alkoxy chains are luminescent not only in the solid, and in solution, but also in the mesophase, and in the isotropic liquid at moderate temperatures. These are the first metal complexes ever reported to show luminescence in the isotropic liquid state.     

Solvent free preparation of amidophosphonates from isocyanides

New amidophosphonates are prepared via a two-step Mannich/Ugi one-pot procedure from isocyanides. Aminophosphonates are readily prepared from primary amines, dialkyl phosphites and carbonyl compounds under LiClO₄ catalysis without any solvent. After completion, addition of an isocyanide, an aldehyde and acetic acid give access to phosphono Ugi-type adducts in good to moderate yields.     

Multicomponent synthesis of 2-imidazolines

[reaction: see text] A multicomponent reaction (MCR) between amines, aldehydes, and isocyanides bearing an acidic alpha-proton gives easy access to a diverse range of highly substituted 2-imidazolines. The limitations of the methodology seem to be determined by the reactivity of the isocyanide and by the steric bulk on the in situ generated imine rather than by the presence of additional functional groups on the imine. Less reactive isocyanides, for example p-nitrobenzyl isocyanide 25a, react successfully with amines and aldehydes, using a catalytic amount of silver(I) acetate. Some of the resulting p-nitrophenyl-substituted 2-imidazolines undergo air oxidation to the corresponding imidazoles. Differences in reactivity of the employed isocyanides are explained with use of DFT calculations. Difficult reactions with ketones instead of aldehydes as the oxo-compound in this MCR are promoted by silver(I) acetate as well.     

Isocyanide based multicomponent reactions of oxazolidines and related systems

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxyethylamino acid amide products are obtained both via a three- or four-component approach from N-alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethylamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated using an ¹⁸O labelling experiment. The carboxylic acid component can be replaced by a range of other acidic nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-aminotetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicomponent reaction products.