Imidazole carbene insertion

Imidazoles react with chloroform at high temperature to form azines by carbene insertion (see CHEC) and trichloromethyl radicals behave similarly (91 Ml 302-04), but carbenes do not always induce... 

Imidazoles react with chloroform at high temperature to form azines by carbene insertion and trichloromethyl radicals behave similarly, but carbenes do not always induce ring expansion. In alkaline medium, chlorodifluoromethane converts benzimidazole and its 2-methyl analogue into the 1-difluoromethyl derivatives 365. Dichlorocarbene under basic conditions N-alkylates benzimidazole, and 1-methylbenzimidazole couples under the influence of the same reagent (Scheme 69), perhaps involving initial attack of the carbene at N(3). 

When imidazole, or 1- and 2-substituted imidazoles react with chloroform at 550 °C the products include 5-chloro- (138) and 4-chloro-pyrimidines, and 2-chloropyrazines. Carbene insertion from the chloroform into either a C—C or C—N bond accounts for the products among which (138) predominates (Scheme 67). With hexachloroacetone at room temperature 2-methylimidazole gives a 5-7% yield of (138 R = Me) (80JCS(P1)1427). 

Carbenoid addition of diazocarbonyl compounds to pyrrole, A -alkylpyrroles, indole, N-alkylindoles, imidazole, and benzimidazole does not result in cyclopropanation, but leads to the formal products of carbene insertion into a heterocyclic C-H bond (see Houben-Weyl, Vol.E19b, ppll58 and 1334). However, Af-acylpyrroles, and Af-acylindoles - " have successfully been converted into 2-azabicyclo[3.1.0]hex-3-ene-exo-6-carboxylates and alkyl-1,la,2,6b-tetrahydrocyclopropa[ ]indole-exo-l-carboxylate, respectively (for an experimental procedure, see Houben-Weyl, Vol.E19b, pll60). 

A route to all three ring systems depends on a rhodium-carbene insertion into the N-H of an amide, then direct dehydrative ring closure to an oxazole, or production of a thiazole with Lawesson s reagent, or of an imidazole with ammonia or a primary amine. ... 

The mononuclear complex 13 was also employed for carbene transfer reactions from ethyl diazoacetate (EDA) in a range of reactions that led to the alkenation of aldehydes, cyclopropanation, and carbene insertion into N—H and O—H bonds [32]. The complex proved particularly adept at the last process, especially aromatic amines and aliphatic alcohols. Addition of the PIN ligand (l-isopropyl-3-(5,7-dimethyl-l,8-naphthyrid-2-yl)imidazol-2-ylidene) to [Ru2(CO)4(OAc)2], foUowed by treatment with Na[BAr 4] gave the dinuclear complex [Ru2(PIN)2(CO)4][[BAr 4] 2, which showed some improved reactivity compared to 13, particularly in the transfer of CH(C02Et) to aldehydes [109]. 

The rates of the thermal cleavage of 7V-alkyl groups from 1,3-dialkyl-imidazolium halides (484 R = R = alkyl, R =H, R = H, Ph, or NO2) have been measured. Deprotonation of 1,2,3-trimethylimidazolium salts (484 R —R = Me R = H) at the 2-methyl group has been investigated in a model study of thiamine catalysis. Photolysis of the 4-diazo-imidazole (485) in the presence of ethanol leads to a mixture of the carbene-insertion products (486) and (487). Treatment of 2-diazo-4,5-dicyanoimidazole (488) with tetramethyl-thiourea gives the stable ylide (489). The photochemical rearrangement of imidazole oxides (490) to 2-imidazolinones (491) has been described. 

Ylide formation, and hence X-H bond insertion, generally proceeds faster than C-H bond insertion or cyclopropanation [1176], 1,2-C-H insertion can, however, compete efficiently with X-H bond insertion [1177]. One problem occasionally encountered in transition metal-catalyzed X-H bond insertion is the deactivation of the (electrophilic) catalyst L M by the substrate RXH. The formation of the intermediate carbene complex requires nucleophilic addition of a carbene precursor (e.g. a diazocarbonyl compound) to the complex Lj,M. Other nucleophiles present in the reaction mixture can compete efficiently with the carbene precursor, or even lead to stable, catalytically inactive adducts L M-XR. For this reason carbene X-H bond insertion with substrates which might form a stable complex with the catalyst (e.g. amines, imidazole derivatives, thiols) often require larger amounts of catalyst and high reaction temperatures. 

Is the stability of 8Ad due to unfavorable kinetics, i.e., the bulky adamantyl groups blocking reaction, or to unfavorable thermochemistry, i.e., loss of aromaticity of the imidazole ring as a result of reaction, or both The distinction is potentially important as understanding could assist in designing stable carbenes. To decide, compare the kinetics and thermodynamics of the insertion of 8Ad into the central CH bond in propane with reactions of 8Me, which should also be aromatic but lacks shielding groups , and 9, which is neither aromatic nor crowded. 

An N-heterocyclic carbene ligand, formed from l,3-bis-(2,4,6-trimethylphenyl)-3//-imidazol-l-ium chloride and cesium carbonate, with dipalladium tris(dibenzylideneacetone) gave excellent yields (93-96% yields) in the Suzuki coupling of 2-chloropurines and arylboronic acids in anhydrous dioxane <2001TL8751>. The combination of an imidazolium-carbene and nickel(O) bis(cyclooctadiene) formed a catalyst capable of insertion into the C-F bond of 6-fluoropurine nucleosides (Scheme 35) <20050L1149>. 

Cyclohexane is a saturated hydrocarbon in which no regioselectivity problems of C-H insertion can occur. The reaction of cyclohexane with ethyl diazoacetate was investigated in a thorough study by Perez et al.14 The /V-heterocyclic carbene ligand IPr (IPr= l,3-bis(diisopropylphenyl)imidazol-2-yliden) was used, all three compounds IPrMCl (M = Cu, Ag, Au) were inactive as catalysts in cyclohexane (Table 12.2, entry 1). Addition of the sodium BARF salt (NaB[3,5-(CF3)2C6H3]4) gave ethyl cyclohexyl acetate as the C-H insertion product of the carbene (Scheme 12.4). 

The electrophilic carbene, 4H-imidazolylidene (63), has been prepared by photodecomposition of 4-diazo-4H-imidazole (64). Reaction with cyclohexane affords the C-H insertion product, 4(5)-cyclohexylimidazole (65), whereas reaction with benzene yields 4(5)-phenylimidazole (66). Analogous addition of 4H-imidazolylid-ene to derivatives of benzene is influenced by the presence and nature of the substituents. 

When IPr.Cl is treated with a base (e.g. BuOK, Bu ONa, K2CO3 or CS2CO3), the catbene lrJ-bis(2,6-diisopropylphenyl)-l,3-dihydro-2H-imidazol-2-ylidene [244187-81-3] M 388.6, m 213-217°, is formed and is stable enough to be isolated, stored and is available commercially. The carbene-carbon atom at C2 coordinates with metals and forms C-C bonds, by C-H insertion, with acetylene, MeCN, HCCI3, PhSOCH3, and the stmctures of some of the products have been confirmed by X-ray analysis [Arduengo et al. Helv Chim Acta 82 2348 1999]. 

The difference between the stability of a diaminocarbene and its reactivity in insertion and addition reactions has been clearly established by hybrid DFT calculations." This study was carried out on the parent imidazol-2-ylidene (34) and its dichlorinated analogue (35). Extension to the reactivity of the saturated carbene gave the same results, the introduction of chlorine substiments making the carbene less reactive. 

Moody reported the synthesis of 2-aryl-5-(trifluoromethyl)imidazole-4-carboxylate by the cyclization of the corresponding 0-ketoamides in the presence of NH4OH-ACOH in refluxing toluene (Scheme 41) [55], The prerequisite d-ketoamides were prepared, in turn, by N-H insertion of rhodium carbenoids to aryl amides. These ketoamides was isolated as their hydrates due to increased electrophilicity of trifluoromethyl ketones. The carbene 0-H insertion, followed by in situ cyclization, also produced the oxazolines as the by-products under these Rh-catalyzed conditions. 

The initial zwitterion A generated from imidazole and cyanophenylacetylene is thought to be transformed into carbene B, which further inserts into the C=0 bond of N-vinylpyrrolecarbaldehyde (shown on the example of N-vinylpyrrole-2-carbaldehyde). Two subsequent rearrangements of adduct C furnish intermediate D, which in its enol form adds to the second molecule of cyanophenylacetylene (Scheme 2.156). 

Rhodium-NHC complexes [Rh( <-Cl)(IPr)( -olefin)]2 and RhCl(IPr)(py)(t/"-olefin) (IPr= l,3-bis(2,6-diisopropylphenyl)imidazol-2-carbene, py = pyridine, olefin = cyclooctene) have been designed as highly active catalysts for hydrothiolation of alkynes RC=CH with R SH. The dinuclear catalyst was found to promote the formation of the linear product RCH=CHSR, whereas the mononuclear catalyst favoured the branched isomer R(R S)C=CH2- A complex interplay between electronic and steric effects exerted by the carbene (IPr), pyridine, and hydride ligands accounts for the observed regioselectivity. DFT calculations suggested that migratory insertion of the alkyne into the rhodium-thiolate bond is the rate-determining step. ... 

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