Isocyanides methyl esters

In 1979, Schollkopf et al. " formed a-isocyano- 3-dimethylamino-acryl methyl esters 86, and Bienayme prepared many similar isocyanides,which can undergo a variety of heterocycles, forming reactions like the synthesis of 88 from 84-87 (Scheme 1.20). 

Synonyms AI3-28280 Aliphatic isocyanate BRN 0605318 CCRIS 1385 EINECS 210-866-3 Isocyanatomethane Isocyanic acid, methyl ester Methyl carbonimide Methyl carbylamine Methyl isocyanide MIC Monoisocyanate NSC 64323 RCRA waste number P064 TL 1450 UN 2480. 

Among the a-acidic isocyanides, isocyano esters (1) (for the first isolated example of a-acidic isocyano ester see [24]), isocyano amides (2) (for the first isolated example of a-acidic isocyano amide see [25]), and arylsulfonyl methyl isocyanides (3) (for the first report of TosMlC see [26]) have been studied predominantly, and therefore this mini review will mainly focus on the MCRs involving these species. 

Synthesis of monomers for the preparation of the methyl ester polyisocyanides begin with a-amino acid esters. These polyisocyanides were developed to yield optically active polymers which could be characterized first as non-electrolytes, and, after hydrolysis, as polyelectrolytes in aqueous media. As predicted, poly[a(carboxymethyl) alkyl isocyanides] are soluble in various solvents. Unfortunately, a low ceiling temperature, some instability to alkali and especially to... 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

A three-component one-pot coupling of 2,6-dimethylphenyl isocyanide, methyl 2,4-dioxopentanoate and alkynoic esters leads to the isatin-like compounds (or fused pyrans) 20 (Scheme 5). The reaction proceeds by initial formation of the zwitterionic intermediate 21, which is protonated by methyl 2,4-dioxopentanoate. Attack of the newly generated nucleophile then forms the intermediate 22. The pyrrolidinone ring is formed upon loss of methanol and electrocyclization then occurs to afford the desired 2//-pyrans (Scheme 5) <2005S1049>. 

Wong and co-workers [22] also applied the methodology in the preparation of a library of neomycin B mimetics (Fig. 6). Two libraries were prepared by a multiple-component condensation of neamine derived aldehyde, f-butyl isocyanide or isocyanoacetic acid methyl ester, CBZ-N amino acids (xl3) and a glycine conjugated polyethylene glycol methyl ether. The products of the reaction were isolated by precipitation. 

Several 3/3-(aryl)-2/3-(3-substituted isoxazol-5-yl)tropanes 375 were synthesized from methyl esters 374 by reaction with the dilithium salt of the appropriate ketone or aldehyde oxime (Scheme 90) <2004JME296>. The same procedure was applied to 7-ethoxycarbonyl-2-azabicyclo[2.2.1]heptanes for the synthesis of novel epibatidine analogues, such as 376 <2004JOC5328>. The reaction of a-bromoketone oximes with isocyanides and sodium carbonate led to 5-aminoisoxazole derivatives in good yields. Probably, isocyanides are involved in a [4-1-1] cycloaddition with nitrosoalkene intermediates <1997TL8027>. 

Phase-transfer catalysts, 220, 221,305-306 Phenanthrenes, 319, 320 9-Phenanthrol, 431 Phenol annelation, 272 Phenoxysulfonyl azide, 377-378 Phenylacetaldehyde, 217 Phenylacetylene, 7 2 (S)-3-Phenyl-1-butene, 36 Phenyl chlorothionocarbonate, 306-307 Phenyl cyanate, 307-308 Phenyldiazomethane, 308 o-Phenylene phosphorochloridate, 91-92 o-Phenylglydne methyl ester, 308 Phenyl isocyanate, 309 Phenyl isocyanide, 309-310 Phenyl iso thiocyanate, 122 Phenyllithium, 5... 

Many ring-fused imidazole derivatives have been synthesized by various methods. Domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates provided a synthesis of 2,3-dihydroimidazo[l,2-a]pyrimidin-5-(l//)-ones <05T5303>. A single step synthesis of 3,5-dialkyl-9-nitroimidazo[l,2-c]quinazolin-2(3//)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitrobenzonitrile has been published <05TL5778>. Diels-Alder reaction of azadienes and benzimidazole-4,7-diones afforded imidazo[4,5-g ]quinoline-4,9-dione derivatives <05EJ01903>. Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 4,5-diphenyl-l,3-dihydro-2//-imidazol-2-one provided a one-pot synthesis of 5//-imidazo[2,l-ft][l,3]oxazine derivatives <05T2645>. Microwave irradiation was employed in the synthesis of 1-ary 1-3-acetyl-1,4,5,6-... 

Ohba and co-workers developed a general synthesis of chiral iV-protected 5-(aminomethyl)oxazoles from a-lithiated isocyanides and Af-protected amino acid esters (Scheme 1.101). Metalation of an alkyl or benzyl isocyanide with n-BuLi or LDA and acylation with an A-Boc-ot-amino acid methyl ester afforded an iV-Boc-a-amino acid acyl isocyanide 369, which cyclized to a chiral A-Boc-5-(aminomethyl) oxazole 370. The products were obtained in > 98% ee based on chiral HPLC analysis. The yields of 370 were somewhat variable, ranging from 45 to 91%. A-Boc-protected glycine, alanine, phenylalanine, proline, serine, and (9-benzyl serine were all compatible with these reaction conditions. 

Ohba s group employed this methodology in two different synthetic strategies for preparing 372, a key intermediate in their synthesis of (-)-normalindine 374 (Scheme 1.102). Acylation of lithiomethyl isocyanide with A-Boc-L-alanine methyl ester gave 370 that was deprotected and alkylated with 2-(3-indolyl)ethyl bromide... 

Wenkert and co-workers prepared a series of 5-alkenyl-substituted oxazolium salts and investigated their intramolecular Diels-Alder reactions as a means to construct alkaloids (Scheme 1.427). The starting oxazoles 1662a-c, 1663, and 1664 were prepared from an acyclic methyl ester and lithiomethyl isocyanide. Methylation of 1662a-c, 1663, and 1664 with methyl trillate then afforded the corresponding iV-methyloxazolium salt quantitatively. The oxazolium salts 1665, 1666, and 1667 were stable for up to 3 h at 90°C. 

CjHgOs, Butanoic acid, 3-oxo-, methyl ester, rhodium complex, 27 292 C,H,N, tert-Butyl isocyanide, chromium, molybdenum, and tungsten complexes, 28 143... 

Ohba and co-workers have demonstrated that A -protected a-amino esters are compatible with the Schollkopf oxazole synthesis cf., 38->39). In the case of ammo esters derived from natural amino acids (e.g., 38), the presence of an additional acidic N-H bond in the AABoc ester substrate necessitated the use of an added excess of metalated isocyanide (2.5 equiv was found to be optimal) to obtain maximal yields. Under optimized conditions, oxazoles (39) were obtained in good yield from iV-Boc glycine, alanine, and phenylalanine. Oxazole formation from iV-Boc serine (which possesses an additional acidic site in its hydroxylic side chain) proceeded in good yield (66%) using 3.5 equiv lithiated methyl isocyanide. Notably, no epimerization was detected in the reaction of N-Boc alanine methyl ester with lithiated methyl or ethyl isocyanide under these conditions. Minor epimerization was observed (91-92% ee product) with substrates that lacked a carbamate NH hydrogen e.g., A -Boc proline methyl ester), however. ... 

C5 sHs 3CI3F6NO8P, 1,1 -Binaphthylmacrocyclicpolyether (R)-phenylgly-cine methyl ester hexafluorophosphate chloroform, 43B, 426 C60H3 iiN2 2Pd, Tetrakis (methyl isocyanide )palladium( 11) tetrakis-(7,7,8,8-tetracyano-p-quinodimethane) diacetonitrile solvate, 42B, 499... 

Ugi reaction of 73 with isopropyl isocyanide,. /V-Boc-2-(indan-2-yl)glycine and leucine methyl ester was applied to the synthesis of compound 296 - oxytocin antagonist with pKi 10.0 [1]. 

Other liquid isocyanides, such as the positional isomeric picolyl isocyanides, on the contrary, do not smell at all. The isocyanide derived from L-phenylglycine methyl ester smells of rhubarb. Toluenesulfonylmethyl isocyanide (TosMIC) and adamantyl isocyanide are not as offensive as others. To avoid the distressing smell of isocyanides, there is a continuous effort among the scientific community to develop fragrant smelling isocyanides. 

Other functional groups that are easily differentiated are cyanide (5c =110-120) from isocyanide (5c = 135- 150), thiocyanate (5c =110-120) from isothiocyanate (5c = 125 - 140), cyanate (5c = 105- 120) from isocyanate (5c = 120- 135) and aliphatic C atoms which are bonded to different heteroatoms or substituents (Table 2.2). Thus ether-methoxy generally appears between 5c = 55 and 62, ester-methoxy at 5c = 52 N-methyl generally lies between 5c = 30 and 45 and. S-methyl at about 5c = 25. However, methyl signals at 5c = 20 may also arise from methyl groups attached to C=X or C=C double bonds, e.g. as in acetyl, C//j-CO-. 

In analogy, Ugi et al. reported on a lactam formation by running a one-pot three components reaction the condensation of L-lysine 7, isobutyraldehyde and methyl isocyanide led to the corresponding a-amino-c-caprolactam 9, but the yield was not given. The authors presumed either a nucleophilic substitution of the ester 8 as the primary Ugi product by the amino function of the side chain or, alternatively, the nucleophilic attack of the NH2-group on an intermediately formed 0-acylamide and a subsequent rearrangement (Scheme 1) [4]. 

In the presence of Bu OK, (benzotriazole-l-yl)methyl isocyanide (BetMIC) 697 undergoes alkylation on the methylene group to give isocyanide 698. The anion derived from 698, upon its treatment with Bu OK, adds to the electron-deficient double bonds of ajl-unsaturated ketones, esters or nitriles to produce pyrroles 699. A similar reaction of isocyanide 698 with Schiff bases provides imidazoles 700. In both cases, use of unsubstituted isonitriles 697 in the reactions leads to heterocycles 699 and 700 with R1 = H (Scheme 108) <1997H(44)67>. 

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