Malonic ester-blocked aliphatic isocyanates

Products formed on pyrolysis of malonic ester-blocked aliphatic isocyanates depend on the enolizability of the blocked isocyanate. Previous work reported that diethyl malonate-blocked aliphatic isocyanates on pyrolysis yield predominantly “abnormal” products rather than the expected isocyanates. It has now been shown that this behavior results from the reactions of the enol forms. A nonenolizable diethyl methylmalonate-blocked isocyanate has been synthesized. On pyrolysis essentially quantitative conversion to isocyanate and diethyl methylmalonate occurs. Significant differences in reactivity with amines and alcohols also result from the difference in enolizability.     

Facile amide bond formation from carboxylic acids and isocyanates

A wide variety of carboxylic acids in the form of their salts condense with aryl isocyanates at room temperature with loss of carbon dioxide to give the corresponding amides in high yield. Application of the reaction to acyl isocyanates gives unsymmetric imides. The reaction is compatible with hydroxyl groups and both Fmoc and Boc protecting groups for amines and is applicable to aliphatic, aromatic, and heteroaromatic acids.     

Facile and convenient synthesis of B-amino-9-borabicyclo[3.3.1]nonanes. Aminoboration of lsocyanates

The reaction of 9-borabicyclo[3.3.1]nonane (9-BBN) with aliphatic and aromatic primary and secondary amines in tetrahydrofuran (THF) at 65°C proceeds rapidly and quantitatively with evolution of hydrogen and the formation of the corresponding B-amino-9-borabicyclo[3.3.1] nonane (B-amino-9-BBN). Simple evaporation of THF from the reaction mixture gives the B-amino-9-BBN derivatives in high yield and purity. These B-amino-9-BBN derivatives are reactive towards alkyl and aryl isocyanates. Consequently, the aminoboration of various isocyanates has been studied using B-phenylamino-9-BBN. Thus, two equivalents of isocyanates react with one equivalent of B-phenylamino-9-BBN to afford, following the hydrolysis of the intermediate with ethanolamine, N, N'-disubstituted-N -(phenylamido)-ureas in excellent yields. A plausible mechanism for this aminoboration reaction of isocyanates is also presented.     

Synthesis of derivatives of 4-alkylthiouracil,cytosine, pyrido[2,3-d]pyrimidine,and pyrimido[4,5-d]pyrimidine from the N,S- and N,N-acetals of diacetylketene and isocyanates

The action of alkyl and aryl isocyanates on the N,S-acetals of diacetylketene leads to the formation of 4-alkylthio-5-acetyl-1-alkyl(aryl)-6-methyl-1H-pyrimidin-2-ones (derivatives of 4-alkylthiouracils). The reaction of the synthesized thiouracils with amines or the reaction of the N,N-acetals of diacetylketene (N,N-ADK) with an equi-molar amount of aryl isocyanates leads to the formation of substituted 4-amino-5-acetyl-1H-pyrimidin-2-ones (derivatives of cytosine). From the latter and isocyanates or directly from N,N-ADK and an excess of the isocyanate, derivatives of 4-methylene-1H,3H, 4H-pyrimido[4,5-d]pyrimidine-2,7-dione were obtained. The exception was the condensation of 3-[N-(4,6-dimethyl-2-pyrimidinyl)diaminomethylene]pentane-2,4-dione with aryl isocyanates, which led to 3H,8H-pyrido[2,3-d]pyrimidine-2,5-diones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2593–2599, November, 1991.     

Synthesis of isocyanates and carbodiimides

The reaction of 1,3-disubstituted ureas and 1-arylsulfonyl-3-alkylureas with phosgene permits the preparation of a number of isocyanates and sulfonyl isocyanates that had not previously been described, or that were difficult to prepare. 1,3-Disubstituted thioureas and 1-aryl-(or alkyl)sulfonyl-3-alkylthioureas give carbodiimides. Thionyl chloride and phosphorus pentachloride react with the urea derivatives in the same way as phosgene. Oxalyl chloride reacts with ureas to form parabanic acid derivatives, whereas with thiourea it gives 2-imino-1,3-thiazolidine-4,5-diones, which can isomerize to parabanic acid derivatives.     

Organosilicon synthesis of isocyanates: I. Synthesis of isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series

A convenient synthesis of known and unknown isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series, involving silylation of starting amines with hexamethyldisilazane or chlorotrimethylsilane, followed by phosgenation of the resulting N-silyl-substituted amines. An unusual high-temperature rearrangement of 3-(methoxycarbonyl)-4,5-dimethylthiophene-2-yl isocyanate into its 5-ethyl isomer. ortho-Fluorine substituent in anilines decreases the yield of isocyanates, whereas 2,3,5,6-tetrafluorophenyl isocyanate exists for only a short time as a 5% toluene solution.     

‘One-flask’ transformation of isocyanates and isothiocyanates to guanidines hydrochloride by using sodium bis(trimethylsilyl)amide

A ‘one-flask’ synthesis of guanidines was developed by reacting isocyanates and isothiocyanates with sodium bis(trimethylsilyl)amide followed by addition of primary or secondary amines with a catalytic amount of AlCl₃. The desired guanidines were obtained in good yields and the reaction was applicable to aliphatic and aromatic substrates. A plausible mechanism was proposed through the generation of cyanamide anion from isocyanates or isothiocyanates with sodium bis(trimethylsilyl)amide. Addition of amines and catalytic amount of AlCl₃ smoothly converted the cyanamides to the desired guanidines.     

Transition-metal-free synthesis of aromatic amines via the reaction of benzynes with isocyanates

An unexpected reaction between benzynes and isocyanates to generate aromatic amines has been developed under transition-metal-free conditions. The in situ prepared anions formed through cleavage of the NC bond in isocyanates, reacted with aryne precursors to afford various aniline derivatives in moderate to excellent yield and tolerated various substituents on the o-silyl aryl triflate and the isocyanate.     

Synthesis and reactions of halogenated thiazole isocyanates

A synthesis of 2-chloro-4-(trifluoromethyl)-5-isocyanatothiazole and 2,5-dichloro-5-isocyanatothiazole is described via the “Curtius Rearrangement” performed under anhydrous conditions. The synthetic procedure described allows for the isolation, storage, and manipulation of these highly reactive isocyanates. A number of derivatives of the above isocyanates were prepared. These include: carbamates, thiocarbamates, ureas, amines, amidines, and amides.     

Organosilicon synthesis of isocyanates: III. Synthesis of aliphatic, carbocyclic, aromatic, and alkylaromatic isocyanatocatboxylic acid esters

A series of aminoacid esters was prepared by treating the aminoacid suspensions in ethanol with thionyl chloride. Best conversion of aminoacid esters to corresponding isocyanates was achieved in the case of aromatic and carbocyclic aminoesters by phosgeneation of their N-silyl derivatives, and in the case of aliphatic and alkylaromatic aminoesters by phosgeneation of O-silyl or N,O-bissilylurethanes on their basis. In the last case additional step of esterification of the by-products isocyanatoalkylcarboxylic acid chlorides is required after phosgeneation. Unusual generation of cynnamates and intramolecular N→O-migration of trimethylsilyl group in the solutions of silylated alkylaromatic β-aminoacid esters were found.     

Effect of polar aprotic solvents and organometallic catalysts on the reaction of alcohols with isocyanates

DMF and DMSO catalyse the reaction of butanol with PhNCO but inhibit that with aliphatic isocyanates, due to formation of an active 1:1 charge transfer complex with the aromatic isocyanate. Similarity was found in the mode of catalysis of the urethane reaction with these solvents to that with tert, amines. Various organometallic compounds were tested as catalysts for urethane formation with aliphatic isocyanates. Those that gave fast addition to the NCO group, such as tributyltin oxide, Zr(OBu)₄ and Zr(acac)₄, were the strongest catalysts. In the presence of organometallic catalysts, urethane formation was the sole reaction and trimerization of the isocyanate was suppressed.     

Reactions of 2-amino-2-thiazolines with isocyanates and isothiocyanates. Chemical and computational studies on the regioselectivity, adduct rearrangement, and mechanistic pathways

2-Amino-2-thiazoline derivatives bearing alkyl or aryl substituents at exocyclic nitrogen have been condensed with different isocyanates and isothiocyanates. The addition occurs at ring endocyclic nitrogen in a regiospecific manner to afford kinetic and enthalpy-favored adducts. The unequivocal assignment of these structures has been confirmed by X-ray diffraction analyses of several compounds. The endo adducts do not rearrange on heating with the sole exception of adducts in which the exocyclic nitrogen remains unsubstituted. Trapping experiments in the presence of other isocyanates or isothiocyanates produce the formation of new endo adducts by acyl exchange in the reaction mixture. Semiempirical PM3 calculations full corroborate the higher stability of endo or exo adducts depending on the substitution pattern. The formation of adducts is compatible with a stepwise reaction mechanism, for which semiempirical transition structures could be located in the potential energy surface, and the global energetics of the process have been determined. The formation of the endo adducts proceeds with a smaller activation barrier.     

Radical fixation of functionalized carbon resources: alpha-sp3C-H carbamoylation of tertiary amines with aryl isocyanates

A new carbamoylation of tertiary amines is reported. This rare C-H transformation features the direct generation of alpha-aminoalkyl radicals from tertiary amines, followed by the addition of the resultant nucleophilic radicals to isocyanates, enabling unique access to N,N-dialkylated amino acid derivatives. The authors put forward a mechanistic proposal that is based on the isolation of borinamides produced by capturing nitrogen radical intermediates with Et3B. The present transformation provides a novel one-step process for producing mepivacaine, a clinically important local anesthetic, from readily available materials.     

Solid-phase synthesis of substituted 3-amino-3′-carboxy-tetrahydrocarbazoles

Two related solid-phase synthesis routes have been developed allowing the synthesis of 3-amino-3′-carboxy substituted tetrahydrocarbazole derivatives. Diversity can be introduced at the amino and carboxy functionalities and at the nitrogen and the aromatic ring of the tetrahydrocarbazole moiety. Both routes rely on Fmoc-protected 1-amino-4-oxocyclohexanone carboxylic acid as central core element. Derivatization of the carboxy function is achieved with amines, derivatization of the amino functionality is possible by reaction with alkyl halides, isocyanates, activated alcohols, sulfonic acid chlorides or carboxylic acids. The tetrahydrocarbazole scaffold is generated by Fischer indole cyclization with phenyl hydrazine derivatives, thereby introducing diversity in the aromatic moiety. N-Alkylation at the indole nitrogen with alkyl halides delivers N-substituted derivatives.     

Research on acyl isocyanates and their derivatives

1-Substituted benzimidazolinethiones, 3-substituted 1-acylbenzimidazolinethiones, and acyl thiobiurets, respectively, are formed in the reaction of acyl, alkyl, and aryl isocyanates with benzimidazolinethione, its 1-acyl derivatives, and thiourea. The IR and UV spectra of the compounds obtained are analyzed.See [1] for communication X.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 695–698, May, 1973.     

New syntheses of aliphatic isocyanates via cyannogen chloride

Alkylation of cyanogen chloride with alkyl chloride and ferric chloride gives an alkyl isocyanide dichloride-FeCl₃ complex 2. Such novel complexes react either with water to give alkylamines, or with alcohol or alcoholate to give the corresponding N-substituted carbamate, or are converted to alkyl isocyanates with various reagents. Cyanogen chloride, isopropyl chloride and ferric chloride give complex 2a which, with zinc oxide, gives isopropylisocyanate. Salts of caiboxylic acids also furnished the isocyanate in good yield. The t-butylisocyanide dichloride-FeCI₃ complex 2b does not react with zinc oxide but was transformed into f-butylisocyanate with trifluoroacetic acid or dimethyl sulphoxide.     

Tandem carbocupration/oxygenation of terminal alkynes

[chemical reaction: see text]. A direct and general synthesis of alpha-branched aldehydes and their enol derivatives is described. Carbocupration of terminal alkynes and subsequent oxygenation with lithium tert-butyl peroxide generates a metallo-enolate. Trapping with various electrophiles provides alpha-branched aldehydes or stereo-defined trisubstituted enol esters or silyl ethers. The tandem carbocupration/oxygenation tolerates alkyl and silyl ethers, esters, and tertiary amines. The reaction is effective with organocopper complexes derived from primary, secondary, and tertiary Grignard reagents and from n-butyllithium.     

Organocatalytic asymmetric synthesis of alpha,alpha-disubstituted alpha-amino acids and derivatives

It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to alpha,beta-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and different aromatic and aliphatic substituted alpha,beta-unsaturated aldehydes, for which the stereoselective reaction proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity. The potential of the reaction is shown for the synthesis of optically active alpha,alpha-disubstituted alpha-amino acids, alpha-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have calculated by DFT-methods the transition-state structures that account for both the diastereo- and enantioselectivity observed for the addition of oxazolones to the alpha,beta-unsaturated aldehydes. For one class of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of the oxazolone with an ortho-hydroxy-phenyl substituent of the alpha,beta-unsaturated aldehyde, whereas the benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more general manner for both aromatic and aliphatic alpha,beta-unsaturated aldehydes.     

A catalyst system for the reaction of carboxylic acids with aliphatic isocyanates

Catalysts have been found for the selective reaction of aliphatic isocyanates with carboxylic acids giving amides after carbon dioxide extrusion. Magnesium and calcium salts lead to a dramatic increase in reaction rates while improving the selectivity when sterically hindered isocyanates and/or carboxylic acids are used.     

Direct amidation of non-activated carboxylic acid and amine derivatives catalyzed by TiCp2Cl2

This paper described a mild and efficient direct amidation of non-activated carboxylic acid and amine derivatives catalyzed by TiCp₂Cl₂. Arylacetic acid derivatives reacted with different amines to afford the corresponding amides in good to excellent yield except of aniline. Aryl formic acids failed to react with aniline but smoothly reacted with aliphatic amines and benzylamine in moderate to good yield, fatty acids reacting with benzyl and aliphatic amines give amides in good to excellent yield. Chiral amino acids derivatives were transformed into amides without racemization in moderate yield. The possible mechanism of direct amidation catalyzed by TiCp₂Cl₂ was discussed. This catalytic method is very suitable for the amidation of low sterically hindered arylacetic acid, fatty acids with different low sterically hindered amines except aniline, as well as the amidation of aryl formic acid with benzyl and aliphatic amines.