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.     

Heterocyclizations of functionalized heterocumulenes with C,N-, C,O-, and C,S-binucleophiles: VII. Reaction of 1-chloroalkyl isocyanates with N,N-disubstituted cyanothioacetamides. A new synthetic route to 6-dialkylamino-4-oxo-3,4-dihydro-2<Emphasis Type="Italic">H</Emphasis>-1,3-thiazine-5-carbonitriles

Reactions of α-chlorobenzyl isocyanates and 1-aryl-2,2,2-trifluoro-1-chloroethyl isocyanates with N,N-disubstituted cyanothioacetamides gave 3,4-dihydro-2H-1,3-thiazin-4-ones and 3-aryl-2-cyano-4,4,4-trifluorobut-2-enethioamides. The effect of substituents in the reactant molecules on the reaction course and product ratio was studied.     

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.     

Kinetic study of polyurethanes formation by using differential scanning calorimetry

Kinetics of polyurethane formation between several polyols and isocyanates with dibutyltin dilaurate (DBTDL) as the curing catalyst, were studied in the bulk state by differential scanning calorimetry (DSC) using an improved method of interpretation. The molar enthalpy of urethane formation from secondary hydroxyl groups and aliphatic isocyanates is 72±3 kJ mol^-1 and for aromatic isocyanates it is 55±2 kJ mol^-1 . In the case of a single second order reaction for aliphatic isocyanates reaction, activation energy is 70±5 kJ mol^-1 with oxypropylated polyols and 50±3 kJ mol^-1 with Castor oil. For aromatic isocyanates and oxypropylated polyols the activation energy is higher around 77 kJ mol^-1 . In the case of two parallel reactions (situation for IPDI and TDI 2-4) best fits are observed considering two different activation energies.     

Isocyanates of N alpha-[(9-fluorenylmethyl)oxy]carbonyl amino acids: synthesis,isolation, characterization,and application to the efficient synthesis of urea peptidomimetics

The Curtius rearrangement of Fmoc-amino acid azides 1 was carried out in toluene by refluxing the solution for 30 min. The resulting isocyanates 2 have been isolated as crystalline solids and are fully characterized by IR, (1)H NMR, (13)C NMR, and mass spectra. They are found to be stable for several months when stored at 4 degrees C. The acyl azides of Asp, Glu, Ser, Tyr, and Lys with side-chain protection having tert-butyl, benzyl, and Boc groups were also converted to the corresponding isocyanates 2h-m. The rearrangement of Fmoc-amino acid azides in toluene to isocyanates 2 under microwave irradiation was also accomplished. The direct exposure of solid azides to microwaves for 60 s led to the completion of the rearrangement. The resulting isocyanates, after recrystallization, were found to be analytically pure. The scale-up of the rearrangement, under microwave irradiation as tested up to 0.75 mol, posed no problems and led to the isolation of the isocyanates in 91-96% yield. The utility of isocyanates as building blocks in the synthesis of urea peptides 4 is demonstrated. Further, the coupling of isocyantes 2 directly with N,O-bis(trimethylsilyl) derivatives of amino acids 6 resulted in urea peptide acids 7 with good yield in high purity. Thus, the synthesis of urea peptide acids 7d-g containing Asp, Glu, Ser, and Tyr with a free side-chain functional group have been carried out.     

Fluorinated Isocyanates and Their Derivatives as Intermediates for Biologically Active Compounds

Fluorinated aromatic isocyanates are valuable intermediates for the production of herbicides and insecticides. Unexpected rearrangements during the synthesis of 2-(trifluoromethyl)phenyl isocyanates provide an entry to N-trifluoromethylaminobenzoyl fluorides, a novel class of compounds having fungicidal properties. Carbamoyl fluorides, the products of HF addition to isocyanates, undergo ready sulfenylation. Use of these intermediates for the synthesis of N-sulfenylcarbamate insecticides led to the discovery of the new principle of detoxification of carbamates by sulfenylation.     

Heterocyclization of Functionalized Heterocumulenes with C,N- and C,O-Binucleophiles. 1. Cyclocondensation of 1-Chloroalkylheterocumulenes and N-(1-Chloroalkylidene)urethanes with 2-Cyanomethylpyridine

The interaction of 1-chloroalkyl isocyanates, 1-chloroalkylcarbodiimides, 1,1-dichloroalkyl isocyanates, and N-(1-chloroethylidene)-O-methylurethanes with 2-cyanomethylpyridine has been investigated. An effect of organic base has been detected on the regioselectivity of the cyclocondensation of 1-chloroalkyl isocyanates, which leads to 2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-1-one or the isomeric 2,3-dihydro-1H-pyrido[1,2-c]pyrimidin-3-one. Irrespective of the cyclization conditions 1-chloroalkylcarbodiimides react with the formation of 1-imino-2,3-dihydro-1H-pyrido[1,2-c]pyrimidines. One type of product, a 1H-pyrido[1,2-c]pyrimidin-1-one, was also isolated from 1,1-dichloroalkyl isocyanates and N-(1-chloroalkylidene)urethanes.     

Solid-state cpmas 13C-NMR studies of the reaction of an epoxy resin with masked isocyanates

It has been shown that incorporation of masked isocyanates in the MY720/DDS epoxy significantly reduces the equilibrium moisture absorption by blocking of residual functional groups ( oxirane group) by the isocyanates released in the deblocking reaction of the masked isocyanates. We have now used high resolution ¹³C-CP/MAS NMR to follow the reactions in the solid state and to identify intermediates and by-products. The deblocking reaction of the masked isocyanates also releases the corresponding alcohol, part of which may evaporate during the curing reaction. The resolution in the solid-state spectra is good enough to identify all the reactants and the intermediates involved in the curing reaction. Difference spectra are used to emphasize changes between systems that differ in treatment or composition.     

Synthesis of 1,1-bis(trifluoromethyl)alkyl isocyanates, carbamates, and ureas

A convenient preparative method for the synthesis of 1,1-bis(trifluoromethyl)alkyl isocyanates was proposed. The reactions of the isocyanates with alcohols, phenols, and alkyl-, aryl-, and hetarylamines were studied. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1205–1209, July, 2000.     

Trifluoroacetic anhydride-catalyzed oxidation of isonitriles by DMSO: a rapid, convenient synthesis of isocyanates

A smooth and efficient oxidation of isonitriles to isocyanates by sulfoxides is catalyzed by trifluoroacetic anhydride. With use of DMSO as the oxidant and 5 mol·% TFAA (dichloromethane, -60 to 0 °C), the process is complete in a few minutes, forming dimethyl sulfide as the only byproduct. The newly formed isocyanates may be used directly or isolated in high purity by solvent evaporation.     

Cycloaddition-elimination reactions of 4-methyl-5-(substituted)-imino-Δ2-1,2,3,4-thiatriazolines with isocyanates

4-Methyl-5-(substituted)imino-1,2,3,4-thiatriazolines 1 (R² ≠ Me) undergo cycloaddition-elimination reactions with isocyanates to yield 4-methyl-5-(substituted)imino-1,2,4-thiadiazolidine-3-ones 5 via the thermodynamically less stable isomers 4 . The latter have not been isolated, except for 4q which was shown to iso-merize rapidly into 5q with phenylsulfonyl isocyanate. The reactions of 1 are accelerated by using less bulky R² substituents and more electrophilic isocyanates, in accordance with the viewpoint that 1 reacts as a masked 1,3-dipole. The products 4i-n (= 5i-n ), derived from 1b , add isocyanates reversibly to give 2,3,4,5-tetrahydro-6aλ⁴-thia-1,3,4,6-tetraazapentalene-2,5-diones 9i-n , which have been isolated and characterized spectroscopically. Such compounds with a hypervalent sulfur atom thus occur as intermediates during the isomerization of 4 to 5 under the influence of isocyanates.     

Synthesis,Structure, and In Vitro Anti-HIV Activity of New Pyrazole, 1,2,4-Thiadiazole,and 1,2,4-Triazole Derivatives

α,α′-Dichloroazo compounds 6 react with Lewis acid to furnish 1-(chloroalkyl)-1-aza-2-azoniaallene salts 4. The cations 4 react with acetylenes, isothiocyanates, isocyanates, and carbodiimides under [3+2]-cycloaddition. The cycloadducts undergo consecutive reactions, e.g., [1,2]-shifts of alkyl groups. The newly synthesized products were evaluated for their anti-HIV-1 and anti-HIV-2 activity in MT-4 cells.     

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.     

Heterocyclizations of functionalized heterocumulenes with C,N-, C,O-, and C,S-binucleophiles: XIII. Synthesis of dialkyl 2-oxo-3-allyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates and their reaction with arylhydroxymoyl chlorides

Dialkyl 2-oxo-3-allyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates obtained by condensation of 1-chlorobenzyl isocyanates with N-allylfumarates reacted regioselectively with arylhydroxymoyl chlorides with the formation of dialkyl 6-aryl-3-[(3-aryl-4,5-dihydro-5-isoxazolyl)methyl]-2-oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates.     

Heterocyclization of functionalized heterocumulenes with C,N-, C,O-, and C,S-binucleophiles: X. 1-Chloroalkyl isocyanates in the synthesis of new 5-aroyldihydropyrimidines

Reactions of 1-chlorobenzyl isocyanates with N,S-aroylketene acetals depending on the conditions provide either 5-aroyl-6-methylsulfanyl-3,4-dihyropyrimidin-2(1H)-ones or 5-aroyldihyropyrimidine-2,4(1H,3H)-diones. 1-Aryl-2,2,2-trifluoro-1-chloroethyl isocyanates in a similar condensation gave 5-aroyl-6-methylsulfanyl-2-trifluoromethyl-2,3-dihyropyrimidin-4(1H)-ones.     

Reaction of N-[(α-acetoxy)-4-pyridylmethyl]-3,5-dimethylbenzamide with alkyl isocyanates

Reaction of N-(α-acetoxy)4-pyridylmethyl]-3,5-dimethylbenzamide 3 with methyl and ethyl isocyanates afforded 1,3-dimethyl and 1,3-diethyl-4-(3,5-dimethylbenzoylamino)-2-oxoimidazolidine-5-spiro-4′-[1′,4′-dihydro-1′-acetyl]pyridine 6a,b , respectively. However, the reaction of 3 with isopropyl, t-butyl and phenyl isocyanates gave the corresponding N,N′-diurea and the dimerization compound 8 . The structure of 6a was confirmed by crystal X-ray diffraction analysis.     

Synthetic and computational studies on intramolecular [2+2] sulfonyl isocyanate-olefin cycloadditions

Novel unsaturated sulfonyl isocyanates were prepared using a boron trichloride promoted thermal cleavage of the corresponding sulfonylcarbamates. Due to their moisture sensitivity, the isocyanates were directly converted into sulfonylureas in good yields. An intramolecular cycloaddition of the olefinic sulfonyl isocyanates to give β-lactam-sulfonamide hybrids was not observed experimentally. Investigation of this cycloaddition by DFT-calculations using the 6-31G* and 6-311+G** basis sets showed it to be endergonic.     

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.     

Preparation, isolation, and characterization of Nalpha-Fmoc-peptide isocyanates: solution synthesis of oligo-alpha-peptidyl ureas

The N(alpha)-Fmoc-peptide isocyanates 3a-q, 4a-c, and 5a-c were prepared by the Curtius rearrangement of N(alpha)-Fmoc-peptide acid azides in toluene under thermal, microwave, and ultrasonic conditions. All the N(alpha)-Fmoc-oligo-peptide isocyanates made were isolated as stable crystalline solids with 71 to 94% yield and were fully characterized by 1H NMR, 13C NMR, and mass spectroscopy. Their utility for the synthesis of oligo-alpha-peptidyl ureas 7a-f and 8a-c by the divergent coupling approach was demonstrated. The coupling of N(alpha)-Fmoc-dipeptide isocyanates with amino acid ester or with N,O-bis(trimethylsilyl)amino acids resulted in N(alpha)-Fmoc-tripeptidyl urea ester and acids containing one each of peptide bond and urea bond. The divergent approach is extended to the synthesis of tetrapeptidyl ureas by the 2 + 2 strategy using bis-TMS-peptide acid as an amino component. To incorporate urea bonds in adjacent positions, N(alpha)-Fmoc-peptidyl urea isocyanates 9a-d were prepared and employed in the synthesis of three tetrapeptidyl ureas 10a-b and 11 containing one peptide bond and two urea bonds in series from the N-terminal end. The protocol was then employed for the synthesis of five urea analogues 13-15, 18, and 21 of [Leu5]enkephalin containing urea bonds at the 2, 3, 4 positions as well as at the 2, 4 and 2, 3, 4 positions. The analogue 2l was made by the convergent synthesis by the N --> C terminal chain extension. Finally, two urea analogues 22 and 23 of repeat units of bioelasto polymers, namely Val-Pro-Gly-Val-Gly-OH and Pro-Gly-Val-Gly-Val-OH, were synthesized incorporating the urea bond by the concomitant isocyanate generation and urea bond formation under thermal conditions.     

4,5-二氢咪唑并[1,2-b]-1',2',4'-三唑-4-酮衍生物的合成与杀菌活性

应用芳基异氰酸酯与烯基膦亚胺1的氮杂Wittig反应, 得到的碳二亚胺2, 再与水合肼作用得到氨基咪唑啉酮衍生物4. 而后用4与芳基异氰酸酯(或酰氯)、三苯基膦、六氯乙烷和三乙胺“一锅”反应, 得到4,5-二氢咪唑并[1,2-b]-1',2',4'-三唑-4-酮衍生物6或7. 探讨了所合成新型稠杂环化合物的生物活性, 结果表明部分化合物表现出良好的杀菌活性. 如7c在50 mg/L浓度时, 对棉花枯萎菌、稻瘟菌、黄瓜灰霉菌和油菜菌核菌的抑制率均达100%.