Bond-switch rearrangement of 3-oxo-Δ4-1,2,4-thiadiazolin-5-yl ureas

5-Amino-3-oxo-Δ⁴-1,2,4-thiadiazolines 5a,b react with isocyanates to yield 1,2,4-thiadiazolidine derivatives 9a-d via bond switching of the corresponding isomers 7 . The same type of products 9e-m was obtained by treatment of 5-amino-1,2,3,4-thiatriazoles 6a-d with two equivalents of isocyanate.     

Synthesis of Pyrano[4,3‐d]pyrimidine Derivative and Its Behaviour towards Nitrogen Nucleophiles and Active Methylenes

Pyrano[4,3‐d]pyrimidine derivative 3 was prepared by reaction of chlorocarbonyl isocyanate 1 with enaminonitrile 2 . Compound 3 reacted with nitrogen nucleophiles 4a‐f to afford 2‐substituted pyrido[4,3d]pyrimidine 5–8 , pyrimido[i]1,5a‐diaza‐9‐oxafluorene 9 and pyrimido[i]5a‐aza‐9‐thiafluorene 10 derivatives. Also, compound 3 reacted with active methylene compounds 4j to yield pyrimidine derivatives 14–16 which on reaction with EtONa 4k afforded 1,5,7‐triaza‐10‐oxaphenanthrene derivatives 17–19 .     

Synthesis of new imidazo[4,5-d][1,3]diazepine derivatives from 5-amino-4-(cyanoformimidoyl)imidazoles

N¹-[(Z) -2- Amino-1,2-dicyanovinyl]formamidines 1a-d react readily with tosyl isocyanate to form novel 8-amino-3-substituted-5-oxo-7-tosylaminoimidazo[4,5-d][1,3]diazepines 6a-d rather than the 6-cyano-2-oxopurine derivatives 5a-d expected. Compound 5a has been synthesized from 1a by reaction with ethyl chloroformate and base-catalyzed cyclization of the resultant 5-ethoxycarbonylamino-4-(cyanoformimidoyl)imidazole. Treatment of the 5-amino-4-cyanoimidazoles 7a and b with tosyl isocyanate under similar conditions gives the 4-cyano-5-(3′-tosylureido)imidazoles 8a and b , which on treatment with ethanolic ammonia cyclizes to the corresponding isoguanines 10a and b .     

Efficient synthesis of 4,4'-bi-1H-imidazol-2-ones from 5-amino-alpha-imino-1H-imidazole-4-acetonitriles and isocyanates

Reactions of 5-amino-alpha-imino-1H-imidazole-4-acetonitriles 1 with alkyl and aryl isocyanates led to efficient syntheses of 5'-amino-5-imino-4,4'-bi-1H-imidazol-2-ones 3 formed by intramolecular cyclization of the corresponding 5-amino-alpha-(N-alkyl/arylcarbamoyl)imino-1H-imidazole-4-acetonitriles 2. The cyclization occurs only slowly in solution but is considerably accelerated by the addition of a catalytic amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The reaction of the N-arylamidine 6b, the synthetic precursor of the imidazole 1b, with benzyl isocyanate also led to the formation of 4,4'-bi-1H-imidazol-2-one 3b in quantitative yield. The imidazole intermediate 2b has been isolated and found to be identical with the compound obtained by reaction of the imidazole 1b and benzyl isocyanate. The N-arylamidine 6c (R = 4-NCC(6)H(4)) reacted with benzyl isocyanate in a similar way, but the electrophilicity of the amidine carbon atom resulted in rapid hydrolysis of the intermediate 7c leading ultimately to the isolation of the urea 9. The N-alkylamidines 6a and 6d behaved differently in their reaction with benzyl isocyanate, and the major product isolated in these reactions is again the urea 9.     

Chemistry of sulfonyl isocyanates and sulfonyl isothiocyanates. XI. Cyclizations with epoxides

4-Toluenesulfonyl isocyanate cyclized with 1,2-epoxy-3-phenoxypropane and 2,3-epoxypropyl 4-methoxyphenyl ether, respectively, to give 3-(4-toluenesulfonyl)-5-phenoxymethylene-2-oxazolidone ( I ) and 3-(4-toluenesulfonyl)-5-(4-methoxyphenoxymethylene)-2-oxazolidone ( II ). Compounds I and II were hydrolyzed in 2 M sodium hydroxide solution to the corresponding uncyclized hydroxy amides, VII and VIII. Compound I was remarkably stable toward 6 M hydrochloric acid and amines. Styrene oxide, 1,2-epoxybutane, 3-chloro-1,2-epoxypropane, and 1-methoxy-2-methylpropylene oxide reacted with the isocyanate to afford 3-(4-toluene-sulfonyl)-4-phenyl-2-oxazolidone (III), 3-(4-toluenesulfonyl)-4-ethyl-2-oxazolidone ( IV ), 3-(4-toluenesulfonyl)-5-chloromethyl-2-oxazolidone ( V ), and 3-(4-toluenesulfonyl)-4,4-dimethyl-5-methoxy-2-oxazolidone ( VI ), respectively. The yield of VI was constant over a temperature range of 25–90°.     

Microwave-assisted synthesis of N-pyrazole ureas and the p38alpha inhibitor BIRB 796 for study into accelerated cell ageing

Microwave irradiation of substituted hydrazines and beta-ketoesters gives 5-aminopyrazoles in excellent yield, which can be transformed to the corresponding N-carbonyl derivatives by treatment with an isocyanate or chloroformate. Derivatization of 4-nitronaphth-1-ol using predominantly microwave heating methods and reaction with an N-pyrazole carbamate provides a rapid route to the N-pyrazole urea BIRB 796 in high purity, as a potent and selective inhibitor of p38alpha mitogen-activated protein kinase for the study of accelerated ageing in Werner syndrome cells.     

Reactions with the Arylhydrazones of α-Cyanoketones: The Structure of 2-Arylhydrazono-3-ketimino-nitriles

Analysis of the IR., UV., and polarographic data of a variety of 2-arylhydrazono-3-ketimino-nitriles indicated that these derivatives exist mainly in the intramolecularly chelated hydrazone structure 1 . Compounds 1 reacted with hydrazine hydrate to yield the corresponding 5-amino-4-arylazopyrazoles ( 3 ). Compounds 3a reacted with acetylacetone, ethyl acetoacetate, and diethyl malonate to yield the pyrazolo[1, 5-a]pyrimidine derivatives 4, 5 , and 7 respectively. Compound 3a also reacted with benzoylisothiocyanate to yield the pyrazolyl thiourea derivative 8 .     

Pyrimidine Derivatives and Related Compounds II: Synthesis of some derivatives of pyrimido[1,2:2′,3′]pyrazolo[1,5-a]pyrimidines,a new ring system

3,5-Diamino-4-phenylazo-pyrazoles ( 1a–1c ) react with acetylacetone and with ethyl acetoacetate to yield the corresponding pyrazolo[1,5-a]pyrimidine derivatives 2a–2c and 3a–3c , respectively. Whereas 1a–1c add readily to methyl acrylate yielding the 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidine derivatives 5a–5c, 1a–1c add to methylacrylonitrile or methyl methacrylate only under drastic conditions to yield 5d–5f . The pyrimido[1,2:2′,3′]pyrazolo[1,5-a]pyrimidine derivatives 10a–10c are prepared by the action of acrylonitrile on 2a–2c . Compounds 10a–10c are readily converted into the corresponding oxo derivatives 12a–12c on treatment with acetic acid-hydrochloric acid mixture.     

Investigation of the preparation of pyrimidine isocyanates

Uracil-5-yl isocyanate and 1,3-dimethyluracil-5-yl isocyanate were prepared from the corresponding new carboazides. 1,3-Dimethyluracil-5-ylmethyl isocyanate obtained from the chloro compound and silver cyanate, was polymerized with an anionic initiator to the cyclic trimer. Attempts to isolate uracil-6-yl isocyanate, 1,3-dimethyluracil-6-yl isocyanate, pyrimidinyl-4-isocyanate, and 2,6-dichloropyrimidinyl-4-isocyanate were unsuccessful. Ethyl carbamate derivatives were made from all new azides and isocyanates. Other new pyrimidine derivatives included N,N'-bis(pyrimidine-4-carbonyl)hydrazine, N,N'-bis(1,3-dimethyluracil-5-yl)urea, N,N'-bis(1,3-dimethyluracil-6-yl)urea and N,N'-bis(2,5,6-trichloro-4-pyrimidinyl)oxamide.     

Acylation of purine-8-thione and benzimidazole-2-thione: A reinvestigation of the site of acylation

Purine-8-thione ( 1 ) is acylated on nitrogen, not on sulfur as was previously reported. Thus, the reactions of 1 with ethyl chloroformate and with acetic anhydride yield, respectively, ethyl purine-8-thione-9( 7 )-carboxylate ( 3 ) and 9 ( 7 )acetylpurine-8-thione ( 7 ) as shown by independent synthesis and spectra. In like manner, benzimidazole-2-thione ( 10 ) reacts with acetic anhydride, ethyl chloroformate, benzoyl chloride, and cyclohexyl isocyanate to yield the corresponding N-acylated derivatives. In addition, 10 yields 1,3-dibenzoylbenzimidazole-2-thione on treatment with 2 equivalents of benzoyl chloride.     

Synthesis and transformation of novel cyclic β-amino acid derivatives from (+)-3-carene

The regio- and stereoselective addition of chlorosulfonyl isocyanate to (+)-3-carene 1 resulted in β-lactam 2, which was converted to N-Boc-β-amino acid 4, β-amino ester 7, and carboxamide derivatives 18 and 20 via N-Boc activation and mild ring opening. The corresponding β-amino ester 7 was transformed to 2-thioxopyrimidin-4-one 11 and 2,4-pyrimidinedione 13. LAH reduction of 5 and 7 resulted in amino alcohols 6 and 8. The reaction of 8 with phenyl isothiocyanate, followed by cyclisation, furnished 1,3-oxazine 15.     

Cyclization of diketones to pyridazine and furan derivatives

Condensation of (±)-2,3-bis(3,4-dimethoxybenzoyl)butane-1,4-dione 1 with different hydrazine bases afforded the corresponding pyridazines 2 and 3 . Refluxing the diketone 1 with methanolic hydrogen chloride yielded the corresponding 3,4-dimethylfuran derivative 5 . Reaction of acetonylacetone 6 with p-sulfamylphenylhydrazine afforded the corresponding 3,6-dimethyl-1H-pyridazine derivative 7 . Reaction of 7 with the appropriate isocyanate and isothiocyanate yielded the corresponding benzenesulfonylurea 8 and thiourea 9 derivatives respectively. The structures of the compounds synthesized were affirmed by microanalyses and spectral studies.     

Reactions of 5-aryl-4-acyl-1-(4-hydroxyphenyl)-3-hydroxy-3-pyrrolin-2-ones with arylamines

The reaction of 5-(4-chlorophenyl)-4-benzoyl-1-(4-hydroxyphenyl)-3-hydroxy-3-pyrrolin-2-one with aromatic amines affords the corresponding 3-arylamino derivatives, and the reactions of 5-aryl-4-acetyl-1-(4-hydroxyphenyl)-3-hydroxy-3-pyrrolin-2-ones with p-toluidine yield 5-aryl-4-(1-p-tolylamino)ethylene-1-(4-hydroxyphenyl)pyrrolidin-2,3-diones.     

Synthesis and chemical properties of 1-ethyl-3-aryl-2-imidazolidinones with a hydroxyurea fragment in the 4 position

Treatment of 2-ethylamino-2-methylpropanol oxime with aryl isocyanates leads to 4-[N-(arylcarbamoyl) hydroxyamino [-1-ethyl-3-aryl-5,5-dimenthyl-2-imidazolidionones, which are acylated by acid chlorides and methyl isocyanate to give the corresponding O-acyl derivatives and are converted to 2-(2-oxo-1-ethyl-3-aryl-5,5-dimethyl-4-imidazolidinyl)-4-aryl-1,2,4-oxadiazolidine-3,5-diones by the action of methyl chlorocarbonate.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 980–983, July, 1980.     

Reactivity of organolanthanide and organolithium complexes containing the guanidinate ligands toward isocyanate or carbodiimide: synthesis and crystal structures

The direct reactions of (C5H5)2LnCl with LiN=C(NMe2)2 proceeded at room temperature in THF under pure nitrogen to yield the lanthanocene guanidinate complexes [(C5H5)2Ln(mu-eta1:eta2-N=C(NMe2)2)]2 (Ln = Gd (1), Er (2)). Treatment of phenyl isocyanate with complexes 1 and 2 results in monoinsertion of phenyl isocyanate into the Ln-N(mu-Gua) bond to yield the corresponding insertion products [(C5H5)2Ln(mu-eta1:eta2-OC(N=C(NMe2)2)NPh)]2 (Ln = Gd (3), Er (4)), presenting the first example of unsaturated organic small molecule insertion into the metal-guanidinate ligand bond. Further investigations indicate that N,N'-diisopropylcarbodiimide does not react with complexes 1 and 2 under the same conditions; however, it readily inserts into the lithium-guanidinate ligand bond of LiN=C(NMe2)2. As a synthon of the insertion product Li[(iPrN)2C(N=C(NMe2)2)], its reaction with (C5H5)2LnCl gives the novel organolanthanide complexes containing the guanidinoacetamidinate ligand, (C5H5)2Ln[(iPrN)2C(N=C(NMe2)2)] (Ln = Yb (5), Er (6), Dy (7)). All complexes were characterized by elemental analysis and spectroscopic properties. The structures of complexes 1, 3, 5 and 7 were determined through X-ray single-crystal diffraction analysis.     

Synthesis of novel interlocked systems utilizing a palladium complex with 2,6-pyridinedicarboxamide-based tridentate macrocyclic ligand

A new protocol for the high yield synthesis of interlocked molecules is described. Palladium(II) complex including a 2,6-pyridinedicarboxamide-based tridentate macrocycle 2 was allowed to react with a 2,6-disubstituted pyridine derivative bearing two hydroxyl groups at both termini 3b to yield the corresponding Pd(II) complex 4b quantitatively. An acid catalyzed end-capping of 4b with a bulky isocyanate gave Pd(II) complex 5b in 96% yield, which was treated with carbon monoxide to afford [2]rotaxane 6b quantitatively.     

An Asymmetric Synthesis of L-694,458, a Human Leukocyte Elastase Inhibitor, via Novel Enzyme Resolution of beta-Lactam Esters

A convergent synthesis of [S-(R,S)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, was achieved via chiral synthesis of key intermediates: (S)-3,3-diethyl-4-[4'-[(N-methylpiperazin-1-yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl isocyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enantioselective lipase hydrolysis of ester 5 to produce (S)-3,3-diethyl-4-(4'-carboxyphenoxy)-2-azetidinone (6) (60% yield, three cycles, 93% ee) with isolation, epimerization, and recycling of the undesired (R)-ester 5. Isocyanate 3 was prepared by chiral addition of Zn(n-Pr)(2) to piperonal (98% yield, 99.2% ee), azide displacement and reduction to (R)-alpha-propylpiperonylamine (11) (58% yield, 85% ee), crystallization as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanate formation (98% yield) with phosgene.     

Zur Synthese 3,5,6-substituierters-Triazin-2,4-dione

The reaction of N-(2-pyridyl)-carbaminates (3), 1-phenyl-3-(2-pyridyl)-urea (5 a) or alkyl and aryl substituted pyridopyrimidinediones (2) synthesized from 2-amino-pyridine with arylisocyanates (4 a, b) yields 3-aryl substituted pyrido-[1,2-a]-s-triazine-2,4-diones (1). 2-Aminopyridine and azamalonic derivatives (ethoxycarbonyl isocyanate, ethyl iminodicarboxylate) react to give the 3-unsubstituted triazine system (1 c). The isolation of monocyclic triazinediones obtained from the reaction of N-phenylbenzamidine (9) with aryl isocyanate (4 a) or ethoxycarbonyl isocyanate failed because of hydrolytic ring opening. The mechanism of the reaction of 3-substituted pyrido-pyrimidinediones (2) and phenyl isocyanate (4 a) is discussed.     

Direct Carboxamidation of Sydnones with Chlorosulfonyl Isocyanate

Various 4-carboxamido sydnones 2 can be prepared in good yield by reaction of the corresponding 3-substituted sydnones (cf. 1) with chlorosulfonyl isocyanate at room temperature.     

Addition-Rearrangement of Aryl- and Alkoxysulfonyl Isocyanates with 5-Methyl-Substituted 3,4-Dihydro-2-methoxy-2H-pyrans. Selective Synthesis of Functionalized 2-Piperidones(1)

3,4-Dihydro-2-methoxy-5-methyl-2H-pyran and 3,4-dihydro-2-methoxy-5,6-dimethyl-2H-pyran undergo addition-rearrangement reactions with arylsulfonyl isocyanates to generate the corresponding 3-formyl- and 3-acetyl-6-methoxy-3-methyl-1-(arylsulfonyl)-2-piperidones. For example, 3,4-dihydro-2-methoxy-5-methyl-2H-pyran and phenylsulfonyl isocyanate afforded 3-formyl-6-methoxy-3-methyl-1-(phenylsulfonyl)-2-piperidone as a separable trans/cis mixture in high yield. The more reactive phenoxysulfonyl and alkoxysulfonyl isocyanates provided analogous results.