NOVEL 2-THIOXOHYDANTOIN KETENE DITHIOACETALS: VERSATILE INTERMEDIATES FOR SYNTHESIS OF METHYLSULFANYLIMIDAZO- [4,5-C]PYRAZOLES AND METHYLSULFANYLPYRROLO- [1,2-C]IMIDAZOLES

ABSTRACT

The novel 2-thioxohydantoin ketene S,S-acetals 3a,b were prepared by the reaction of 2-thioxohydantoins 1a,b with carbon disulfide, followed by alkylation with methyl iodide of the produced sodium dithiolate salts 2a,b. The reaction of compounds 3a,b with nucleophiles afforded different fused methylsulfanylimidazoles.     

Synthesis of Some Novel α-Cyanoketene-N,S-acetals Derived from Secondary Aliphatic Amines and Their Use in Pyrazole Synthesis

New α-cyanoketene-N,S-acetals 2(a–g) and β-dialkylamine-α-cyanoacrylates 3(g–i) were synthesized in good to excellent yields by the reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate 1 with secondary aliphatic amines (i.e., N-methylalkyl- and N-ethylalkylamines), and pyrrolidine, in the presence of triethylamine, under reflux in ethanol, for 1–16 h, depending on the amine used. Five N-methylalkyl amines and pyrrolidine yielded exclusively mono-substituted N,S-acetals 2(a–f) in good yields. On the other hand, N-ethylbenzylamine gave a mixture of monosubstituted products including N,S-acetal 2g in 35% yield and the unexpected product ethyl 3-[benzyl(ethyl)amino]-2-cyanoacrylate 3g in 50% yield. N-Ethylcyclohexylamine and N-ethylbutylamine did not produce N,S-acetals and gave only the unexpected products ethyl 2-cyano-3-[cyclohexyl(ethyl)amino]acrylate 3h and ethyl 3-[butyl(ethyl)amino]-2-cyanoacrylate 3i in good yields. The α-cyanoketene-N,S-acetals 2(a–f), 2j, and 2k underwent cyclization with the binucleophile hydrazine in ethanol under reflux to afford substituted pyrazoles 4(a–f), 4j, and 4k in good yields.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resources: Full experimental and spectral details.]     

Facile Synthesis of Nicotinic Acid Derivatives with Unsymmetrical Substitution Patterns

Abstract

Two novel methods for synthesis of nicotinic acid derivatives with unsymmetrical substitution patterns were presented via ketene dithioacetals. The ketene N,S-acetals 2 reacted with β-ketoesters or β-cyanoesters to give 4-amino-5-cyano-2-alkyl-6-methylthio-nicotinic acid derivatives 3 or 2,4-diamino-5-cyano-6-methylthio-nicotinic acid ethyl ester 4. However, 6-amino-5-cyano-2-alkyl-4-methylthio-nicotinic acid esters 6 were obtained by the reaction of the ketene dithioacetals 1 and β-amino-crotonates.     

Acetyl ketene aminals in Nenitzescu reaction

Nenitzescu reaction of acetyl ketene aminals (N,N-acetals) was investigated. The interaction of 2-acetyl-1-amino-1-anilinoethene with benzoquinone gave 3-acetyl-2-amino-7a-hydroxy-1-phenyl-5,7a-dihydro-1H-indol-5-one, which was then transformed into 3-acetyl-2-amino-6-chloro-5-hydroxy-1-phenylindole. The reaction of benzoquinone with 2-acetyl-1-amino-1-benzoylaminoethene led to the corresponding hydroquinone-adduct which was oxidized to 4-acetylamino-5-(2,5-dihydroxyphenyl)-2-phenyloxazole. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 160–165, January, 1999.     

Nitroketene acetal chemistry: efficient synthesis of 2-amino-3-nitro-4H-chromenes

Base-catalyzed reaction of the nitroketene N,S-acetals and the ring substituted 2-hydroxybenzaldehydes afforded a combinatorial library of the 2-alkylamino-3-nitro-4-alkylsulfanyl 4H-chromenes in excellent yields. Nucleophilic displacement of the C4 alkylsulfanyl group with different thiols afforded 4H-chromenes with structural diversity.     

An efficient synthesis of highly substituted pyrroles from β-oxodithiocarboxylates

α-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinate hydrochlorides with β-oxodithiocarboxylates followed by alkylation, underwent cyclization in presence of chloromethyleneiminium salt derived from POCl₃/DMF to afford alkyl-3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates in excellent yields. Alkyl-3-aryl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates were formed in moderate yields when the same N,S-acetals were treated with DBU.     

Stereoselective radical cyclizations of N-(2-halobenzoyl)-cyclic ketene-N,X(X=O, S)-acetals

2-Alkyloxazolines and 2-alkylthiazolines react with 2-halobenzoyl chlorides to form N-(2-halobenzoyl)-cyclic ketene-N,O-acetals and N-(2-halobenzoyl)-cyclic ketene-N,S-acetals in excellent yields, respectively. These ketene acetals readily undergo stereocontrolled aryl radical cyclizations to afford the central six-membered rings of substituted-2,3,10,10α-tetrahydrooxazolo[3,2-b]isoquinolin-5-ones and their 2,3,10,10α-tetrahydrothiazolo[3,2-b]isoquinolin-5-one analogs. The tertiary N,O- and N,S-radicals formed upon aryl radical reaction at the ketene-N,X(X=O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from both Bu₃SnH and (Me₃Si)₃SiH was investigated. The N,S-heterocyclic fused ring products may have potential medical value.     

Use of Tetrahydro-2H-1,3-Oxazinones as Aminopropylation Agents

Treatment of tetrahydro-2H-1,3-oxazin-2-one (1) or the 3-methyl derivative 2 with aniline salts or thiophenols at 180 °C affords the corresponding N-aryl-1,3-propanediamines 3 or 3-(arylthio)propanamines 4 in good yields.     

Addition reaction of zinc acetylides to thioiminium salts leading to 3-amino-1-sulfenyl-1,4-enynes

The reaction of thioiminium salts with zinc acetylides took place at 60 °C to give 3-amino-1-sulfenyl-1,4-enynes in moderate to good yields. Two molecules of acetylides were incorporated into the products. Nucleophilic attack of zinc acetylides to thioiminium salts may initially occur to form alkynyl S,N-acetals, followed by their [1,3]-rearrangement to give 3-sulfenyl-1-aminoallenes.     

Reactions of pyridinium or isoquinolinium ketene dithioacetals with aromatic N-imines and S-imines

Reactions of ketene dithioacetals, 1-[1-substituted 2,2-bis(methylthio)ethenyl]pyridinium 1a-i or -isoquinolinium 2a,b iodides with aromatic N-imines, 1-aminopyridinium 3a-1,1 -aminoquinolinium ( 4 ), and 2-amino-isoquinolinium ( 5 ) mesitylene sulfonates gave the corresponding 2-methylthioimidazo[1,2-a]pyridines 9a-k , 2-methylthiopyrazolo[1,5-a]pyridines 11a-q , 2-methylthioimidazo[2,1-a]isoquinoline derivatives 10a,b and 2-methylthiopyrazolo[1,5-a]quinoline ( 12 ). The benzoyl compounds, 1-[1-benzoyl-2,2-bis(methylthio)ethenyl]-pyridinium iodides 1g,h,i reacted with N-imine 3a to give the 3-benzoyl-2-methylthioimidazo[1,2-a]pyridines 9h-k . The reaction of pyridinium ketene dithioacetals 1a,f,g (R¹ = COOE_t, COPh, and CN) with substituted pyridinium N-imines having an electron-withdrawing group on the pyridine ring afforded only the corresponding pyrazolo[1,5-a]pyridine derivatives 11j-r in good yields. Reactions of ketene dithioacetals with various S-imines are also described. Possible mechanisms for the formation of 9 and 11 are described.     

A convenient synthesis of some α-oxoketene-N,S- and N,N-acetals

Some α-oxoketene-N,S- and N,N-acetals were selectively synthesized in good to excellent yields by the reaction of 1,1-dimethoxy-4,4-di(methylthio)-3-buten-2-one with primary and secondary amines under moderate conditions. Secondary amines in reaction with α-oxoketene dithioacetal yielded double-substitution products exclusively, whereas primary amines under the same conditions yielded the mono-substituted products as exclusive or main products.     

Intramolecular cyclization of ketene containing both acyl andN-alkylimidoyl substituents. Synthesis and crystal and molecular structure of 3-benzoyl-5-phenyl-2H,4H-furo[3,2-c] isoquinolin-2-one

Thermal decarbonylation of 1-benzyl-4,5-dibenzoyl-2,3-dihydropyrrole-2,3-dione yields benzoyl[N-benzyl(phenylglyoxalimidoyl)]ketene. The latter undergoes intramolecular cyclization to 3-benzoyl-5-phenyl-2,3,4,5-tetrahydrofuro[3,2-c]isoquinolin-2-one. Which is oxidized to 3-benzoyl-5-phenyl-2H,4H-furo[3,2-c]isoquinolin-2-one under the reaction conditions. The crystal and molecular structure of the title compound was studied by X-ray structural analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 563–565, March, 1997.     

N,N′-Linked 1,2-benzisothiazol-3(2H)-one 1,1-dioxides: synthesis, biological activity, and derived radicals

A number of N,N′-linked benzoannelated isothiazol-3(2H)-one 1,1-dioxides, not available via oxidation of isothiazolium salts, were obtained with good yields by reaction of N-amino heterocycles with 2-chlorosulfonylbenzoyl chloride and evaluated for their inhibitory activity toward human leukocyte elastase (HLE) and acetylcholinesterase (AChE). 2-(Phthalimid-1-yl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide and 2-(2-methyl-4-oxo-3(4H)-quinazolinyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide were found to be inhibitors of HLE and tested as potential precursors of nitrogen-centered radicals using 266 nm laser flash photolysis.     

Cyclization of functionalized ketene-N,S-acetals to substituted pyrroles: applications in the synthesis of marine pyrrole alkaloids

α-Oxoketene-N,S-acetals, prepared by the reaction of alkyl glycinates with β-oxodithiocarboxylates followed by alkylation, underwent cyclization in the presence of the Vilsmeier reagent to afford alkyl 3-aryl-4-formyl-5-(alkylsulfanyl)-1H-pyrrole-2-carboxylates in excellent yields. When the reaction was extended to β-oxodithiocarboxylates derived from deoxyanisoin, 3,4-diarylpyrrole-2-carboxylates, the key intermediates in the synthesis of lukianol A and lamellarin Q were formed.     

Efficient Chemoselective Mild Deprotection of S,Sand S,O-Acetals and Ketals with Electrophilic Halogens

A novel and simple method for the chemoselective deprotection of S,S- and S,O-acetals and ketals in the presence of their O,O-analogs with electrophilic halogens to their corresponding carbonyl compounds is described using N-bromosuccinimide, N-chlorosuccinimide, 2,4,4,6-tetrabromo-2,5-cyclohexen-1-one, trichlorocyanuric acid, or molecular bromine in aqueous acetonitrile. The use of these reagents in the presence of hydrated silica gel provide efficient, novel, and mild procedures for the deprotection of cyclic and acyclic O,O-, S,S-, and S,O-acetals and ketals in excellent yields in short reaction times.     

Synthesis of 3-(2-benzothiazolylthio)propanenitrile and related products

The reaction of 2-mercaptobenzothiazole, 2-mercaptobenzoxazole or 5-chloro-2-mercaptobenzothiazole with either acrylonitrile or acrylamide under basic conditions afforded the N-cyanoethylated products 1, 2 and 3 or the N-amidoethylated products 4, 5 and 6 , respectively. The reaction of the sodium salts of the same thiazolethiols with 3-chloropropionitrile furnished a mixture containing the N-cyanoethylated products 1, 2 and 3 and the unknown S-cyanoethylated products 7, 8 and 9 , respectively. Whereas, substituting 3-chloropropionamide for 3- chloropropionitrile in the same reaction gave only the S-substituted products 10, 11 , and 12 , respectively. The treatment of 10, 11 or 12 with phosphorus oxychloride or thionyl chloride in DMF afforded 7, 8 and 9 in excellent yields. Possible mechanisms and supporting nmr data are discussed.     

Solid‐State Emissive Aroyl‐S,N‐Ketene Acetals with Tunable Aggregation‐Induced Emission Characteristics

N‐Benzyl aroyl‐S,N‐ketene acetals can be readily synthesized by condensation of aroyl chlorides and N‐benzyl 2‐methyl benzothiazolium salts in good to excellent yields, yielding a library of 35 chromophores with bright solid‐state emission and aggregation‐induced emission characteristics. Varying the substituent from electron‐donating to electron‐withdrawing enables the tuning of the solid‐state emission color from deep blue to red.     

An eco-friendly procedure for the efficient synthesis of arylidinemalononitriles and 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) in aqueous media

Abstract

Commercially available lithium hydroxide monohydrate (LiOH·H₂O) was found to be a novel “dual activation” catalyst for Knoevenagel condensation between malononitrile (1) or 3-methyl 1-phenyl-1H-pyrazol-5-(4H)-one (6) with aromatic aldehydes 2a–e leading to an efficient and easy synthesis of arylidenemalononitriles 3a–d and 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) 7a–c in short times. The reaction of aryl aldehydes with malononitrile afforded excellent yields after 1–6 min in aqueous media at room temperature. In case of 3-methyl-1-phenyl-1H-pyrazol-5-(4H)-one (6) and aromatic aldehydes afforded good yields after 60–75 min at 90°C.     

CuCl-catalyzed radical cyclisation of N-α-perchloroacyl-ketene-N,S-acetals: a new way to prepare disubstituted maleic anhydrides

The copper-catalyzed radical cyclization (RC) of N-α-perchloroacyl cyclic ketene-N,X(X=O, NR, S)-acetals was studied. While the RC of N-acyl ketene-N,O-acetals was unsuccessful, the 5-endo cyclization of the other ketene acetals provided much better results, with the following order of cyclization efficiency: hexa-atomic cyclic ketene-N,NR-acetals<penta-atomic cyclic ketene-N,S-acetals<hexa-atomic cyclic ketene-N,S-acetals. Invariably the catalytic cycle begins with the formation of a carbamoyl methyl radical. This leads to a cascade of reactions, including a radical polar crossover step, which ends with the formation of the maleimide nucleus, or precursors of this. Products from the RC of the hexa-atomic cyclic ketene-N,S-acetals, were efficiently transformed into disubstituted maleic anhydrides.     

A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an S_N2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH₄. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature.