From thiourea to bicyclic structures: an original route to imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines,and 2H,6H-pyrimido[2,1-b][1,3]thiazines

We report an example of an efficient regioselective synthesis of biheterocyclic compounds using thiourea as starting material. In fact, N,N'-bis(dimethylaminomethylene)thiourea (1), easily prepared by double condensation of N,N-dimethylformamide dimethyl acetal with thiourea, can be reacted with haloketones or acrylic dienophiles to give thiazolic (2) and thiazinic (3) diazadienes, respectively, themselves undergoing cyclization reactions to yield imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines, and 2H,6H-pyrimido[2,1-b][1,3]thiazines without any regioisomeric ambiguity. This straightforward route represents an original and unambiguously regioselective pathway to these valuable heterocycles.     

Fluoro-containing Heterocycles. IV. Synthesis of Benzimidazole Derivatives

2-Mercapto-5,6-difluorobenzimidazole reacts with aliphatic and alicyclic ketones in acetic acid in the presence of catalytic amount of sulfuric acid to afford fluorinated derivatives of 2,3-disubstituted benz[4,5]imidazo[2,1-b][1,3]thiazoles. Reaction with aromatic -haloketones occurs in another way: to furnish 2-phenylacylthio-5,6-difluorobenzimidazoles that in the system acetic anhydride-pyridine undergo cyclization into the corresponding fluorinated derivatives of benz[4,5]imidazo[2,1-b][1,3]thiazoles.     

Research in the imidazole series

The synthesis of 9-acyl- and 8-alkyl-9-acyl-substituted naphth[1,24,5]imidazo[2,1-b]thiazoles was accomplished by the reaction of 2-acylmethylthionaphth[1,2-d]imidazole with acylating agents and of 2-mercaptonaphth[1,2-d]imidazole with 3-chloro-2,4-pentanedione.See [1] for communication LXVII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 30–32, January, 1972.     

Formation of bromo-substituted imidazo[1,2-a]pyridines and their aza and thia analogs when the chichibabin reaction is carried out in dimethyl sulfoxide

The reactions of bromomethyl ketones with 2-aminopyridine, 2-aminopyrimidine, 2-aminothiazole, and 2-aminobenzothiazole in dimethyl sulfoxide lead to bromo-substituted (with respect to the position of the imadozole ring) imidazo[1,2-a] pyridines, imidazo[1,2-a]pyrimidines, imidazo[2,1-b]thiazoles, and imidazo[2,1-b]-benzothiazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 258–262, February, 1978.     

Pd-Catalyzed Heterocyclization During Sonogashira Coupling: Synthesis of 3-Aryl-substituted Imidazo[2,1-b]thiazoles

Abstract

The reaction of 4,5-diphenyl-2-propargylmercaptoimidazole with various aryl iodides catalyzed by Pd-Cu in the presence of triethylamine as base in dimethyl formamide (DMF) leads to the formation of 3-aryl-substituted imidazo[2,1-b]thiazoles.     

Reactivity of Amidinium Salts' Access to Benzo[4,5]imidazo[2,1-b]Thiazoles

Abstract

We present the synthesis of benzimidazole substituted at the 1 and 2 positions. The appropriate 2-thioalkyl-substituted benzimidazoles undergo intramolecular cyclization for occuring [4,5] imidazo[2,1-b] thiazoles derivatives.     

Some cyclization reactions of ω-chloro-ω-acylamidoacetophenones

Substituted thiazoles, 1,4-benzothiazines, imidazo[2,1-b]thiazoles, and imidazo[1,2-a]pyridines containing acylamide residues as substituents were obtained by reaction of ω-chloro-ω-acylaminoacetophenones with thioamides, o-aminothiophenol, 2-aminothiazole, and 2-aminopyridine. Some of these substances can be used for the synthesis of heterocyclic bases with an unsubstituted amino group.     

Features of the reaction of unsymmetrical 2-mercapto-imidazoles with aromatic and aliphatic ketones

The cyclization of unsymmetrical 2-mercaptoimidazoles with aliphatic and aromatic ketones has been studied. Using ¹H NMR and X-ray analysis it has been shown that 4-R¹-1H-2-mercaptoimidazoles undergo selective oxidative cyclization to the corresponding 3-R³-2-R²-6-R¹-imidazo[2,1-b][1,3]thiazoles while 6-R⁴-1H-2-mercaptobenzo[d]imidazoles give a mixture of 6-R⁴-3-R²-2-R³-benzo[4,5]imidazo[2,1-b][1,3]thiazole and 7-R⁴-3-R²-2-R₃-benzo[4,5]imidazo[2,1-b][1,3]thiazole in the ratio 1: 1. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 115–122, January, 2007.     

Mannich bases and methiodides of 6-(2-furyl)imidazo[2,1-b]thiazole and its substituted derivatives

The Mannich reaction in a number of 6-(2-furyl)-substituted imidazo[2,1-b]thiazoles is realized initially in the 5 position of the imidazothiazole system, whereas it is also realized in the 5 position of the furan ring in the presence of excess reagents if the latter position is not substituted. Iodomethylation occurs at the N₇ atom of imidazothiazole. The Mannich bases of 6-(5-nitro-2-furyl)imidazo[2,1-b]thiazole are iodomethylated only at the aminomethyl group. The pK_a values of the series of compounds were measured.     

Ligand-free copper-catalyzed regioselective C-2 arylation of imidazo[2,1-b]thiazoles

An effective, regioselective C-2 arylation of imidazo[2,1-b]thiazoles catalyzed by Cu(I) has been developed. This arylation proceeded smoothly without promotion of the ligands, and various functional (22 samples) groups were well tolerated. Preliminary mechanistic studies of this arylation are also reported.     

Cycloaddition reactions of thiazolium azomethine ylides: application to pyrrolo[2,1-b]thiazoles

Thiazolium azomethine ylides, equipped with a C-2 methanethiol group, participate in an efficient [3 + 2] cycloaddition reaction with acetylene derivatives to yield unique pyrrolo[2,1-b]thiazoles. The elimination of the methanethiol leaving group from the cycloadduct has replaced the need for a separate oxidation step and suppresses ring-opening side reactions. Products were obtained in short synthetic sequences to demonstrate their use as a scaffold for compound libraries.     

Studies on the imidazole series

The reaction of 2-mercaptoimidazole and its 4(5)-aryl- and 4,5-diaryl-substituted derivatives with -halogenoketones has yielded a number of alkyl-, acyl-, and aryl-substituted imidazo[2,1-b]thiazoles.For part XLV, see [1].     

The synthesis of dinaphthothiophenes

The synthesis of dinaphtho[1,2-b:2′,3′-d]thiophene ( 6 ), dinaphtho[2,1-b:2′,3′-d]thiophene ( 15 ), dinaphtho-[1,2-b:1′,2′-d]thiophene ( 20 ), dinaphtho[2,1-b:1′,2′-d]thiophene ( 26 ), dinaphtho[2,3-b:2′,3′-d]thiophene ( 37 ) and dinaphtho[1,2-b:2′,1′-d]thiophene ( 45 ) has been accomplished.     

New oxidative cyclizations of 1,3,4,6-tetraketones. Synthesis and structure of (Z)-2-acyl-5-alkyl(aryl)-1,4-dioxaspiro[2.4]hept-5-en-7-ones

Iodosobenzene diacetate oxidation of 1,3,4,6-tetraketones 1a-c yielded (Z)-2-acyl-5-alkyl(aryl)-1,4-dioxa-spiro[2.4]hept-5-en-7-ones (4a-c) in addition to 2-acyl-6-alkyl(aryl)-3-hydroxy-4-pyrones (3a-c). The structure of new spiro-heterocycles 4 was inferred from chemical and spectroscopic data, and the stereochemistry was fully defined by a single-crystal X-ray analysis. Alternative cyclization pathways can be rationalized as proceeding through carbocation intermediates derived from both forms of the ring-chain tautomerism of 1,3,4,6-tetraketones 1.     

Condensed isoquinolines 30. Acylation and alkylation of 5,13-dihydro-11H-isoquino-[3,2-<Emphasis Type="Italic">b</Emphasis>]quinazolin-11-one

It was shown that 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed when 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one is heated with the chlorides and anhydrides of carboxylic acids in the presence of bases (pyridine, NaOAc) while 5-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones are formed in the presence of NaH. In the presence of NaH 6-acyl-5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-ones form the products from acylation and alkylation at position 5. The action of heat on 5,13-dihydro-11H-isoquino[3,2-b]quinazolin-11-one in oxalyl chloride leads to 7H,8H-2a,7a-diazacyclopenta[fg]naphthacene-1,2,8-trione. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 741–750, May, 2008.     

Ring contraction during the 6pi-electrocyclisation of naphthopyran valence tautomers

The thermal and photochemical ring-opening of spiro(3H-naphtho[2,1-b]pyran-3,9'-thioxanthene-10,10-dioxide) results in the facile ring-contraction to 9-(naphtho[2,1-b]furan-2-yl)-9H-thioxanthene-10,10-dioxide . Similar behaviour is displayed by the isomeric spiro(2H-naphtho[1,2-b]pyran-2,9'-thioxanthene-10,10-dioxide) affording 9-(naphtho[1,2-b]furan-2-yl)-9H-thioxanthene-10,10-dioxide , though more severe reaction conditions were required. The comparative ease of this rearrangement for the isomers and was rationalised on the basis of the relative isomer populations of the ring-opened naphthopyrans. The rearrangement of simple mono- and bis-methylsulfonylphenyl substituted photochromic naphthopyrans , was examined; the former failed to rearrange whereas the latter could be induced to rearrange only under prolonged UV irradiation. The photochromism of diastereoisomerically pure sulfoxides derived from the oxidation of spiro(3H-naphtho[2,1-b]pyran-3,9'-thioxanthene) and spiro(2H-naphtho[1,2-b]pyran-2,9'-thioxanthene) resulted in conversion to the most thermodynamically stable trans-isomer in each case.     

Imidazo[2,1-b]benzothiazoles. II. Synthesis and antiinflammatory activity of some imidazo[2,1-b]benzothiazoles

3-[2-[p-(Un)substituted phenyl]imidazo [2,1-b]benzothiazol-3- yl]propionic acid derivatives (2a--e) were prepared via the interaction of the corresponding 2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazoles (1a--e) with acrylic acid in the presence of acetic anhydride and acetic acid. Esterification of 2a--e produced methyl esters (3a--e). Upon the interaction of 3a with m-chloroperbenzoic acid, the S-dioxide (4a) was obtained. Compound 5a was prepared from 4a by alkaline hydrolysis. Vilsmeier formylation for 1a--e produced novel [2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol-3- yl]formaldehyde derivatives (6a--e). Derivatives 6a--e reacted with ethyl bromoacetate to give ethyl 3-hydroxy-3-[2-[p-(un)substituted phenyl]imidazo[2,1-b]benzothiazol- 3-yl]propionate esters (7a--e). Compound dl-7a was resolved with l-(+)-tartaric acid. Compounds 2a--e showed weak or no activity in the carrageein-induced paw edema assay. Compound 4a significantly inhibited the leakage of pontamine-sky blue dye into the peritoneal cavity of mice, in the capillary permeability inhibition assay. Compound 5a inhibited the writhing by 62% in the acetic acid-induced writhing assay.     

Photochromic properties and reaction mechanism of naphthopyran

The photochromic properties and reaction mechanism of title compounds have been examined with steady method on compounds 3-phenyl-3-[3-methylbenzothiophene-2-yl]-3H-naphtho[2,1-b]pyran (1) and 3-phenyl-3-[benzofuran-2-yl]-3H-naphtho[2,1-b]pyran (2) and nanosecond laser flash photolysis techniques on compound 3-phenyl-3-[1,2-dimethylindol-3-yl]-3H-naphtho[2,1-b]pyran (3). The influence of oxygen on transient spectra and decay kinetics of compound 3 has been investigated. Both excited singlet state and triplet state are involved in the photochromic mechanism of compound 3. The influence of molecular structure on photochromic behavior has been studied also. Decay kinetics indicated that the lifetime of colored forms of 1 and 2 were several orders of magnitude longer than that of 3.     

Deoxypegan-1-one derivatives. synthesis and borohydride reduction of 3-[(E)-arylmethylidene]-3,9-dihydropyrrolo[2,1-b]quinazolin-1(2H)-ones

3-[(E)-Arylmethylidene]-3,9-dihydropyrrolo[2,1-b]quinazolin-1(2H)-ones were prepared by reaction of quinazolyl-2-propionic acid hydrochloride with aromatic aldehydes in acetic anhydride in the presence of Et₃N. 3-[(E)-Arylmethylidene]-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-1-ols were formed by reduction of the 3-arylidene derivatives with sodium borohydride in methanol, readily lost water when heated with acids, and were converted into 3-[(E)-arylmethylidene]-3,9-dihydropyrrolo[2,1-b]quinazolines. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 463–467, September–October, 2006.     

Determination of trace levels of ethylenethiourea by HPLC following derivatisation with phenacyl halides

Summary The HPLC determination of ethylenethiourea (ETU, imidazolidine-2-thione) has been carried out by derivatisation with phenacyl halides to give imidazole-[2,1-b]thiazoles, which were separated on a polystyrenedivinylbenzene (PS-DVB) column. A number of different phenacyl halides including p-phenyl-, and naphthyl, were studied and the p-nitro reagent was selected as the most suitable for residue analysis. The analysis was more sensitive than direct HPLC analysis and had a limit of detection of 0.04 ng ETU. Presented at the 15th International Symposium on Chromatography, Nürnberg, October 1984