Utilization of 2-substituted 3, 1-benzoxazin-4-ones in synthesis of some quinazoline annulated derivatives

Abstract

In this study, a new series of quinazoline and their annulated derivatives have been synthesized. A number of quiazolinone derivatives substituted at position-3 were prepared from 3, 1-benzoxazinone by the treatment of 3,1-benzoxazinone with different nitrogen nucleophiles such as, hydrazine hydrate, phenylhydrazine, ethanolamine, and cyano acetohydrazide afforded the quinazolinone derivatives 7–11. The reaction of hydrazide derivative 5 with aromatic aldehydes gave the Schiff’s bases derivative 16a–c. Some of the synthesized compounds were tested against the breast cancer cell line (MCF-7). The structures of all the newly synthesized compounds were established based on IR, ¹H, ¹³C NMR, mass spectral data, and elemental analyses.     

Synthesis and interconversion of isomeric pyrrolotriazolopyrimidines

4‐Hydrazino‐7H‐pyrrolo[2,3‐d]pyrimidines 4 were cyclocondensed with formic acid or triethyl orthoformate to give 7H‐pyrrolo[3,2‐e][1,2,4]triazolo[1,5‐c]pyrimidines 6 and 7H‐pyrrolo[3,2‐e][1,2,4]triazolo[4,3‐c]pyrimidines 7 , respectively. The [4,3‐c] isomers 7 were rearranged into thermodynamically more stable [1,5‐c] isomers 6 . The identical compounds 6 were prepared using another route by reacting 3‐amino‐4‐imino‐7H‐pyrrolo[2,3‐d]pyrimidines 3 with formic acid or triethyl orthoformate. The reaction of 2‐amino‐3‐cyanopyrroles 1 with triethyl orthoformate gave N‐ethoxymethylene‐2‐amino‐3‐cyanopyrroles 2 . Further reaction with an equivalent of hydrazine hydrate provided 3‐amino‐4‐imino‐7H‐pyrrolo[2,3‐d]pyrimidines 3 , whereas treatment with excess of hydrazine hydrate, 3 rearranged to 4‐hydrazino‐7H‐pyrrolo[2,3‐d]pyrimidines 4 . Compounds 4 were also obtained by the treatment of N‐ethoxymethylene‐2‐amino‐3‐cyanopyrroles 2 in excess of hydrazine hydrate. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:265–273, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20295     

Synthesis and reactions of 2,3-dimethylfuro[3,2-c]pyridines

Summary A number of substituted 2,3-dimethylfuro[3,2-c]pyridines was synthesized. 3-(4,5-Dimethyl-2-furyl)propenoic acid (1) was converted to the acid azide2, which in turn was cyclized to give 2,3-dimethyl-5H-furo[3,2-c]pyridine-4-one (3) by heating at 240°C in Dowtherm. The pyridone3 was chlorinated with phosphorus oxychloride to give4, which was reduced with zinc and acetic acid to 2,3-dimethylfuro[3,2-c]pyridine (5). Treatment of4 with several secondary heterocyclic amines led to compounds6a–6c. Reaction of pyridone3 with phosphorus pentasulfide rendered the thione7, which was methylated to8a. The 4-methoxy derivative8b was obtained from4 with sodium methoxide. 2,3,5-Trimethylfuro[3,2-c]pyridine-4-one (9) was obtained by reaction of3 with methyl iodide.Dedicated to Professor Dr.Fritz Sauter on the occasion of his 65th birthday     

Cationic and mesoionic 1,3‐thiazolo‐[3,2‐c]quinazoline derivatives

4‐Allylthio‐2‐arylquinazolines 4a–c undergo cyclization by action of bromine to furnish 5‐aryl‐3‐bromomethyl‐2,3‐dihydrothiazolo[3,2‐c]quinazolin‐4‐ium bromides 5a–c . Compounds 5a–c undergo ring opening by action of water under acid catalysis to afford the corresponding dibromide derivatives 6a–c . Bromination of 3‐allyl‐2‐aryl‐4(3H)quinazolinethiones 7a–c leads to 5‐aryl‐2‐bromomethyl‐2,3‐dihydrothiazolo[3,2‐c]quinazolin‐4‐ium bromides 8a–c . However, anhydro‐3‐hydroxy‐5‐aryl‐1,3‐thiazolo[3,2‐c]quinazolin‐4‐ium hydroxide 10a–c were prepared by the cyclodehydration of the corresponding thioglycolic acids 9a–c with Ac₂O. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:576–580, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10148     

Syntheses of New Unsymmetrical 2,5‐Disubstituted‐1,3,4‐oxadiazoles and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles Bearing Thieno[2,3‐c]pyrazolo Moiety

New series of (thieno[2,3‐c]pyrazolo‐5‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles 10a , 10b , 10c and (thieno[2,3‐c]pyrazol‐5‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)ethanones 6a , 6b , 6c has been synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by multistep reaction sequence. (5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐1H‐thieno[2,3‐c]pyrazoles 4a , 4b , 4c were also synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by cyclization with various aromatic carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3‐c]pyrazole‐5‐carboxylate 2 with hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde 1 and 2‐ethyl thioglycolate in presence of sodium alcoholate in good yield.     

The synthesis of 5H-thiazolo[2,3-c][1,2,4]triazine derivatives and substituted 3-(2-acylvinylthio)-1,2,4-triazin-5-ones from 6-methyl-3-thioxo-1,2,4-triazin-5-one, 1-acyl-2-bromoacetylenes,and α-acetylenic ketones. X-ray study of 3-benzoyl-6-methyl-5H-thiazolo[2,3-c][1,2,4]triazin-5-one

3-Acyl-6-methyl-5H-thiazolo[2,3-c][1,2,4]triazines were synthesized by reaction of 1-acyl-2-bromoacetylenes with 6-methyl-3-thioxo-1,2,4-triazin-5-one in methanol in the presence of triethylamine at 20 °C. The structure of 3-benzoyl-6-methyl-5H-thiazolo[2,3-c][1,2,4]triazine was established by X-ray structural analysis. Substituted 3-(2-acetylvinylthio)1,2,4-triazin-5-ones were obtained by the reaction of -acetylenic ketones with 6-methyl-3-thioxo-1,2,4-triazin-5-one under the same conditions. The structures of the new compounds were confirmed by IR,¹H, and¹³C NMR spectroscopy.Deceased.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2971–2975, December, 1996.     

Unusual open chain quinolinyl peroxol and its alcohol counterpart obtained through a modified Skraup–Doebner–Von Miller quinoline synthesis: theoretical studies and complete 1H‐ and 13C‐NMR assignments

Because of their extreme instability, it is generally difficult to synthesize and fully characterize open chain peroxides, also known as peroxols. In our attempt to investigate the mechanism of the Skraup–Doebner–Von Miller quinoline synthesis, we were able to obtain an unusual open chain peroxy‐quinoline, namely, 4‐(8‐ethoxy‐2,3‐dihydro‐1H‐cyclopenta[c]quinolin‐4‐yl)butane‐1‐peroxol (1), and its alcohol counterpart, namely 4‐(8‐ethoxy‐2,3‐dihydro‐1H‐cyclopenta[c]quinolin‐4‐yl)butan‐1‐ol (2) obtained as a side product during the same reaction. Although structurally similar, these two compounds appeared to display some very distinct physical and spectroscopic characteristics. This work reports detailed NMR studies and full ¹H and ¹³ C NMR assignments for these two compounds. These assignments are based upon the analysis of the NMR spectra of these compounds including ¹H, ¹³ C, COSY, gHSQC and gHMBC. The effect of the peroxide functional group on the chemical shift of neighboring carbons and protons was also investigated by comparing the NMR data of these two compounds. Furthermore, the effects of potential hydrogen bondings in 1, 2, and possible 1–1 dimer, 2–2 dimer and in prototypical model systems, as well as the stability of these compounds, were investigated computationally. The computed dissociation energies and NMR data support the interpretation of the experimental data. Copyright © 2012 John Wiley & Sons, Ltd.     

Design,synthesis, and antimicrobial activity of some new pyrazolo[3,4‐d]pyrimidines

2‐Benzyl‐ and 2‐aryloxymethyl‐3‐amino‐1‐phenyl‐pyrazolo[3,4‐d]pyrimidine‐4‐ones 5a–f have been synthesized by reacting the corresponding arylacetylamino derivatives 3a–f with hydrazine hydrate. Thionation of compounds 5d–f by action of P₂S₅ in pyridine yielded 2‐aryloxy‐methyl‐3‐amino‐1‐pheny‐lpyrazolo[3,4‐d]pyrimidin‐4‐thions 6a–c . 2,5‐Diphenyl‐2,3‐dihydro‐1H‐pyrazolo[5′,1′:4:5]pyrazolo[3,4‐d]pyrimidine‐8‐one ( 8 ) was also obtained via reaction of ethyl‐2‐cinnamoylamino‐1‐phenyl‐pyrazole‐4‐car‐boxylate ( 7 ) with hydrazine hydrate. The prepared compounds were screened in vitro for their antimicrobial activity. Some of the tested compounds were found to be active at 100 μg/ml compared with reference compounds (Ampicillin and Trivid) as antibacterial agents and claforan as antifungal agent. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:530–534, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10187     

The synthesis of methyl 2-(benzyloxycarbonyl)amino-3-dimethylaminopropenoate. The synthesis of trisubstituted pyrroles, 3-amino-2H-pyran-2-ones,fused 2H-pyran-2-ones and 4H-pyridin-4-ones

Methyl 2-(benzyloxycarbonyl)aimno-3-dimemylaminopropenoate ( 2 ) was prepared from methyl N-(benzyloxycarbonyl)glycinate ( 1 ) and t-butoxybis(dimethylamino)methane, and used as a reagent for preparation of substituted 3-(benzyloxycarbonyl)amino-4H-quinolizin-4-ones 5 and 6 , ?2H-pyran-2-ones 17–19 , ?2H-1-benzopyran-2-ones 28–31 , and -naphthopyrans 32–35 , ?2H-pyrano[3,2-c]pyridine-2,5-dione 46 , -pyrano-[4,3-b]pyran-2,5-dione 47 , -pyrano[3,2-c]benzopyran-2,5-dione 48 , -pyrano[2,3-c]pyrazol-6-ones 49 and 50 , -pyrano[2,3-d]pyrirnidin-7-ones 51 and 52 derivatives. In the reaction of 2 with 1,3-diketones trisubsti tuted pyrroles 14–16 were formed. Selective removal of benzyloxycarbonyl group was achieved by cat alytic transfer hydrogenation with Pd/C in the presence of cyclohexene to afford free 3-amino compounds 7 , 8 , 20 , 36–38 and 53–57 in yields better than 80%.     

Furopyridines. XXI. Synthesis of cyano derivatives of furo-[2,3-b]-, -[2,3-c]- and -[3,2-c]pyridine and their conversion to derivatives having another carbon-substituent

Cyanation of furo[2,3-b]-, -[2,3-c]- and -[3,2-c]pyridine N-oxides 1a, 1b and 1c by the Reissert-Henze method, reaction with benzoyl chloride and trimethylsilyl cyanide in dichloromethane and the reaction with trimethylsilyl cyanide and triethylamine in acetonitrile afforded 6-cyanofuro[2,3-b]- 2a , 7-cyanofuro[2,3-c]- 2b and 4-cyanofuro[3,2-c]pyridine 2c in moderate to excellent yield. The cyano group in 2a, 2b and 2c was converted to carboxamides 3a, 3b and 3c , ethyl imidates 5a, 5b and 5c and ethyl carboxylates 6a, 6b and 6c . Reaction of the N-oxides with trimethylsily bromide in acetonitrile gave the deoxygenated furopyridine 7a and 7d , bifuropyridyl 8b and 8c , and the N-oxide 9 of 8c .     

Cyclobutane-substituted diacetamido sulfides and 2,5-diacylthiophenes

A general and convenient route for the synthesis of 2,5-di[1-methyl-1-arylcyclobutane-3-yl]- thiophenes 4a–c and bis[1-methyl-1-arylcyclobutane-3-yl]-2-(2-oxyethtylamido)thiazole sulfides 7a–c is reported. The characterization of these compounds was obtained by elemental analyses, IR, ¹³C, and ¹H NMR techniques. © 2003 Wiley Periodicals, Inc. 15:26–31, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/.hc10207     

The Thermal Benzoxazinone-Benzoxazole Conversion,a Reexecution of a Mass Spectrometric Decay by Thermolysis

The base peak in the mass spectrum of several 1,4,2-benzoxazinone derivatives 1a–f (cf. Scheme 1 and the Table) suggests a clean carbon monoxide elimination leading to benzoxazole radical cations 2a–f . This benzoxazinone-benzoxazole conversion can be reproduced quantitatively by flash vacuum thermolysis. The isomeric 2,4,1-benzoxazinone 4 (cf. Scheme 2) eliminates carbon dioxide – the resulting biradical species 5 does not recombine to benzazete 10 but fragments into nitrile and benzyne (7).     

Furopyridines. V. A simple synthesis of furo[2,3-c]pyridine and its 2-and 3-methyl derivatives

A simple synthesis of furo[2,3-c]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxyisonicotinate ( 2 ) is described. The hydroxy ester 2 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 3a or 3b . Cyclization of compound 3a afforded ethyl 3-hydroxyfuro [2,3-c]pyridine-2-carboxylate ( 4 ) which was hydrolyzed and decarboxylated to give furo[2,3-c]pyridin-3(2H)-one ( 5a ). Cyclization of 3b gave the 2-methyl derivative 5b . Reduction of 5a and 5b with sodium borohydride yielded the corresponding hydroxy derivative 6a and 6b , respectively, which were dehydrated with phosphoric acid to give furo[2,3-c]pyridine ( 7a ) and its 2-methyl derivative 7b . 4-Acetylpyridin-3-ol ( 8 ) was O-alkylated with ethyl bromoacetate to give ethyl 2-(4-acetyl-3-pyridyloxy) acetate ( 9 ). Saponification of compound 9 , and the subsequent intramolecular Perkin reaction gave 3-methylfuro[2,3-c]pyridine ( 10 ). Cyclization of 9 with sodium ethoxide gave 3-methylfuro[2,3-c]pyridine-2-carboxylic acid, which in turn was decarboxylated to give compound 10 .     

Synthesis of 7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines and their reductive ring cleavage to 4-aminopyrrolo[2,3-d]pyrimidines

Some new 7,9-disubstituted 7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 5 have been synthesized either by diazotization of 4-hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4 obtained by hydrazinolysis of 4-chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 3 or via a substitution reaction between 3 and sodium azide. 5,7-Disubstituted-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-ones 2 were obtained by cyclocondensation of 2-amino-3-cyano-1,4-disubstituted pyrroles 1 with formic acid which on chlorination using phosphorus oxychloride afforded 3 . A novel route for the synthesis of 4-amino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 6 by the reductive ring cleavage of 5 has been reported.     

Practical synthesis of thiirene 1‐oxides that possess two bulky alkyl substituents

Acetylenes that possess two bulky alkyl substituents reacted with sulfur dichloride to furnish the corresponding 2,3‐dialkyl‐2,3‐dichlorothiiranes ( 5 ) nearly quantitatively. The alkaline hydrolysis of 5 afforded 2,3‐dialkylthiirene 1‐oxides ( 10 ) in high yields. These two reactions could be successively carried out in one flask, and 2,3‐di‐tert‐butyl‐, 2,3‐di‐(1‐adamantyl)‐, and 2‐(1‐adamantyl)‐3‐tert‐butylthiirene 1‐oxides ( 10a–c ) were obtained in 70, 80, and 90% yields, respectively, based on the starting acetylenes, thus providing the most convenient synthesis of thiirene 1‐oxides. Disulfur dichloride also reacted with acetylenes to give 5 in good yields with the elimination of one sulfur atom. Although the alkaline hydrolysis of 5 provided 10 exclusively, acid hydrolysis gave a mixture of α‐oxothioketone 9 and thiirene 1‐oxide 10 in modest yields. All thiirene 1‐oxides 10a–c isomerized to produce α‐oxothioketones 9 in high yields when heated in boiling toluene. Reactions of a bis‐acetylene ( 18 ) with disulfur dichloride and with sulfur dichloride gave a dihydropentathiepin ( 19 ) in high yields. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:424–430, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10070     

Furopyridines. X. Synthesis of tricyclic heterocycles,furo[2,3-b:4,5-c']-, furo[3,2-b:4,5-c']-, furo[2,3-c:4,5-c']- and furo[3,2-c:4,5-c']dipyridine

This paper describes the synthesis of four tricyclic heterocycles, furo[2,3–6:4,5-c']- ( 5a ), furo[3,2-b:4,5-c']- ( 5b ), furo[2,3-c:4,5-c']- ( 5c ) and furo[3,2-c:4,5-c']dipyridine ( 5d ). Starting with 2-formylfuropyridines ( 1a-d ), β-(2-furopyridyl)acrylic acids 2a-d were obtained by condensing with malonic acid. The acrylic acids were converted to the acid azides by reaction with ethyl chloroformate and the subsequent reaction with sodium azide. Heating of the acid azides at 230–240° with diphenylmethane and tributylamine gave tricyclic pyridinones 3a-d , which were converted to the respective chloro derivatives 4a-d by reaction with phosphorus oxychloride. Reduction of the chloro compounds over palladium-charcoal yielded compounds 5a-d respectively. All the compounds 2 to 5 were characterized by elemental analysis and spectral data. The H and ¹³C nmr and electronic spectral features of the furodipyridines were discussed comparing with those of the parent furopyridines.     

Synthesis,Modification, and Anticonvulsant Activity of 3′‐R1‐Spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones Derivatives

Previously unknown 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazoline]‐2,2′‐(7′H)‐diones and their N‐substituted analogues were obtained via reaction of 6‐R¹‐3‐(2‐aminophenyl)‐1,2,4‐triazin‐5‐ones with isatin and its substituted derivatives. It was shown that alkylation of 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′‐(7′H)‐diones by N‐R³‐chloroacetamides or chloroacetonitrile in the presence of а base proceeds by N‐1 atom of isatin fragment. The spectral properties (¹H and ¹³C NMR spectra) of synthesized compounds were studied, and features of spectral patterns were discussed. The high‐effective anticonvulsant and radical scavenging agents among 3′‐R¹‐5‐R²‐spiro[indoline‐3,6′‐[1,2,4]triazino[2,3‐c]quinazolin]‐2,2′(7′H)‐diones and their N‐substituted derivatives were detected. It was shown that compounds 2.2 , 2.8 , and 3.1 exceed or compete the activity of the most widely used in modern neurology drug—lamotrigine on the pentylenetetrazole‐induced seizures model. The aforementioned fact may be considered as a reason for further profound study of synthesized compounds using other pathology models.     

Novel synthesis of cyclic methylvinylsiloxanes by the reaction of methylvinyl diethoxysilane with phosphorous pentachloride

We report a novel synthesis of the cyclic oligomers [(H₂C?CH)(CH₃)SiO]_n obtained by the reaction between phosphorous pentachloride and methylvinyl diethoxysilane. According to gas chromatography/mass spectrometry data, the reaction product consisted of a mixture of cyclic oligomers in which the most important fractions were composed of cycles with n = 5, 6, or 7. The reaction product was also characterized by Fourier transform infrared and ¹H and ¹³C NMR spectroscopy. Experimental results suggested a new kind of reaction between the phosphorous pentachloride and terminal olefins directly bonded to silicon, which was probably associated with sterical effects favoring C? O? Si bond cleavage of ethoxy groups instead of the conventional addition of phosphorous pentachloride to olefinic linkages. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 3182–3189, 2002     

Synthesis of 5H-naphtho[2,3-c]phenothiazine-8,13-diones from 1-arylthio-2-azidoanthraquinones

Thermolysis of 1-arylthio-2-azidoanthraquinones in DMSO at 150 °C afforded substituted 5H-naphtho[2,3-c]phenothiazine-8,13-diones. These compounds were also formed upon photolysis of azides at 77 K and were prepared in quantitative yields by the reactions of 1-arylthio-2-azidoanthraquinones with KOH in DMSO at 20 °C.     

Furopyridines. XX. Wittig-horner reaction of a phosphonate of reissert analogues of furo[3,2-c]-, -[2,3-c]- and -[3,2-b]pyridines

Furo[3,2-c]-( 1a ), -[2,3-c]- ( 1b ) and -[3,2-b]pyridine ( 1c ) were reacted with isopropyl chloroformate and trimethyl phosphite to give dimethyl 5-isopropoxycarbonyl-4,5-dihydrofuro[3,2-c]pyridine-4-phosphonate ( 2a ), dimethyl 6-isopropoxycarbonyl-6,7-dihydrofuro[2,3-c]pyridine-7-phosphonate ( 2b ) and dimethyl 4-isopropoxycarbonyl-4,7-dihydrofuro[3,2-b]pyridine-7-phosphonate ( 2c ) as unstable syrups. Reaction of 2b and 2c with n-butyllithium and then with benzaldehyde, p-methoxybenzaldehyde, p-cyanobenzalde-hyde or propionaldehyde afforded the normal Wittig reaction products 5b-H, 5b-OMe, 5b-CN, 5b-Et, 5c-H, 5c-H, 5c-OMe and 5c-CN , except for 2b with propionaldehyde. While, the same reactions of compound 2a and the reaction of 2b with propionaldehyde afforded the unexpected products, 5-isopropoxycar-bonylfuro[3,2-c]pyridinio-4-aryl-(or ethyl)methoxides 3a-H, 3a-OMe, 3a-CN and 3a-Et , 4-(1′-aryl(or ethyl)-1′-hydroxymethyl)furo[3,2-c]pyridines 4a-H, 4a-OMe, 4a-CN and 4a-Et accompanying formation of the normal products. Treatment of the normal Wittig reaction products with lithium diisopropylamide and then with acetone gave the derivatives alkylated at the 2-or the benzylic positions.