Definitive structural assignment of condensation products from anthranilamide and 3-amino-2-carbamoylthiophene with ketones. Formation of tetrahydroquinazolinones and their thiophene isosteres

Products formed from dehydrative cyclization of cyclopentanone, cyclohexanone, and cycloheptanone with anthranilamide ( 2 ) under neutral or acidic conditions are established as the spiro compounds 2,2-polymethylene-1,2,3,4-tetrahydroquinazolin-4-ones 6 by means of (a) the presence of a ¹³C nmr signal at 66–79 ppm for atom C-2 and (b) X-ray crystallography on the tetramethylene compound 6a . Analogously, products from reactions of these cycloalkanones with 3-amino-2-carbamoylthiophene are now shown by ¹³C nmr spectra to have structures isosteric to 6 , i.e. 5,5-polymethylene-4,5,6,7-tetrahydrothieno[2,3-e]pyrimidin-7-ones 5 , rather than the chelate ring structures previously proposed. Additionally, conflicting literature reports on product 3 from reaction of acetone with 2 are partially clarified. Correlation of ¹³C chemical shifts in systems 3, 5 , and 6 is presented.     

Synthetic and spectroscopic study of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones

5-Amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 can be synthesized from 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) via a selective acylation with an acid anhydride in pyridine. The ¹H nmr spectral characteristics of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 is in particular, compared with 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) and 5-amino-2-alkyl-1,2,4-thiadiazolin-3-ones 1–2, 1–3 . The 5-amino group of 2–1 appeared as two peaks in its ¹H nmr spectrum, which merged to a single peak at a higher temperature, while those of compound 1–1, 1–2 and 1–3 appear only as a single peak. The restricted rotation of the C(5)-N(5) (at amino) bond of 5-amino-2-acetyl-1,2,4-thiadiazolin-3-one (2a-1) is about 14.5 Kcal/mol.     

Investigation of the reactions of fluorine containing 3-hydrazino-5H-1, 2, 4-triazino[5, 6-b]indoles with ethyl acetoacetate. Synthesis of some novel tetracyclic ring systems

Novel tetracyclic ring systems viz. 3-methyl-1-oxo-12H-1, 2, 4-triazepino[3′,4′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 4a ) and 3-methyl-5-oxo-12H-1, 2, 4-triazepino[4′,3′:2, 3][1, 2, 4]triazino[5, 6-b]indole ( 5a ), having angular and linear structures respectively, were synthesized by the cyclization of 3-oxobutanoic acid [5H-1, 2, 4-triazino-[5, 6-b]indole-3-yl]hydrazone ( 3a ). However, cyclization of 3b (R = CH_a, R¹ = R² = H) afforded the angular product 4b exclusively. Moreover, cyclization of 3c (R = R³ = H, R¹ = F) yielded 7-fluoro-1-0xo-10H-1, 3-imidazo[2′,3′:3, 4][1, 2, 4]triazino[5, 6-b]indole ( 6c ) and 7-fluoro-3-oxo-10H-1, 3-imidazo[3′,2′:2, 3][1, 2, 4]triazino-[5, 6-b]indole ( 7c ) instead of the expected triazepinone derivatives. Compound 3d (R = R¹ = H, R² = CF₃) also gave an imidazole derivative but only one angular product was obtained. In all these reactions, formation of the angular product involving cyclization at N-4 is favoured. Characterization of these products have been done by elemental analyses, ir, pmr, ¹⁹F nmr and mass spectral studies.     

Synthesis and spectroscopic characterizations of both 4b,5-dihydro-4b-methyl-11H-isoindolo[2,1-a]benzimidazol-11-ones and 2,3,3a,4-tetrahydro-3a-methyl-1H-pyrrolo[1,2-a]benzimidazol-1-ones

The complete assignment of the ¹H and ¹³C nmr spectra of some derivatives of both 4b,5-dihydro-4b-methyl-11H-isoindolo[2,1-a]benzimidazol-11-one I and 2,3,3a,4-tetrahydro-3a-methyl-1H-pyrrolo[1,2-a]-benzimidazol-1-one II was herein reported by the combined use of one and two-dimensional nmr techniques. Eight compounds, three of which are novel, 2a, 3, 6 , were thus prepared. Their uv and ir spectra were also obtained. In addition, the mass spectra of compounds 1, 2a, 2b, 3 and 6 are reported.     

Addition-rearrangement reactions of 5-imino-Δ3-1,2,4-thiadiazolines with trichloroacetonitrile

The reactions of 2-alkyl-3-phenyl-Δ³-1,2,4-thiadiazolin-5-imines 5a,b with trichloroacetonitrile at room temperature yield rearranged products, which are shown by ¹ H and ¹³C nmr spectroscopy to exist in two tautomeric structures 6 and 7 .     

A regioselective route to 3-alkyl-1-aryl-1H-pyrazole-5-carboxylates: Synthetic studies and structural assignments

Ethyl 2,4-dioxooctanoate ( 1 ) was selectively protected as the 2-(methoxyimino) derivative 2 . When 2 was reacted with phenylhydrazine hydrochloride, ethyl 3-butyl-1-phenyl-1H-pyrazole-5-carboxylate ( 4 ) was favored over the corresponding 5-butyl-1-phenyl-1H-pyrazole-3-carboxylate product 5 by a ratio of at least 6:1, a complete reversal of the regioselectivity observed for 1 . The structures of 4 and 5 were assigned definitively by NOE difference experiments. Regiochemical and configurational assignments of the mono- and bis(methoxyimino) derivatives of 1 were also achieved by ID and 2D ¹H and ¹³C nmr methods.     

Mechanistic observations in the gewald syntheses of 2-aminothiophenes

The Gewald syntheses were employed to prepare a series of 2-amino-3-carboethoxythiophenes, and the syntheses of two of these, namely, the 3,4-trimethylene ( 1f ) and 3,4-tetramethylene ( 1g ) derivatives, were examined in detail. In two preparations of 1f , octahydro-6a-(4-morpholinyl)-2-thioxocyclopenta[b]pyrrole-3-carboxylic acid ( 7 ) was a co-product. The structure of 7 was ascertained from its 300 MHz ¹H nmr and ¹³C nmr spectra, and by its conversion to 1,4,5,6-tetrahydro-2-mercaptocyclopenta[b]pyrrole-3-carboxylic acid ethyl ester ( 8 ). Isolation of 7 and other observations led to postulated mechanisms for three of the Gewald thiophene syntheses.     

Chemistry of thienopyridines. XXXVI. Further studies on nitration in the thieno[2,3-b]- and thieno[3,2-b]pyridine systems

Three compounds, thieno[3,2-b]pyridine 4-oxide, 7-nitrothieno[3,2-b]pyridine 4-oxide ( 1 c), and 6-cyano-thieno[2,3-b]pyridine, undergo nitration by means of a mixture of nitric and sulfuric acids to yield 3,7-dinitro-thieno[3,2-b]pyridine (3%), 3,7-dinitrothieno[3,2-b]pyridine 4-oxide ( 1d ) (26%), and 6-carbamoyl-5-nitrothieno[2,3-b]pyridine ( 6b ) (11%), respectively. Structures of the products were ascertained by spectral means, notably infrared, ¹H nmr, and ¹³C nmr. It is proposed that 1d exists (at least in part) as a tricyclic structure and that 6b may result from an intramolecular mechanism of nitration. An attempt to de-N-oxygenate 1c with excess triphenylphosphine removes more than one oxygen atom per molecule (as triphenylphosphine oxide) without producing an identified thienopyridine product.     

Nuclear magnetic resonance data of pyrido[2,3-B] pyrazines and their σ-adducts with amide ion and water

¹³C nmr spectral data of the parent substance pyrido[2,3-b]pyrazine and several of its derivatives (containing one or more chloro, amino, oxo, bromo, fluoro, phenyl, methyl, hydrazino or t-butyl substituents) are reported. The ¹³C nmr spectrum of the parent substance has been assigned conclusively by ¹³C-labelling. Additionally we proved, the existence of anionic 1:1 σ-adducls i.e., 3-amino-3,4-dihydropyrido[2,3-b]pyrazine, the formation of 3-amino-2-t-butyl-6-chloro-3,4-dihydropyrido[2,3-b]pyrazinide ion and by ¹H nmr spectroscopy 2-amino-1,2-dihydro-3-phenylpyrido[2,3-b]pyrazinide ion. The ¹³C nmr data of the cation of the dihydrale 2,3-dihydroxy-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine, present in a solution of the parent compound in N hydrochloric acid, are given.     

STEREOCHEMICAL PROPERTIES OF THE 1-CHLORO-1- PHENYL-2,5-DIMETHYL-2-PHOSPHOLENIUM ION AND DERIVED OXIDE AND PHOSPHINE

Abstract

The cycloaddition of phenylphosphonous dichloride and trans, trans-2,4-hexadiene, or the addition of chlorine to trans-1-phenyl-cis-2,5-dimethyl-3-phospholene, gave 1-chloro-1-phenyl-2,5-dimethyl-2-phospholenium chloride. This compound shows no evidence in its ³¹P and ¹H nmr spectra for the existence of cis, trans isomers, yet on hydrolysis or dehalogenation with magnesium the resulting oxide and phosphine, respectively, are seen to be isomer mixtures. This phenomenon is explained by a rapid equilibration of the cis, trans form of the I-chloro ion through a pentacovalent species. Structures of the oxides and phosphines were assigned by ¹H and ¹³C nmr relations. The 1-phenyl-cis-2,5-dimethyl-3-phospholenium ion and related compounds were also characterized.     

Reactions of 6-thiotheophylline with alkylating agents and epichlorohydrin: Isolation of S-alkylated 6-thiotheophylline and 7-(2,3-thioepoxypropyl)theophylline

Alkylation of 6-thiotheophylline ( 1 ) under the aprotic basic condition affords S-alkylated 6-thiotheophylline ( 3 ) together with an N⁷ -alkylated product 4 . There is a tendency that the more reactive the alkylating agents are, the higher the yields of S-alkylated products are. On the other hand, treatment of 6-thiotheophylline ( 1 ) with epichlorohydrin afforded an unexpected product, 7-(2,3-thioepoxypropyl)theophylline ( 6 ), neither an S-alkylated compound 3g nor an N⁷ -alkylated compound 4g . The chemical structure was determined by nmr spectroscopic analysis.     

1,6- and 1,7-naphthyridines. II. Synthesis from acyclic precursors

A number of 8-hydroxy-6-methyl-1,6-naphthyridin-5(6H)-one-7-carboxylic acid alkyl esters 3 and the isomeric 5-hydroxy-7-methyl-1,7-naphthyridin-8(7H)-one-6-carboxylic acid alkyl esters 4 were synthesized from acyclic precursors obtained starting from quinolinic anhydride 5. Thus, methanolysis of 5 afforded the hemiester 6 which treated with oxalyl chloride and sarcosine ethyl ester gave 3-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-2-carboxylic acid methyl ester 8. Compound 8 was cyclized to naphthyridines 3a-e with sodium alkoxides. The isomeric naphthyridines 4a-c were obtained by cyclization of the open intermediary 2-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)pyridine-3-carboxylic acid methyl ester 9 obtained by a route that involves treatment of 5 with sarcosine ethyl ester and esterification with diazomethane. Spectroscopic properties (¹H nmr, uv, ir) of compounds 3 and 4 are discussed and confirmed the proposed structures.     

Regioselectivity in lateral deprotonation of an isoxazolecarboxamide of (S)-prolinol. Conformational correlation by crystal structure solid state solution 13C NMR

The conformation at the amide functional group in 3,5-dimethylisoxazole-4-(S-2′-hydroxymethyl-N-pyrrolidino) carboxamide (1) has been determined by a single crystal X-ray determination. The ¹³C nmr in both deuteriochloroform solution and solid state show close agreement. The metalation behaviour of the amide is dependent upon the substitution on the 2′-hydroxymethyl moiety. Dianion studies indicate C-5 lateral metalation under both thermodynamic and kinetic conditions. Protection of this substituent as the methyl ether, 2 , gives rise to predominant C-3 lateral metalation under kinetic conditions and C-5 lateral metalation on equilibration. These observations can be explained using the Ireland-Evans model for chelation directed deprotonation.     

Pyrimidines,Part XXXI . Synthesis,reactions and properties of 6-acyl-1,3-dimethylpyrrolo[2,3-d]pyrimidine-2,4-diones

Acylations of 1,3-dimethyl- ( 1 ) and 1,3,7-trimethylpyrrolo[2,3-d]pyrimidine-2,4-dione ( 2 ) with anhydrides in the presence of trifluoroacetic acid proceed well to give in good yields the corresponding 7-acyl derivatives 3–11 . The 6-trichloroacetyl derivatives 5 and 6 are sensitive towards nucleophiles, which displace the trichloromethyl group easily by formation of the corresponding 6-carboxylic acid derivatives 12–23. The newly synthesized compounds have been characterized by elemental analysis, uv and ¹H nmr spectra and pK_a, determinations.     

A facile synthesis and antimicrobial activity of 2,10‐dichloro‐6‐(aryloxy/thiophenoxy)‐4,8‐dinitrodibenzol[d,g][1,3,6,2]‐dioxathiaphosphocin‐ 6‐oxides

Novel 6‐substituted 2,10‐dichloro‐4,8‐dinitrodibenzo[d,g][1,3,6,2]dioxathiaphosphocin‐6‐oxides 4 were synthesized by reacting 5,5′‐dichloro‐3,3′‐dinitro‐2,2′‐dihydroxydiphenyl sulfide ( 2 ) with different aryl phosphorodichloridates, trichloromethylphosphonic dichloride and O‐2‐chloroethyl phosphoryldichloride (3) in the presence of triethylamine at 55–60°. Some of these compounds are prepared by reacting the monochloride, 2,6,10‐trichloro‐4,8‐dinitrodibenzo[d,g][1,3,6,2]dioxathiaphosphoein‐6‐oxide ( 5 ) in situ with substituted phenols and thiols. 5 is prepared by condensing 2 with phosphorus oxychloride. The ¹H nmr chemical shifts of the dibenzodioxathiaphosphocin moiety indicates the presence of more than one conformer in solution. However the presence of more than one conformer in each example cannot be entirely eliminated. Interestingly 4d on oxidation to 12‐sulphone by H₂O₂ in acetic acid medium yielded only 12‐sulphoxide 6a . The ir, ¹H, ¹³C, ³¹P nmr and mass spectral data are discussed. Some of these compounds were screened for antifungal activity against Curvularia lunata and Aspergillus niger and antibacterial activity on Bacillus subtilis and Klebsiella pneumoniae. A few of them possess significant activity.     

Synthesis of some substituted tetrahydropyrimido[4,5-b][1,6]naphthyridines as potential antitumor agents

Cyclocondensation of two disubstituted 6-aminopyrimidines 11 and 12 with 1-benzyl-3-hydroxymethylene-4-piperidone afforded new tricyclic, linear disubstituted 6,7,8,9-tetrahydropyrimido[4,5-b][1,6]naphthyridines 4 and 5 respectively. Similar cyclocondensation of 11 with 1-benzoyl-1,2,3,6-tetrahydropyridine-5-carboxalde-hyde gave the corresponding benzoylated tetrahydropyrimido[4,5-b][1,6]naphthyridine 6 . Debenzoylation of 6 afforded 7 . 1-Benzyl-3-aminomethylene-4-piperidone when cyclocondensed with 11 also afforded 4 . The linear structures were established by ¹H nmr and ¹³C nmr. The growth of leukemia L1210 cells in culture was inhibited about 50% by 4,5,6 and 7 at 100 μM.     

Synthesis and exchange reactions of 5-alkyl-2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acids

An improved preparation of 2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acid 3, a potent inhibitor of dihydroorotase is presented. Trans-5-alkyl-2-oxo-6-thioxohexahydropyrimidine-4-carboxylic acids 12a-c were synthesised via the thiation of the p-methoxybenzyl esters of 5-alkyldihydroorotic acids with Lawesson's reagent followed by subsequent de-protection. The corresponding cisisomers were prepared by reduction of 5-alkyl-6-thioxoorotic acids with zinc in acetic acid. The stability and exchange reactions of 12a-c under physiological conditions were investigated by ultra-violet and ¹H nmr spectroscopy. The attempted synthesis of 16 , a fused cyclopentyl derivative of 3 is also presented.     

Die Hydrolyse des 1, 1, 3, 3-Tetrakis(dimethylamino)-1λ5, 3λ5-diphosphets

Hydrolysis of 1,1,3,3-Tetrakis(dimethylamino)-1λ⁵, 3λ⁵ -diphosphete Hydrolysis of 1,1,3,3-Tetrakis(dimethylamino)-1λ⁵, 3λ⁵ -diphosphet ( 2 ) yields in the first step Bis(dimethylamino)phosphorylmethyliden-methyl-bis(dimethylamino)phosphorane ( 5 ). In the second step Bis(dimethylamino)phosphoryl-methyl(dimethylamino)phosphosphonylmethylen ( 6 ) is the main product of hydrolysis. In addition small amounts of methylphosphonic-bis(dimethylamide) ( 7 ) are formed. Properties, nmr and mass spectra of 5 and 6 are described, their mechanism of formation is discussed.     

The synthesis of imidazole-2-thione nucleosides

Ribosylation of the trimethylsilyl derivative ( 1b ) of imidazole-2-thione ( 1a ) using either stannic chloride or silver perchlorate as catalyst resulted in the formation of the acylated derivatives of 1-(β-D-ribofuranosyl)imidazole-2-thione ( 3c ) and 1,3-di-(β-D-ribofuranosyl)imidazole-2-thione ( 4c ) with the latter predominating ( 4c:3c , ca. 2:1 ). The diribosylated nucleoside 4c was shown to be the N,N-disubstituted product rather than the N,S-disubstituted product by ¹H nmr and ¹³C nmr spectroscopy. Employment of the iodine-catalyzed fusion procedure reversed the aforementioned product ratios and provided the monoriboside 3c in excellent yield. When the trimethylsilyl derivative ( 5b ) of 2-methylthioimidazole ( 5a ) was reacted with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2d ) in acetonitrile, the major product was 1,3-di-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-imidazole-2-thione ( 4b ). The formation of 4b in this reaction is thought to arise via the Hilbert-Johnson mechanism.     

Nitrogen bridgehead compounds. Part 72 Straightforward synthesis of 1,2,3,4-tetrahydrorutaecarpine and derivatives

In polyphosphoric acid, the Fischer indolization of 6-arylhydrazono-1,2,3,4,6,7,8,9-octahydro-11H-pyrido-[2,1-b]quinazolin-11-ones, obtained from 1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1-b]quinazolin-11-ones by three pathways, afforded substituted 1,2,3,4,7,8-hexahydro-5H-13H-indolo[2′,3′:3,4]pyrido[2,1-b]quinazolin-5-ones in high yields. The structures of the 6-substituted octahydropyridoquinazolinones and hexahydroindo-lopyridoquinazolinones were characterized by uv, ¹H and ¹³C nmr data.