as-Triazine chemistry. V.The oxidative ring-opening of 5,6-diphenyl-as-triazine-3(2H)-ones with Organic Peracids

The structures of the oxidation products of 5,6-diphenyl-as-triazine-3(2H)-ones (Ia-b) with organic peracids were chemically and spectroscopically reinvestigated and it was concluded that the products were 1,4-dibenzoyl semicarbazide (IIa) and the 2-methyl analogue (IIb).     

The synthesis of benzofuroquinolines. I. Some benzofuro[2,3-b]quinoline and benzofuro[3,2-c]quinoline derivatives

Benzofuro[2,3-b]quinoline ( Ia ) and its 11-methyl derivative ( Ib ) were synthesized by demethylcyclization of 3-(o-methoxyphenyl)-1,2-dihydroquinolin-2-ones (VIa,b). Benzofuro[2,3-b]quinoline-11-carboxylic acid (Id) was synthesized by chlorination followed by the action of potassium hydroxide of a lactone (IX) prepared by demethyl-cyclization of 3-(o-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-4-carboxylic acid (VIII). Isomeric benzofuro[3,2-c]quinoline (Ha) and its 6-methyl derivative (IIb) were synthesized by demethyl-cyclization of 3-(o-methoxyphenyl)-1,4-dihydroquinolin-4-ones (XIa,b). Both the methyl derivatives (Ib and IIb) were converted to the carboxylic acids (Id and IId) through condensation with benzaldehyde followed by oxidation. The benzofuroquinolines (Ia,b,d and IIa,b) thus obtained were oxidized to the corresponding N-oxides (IIIa,b,d and IVa,b).     

1,2,4-Triazoles. V. Nuclear magnetic resonance study of N-Methyl derivatives of 1,2,4-triazoles

The chemical shifts of the N-methyl protons of a number of N-methylated-1,2,4-triazoles were studied. Substitution of methyl and methylthio groups in position 3 causes upfield shifts of the N-methyl signals, while substitution of α-pyridyl, γ-pyridyl, and phenyl groups causes downfield shifts. In 3,5-disubstituted 1,2,4-triazoles, substituents in positions 3 and 5 have additive effects on the chemical shifts of N-methyl groups, so that the chemical shifts of the N-methyl groups of such compounds can be calculated. In this way, it was possible to assign the peaks of mixtures of N-monomethylated derivatives obtained by methylation of 1,2,4-triazoles.     

Reactions with heterocyclic amidines. VI. Synthesis and chemistry of pyrazol-5-yl,and 1,2,4-triazol-5-ylhydrazonyl chlorides

The 4-bromo-3-phenylpyrazol-5-ylhydrazonyl chlorides (Ia,b) and 1,2,4-triazol-5-ylhydrazonyl chlorides (IIa,b) were prepared via coupling of diazotized 4-bromo-3-phenyl-5-aminopyrazole (III) and 5-amino-1,2,4-triazole (IV) with α-chloro derivatives of acetylacetone and of ethyl aceto-acetate. Compounds Ia and IIa,b were utilised for the synthesis of several new heterocyclic derivatives.     

Novel Copolymers of Styrene. 1. Alkyl Ring-Substituted Butyl 2-Cyano-3-Phenyl-2-Propenoates

Novel trisubstituted ethylenes, alkyl ring-substituted butyl 2-cyano-3-phenyl-2-propenoates, RPhCH=C(CN)CO₂C₄H₉ (where R is 2-methyl, 3-methyl, 4-methyl, 2-ethyl, 4-ethyl, 4-butyl, 4-t-butyl, 4-i-butyl) were prepared and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and butyl cyanoacetate, and characterized by CHN analysis, IR, ¹H and ¹³C-NMR. All the ethylenes were copolymerized with styrene (M₁) in solution with radical initiation (ABCN) at 70°C. The compositions of the copolymers were calculated from nitrogen analysis and the structures were analyzed by IR, ¹H and ¹³C-NMR. The order of relative reactivity (1/r₁) for the monomers is 4-ethyl (4.69) > 3-methyl (4.18) > 4-t-butyl (2.98) > 2-ethyl (2.52) > 4-butyl (2.47) > 4-methyl (1.86) > 4-i-butyl (0.94) > 2-methyl (0.87). Decomposition of the copolymers in nitrogen occurred in two steps, first in the 200–500°C range with residue (3–8% wt), which then decomposed in the 500–800°C range.     

Tautomer chemistry of thiazolidines. 1-Thia-4-azaspiro[4,5] decanes

The thiazolidine, 1-thia-4-azaspiro[4,5] decane (Ia), which is derived from cyclohexanone and 2-aminoethanethiol (X), forms a thiazolidone (VIII) with mercaptoacetic acid more slowly and in lower yield than with 2-phenylthiazolidine, a case reported previously. A thiazolidine which is related to a non-conjugate chain tautomer such as Ic, might be expected to behave in this way. Alkylation, as another possible example of tautomer chemistry, was studied, and N-, S-, and C-alkylation were all observed under varying circumstances. Thus, thiazolidine la undergoes alkylation with methyl iodide in ethanol to form the N-methylthiazolidine (IIa), and in sodium-liquid ammonia to give the S-methyl derivative (III). In the latter case, alkylation occurs with reductive cleavage. Although no trace of other tautomer derivatives (IV, V) was to be found in the methyl iodide alkylation, I with acrylonitrile did in fact give C-alkylation. An analytically pure mixture of tautomers was obtained, from which 2-oxocyclohexanepropionitrile (VI) was isolated on hydrolysis. In a manner similar to the formation of III, IIa was S-alkylated by treatment with sodium-liquid ammonia followed by benzyl chloride to give a saturated product (XVII). Although such a process might be identified with a chain tautomer (IIb), the evidence is to the contrary, since the intermediate (XIV), which might be involved in such a process, fails to undergo a similar reduction with sodium-liquid ammonia. A greatly improved procedure for the preparation of thiazolidine (XI, 86% yield) is also reported.     

Studies on the syntheses of analgesics. Part XXXI. Synthesis of 1,2,3,4,5,6-Hexahydro-3-methyl-6-phenyl-2,6-melhano-2,3-benzo[g] diazocine [studies on the syntheses of heterocyclic compounds. Part CDLXXIX]

1,2,3,4,5,6 Hexahydro-8-methoxy-3-methyl-6-phenyl-2,6-methano-2,3-benzo[g]diazocine (IIa) was synthesized from 1-(3-methoxyphenyl)phenylaeetonitrile (III), readily available by the benzyne reaction of o-chloroanisole with phenylacetonitrile, through several steps. Treatment of IIa with 47% hydrobromic acid afforded 1,2,3,4,5,6-hexahydro-8-hydroxy-3-methyl-6-phenyl-2,6-methano-2,3-benzo[g]diazocine (IIb).     

Novel Copolymers of 4-Fluorostyrene. 1. Alkyl Ring-Substituted 2-Phenyl-1,1-dicyanoethylenes

Novel copolymers of trisubstituted ethylene monomers, alkyl ring-substituted 2-phenyl-1,1-dicyanoethylenes, RC₆H₄CH = C(CN)₂ (where R is 2-methyl, 3-methyl, 4-methyl, 4-ethyl, 4-i-propyl, 4-butyl, 4-i-butyl, and 4-t-butyl) and 4-fluorostyrene were prepared at equimolar monomer feed composition by solution copolymerization in the presence of a radical initiator (ABCN) at 70°C. The composition of the copolymers was calculated from nitrogen analysis, and the structures were analyzed by IR, ¹H and ¹³C-NMR. The order of relative reactivity (1/r ₁) for the monomers is 4-ethyl (42.6) > 4-butyl (29.4) > 4-t-butyl (26.7) > 4-i-butyl (1.6) > 4-i-propyl (1.29) > 3-methyl (1.26) > 2-methyl (0.8) > 4-methyl (0.4). High T _g of the copolymers, in comparison with that of poly(4-fluorostyrene) indicates a substantial decrease in chain mobility of the copolymer due to the high dipolar character of the trisubstituted ethylene monomer unit. Decomposition of the copolymers in nitrogen occurred in two steps, first in 183–500°C range with residue (5–30% wt.), which then decomposed in the 500–800°C range.     

Furopyridines. III. A new synthesis of furo[3,2-b]pyridine

A convenient synthesis of furo[3,2-b]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxypiconate ( 1 ) is described. The hydroxy ester 1 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 2a or 2b . Cyclization of compound 2a afforded ethyl 3-hydroxyfuro[3,2-b]pyridine-2-carboxylate ( 3 ) which in turn was hydrolyzed and decarboxylated to give furo[3,2-b]pyridin-3-(2H)-one ( 4a ). Cyclization of 2b gave the 2-methyl derivative 4b . Reduction of 4a and 4b with sodium borohydride yielded the corresponding hydroxy derivative 5a and 5b respectively, which were dehydrated with phosphoric acid to give furo[3,2-b]pyridine ( 6a ) and its 2-methyl derivative ( 6b ). 2-Acetylpyridin-3-ol ( 8 ) was converted to the ethoxycarbonylmethyl ether ( 9 ) by O-alkylation with ethyl bromoacetate, which was cyclized to give 3-methylfuro[3,2-b]pyridine-2-carboxylic acid ( 10 ). Decarboxylation of 10 afforded 3-methylfuro[3,2-b]pyridine ( 11 ).     

Application of photoelectron spectroscopy to biologically active molecules and their constituent parts. II. 1,4-Benzodiazepines

The Hel photoelectron (PE) spectra of 5-phenyl-7-chloro-2H-1,4-benzodiazepin-2-one ( 1 ), its 1-methyl derivative ( 2 ), 3-hydroxy derivative ( 3 ), 1-methyl-3-hydroxy derivative ( 4 ), 3-(S)-methyl derivative ( 5 ), and 1-methyl-3-(S)-methyl derivative ( 6 ) have been recorded. The electronic structure of these compounds is discussed on the basis of the observed ionization energies, and of the semiempirical CNDO/2 calculations on model compounds 1a-6a , which have a hydrogen instead of the phenyl group in the 5-position. As a result the character of the seven highest occupied orbitals in 1–6 have been assigned.     

Furopyridines. xvi. Photo[2+2]cycloaddition of furo-[3,2-c]pyridin-4(5H)-one with acrylonitrile

The photocycloaddition of furo[3,2-c]pyridin-4(5H)-one (1) and its N-methyl derivative (1-Me) to acrylonitrile has been studied. The structures of the photoadducts isolated by column chromatography were determined on the basis of the nuclear magnetic resonance spectroscopy. The cycloaddition of 1 afforded an adduct 2 at the carbonyl oxygen and four possible isomers 3a, 3b, 3c and 3d of cyclobutane-fused adduct at the 6- and 7-position of 1 , and the addition of 1-Me the N-methyl derivatives 3a-Me, 3b-Me, 3c-Me and 3d-Me.     

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 .     

P-N compounds. 30. Phosphaminimides. 5. N-phosphinylimino-1,2,5,6-tetrahydropyridines

N-[ (Diethoxyphosphinyl)imino] and N-[ (diphenylphosphinyl)imino]-5-methyl-1,2,5,6-tetrahydropyridines were prepared by sodium borohydride reduction of the corresponding pyridinium and 3-methyl pyridinium inner salts. The carbonyl analog of this latter precusor was resynthesized and its structure completely verified.     

Substitution in the hydantoin ring. Part IX. N-cyanohydantoins

The N₁-and N₃-cyanohydantoins, a new series of derivatives, were prepared by reaction of the parent hydantoin with a base and a cyanogen halide. Analysis of ir, pmr, and mass spectral data allowed the assignment of ring position-3 to the cyano group in derivatives IIa,b of 1,3-unsubstituted hydantoins. 3-Cyanohydantoins can transfer the cyano substituent to strong nucleophiles via an addition-elimination process.     

Novel copolymers of styrene. 1. Alkyl ring-substituted propyl 2-cyano-3-phenyl-2-propenoates

Trisubstituted ethylenes, alkyl ring-substituted propyl 2-cyano-3-phenyl-2-propenoates, RPhCH?C(CN)CO₂C₃H₇ (where R is H, 2-methyl, 3-methyl, 4-methyl, 4-ethyl, 4-propyl, 4-i-propyl, 4-butyl, 4-i-butyl, 4-t-butyl) were prepared and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and propyl cyanoacetate, and characterized by CHN analysis, IR, ¹H and ¹³C-NMR. All the ethylenes were copolymerized with styrene (M₁) in solution with radical initiation (ABCN) at 70°C. The compositions of the copolymers were calculated from nitrogen analysis and the structures were analyzed by IR, ¹H and ¹³C-NMR. Decomposition of the copolymers in nitrogen occurred in two steps, first in the 250–500°C range with residue (2–4% wt.), which then decomposed in the 500–800°C range.     

Synthesis of some new 5-chloro-7-mercapto-1-methyl/phenyl-1,2,4-triazolo[4,5-b]pyrazin-2(1H)-ones and 5-chloro-3-thiopyrazin-2(1H)-one derivatives as possible antibacterial and antifungal agents

Several new 5-chloro-7-mercapto-1-methyl/phenyl-1,2,4-triazolo[4,5-6]pyrazin-2(1/H)-ones V and their disul-phides VI, 5-chloro-3-mercapto-2(1H)-pyrazinonones III, 5-chloro-3-(N-aryl-N-acetylthioureido)-1-methyl/-phenyl-2(1H)-pyrazinones VII, 5-chloro-1-methyl/phenyl-3-sulphonamido-2(1H)-pyrazinones X and chloro-2-methyl/phenyl-(3-methyl)-3-thio-2(1H)-pyrazinones XI were synthesized starting from 3,5-dichloro-1-methyl/phenylpyrazin-2(1H)-ones I. Fifteen of these compounds were screened for their antibacterial and antifungal activity against two bacteria B. subtilis and S. aureus, and two fungi A. niger and H. oryzae. A possible structure activity relationship is given.     

Three novel anabaenopeptins from the cyanobacterium Anabaena sp.

Three new cyclic peptides, anabaenopeptins NZ825, NZ841, and NZ857, were isolated from the hydrophilic extract of the cultured cyanobacterium Anabaena sp. The planar structure of the compounds was determined by homonuclear and inverse-heteronuclear 2D-NMR techniques as well as high-resolution mass spectrometry. The absolute configuration of the asymmetric centers was studied using Marfey's method for HPLC. This is the first report of anabaenopeptins that contain N-methyl glycine instead of the common N-methyl alanine. The incorporation of N-methyl glycine into the cyclic portion of the compounds results in their appearance as a mixture of two, equally stable, conformers, instead of the one distinct conformer in anabaenopeptins that contain N-methyl alanine or N-methyl homotyrosine. The three compounds were tested for inhibition of serine proteases and found to be not active.     

Chromium trioxide oxidation products from 4-spiro-1-phenylisochromans

Chromium trioxide oxidation of 1-phenylisochroman-4-spiro-1′-cyclopentane (Ia) in acetic acid led to the expected 1-(2-benzoylphenyl)cyclopentanecarboxylic acid (IIa), while its 6,7-dimethoxy analogue Ib and 6,7-dimethoxy-1-phenylisochroman-4-spiro-4′-(1′-methyl)piperidine (Ic) under the same conditions gave a mixture of their related 1-hydroxy derivatives VIIIb and VIIIc and of the p-benzoquinones, 1-benzoyloxymethyl-1-(2,5-dioxo-4-methoxyphenyl)cyclopentane (IXb) and 1-benzoyloxymethyl-1-(2,5-dioxo-4-methoxyphenyl)-1-methylpiperidine (IXc). Cyclization of Ila with hydrazine or monomethylhydrazine led to the 5-spiro-substituted 1-phenyl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones IIIa or XIa.     

An experimental and theoretical study of dipole moments of N-alkyl-1,3-bis-(p-chlorophenyl)triazenes and 1-(3,4-dimethyl-5-isoxazolyl)-3-aryltriazenes

The dielectric constants, densities, and the refractive indices of dilute benzene solutions have been used to obtain the experimental dipole moments of 1,3-diphenyltriazene (1a), 1,3-diphenyl-3-methyltriazene (Ib), 1,3-bis(p-chlorophenyl)triazene (IIa), its N-alkyi derivatives (IIb-IIg), and 1-(3,4-dimethyl-5-isoxazolyl)-3-phenyltriazene (IIIb) and its N-methyl derivative (IIIc). The results show that the dipole moment of IIa is increased by an increment of about 0.77 D (average value for methyl, ethyl, n-propyl, allyl, and benzyl) on N-alkyl substitution. The increment for the n-butyl group is Δμ = 1.19 D. Some of the experimental values are compared with those from PPP and CNDO/2 calculations.     

Reactions with diazoazoles. Part VI. Unequivocal synthesis of 3-methyl-3h-azolotetrazoles. Correction of the formerly described 3-methylazolotetrazoles in favour of mesoionic 2-methylazolotetrazoles

3-Methyl-3H-pyrazolo[1,5-d]tetrazoles 2 and 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) have been unequivocally synthesized by annulation of the tetrazole moiety to the pyrazole resp. 1,2,4-triazole system. The constitution of some N-methyl substituted azolotetrazoles, formerly described as 3-methyl-3H-pyrazolo[1,5-d]tetrazoles 2, 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) and 1-methyl-6-phenyl-1H-1,2,4-triazolo[4,3-d]tetrazole (5), has to be revised in favour of the corresponding mesoionic 2-methyl derivatives 2′, 4′, 5′. The structures of 3-methyl-3H- as well as of 2-methyl-2H-pyrazolo[1,5-d]tetrazole derivatives 2a, 2c, 2′a have been determined by X-ray analyses. The azapentalenic system is aromatic in all three measured compounds and mesoionic in the case of the 2-methyl-2H- substitution pattern. The phenyl and ester substituents are coplanar with the azapentalene system. 3-, 2-, and 1-Methylpyrazolo[1,5-d]tetrazoles exhibit different behaviour when allowed to react with stannous chloride or sodium ethoxide. Azolotetrazoles with a methyl substituent at N-1, N-2 or N-3 of the tetrazole moiety can be distinguished by a combination of ¹H and ¹³C nmr with respect to the chemical shifts of the N-methyl group and the bridgehead carbon. Results of semiempirical calculations of the pyrazolo[1,5-d]tetrazole anion and of its N-methyl derivatives are discussed.