Baeyer-villiger oxidation of C19-nor Ketosteroids

The Baeyer-Villiger oxidation of 1 in chloroform with perbenzoic acid yielded 3,4, 5, 7 and 8. Similarly, the ketone 2 provided 9 and 10. The mechanism involved in the formation of abnormal Baeyer-Villiger products has been suggested.     

Die photolytische α-spaltung von benzoinalkyläthern in sauerstoffhaltigem methanol

The primary step in the photolytical α-cleavage of benzoin alkyl ether in oxygen saturated methanol at room temperature is the formation of a benzoyl (1) and an α-alkoxybenzyl radical (2), which react via their peroxi radicals 3 und 4 to the final products yielding perbenzoic acid (5), alkyl benzoate (7), benzaldehyde (11), benzaldehyde dimethylacetal (10) and benzil to 100%. Product analysis of the final products of the photolysis of specifically deuterated benzoin methyl ethers shows that methyl benzoate, benzaldehyde and benzaldehyde dimethylacetal are formed via the α-methoxybenzyl radical (2) while the perbenzoic acid results from the benzoyl radical (1). Both the peroxi radicals 3 and 4 have an independent reaction pathway to the final products. Hydrogen abstraction of 3 and 4 from the solvent methanol give rise to hydroxy methyl radicals which yields formic acid, hydrogen peroxide, performic acid and formaldehyde via their hydroxy methyl peroxi radicals. The reaction pathway of the primary radicals is discussed.     

Studies in sesquiterpenes—L : 3-hydroxylongifolaldehyde,the elusive intermediate in the abnormal perbenzoic acid oxidation of longifolene

The isolation and stereochemistry of 3-hydroxylongifolaldehyde (4), the missing key-compound in the earlier proposed mechanism for the abnormal perbenzoic acid oxidation of longifolene is described. Rearrangement of hydroxyaldehyde (4) to hydroxyketone (6) during exposure to LAH is reported.     

Specific features of the reactions of quinazoline and its 4-hydroxy and 4-chloro substituted derivatives with C-nucleophiles

Reactions of quinazoline 1 with indole, pyrogallol and 1-phenyl-3-methylpyrazol-5-one in the presence of acid led to C-4 adducts 2, 3 and 5. Adduct 4 is formed by heating 1 with 1,3-dimethylbarbituric acid without acid catalysis. 1-Phenyl-3-methylpyrazol-5-one reacts with 1 without acid catalysis to form dipyrazolylmethane 6. 4-Chloroquinazoline 8 reacts with 1-phenyl-3-methylpyrazol-5-one to form 4-(1-phenyl-3-methyl-5-oxopyrazol-4-yl) quinazoline 9 and dipyrazolylmethane 6. Heating 8 with 2-methylindole leads to the formation of 4-(2-methylindol-3-yl) quinazoline 10 and tris(2-methylindol-3-yl)methane 11.     

Knoevenagel condensation of 2-carbethoxycyclohexanone and malononitrile: Synthesis of 4-cyano-3-ethoxy-1-hydroxy-5,6,7,8-tetrahydroisoquinoline,an isomer of the abnormal product

The structure of the abnormal product 1a formed in the Knoevenagel condensation of 2-carbethoxycyclohexanone and malononitrile has been further confirmed. Oxidation of the tetrahydroisoquinoline 3b using Na₂Cr₂O-AcOH-H₂SO₄ gave the keto isoquinoline 3d and the isoquinoline-1-carboxylic acid 5a. The acid chloride of 5a was condensed with diethyl ethoxymagnesiomalonate to afford after decarbethoxylation the methyl ketone 5d which on Baeyer-Villiger oxidation gave a mixture of the acetate 1g and the title compound 1b. The unambiguous synthesis of 1b confirms the structure assigned earlier to the title compound also formed during the partial hydrolysis of the diethoxy compound 1c. Condensation of 2-acetylcyclohexane-1,3-dione with malononitrile gave the quinoline derivative 4c which on ethylation yielded the ketoquinoline 4d. The present studies have confirmed that the quinoline compound 4a is also formed in the condensation of 2-acetylcyclohexanone and cyanoacetamide.     

Synthesis of labda-8(17),13(14)-diene-15,16-olide and 15,16-epoxy-labda-8(17),13(16)-14-triene and their rearrangement to clerodane derivatives

The title compounds 1b and 1c were synthesized from manool. On treatment with either trifluoroacetic acid or formic acid 1b provided in nearly 100% yield 4a with a rearranged labdane skeleton. With sulfuric acid, however, 1b gave solely Δ^8,9-isomer 5. Reduction of 4a with lithium diisobutylaluminum hydride afforded 4b. On treatment with sulfuric acid 4a reverted to 5. Rearrangement of the epoxide 6 with boron trifluoride- etherate led to a complex product mixture from which no pure substance was obtained.     

A study of the reaction of 2-thiazolin-4-ones with some electrophiles under microwave irradiation versus conventional condition

Coupling of 5-dimethylaminomethylene-3-methyl-2-(pyridine-2-ylimino)-thiazolidin-4-one (3) with diazotized methyl anthranilate afforded the 3-methyl-5-(2-methoxycarbonylphenylhydrazono)-2-pyridine-2-ylimino)thiazolidin-4-one (5). Reaction of 2-(arylamino)thiazol-4-ones 1a,b with arylidenemalononitriles under microwave irradiation gave 2-substituted amino-5-arylidenethiazolin-4-ones 9a–f. Alternatively, compound 9 could also be obtained by reacting compound 1 with aromatic aldehydes. Treatment of compound 9 with acetic acid yielded the corresponding thiazolin-2,4-diones 10. However, the reaction of 1 with cyanoacetic acid yielded the corresponding 4-cyanoacetyl derivative 12, in good yield. The ¹H, ¹³C NMR spectra of some representative products and X-ray crystal structure determination are discussed.     

Reactions with β-cyanoethylhydrazine—II: Synthesis of some 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine derivatives

β-Cyanoethylhydrazine 1 reacts with benzoylacetonitrile 2 in refluxing ethanol to yield 5-amino-1-β-cyanoethyl-3-phenylpyrazole 4; in acetic acid acetyl-β-cyanoethylhydrazone 8 was obtained. Compounds 4 and 8 were readily cyclized into 2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-5-one 5 by acetic acid-hydrochloric acid. 3-p-Chlorophenylazo-2-phenyl-4,5,6,4-tetrahydropyrazolo[1,5-a]pyrimidin-5-one 15 was synthesized by the action of 1 on the p-chlorophenylazo derivative of 2 and cyclization of the resulting aminopyrazole 12 by concentrated sulphuric acid. The arylidene derivative of benzoylacetonitrile 16 reacts with 1 in acetic acid to yield the correspondings β-cyanoethylhydrazones 17. Cyclization of 17 with acetic acid-hydrochloric acid led to the formation of the pyrazolo (1,2-b) pyrazole derivative 19. On the other hand, the 1-β-carboxyethylpyrazole derivative 20 was obtained by the action of 3% aqueous NaOH.     

Solvent-dependent reactivities of acyclic nitrones with β-diketones: catalyst-free syntheses of endiones and enones

Reactions of the nitrones ^?O⁺N(Me)C(H)Ar 1 (Ar=phenyl 1a, 4-methylphenyl 1b, 2,4,6-trimethylphenyl 1c, and anthracen-9-yl 1d) with the cyclic β-diketones 1,3-indandione 2 or barbituric acid 3 in CH₂Cl₂, afford the corresponding endiones 2′a–2′d or 3′a–3′d. In contrast, dimedone 4 reacts with 1a or 1b to give the endione 4′a or 4′b and the bis-adduct 4″a or 4″b. Nevertheless, reaction of 4 with 1c or 1d in CH₂Cl₂ furnishes only the endione adducts 4′c or 4′d. However, the reaction of 4 with 1a or 1b in methanol gives only 4″a or 4″b, respectively. Among acyclic β-diketones only malonic acid 7 reacts with 1a–1c. Reaction of 7 with 1a in CH₂Cl₂ forms cinnamic acid 7″a, whereas in the case of 1b, the endione 7′b and (E)-3-p-tolylacrylic acid 7″b are obtained. The nitrone 1c reacts with 7 in CH₂Cl₂ to afford the endione 7′c or with acetone yielding (E)-4-mesitylbut-3-en-2-one 8. X-ray analyses are reported for 4′c, 5, and 7″b. In addition, the calculated acidity of the hydrogen at the α-C atom is shown to correlate with the reactivity of the β-diketones with nitrones.     

The baeyer-villiger reaction of strained cage compounds, 1,3-bishomocubanones,via carbocations

The Baeyer-Villiger oxidation of 1,3-bishomocubanone 1a in chloroform with m-chloroperbenzoic acid (m-CPBA) at room temperature proceeds quite rapidly and gives the ordinary lactone, 10-oxapentacy-clo[5.4.0.0^2.5.0^3.9.0^4.8]undecan-11-one 2a and the skeletal rearrangement product, 11-oxapentacy-clo[6.3.0.0^2.4.0^3.7.0^5.9]undecan-10-one 4a. Methyl substituted homologs (1d, 1e, 1f) of 1a give the corresponding ordinary and rearranged lactones (2d, 2e, 2f, 4d, 4e, 4f). In these oxidations, the mechanism via carbocations, cyclobutyl 18 and cyclopropylcarbinyl cations 19, plays a major role different from the ordinary concerted migration mechanism. Solvent effects, kinetic treatments, and methyl substituent effects on product ratios support this carbocation mechanism. The adduct formation process between a ketone and m-CPBA must be rate-determining.     

Phosgenation of benzyltetrahydroisoquinolines: A new method of berbines and berbin-8-ones synthesis

A novel synthesis of the berbine ring skeleton by the way of the berbin-8-ones is reported. Treatment of 1-benzyl-1,2,3,4-tetrahydroisoquinolines 1a-d with phosgene gas gave a new series of N-chloroformyl derivatives 2a-d. Intramolecular ring closure of these compounds in presence of a Lewis acid catalyst afforded berbin-8-ones 3a-d in good yield. The choice of the cyclization catalyst is discussed. Reduction of products 3a-d with lithium aluminium hydride gave the berbines 4a-d. Hydrolysis of berbines 4b,c gave the new 3-hydroxyberbines 4e,f. Preparation of new starting benzyltetrahydroisoquinolines 1b,c are described.     

Studies on organophosphorus compounds—XXXVI: Simple new routes to phosphorins from 2-hydroxy-, 2-mercapto-, and 2-aminobenzoic acids and their derivatives

2-Hydroxybenzoic acid heated with 2,4 - bis(4 - methoxyphenyl) - 1,3,2,4 - dithiadiphosphetane - 2,4 -disulfide, 1, gave 2 - (p - methoxyphenyl) - 4$\text{H}$ - 1,3,2 - benzoxathiaphosphorin - 4 - one 2 - sulfide, 3, and its thio-analogue, 4, while its ethyl or phenyl esters gave 4 as the sole product. 2 - Mercaptobenzoic acid and its ethyl ester when heated with 1 produced 3$\text{H}$ - 1,2 - benzodithiole - 3 - one, 8, 3$\text{H}$ -1,2 - benzodithiole - 3 - thione, 9, and 2- (p - methoxyphenyl) - 4$\text{H}$ - 1,3,2 - benzodithia - phosphorin - 4 - one 2 - sulfide, 10. The reaction of 2 -aminobenzoic acid with 1 gave 1,2 - dihydro - 2 - (p - methoxyphenyl) - 4$\text{H}$ - 3,1,2 - benzoxaphosphorin - 4 - one 2 - sulfide, 12. Reactions of 1 with methyl 2 - aminobenzoate and 2 - aminobenzamides are described. Mechanistic considerations for the formation of the heterocyclic phosphorus compounds are presented.     

2,5,5-Trimethyl-2-oxazolin-4-one,its perchlorate,and α-acetoxyisobutyronitrile by acetylation of acetone cyanohydrin

Acetone cyanohydrin (1) yields on acylation and ring closure with anhydrides and perchloric acid. 2-oxazolin-4-onium perchlorates 5a, 5c or 5d. The same perchlorates (5a, 5b) may be obtained under similar conditions from acyloxy-nitriles (2) or -amides (4). Perchlorates 5 may be deprotonated in pyridine to 2-oxazolin-4-ones (6), but in aqueous solution they undergo ring opening to acyloxy-amides 4a.c.d. or to N-benzoyl-α-hydroxy-isobutyramide 7b.     

The reaction of N-cyanoamines with 1-(t-butyl)-3,3-diphenylaziridinone: A general method for the synthesis of 1-alkyl-, 1-aralkyl- and 1-aryl-5,5-diphenylhydantoins and -glycocyamidines

N-Cyanomanines react with aziridinone1 to yield the amides2. Base catalysed ring closure of the latter furnished the glycocyamidines3. Acid catalysed de-t-butylation, and deimination combined with de-t-butylation of the compounds3 leads to 1-substituted 5,5-diphenylglycocyamidines (4) and -hydantoins (5), respectively. Part of the hydantoins5 were also directly obtained by hydrochloric acid treatment of amides2. Selective de-t-butylation in position 3 of the glycocyamidine3 (R = t-Bu) was brought about by heating with methanolic NH₃ in the presence of NH₄I. Reaction of1 with the un substituted N-cyanoamine furnished carbodiimide7 which was cyclized to the glycocyamidine8. The mass spectra of some glycocyamidines4 and hydantoins5, as well as of compounds7 and8 are discussed.     

Phosphoramides—V: Synthesis of 4,6-bis(dimethylamino)thieno[2,3-b]pyridines by an HMPT induced ring closure reaction

2-Acetamido-3-thiophenecarboxylic acid ethyl esters 1 have been heated in HMPT to reflux temperature to produce 4,6-bis(dimethylamino)thieno[2,3-b]pyridines 7. Substituents in the 4 position of the thiophene ring were found to exert steric hindrance on the reaction. Only a multistep mechanism can account for the product 7. The intermediates 2–5 were also isolated in the reaction of 1a with HMPT.     

Masked constrained cysteines: diastereoselective and enantioselective synthesis of 1-amino-2-mercaptocyclopropanecarboxylic acid derivatives

A diastereoselective and enantioselective synthesis of (Z)-1-benzoylamino-2-tritylsulfanylcyclopropanecarboxylic acid derivatives 8a,b and 9a,b was achieved starting from (−)- or (+)-menthyl 2-benzoylamino-3-tritylsulfanylacrylates 3a,b. Compounds 3 were reacted with diazomethane giving the corresponding pyrazolines 4a,b and 5a,b. These compounds, on melting, were transformed, under steric control, into the cyclopropaneamino acid derivatives (R,R)-8a,b and (S,S)-9a,b. The synthesis of a large class of chiral 2-S-alkyl-1-aminocyclopropanecarboxylic acid derivatives is possible after removing the trityl protecting group and subsequent alkylation reactions.     

Synthesis and antimicrobial activity of Schiff bases and 2-azetidinones derived from quinazolin-4(3H)-one

A series of 2-oxo-azetidinyl-quinazolin-4(3H)-ones 5a–k have been synthesized from Schiff bases 4a–k. Schiff bases were synthesized by the condensation reaction of compound 3 with substituted aromatic aldehydes. The benzoxazinone 2 was prepared by the cyclization reaction of acid chloride 1 with 5-bromo anthranilic acid. Further reaction of benzoxazinone 2 with hydrazine hydrate yielded compound 3. The structures of the synthesized compounds were elucidated on the basis of elemental analyses as well as IR and NMR spectral data. Schiff bases 4a–k and 2-azetidinones 5a–k were screened for antibacterial and antifungal activities in vitro. Compounds having chloro and methoxy groups exhibited good antimicrobial activity.     

Synthesis of a new series of pyridine and fused pyridine derivatives

The reaction of 4-methyl-2-phenyl-1,2-dihydro-6-oxo-5-pyridine- carbonitrile (1) with arylidene malononitrile afforded isoquinoline derivatives 2a,b. 6-Chloro-4-methyl-2-phenyl-5-pyridinecarbonitile (3) obtained by chlorination of compound 1 with phosphoryl chloride was converted into 6-amino-4-methyl-2-phenyl-5-pyridinecarbonitrile (4) and 6-hydrazido-4-methyl-2-phenyl-5-pyridinecarbonitrile (5) in good yield, through reactions with ammonium acetate and hydrazine hydrate, respectively. Treatment of 4 with ethyl acetoacetate, acetic anhydride, formic acid, urea and thiourea gave the corresponding pyrido [2,3-d] pyrimidine derivatives 7-10a,b. A new series of 6-substituted-4-methyl-2-phenyl-5-pyridine carbonitriles 11-13 has been synthesized via reaction of 4 with phenyl isothiocyanate, benzenesulphonyl chloride and acetic anhydride. Treatment of 4 with malononitrile gave 1,8-naphthyridine derivative 14. The reactivity of hydrazide 5 towards acetic acid, phenylisothiocyanate and methylacrylate to give pyrazolo-[3,4-b]-pyridine derivatives 15-17 was studied. Treatment of 5 with acetic anhydride, phthalic anhydride and carbon disulphide gave pyridine derivatives 18,19 and 1,2,4-triazolo-[3,4-a]-pyridine derivative 20.     

The regioselectivity of the formation of 2-pyrazolylthiazoles and their precursors from the reaction of 2-hydrazinothiazoles with 4,4,4-trifluoro-1-hetaryl-1,3-butanediones

Reaction of 2-hydrazinothiazoles 1 with 1-thienyl- and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2. Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c.     

Chemistry of strained polycyclic compounds—IX: The synthesis and homoketonization of 4-substituted homocuneane acetates

The synthesis of three bridgehead homocuneanes acetates viz 1-bromopentacyclo [4.3.0.0^2.4.0^3.8.0^5.7]nonan-9-one ethylene ketal 4-acetate (10), 1-bromopentacyclo[4.3.0.0^2.4.0^3.8.0^5.7]nonane 4-acctate (22) and pentacyclo[4.3.0.0^2.4.0^3.8.0^5.7]nonane-9-one ethylene ketal 4-acetate (31) is described, starting from the readely available homocubane carboxylic acid (4). The base and acid catalyzed homoketonization reaction of these acetates has been studied. Under basic conditions the acetates (10, 22 and 31) are converted into tettacyclo[4.3.0.0^2.4.0^3.8]nonane derivatives by a cyclopropanol ring cleavage. This homoketonization reaction is a stereospecific process proceeding with retention of configuration. The effect of cage strain on the stereochemistry of base induced homoketonization of bridgehead cage alcohols is discussed.The acid catalyzed homoketonization of acetate (10) was also found to occur exclusively with retention of configuration.