Solid phase synthesis and application of trisubstituted thioureas

Resin-bound amines 1a-e condense with isothiocyanates to give thiourea resins 2a-i. Resins 2a-g subsequently react with iodomethane followed by cleavage affording S-methyl isothioureas 4a-g, and resins 2a-b,h-i react with acyl chlorides to afford N-acylated thioureas 6a-d. N-Acylthioureas 8a-f (R(2) = H) were prepared directly from resin-bound amines 1a-d with acyl isothiocyanates. N-Acylthioureas 8a-d,f(R(2) = H) were used for the preparation of S-methyl-N-acylisothioureas 10a-e. Alkylation was performed using methyl iodide. Resin-bound S-methyl-N-acylisothioureas 10a,b,d are converted by an action of hydrazines into 3-amino-1,2,4-triazoles 13a-d. Condensation of resins 8a-e (R(2) = H) with 2-bromoacetophenones in the presence of TEA affords thiazoles 15 a-e. All transformations proceeded in high yields and gave products of good purities.     

Enantioselective Synthesis of Chiral 1-Ferrocenyl Alcohol via CBS-Reduction

In recent years present interest in the synthesis of chiral ligands has directed attention to the preparation of optically active compounds bearing a ferrocenyl or other organometallic group at the alpha carbon atom. The chirality of all the optically active ferrocenes is due to the ferrocene planar chirality. And many chiral phosphines or amines bearing a ferrocene unit have been used as ligands for transition metal catalyzed asymmetric transportations1. These complexes have been convenien…     

Reactions of 2,3-bishydroxyimino-1,2,3,4-tetrahydro-quinoxalines and 2,3-bishydroxyimino-2,3-dihydro-4H-1,4-benzoxazines with ethyl chloroformate

Bishydroxyiminoquinoxalines 3a-b react with ethyl chloroformate 4 to afford the furazano[3,4-b]quinoxalines 5a-b . Bishydroxyiminobenzoxazines 6a-c on treatment with 4 are converted into the fused oxadiazolones 7a-c and 8a-c along with the bisethoxycarbonyloxyimino-derivatives 9a-c . From the reactions of 4 with the oxanilide dioximes 12a-c compounds 13a-c and 14a-b are obtained.     

Preparation and reactions of 3,4-dihydro-2H-pyran-2-ones

The Michael reaction of ethyl cinnamates with deoxybenzoin gave ethyl 3,4,5-triaryl-5-oxopentanoates which were hydrolysed to the corresponding acids. The latter could be cyclized to the respective 3,4-dihydro-2H-pyran-2-ones which underwent ring opening with several nucleophiles to the corresponding acid derivatives. However, their reaction with ammonium acetate led to the formation of 3,4-dihydro-2-pyridones. The 3,4-dihydro-2-pyrones and pyridones were dehydrogenated to the corresponding 2-pyrones and 2-pyridones by fusion with sulfur.     

Synthesis of 1,2,4-triazole, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives of benzotriazole

A novel series of 1-(1-carbonylmethyl-1H-benzotriazole) thiosemicarbazides 3a-e was synthesized and then cyclized with sodium hydroxide to afford 1-(4-substituted-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazoles 4a-e , which were alkylated with ethyl iodide to l-(3-ethylthio-4-substituted-4H-1,2,4-triazol-5-yl)-methyl-1H-benzotriazoles 5b-e . The reaction of 1H-benzotriazol-1-acetic acid hydrazide ( 2 ) with carbon disulphide and potassium hydroxide followed by hydrazine hydrate gave 1-(4-amino-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazole ( 6 ). Its subsequent condensation with carboxylic acids in the presence of phosphorus oxychloride or with phenacyl bromides afforded two series of fused heterocycles namely; 6-substituted-3-[1-(1H-benzotriazole)methyl]-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 7a-e and 6-substituted phenyl-3-[1-(1H-benzotriazole)methyl]-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 8a-e respectively. The structure of the newly synthesized compounds was elucidated by elemental analyses, ir and nmr spectra.     

Simple and efficient synthesis of 3,4-dihydro-2-pyridones via novel solid-supported aza-annulation

A diverse array of 3,4-dihydro-2-pyridones 13 were produced utilizing the unique properties of solid-supported reactions to both drive the reactions to completion and isolate the desired products. The pyridones were synthesized in high purity by a simple sequence of novel steps commencing from an acetophenone-functionalized resin. The para-substituted acetophenone 9 could be anchored to the resin through either a sulfonamide or a carboxamide linkage. The sulfonamide resin 9a, which gave the best results, was treated with several aryl aldehydes and ethoxide to give a variety of chalcones 10a-k in excellent yield (82-99%) upon TFA cleavage. Addition of either methyl or allyl malonate and DBU to 10a-k afforded smoothly the Michael adducts 11a-j (70-99%) which were subsequently cyclized in one step employing acetic acid as a catalyst and several diverse amines to give pure 3,4-dihydro-2-pyridones 13a-p in moderate to excellent yields (30-98%).     

Synthesis of [1]Benzopyrano[3,4-c][2]benzazepine-6, 8, 13(7H)-triones

Hitherto unknown [1] benzopyrano [3,4-c] [2] benzazepine-6,8,13(7H)-triones (4a-e) have been synthesized by the intramolecular cyclodehydration of N-(2-oxo-2H-1-benzopyran-3-yl) phthalamic acids (3a-e) obtained by the reaction of 3-amino coumarins (1a-e) with phthalic anhydride (2)     

Electrospray ionisation and ion-trap fragmentation of substituted 3,4-dihydro-2(1H)-pyridin-2-ones

A variety of 5-alkoxycarbonyl-4-aryl-6-methyl-3,4-dihydro-2(1H)-pyridones and hexahydrofuro[3,4-b]-2(1H)-pyridones have been investigated by electron impact (EI) and electrospray ionisation (ESI) techniques. Sequential product ion fragmentation (MS(n)) was performed to elucidate the degradation pathways for these compounds. Comparisons are made between positive and negative even-electron ions from ESI spectra and the molecular radical cations obtained under EI conditions. The data collected in this paper provide information on the strong impact that different substituents have on the ion fragmentation process.     

A facile approach to polysubstituted 2-pyridones. Application to the synthesis of 3,4-disubstituted isoquinolinone and total synthesis of oxyisoterihanine

A facile approach to polysubstituted 2-pyridones from 1-benzyl-5,6-dialkyl-3-(4-toluenesulfonyl)pyridin-2-one was described. A new approach to 3,4-disubstituted isoquinolinone and total synthesis of oxyisoterihanine will also be reported.     

Ring transformations of 4H-pyrans. Pyridines from 2-amino-4H-pyrans

Ring transformations of 4H-pyrans into pyridines are reported. Treatment of 2-amino-4,6-diaryl-3,5-dicyano-4H-pyrans (I) with nitrosylsulfuric acid brings about their transformation into 3,5-dicyano-4,6-diaryl-2-pyridones (VI) which can also be obtained from α-benzoylcinnamonitriles (IX) and cyanoacetamide. Similarly, 2-amino-4,6-diaryl-5-carbethoxy-3-cyano-4H-pyrans (II) lead to 4,6-diaryl-5-carbethoxy-3-cyano-2-pyridones (VII). Treatment of both series of pyrans with sulfuric acid results in the formation of the corresponding 3,4-dihydro-2-pyridones (IV and V). Reaction of pyrans II with ammonium acetate in acetic acid yields 2-amino-4,6-diaryl-5-carbethoxy-3-cyanopyridines (XII). Pyrans I undergo an entirely different type of reaction upon treatment with this reagent leading to 2,4,6-triaryl-3,5-dicyano-1,4-dihydropyridines (XV).     

Synthesis of 3-substituted 4-piperidinones via a one-pot tandem oxidation-cyclization-oxidation process: stereodivergent reduction to 3,4-disubstituted piperidines

A novel approach to 3-substituted 4-piperidinones is described. The one-pot tandem oxidation-cyclization-oxidation of unsaturated alcohols 1a-e by PCC or PCC and trifluoromethanesulfonic acid affords piperidinones 2a-e in good yield. Reduction of 2a-e by L-Selectride gives the corresponding cis 3,4-disubstituted piperidines with diastereomeric ratios of >99:1. By contrast, reduction of 2a-e by Al-isopropoxydiisobutylalane gives the trans products with diastereomeric ratios of up to 99:1.     

A new route to the improved synthesis of 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils

A new route to C-6-selenenyl analogs of compound 1a from 5-alkyl-6-chlorouracils 6a-b has been described. A mild and highly efficient synthesis of 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils 8a-e has been accomplished from 6a-b in good yields using a two step procedure. Silylation of 5-alkyl-6-chlorouracils 6a-b using N,O-bis(trimethylsilyl)acetamide followed by regioselective alkylation of the silylated intermediate with ethyl or benzyl chloromethyl ether in dichloromethane afforded the desired 1-(alkoxymethyl)-5-alkyl-6-chlorouracils 7a-d in 88–94% yields. Compounds 7a-d readily underwent addition-elimination reaction with an appropriate arylselenol in the presence of ethanolic sodium hyroxide to produce the corresponding 1-(alkoxymethyl)-5-alkyl-6-(arylselenenyl)uracils 8a-e in excellent yields (94–99%).     

Quinone chemistry. Synthesis and tautomerism of 4,7-indazolequinones

The reaction of 1 with hydrazines provided hydrazinium-4,7-dioxo-4,7-dihydroindazol-3-olates 2a-e and 4,7-indazolequinones 3f,g depending upon the nature of the substituent present in the reactants. Compounds 3a-g were obtained by treatment of 2a-e with sodium hydroxide. Fixed tautomers 4a-b and 5c-f were synthesized by methylation of the corresponding 3a-f or 2a-2e with diazomethane. Migration of a methyl group of 5c-f from the oxygen at C₃ to N₁ on heating afforded 6c-f . The tautomerism of 2a-e and 3a-g has been studied by comparing ir, uv, ¹H nmr and ¹³C nmr spectra with those of the fixed tautomers.     

Phase Transfer Catalyzed Synthesis and Antibacterial Activity of Water-soluble S-Triazolo[3,4-b][1,3,4]thiadiazoles Containing Piperazine Group

6/3-（4-Chlorophenyl）-s-triazolo[3, 4-b][1, 3, 4]thiadiazoles （2,a-e） and （Sa-e） were synthesized respectively by intermolecular cyclization of 5-aryl / 4-chlorophenyl-4-amino-3- mercapto-1, 2, 4-triazoles （la-e） and （4） with 4-chlorobenzoic acid / aryl acids, which were condensed with piperazine under phase transfer catalyst TBAB to yield the corresponding free bases of monopiperazine derivatives and followed to form water-soluble salts （3a-e） and （6a-e） with hydrochloric acid in good yields. The in vitro biological results showed that piperazine group conjugated with the above fused heterocycles played an important role in antibacterial activity. The structures of novel compounds were confirmed by IR, ＇H NMR, MS and elemental analysis.     

Studies on Quinazolines. Part I. Annelation to the Quinazoline Ring Utilizing Amino Acid Esters

The reaction of quinazoline-4(3H)-thiones 2a-d with amino acid ester hydrochlorides in boiling solvents, under the basic catalysis, afforded the corresponding substitution products (3-6)a-e in low yield. The reaction could be improved by carrying it without a solvent yielding imidazo[1,2-c]- and pyrimido[1,2-c]quinazolines (7-10)a-e . The antibacterial and antifungal activities of the prepared compounds were tested.     

Synthesis of some new 4,5-substituted-4H-1,2,4-triazole-3-thiol derivatives

In this study appropriate hydrazide compounds, furan-2-carboxylic acid hydrazide (1) and phenylacetic acid hydrazide (2) were converted into 1,4-substituted thiosemicarbazides 4a-e and 5a-e and 4-amino-5-(furan-2-yl or benzyl)-4H-1,2,4-triazole-3-thiols 7 and 10. The 1,4-substituted thiosemicarbazides were then converted into 5-(furan-2-yl or benzyl)-4-(aryl)-4H-1,2,4-triazole-3-thiols 8a-e and 9a-e. In addition, the azomethines 11a-d and 12a-d were prepared from the corresponding arylaldehydes and the 4-amino-5-(furan-2-yl or benzyl)-4H-1,2,4-triazole-3-thiols 7 and 10. The structures of all the synthesized compounds were confirmed by elemental analyses, IR, (1)H-NMR and(13) C-NMR spectra.     

Synthesis and pancreatic lipase inhibitory activities of some 1,2,4-triazol-5(3)-one derivatives

In this study, starting from 4-amino-5-(4-chlorobenzyl)-2,4-dihydro-3H-1,2,4-triazole-3-one ( 1 ), the 4-Amino-5-(4-chlorobenzyl)-2-undecyl-2,4-dihydro-3H-1,2,4-triazol-3-one ( 2 ) was first synthesized and this compound was converted to Schiff base derivatives ( 3a-e ). In the second step of the study, the 2-[3-(4-chlorobenzyl)-5-oxo-1-undecyl-1,5-dihydro-4H-1,2,4-triazole-4-yl]-acetohydrazide ( 6 ), which was used as a key product in the synthesis of many heterocyclic compounds was synthesized in four steps, and then this compound was converted into methylidene acetohydrazide ( 7a-e ), thiosemicarbazide ( 8a-e ), and 1,2,4-triazole-5-thione ( 9a-e ) derivatives. Also, in the last part of the study, 1,2,4-triazole-5-thione derivatives were changed into Mannich bases ( 10a-b ) bearing a 4-phenylpiperazine ring. These new compounds were tested with regard to pancreatic lipase (PL) inhibition activity, and compound 3b , 3d , 7d , 8d , and 9d showed a considerable anti-lipase activity at various concentrations. The activity of compounds 7b (IC₅₀ = 1.45 ± 0.12 μM) was the highest in terms of IC₅₀, comparable to that of orlistat, a well-known PL inhibitor used as an antiobesity drug.     

Heterocycles. Part V. Reaction of α,β-unsaturated carbonyl compounds with arylacetamides. A synthesis of 2-pyridone derivatives

The reaction of 1,3-diaryl-2-propene-1-ones I with arylacetamides II, in the presence of sodium ethoxide under reflux, for two hours, gave the corresponding 3,4,6-triaryl-3,4-dihydro-2(1H)-pyridones IV. However, when the reaction of these ketones was carried out in the presence of sodium hydride, they gave the corresponding 3,4,6-triaryl-2(1H)-pyridones VI or a mixture of IV and VI. When 1,3-diaryl-2-propyne-1-ones V were reacted with arylacetamides, in the presence of sodium hydride, they yielded the corresponding 2-pyridones VI. Treatment of compounds IV with selenium produced the corresponding 2-pyridones VI. Acetylation of the latter compounds gave the corresponding 2-acetyl derivatives VIII. The structure of all products was confirmed by chemical and spectroscopic evidence, and the mechanism of the reactions was discussed.     

Syntheses of the first amine-dicarboxyboranes and their bis(methylester) and bis(N-ethylamide) derivatives

Amine-bis(N-ethylcarbamoyl)boranes [A.BH(CONHEt)(2), 3; A = trimethylamine (Me(3)N, a), quinuclidine (Q, b), pyridine (py, f), 4-picoline (pic, g)] have been prepared after deprotonation of [amine-bis(C-hydroxy-N-ethylimidate)hydroboron(2+)] cations (2), which were formed by the hydrolysis of [amine-bis(ethylnitrilium)hydroboron(2+)]tetrafluoroborates (1). Numerous representatives of 3 [A = diethylamine (Et(2)NH, c), piperidine (pip, d), pyrrolidine (pyrr, e), 4-aminopyridine (4-NH(2)-py, h), 4-(dimethylamino)pyridine (DMAP, i), imidazole (Him, j), 1-methylimidazole (Mim, k)] have been prepared by base exchange reactions from 3a. 3a-e are extremely stable in aqueous media, either acidic or alkaline, probably because of the considerable steric hindrance of possible reaction centers. However, they were transformed into amine-dicarboxyboranes [A.BH(COOH)(2), 4a-e] in acidic medium under vigorous conditions (100-130 degrees C). This transformation was accompanied by significant decomposition, probably owing to the protonation on the N atom, resulting in the rupture of the B-N bond. As an exception, 4b, where N atom in a rigid bicycle is not prone to attacks, could be isolated in very good yield. On the other hand, amine-bis(N-ethylcarbamoyl)boranes containing amines with sp(2)-hybridized N atoms (3f-k) undergo complete decomposition under similar conditions probably because of the increased hydridic character of the hydrogen adjacent to boron. Base exchange reactions starting from 4b resulted in the ammonium salts of 4c-e, h, i of composition [A.BH(COOH)(COO(-))][AH(+)], which in turn could be transformed into the diacids 4, except 4h, by protonation. As salt formation indicates, the 4 compounds are stronger acids as univalent acids than the corresponding A.BH(2)(COOH) complexes. 4a-e, i were readily esterified into amine-bis(methoxycarbonyl)boranes (5a-e, i) in methanol, employing a catalytic amount of HBr. 5a-e, i are stable in alkaline medium but are readily hydrolyzed in acidic medium. Hydrolysis of [amine-bis(C-methoxy-N-ethylimidate)hydroboron(2+)] cations did not give the corresponding bisesters 5 in alkaline, neutral, or acidic medium.     

Scandium-catalyzed carbon-carbon bond formations using alpha-organosulfanyl and organoselanyl-alpha-fluoroacetic acid derivatives

The scandium-catalyzed reactions of alpha-organosulfanyl and organoselanyl-alpha-fluoroacetates 1-2, acetamides 3-4 and acetonitrile 5 with soft nucleophiles proceeded to give the products 6a-b, 7a-c, 8a-c, 9a-e in good to high yields. We also successfully performed the scandium-catalyzed intramolecular cyclization reactions and obtained the unique 5-methylene-2-oxotetrahydropyrans 16-17.