N-Arylsulfonyl-N′-(pyrimidin-4-yl)ureas-synthesis and reaction with dimethyl sulfoxide

The N-arylsulfonyl-N′-(pyrimidin-4-yl)ureas ( 3a – 1 ) were synthesized by reaction of arylsulfonyl isocyanates ( 1 ) with 4-amino-2,6-dialkylpyrimidines ( 2 ). Treatment of 3 with alkali or of 1 with an excess of 4-amino-2,6-dimethylpyrimidine ( 2a ) gave the salts 4a – e . Reaction of the ureas 3a – c with dimethyl sulfoxide at 90 to 120°C afforded N,N′-bis(2,6-dimethylpyrimidin-4-yl) ureas 8a – c . The reaction is assumed to involve a four-centre mechanism with 5 as intermediate.     

Synthesis of pyrazolo[4′,3′:5,6]pyrazino[2,3-c]pyrazoles and pyrazolo[4′,3′:5,6]pyrazino[2,3-d]pyrimidines and their application to polyester fibres

4-Nitroso-1-phenyl-3-methyl-5-aminopyrazole ( 1 ) was condensed with ethylcyanoacetate ( 2 ), malononitrile ( 4a ) and 2-cyanomethylbenzimidazole ( 4b ) to yield 6-hydroxy-5-cyano, 6-amino-5-cyano and 6-amino-5-(benzimidazol-2-yl)-3-methylpyrazolo [3,4-b]pyrazines 3, 5a and 5b , respectively. 5-Cyano-6-chloro derivative 6 obtained from 3 was converted to 3-aminopyrazolo[4′,3′:5,6]pyrazino[2,3-c]pyrazoles 8a and 8b by the treatment with hydrazin hydrate ( 7a ) and phenylhydrazine ( 7b ), respectively. Compound 5a was treated with formamide ( 9a ), urea ( 9b ) and thiourea ( 9c ) to give 4-aminopyrazolo[4′,3′:5,6]pyrazino[2′3′-d]pyrimidines 10a–10c. With refluxing acetic anhydride compounds 8a, 8b and 10a gave corresponding acetamido derivatives 8c, 8d and 10d. Compound 5a was treated with ethylorthoformate ( 11 ), acetic anhydride ( 12 ) or benzoylchloride ( 13 ) to give fused benzimidazopyrazolo[4′,3′:5,6]pyrazino[2′,3′-d]pyrimidines, viz., benzimidazol[1,2-c]pyrazolo[4,3-g]pteridines ( 14a–14c ). Some of the compounds 8, 10 and 14 were applied to polyester as disperse dyes and their fastness properties were studied.     

Funktionallsierung von lodprazolen mit D-Glucopyranose bzw. mit Aminoalkoholen

Functionalisation of Iodopyrazoles with D-Glucopyranose and with Aminoalcohols, Respectively . 3, 4, 5-Triiodo-pyrazole ( 1a ) and 3, 4-diiodo-5-methyl-1 H-pyrazole ( 1 b ) were silylated with hexamethyldisilazane without isolation of the N-trimethylsily derivatives and than glucosilated to give the β-N-nucleosides 2a and 2b , respectively, with 2, 3, 4, 6-tetra-O-acetyl-α-D-glucopy-ranosylbromide or -fluoride in the presence or absence of SnCl₄. The corresponding deacetylated derivatives 3 a – b can be easily obtained by treatment of 2 a – b with sodium methanolate in methanol. Furthermore, 1 a and 1 b as well as 3(5)-methoxycarbonyl-4-iodo-1-H-pyrazole ( 1 c ) were alkylated with methyl bromoacetate-acetate to form the corresponding pyrazole-1-yl-methylacetates 4 a – c . These compounds could be amidated by short heating with N-methylglucamine and 1-amino-propane-2, 3-diol (isoserinol), respectively, in methanol to form the corresponding amides 5 a – c and 6 a – c . The diamide 7 c was prepared bylongtime heating of 4 c with excess isoserinol in n-propanol.     

Addition of arylureas to aroyl isothiocyanates and the synthesis of 1-aroyl-5-aryl-2-thiobiurets and 2-aryl-5-aroylamino-2,3-dihydro-1,2,4-thiadiazol-3-ones

The hitherto unknown 1-aroyl-5-aryl-2-thiobiurets ( 5a – h ) were synthesized by addition of mono arylureas ( 4 ) to aroyl isothiocyanates ( 3 ). Treatment of 1-aroyl-5-aryl-2-thiobiurets ( 5a – h ) with alkali gave 5-aryl-2-thiobiurets ( 6a – e ). Oxidation of 1-aroyl-5-aryl-2-thiobiurets ( 5d , f , h ) with hydrogen peroxide in the presence of hydrochloric acid or bromine in chloroform gave 2-aryl-5-aroylamino-2,3-dihydro-1,2,4-thiadiazol-3-ones ( 7a – c ).     

The STOBBE condensation. XI. The cyclisation of (Z)- and (E)-3-methoxycarbonyl-2-methyl-4-(2′-naphthyl)-4-phenyl-but-3-enoic acids to the corresponding polysubstituted phenanthrene and naphthalene derivatives

(Z)- and (E)-3-methoxycarbonyl-2-methyl-4-(2′-naphthyl)-4-phenyl-but-3-enoic acids 1 a and 4 a have been converted into methyl-4-acetoxy-3-methyl-1-phenylphenanthrene-2-carboxylate 2 a and methyl 4-acetoxy-3-methyl-1-(2′-naphthyl)-2-naphthoate 5 a . The derived phenolic acids 2 b and 5 b are converted to methyl 4-methoxy-3-methyl-1-phenyl-phenanthrene-2-carboxylate 2 c and methyl 4-methoxy-3-methyl-1-(2′-naphthyl)-2-naphthoate 5 c ; which are saponified to the corresponding methoxy acids 2 d and 5 d . Alcoholysis of the anhydrides 3 and 6 gives the corresponding half-esters 1 c and 4 c , respectively.     

Novel Pyridine-Based Hydroxamates and 2′-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity

Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide ( 5 b ) previously described by us as a HDAC inhibitor, we prepared four aza-analogues, 6 – 8 , 9 b , as regioisomers containing the pyridine nucleus. Preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide ( 9 b ) as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates ( 9 a , 9 c – f , and 11 a – f ) and 2′-aminoanilides ( 10 a – f and 12 a – f ), related to 9 b , to be tested against HDACs. Among them, the nicotinic hydroxamate 11 d displayed sub-nanomolar potency (IC₅₀: 0.5 nM) and selectivity up to 34 000 times that of HDAC4 and from 100 to 1300 times that of all the other tested HDAC isoforms. The 2′-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12 d being the most effective (IC₅₀^HDAC3=0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9 e , 11 c , and 11 d blocked over 80 % of cells in G2/M phase, whereas the anilides did not alter cell-cycle progress. In the same cell line, the hydroxamate 11 c and the anilide 10 b induced about 30 % apoptosis, and the anilide 12 c displayed about 40 % cytodifferentiation. Finally, the most potent compounds in leukemia cells 9 b , 11 c , 10 b , 10 e , and 12 c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC₅₀ values at single-digit to sub-micromolar level.     

Studies on aminoazoles: Synthesis of Pyrazolo[1,5-a]-pyrimidines and their aza derivatives

The reaction of 4-arylazo-3-aminopyrazol-5-ones ( 1a – i ) with α,β-unsaturated nitriles, active methylene reagents and nitrile imines are reported. They lead to new polyfunctional derivatives of pyrazolo[1,5-a]pyrimidine ( 5a – c , 6 , 10a – i , 13a – c , 14a – c , 17a – d , 15 ), pyrazolo-[5,1-c]-1,2,4-triazine ( 22a – i ) and pyrazolo[5,1-c]-1,2,4-triazole ( 25a – c ). The structures of these products and the mechanisms of their formation are reported.     

氮杂甾体吡啶类衍生物的合成及抗肿瘤活性

利用药物设计的拼合原理,以黄体酮为原料,经过氧化开环、闭环、还原及缩合反应等步骤,设计合成了9个目标化合物,其结构经IR、NMR和HR-MS确证。以阿比特龙和5-氟脲嘧啶为阳性对照,采用MTT法初步评价目标化合物对体外人前列腺癌细胞PC-3、人卵巢癌细胞Skov3、人恶性黑色瘤细胞A375和人正常前列腺上皮细胞RWPE-1的抗增殖活性。结果显示,2-氨基-4-吡啶-4-基-6-(4′-氮杂孕甾-3′-酮-17′-基)烟腈、2-氨基-4-呋喃-2-基-6-(4′-氮杂孕甾-3′-酮-17′-基)烟腈对PC-3和Skov3细胞抗增殖活性优于阳性对照药阿比特龙和5-氟脲嘧啶。特别是2-氨基-4-吡啶-4-基-6-(4′-氮杂孕甾-3′-酮-17′-基)烟腈对PC-3细胞的IC₅₀值为(2.73±0.80)μmol/L,明显优于阿比特龙,值得进一步研究。     

Action of Grignard reagents on thiophthalic anhydride, 3-benzal-2-thiophthalide, 3-p-chloro- and 3-p-methoxybenzalphthalides

Thiophthalic anhydride 1 reacts with the GRIGNARD reagents 2a – e (1:1 mol.) to give the corresponding 3-aryl(alkyl)-3-hydroxy-2-thiophthalides 3a – e . The interaction of 1 with 2c and f (1:2 mol.) yields the corresponding 1,2-diaroylbenzene derivatives 4 . On the other hand, 1 reacts with 2b (1:2 and 1:3 mol.) to give 5 and 6 , respectively. When 3-benzal-2-thiophthalide 7a and 3-p-chlorobenzalphthalide 7b are allowed to react with the GRIGNARD reagents 2c – f , the corresponding indenone derivatives 8 are obtained. On the other hand, the reaction of 7a and b with 2b (1:2 mol.) yields 6 and 9 , respectively. 7a and p-methoxybenzalphthalide 7c react with 2b (1:1 mol.) to give 5 and 10 ( a and b ). The constitution of the products has been investigated by means of IR and UV spectra.     

Synthesis and characterization of new bis(crown ether)s of Schiff base type containing recognition sites for sodium and nickel guest cations

New bis(crown ether) ligands of Schiff base type ( 2 – 4 ) containing recognition sites for sodium and nickel guest cations have been synthesized by the condensation of two equivalents of 4′-formyl-5′-hydroxy(benzo-15-crown-5) ( 1 ) with diamines, H₂N–(CH₂)_n–NH₂(n = 2–4). Homonuclear ditopic crystalline 2 : 1 (Na⁺ : ligand) complexes ( 2a – 4a , 2b – 4b ) of the ligands with NaSCN and NaClO₄ have been prepared. The NaClO₄ complexes of 3 and 4 ( 3b and 4b ) form heteronuclear tritopic crystalline complexes with Ni²⁺ cations of stoichiometry 2 : 1 : 1 (Na⁺ : Ni²⁺ : ligand). A homonuclear monotopic Ni²⁺ complex has also been prepared by the reaction with Ni(CH₃COO)₂ · 6H_2O. The UV-VIS spectra of 2 – 4 and their NaClO₄ complexes ( 2b – 4b ) are studied in different solvents including acidic and basic media. In polar solvents, tautomeric equilibria (phenol–imine, O–H…︁N and ketoamine, O…︁H–N forms) are present, as supported by the UV-VIS data.     

Reactions with substituted acrylonitriles: A novel Synthesis of Polysubstituted Pyrimidines

3-Arylacrylonitrile-2-thiocarboxamides ( 1a – d ) reacted with S-methylisothiourea to give 4-amino-6-aryl-2-methylmercaptopyrimidine-5-carbonitriles ( 3a – d ). The products 3a – d were also obtained via the reaction of 3-arylacrylonitrile-2-carbonitriles ( 4a – d ) with S-methylisothiourea. Compounds 4a – d reacted with thiourea and urea to yield 4-amino-6-aryl-2-mercaptopyrimidine-5-carbonitriles ( 5a – d ) and 2-hydroxy derivatives ( 5e – h ) respectively. Oxidation of 5a – d with hydrogen peroxide afforded 5e – h . 5a – h were readily alkylated with methyl iodide to give 3a – d .     

Transition metal catalyzed oxidations. 13

The secondary N-aryl-N-alkyl amines 1 – 3 and 5 are oxidized by the Zr(O-t-Bu)₄/TBHP system to nitrobenzene ( 6 ) and the corresponding carbonyl compounds with cleavage of the C–N bond. Nitrones are postulated as reaction intermediates as demonstrated by the cleavage of 9 – 11 to nitrobenzene ( 6 ) and the benzaldehydes 12 – 14 by the same catalytic oxidation system.     

Nitriles in organic synthesis: The Reaction of Cinnamonitriles with cyclohexanone and acetylacetone

The reaction of 1 a , b with cyclohexanone afforded hexahydronaphthalene derivatives ( 3 a , b ). In contrast to the behaviour of 1 a , b , cyclohexanone reacts with 4a – c to yield the propenylidenecyclohexanone derivatives ( 5a – c ). The reaction of 1a with acetylacetone gives 4H-pyran 6 and a 1:2-adduct 8 a . On treatment of 8 a with sodium metal in the presence of dioxane, the pyrano [2, 3-b]pyridine ( 9a ) was obtained. When 1 b , c reacted with acetylacetone, the only isolable products were 8 b , c . Reaction of 4a with acetylacetone gives acyclic compound 10 . This on treatment with basic reagents, gives the pyran derivative ( 13 ).     

Synthese und Reaktionen von N-Phthalimido-keten-S,S-acetalen

Synthesis and Reactions of N-Phthalimido-ketene-S,S-acetals N-substituted phthalimido derivatives 1a – f react in the presence of bases (NaH, t-BuONa) with carbon disulfide to the N-phthalimido-ketene-S,S-acetals 3 , 4 , 5 and 6 , respectively. 2-Amino-ketene-S,S-acetals 7a – c are formed by reaction of 3a , b or 5a with hydrazine hydrate. 3c produces with phenylhydrazine the pyrazole 8 , and with piperidine and pyrrolidine the E/Z mixture of the corresponding ketene-S, N-acetals 9a , b . 1c is transformed into 10a – c (E/Z-mixture)by treatment with phenylisothiocyanate under basic condition followed by alkylation.     

The STOBBE Condensation,Part IX. The cyclisation of (E)-3-Methoxycarbonyl-4-(5′-methyl-2′-thienyl)-but-3-enoic acid,and α,β-bis-(5-methyl thenylidene)-succinic anhydride,to benzothiophen derivatives

The condensation of 5-methyl-thiophen-2-aldehyde with dimethyl succinate in the presence of potassium t-butoxide or sodium hydride gave predominantly (E)-3-methoxy-carbonyl-4-(5′-methyl-2′-thienyl)-but-3-enoic acid 1a , whose configuration is proved by cyclisation with sodium acetate in acetic anhydride to the corresponding benzothiophen derivatives 2 . Alcoholysis of the derived (E)-carboxy-4-(5′-methyl-2′-thienyl)-but-3-enoic anhydride 3 gives the half-ester 1c which is isomeric with the half-ester 1a . Condensation also gave the α,β-bis-(5-methyl thenylidene)-succinic acid 4a in small amounts. The derived anhydride 5 yields on pyrolysis 4-(5′methyl-2′-thienyl)-2-methyl-benzothiophen-5,6-dicarboxylic anhydride 6 .     

Cyclofunktionalisierung von 2-Allyl-phenolen mit Schwefelchloriden 2,3-Dihydrobenzofurfurylthioether aus 2-Allyl-phenolen und aromatischen Sulfenylchloriden

Cyclofunctionalization of 2-Allyl-phenols with Sulfur Chlorides. Synthesis of 2,3-Dihydrobenzofurfuryl Thioethers by the Reaction of 2-Allyl-phenols with Aromatic Sulfenyl Chlorides Reactions of different substituted 2-allyl-phenols ( 2a – h ) with either phenylsulfeny chloride ( 3 ) or 4-methyl phenylsulfenyl chloride ( 4 ) yield the products of a cyclofunctionali zation 2-phenylthiomethyl 2,3-dihydrobenzofuranes ( 6a – h ) or 2-(4′-methylphenyl) 2,3-dihydrobenzofurane ( 7a – g ), respectively. The identification of the products was carried out by mass spectroscopy and ¹H-n.m.r.-spectroscopy. Isomeric compounds, i.e. 3-phenylthio 2,3-dihydrobenzopyranes ( 10 ) were not obtained. The reaction is Markovnilov-directed. In the case of the treatment of 2-allyl-phenols with 2-nitro phenylsulfenyl chloride ( 5 ) we have obtained mixtures of 2-(2′-nitrophenyl) thiomethyl 2,3-dihydrobenzofuranes ( 8a – d ) and of simple Markovnikov adducts, so-called β-chlorothioethers. The mixtures were identified by ¹H-n.m.r.- and mass spectroscopic ( 9a – d ) methods.     

Ringöffnungs- und SubstitutionsReaktionen von 4,4-Dihalogen-pyrazolin-5-onen durch Nucleophile

Ring Opening and Substitution Reactions of 4,4-Dihalo-pyrazolin-5-ones with Nucleophiles 1-Aryl-4,4-dihalo-3-methyl-pyrazolin-5-ones ( 1a – c ) undergo ring opening with alkoxides and form alkyl 3-arylazo-2-halo-2-butenoats ( 2a – d ). Analogous reactions take place with ammonia and amines. 4-Nitro-phenoxide reacts with substitution of both halogens to the 4,4-bis(4-nitro-phenyl)-compound ( 5 ). Phenols are selectively orthobrominated by the title compounds 1a and b .     

Cyclopropyl Building Blocks for Organic Synthesis,Part 100. Advanced Syntheses of Cyclopropylideneacetates –Versatile Multifunctional Building Blocks for Organic Synthesis

A well reproducible and inexpensive preparation of the cyclopropylideneacetates 2 – 4 has been developed. The key intermediate 2‐(1′‐mesyloxycyclopropyl)acetic acid ( 8 ), produced either from methyl phenylacetate ( 1 ) or 3,3‐dimethoxypropionate ( 5 ‐Me) and 3,3‐diethoxypropionate ( 5 ‐Et) in a sequence of Kulinkovich reductive cyclopropanation, mesylation and oxidative cleavage or cleavage and oxidation, respectively, was either converted to the benzyl ester 11b , or chlorinated (brominated) via the in situ formed acid chloride. The α‐chloro‐ 12a and α‐bromo ester 12b were dehydromesylated by treatment with triethylamine to furnish methyl 2‐chloro‐2‐cyclopropylideneacetate ( 3 ‐Me) and the 2‐bromo analogue 4 ‐Me with an overall yield of 68% (65%, 68%) and 52% (49%, 51%) respectively, starting from 1 ( 5 ‐Me, 5 ‐Et). The parent benzyl cyclopropylideneacetate 2 ‐Bn was obtained by dehydromesylation of 11b with potassium t‐butoxide in t‐butyl methyl ether with an overall yield of 60% (57%, 9%) from 1 ( 5 ‐Me, 5 ‐Et).     

Action of acrylonitrile on 4-cyano- and 4-carbethoxy pyridazin-3(2H)-ones and their 3-mercapto derivatives. A novel Synthesis of Pyrano and Thiinopyridazines

Reaction of acrylonitrile with 4-cyano-5,6-diphenyl pyridazin-3(2H)-one and 3(2H)-thione derivative ( 1a, b ) at elevated temperature gave 7H-5-amino-6-cyano-3,4-diphenylpyrano and thiino [2,3-c] pyridazines ( 2a, b ), respectively. However, the reaction of 4-carbethoxy pyridazine derivatives ( 1c, d ) with the same reagent, under the same conditions afforded 6H, 7H-6-cyano-3,4-diphenyl-5-oxopyrano ( 3a ) and thiino [2,3-c] pyridazine ( 3b ), respectively. In addition, treatment of ( 1a, c ) and ( 1b, d ) with acrylonitrile ar reflux in alkaline medium give the respective 3-(2′-cyanoethyloxo) ( 7a, c ) and 3-2′-cyanoethylthio ( 7b, d ) pyridazine derivatives. Prolonged alkaline hydrolysis of either ( 1a, c ) or ( 7a, c ) yielded the same product ( 8a ). Also hydrolysis of ( 1b, d ) and ( 7b, d ) afforded one and the same product ( 8b ). The structures of the products were assigned on the basis of satisfactory analytical and spectroscopic data.     

Amino-thieno[2,3–c]pyrazole und Amino-thieno[2,3–b]pyrrole

Amino-thieno[2,3–c]pyrazoles and Amino-thieno[2,3–b]pyrroles The synthesis of thieno[2,3–c]pyrazoles and thieno[2,3–b]pyrroles is described. From the dithioliumsalt ( 1 ) and potassium hydroxide the potassium-(2,2-dicyan-1-methylthio-ethen-1-yl)-thiolate ( 2 ) is formed. This reacts with hydrazine hydrate to form the 3-amino-5-thioxo-pyrazol-4-carbonitrile ( 3 ) S-Alkylation with α-chlorocarbonyl compounds yielding ( 6a–c ) leads via Thorpe-Ziegler-cyclization to 3,4-diamino-thieno[2,3–c]pyrazoles ( 9 ) if the position 1 is alkylated ( 8 ). Acetyl acetone yields 2-mercapto-pyrazolo[1,5–a]pyrimidine ( 5 ). After S-alkylation ( 10a–d ) are immediately cyclized to thieno [2′,3′:3,4]pyrazolo[1,5-a]pyrimidine ( 11a–d ). The ketone ( 6a ) can be cyclized to the pyrazolo [5,1–b]thiazole ( 12 ). 3 reacts with oxalyl chloride to form the 2,3-dioxo-6-thioxo-imidazo[1,2-b]pyrazole ( 13 ) of which S-phenacyl derivative ( 14 ) because the NH-proton cannot be cyclized. The 5-amino-3,4-dicyano-pyrrol-2-thiolate ( 16 ) shows the analogous behaviour. The S-alkylation is followed by cyclization, and 3,5-diamino-thieno[2,3–b]pyrroles ( 18a–b ) arise. Reaction of 5-amino-2-alkylthio-pyrrol-3,5-dicarbonitrile ( 17 ) with acetyl acetone provides pyrrolo[1,2-a]pyrimidine ( 20a–c ) which can be cyclized to form thieno[3′,2′:4,6]pyrimidines ( 21a–c ) very easily.