A new synthesis of 1,5-dihydropyridazino[3,4-b]quinoxalines and 2-(pyrazol-4-yl)quinoxalines

The reaction of 6-chloro-2-(l-methylhydrazino)quinoxaline 1-oxide 3 with acetylenedicarboxylates gave the 8-chloro-1-memyl-1,5-dihydropyridazino[3,4-b]quinoxaline-3,4-dicarboxylates 4a,b and 2-(pyrazol-4-yl)quinoxaline 1-oxides 5a,b . The formation of compounds 4a,b would follow the 1,3-dipolar cycloaddition reaction, subsequent 1,2-hydrazino migration, and then dehydrative cyclization, while the production of compounds 5a,b would proceed via the addition of the hydrazino group to acetylene-dicarboxylate leading to the construction of a pyrazole ring, followed by rearrangement of the pyrazole ring. Compounds 5a,b were deoxidized with phosphoryl chloride/N,N-dimethylformamide to change into the 4-(quinoxalin-2-yl)pyrazole-3-carboxylates 8a,b .     

Studies in spiroheterocycles,Part XV. Investigation of the reaction of 3-(2-oxocycloalkylidene)-indol-2-ones with thiourea and urea derivatives

The reaction of 3-(2-oxocycloalkylidene)indol-2-one 1 with thiourea and urea derivatives has been investigated. Reaction of 1 with thiourea and urea in ethanolic potassium hydroxide media leads to the formation of spiro-2-indolinones 2a-f in 40–50% yield and a novel tetracyclic ring system 4,5-cycloalkyl-1,3-diazepino-[4,5-b]indole-2-thione/one 3a-f in 30–35% yield. 3-(2-Oxocyclopentylidene)indol-2-one afforded 5′,6′-cyclopenta-2′-thioxo/ oxospiro[3H-indole-3,4′(3′H)pyrimidin]-2(1H)-ones 2a,b and 3-(2-oxocyclohexylidene)indol-2-one gave 2′,4′a,5′,6′,7′,8′- hexahydro-2′-thioxo/oxospiro[3H-indole-3,4′ (3′H)-quinazolin]-2(1H)-ones 2c-f . Under exactly similar conditions, reaction of 1 with fluorinated phenylthiourea/cyclohexylthiourea/phenylurea gave exclusively spiro products 2g-1 in 60–75% yield. The products have been characterized by elemental analyses, ir pmr. ¹⁹F nmr and mass spectral studies.     

The rearrangement of 2-benzyl-5-mesitoyl-3(2H)-isothiazolone to 2-phenyl-6-mesitoyl-3,4-dihydro-1,3-thiazin-4(2H)-one

2-Benzyl-5-mesitoyl-3(2H)-isothiazolone ( 8 ) has been prepared from 3-mesitoylpropionic acid ( 5 ). Reaction of the isothiazolone 8 with sodium ethoxide in ethanol has been found to yield an isomeric rearranged compound, which was characterized as 2-phenyl-6-mesitoyl-3,4-dihydro-1,3-thiazin-4(2H)-one ( 9 ). This unexpected rearrangement is attributed to the abstraction of a benzylic hydrogen atom from the N-benzyl group, followed by ring enlargement through cleavage of the isothiazolone S? N bond.     

Thermische Umwandlung von Penta-2, 4-dienyl-phenyläthern in 4-(Penta-2, 4-dienyl)-phenole; [5s, 5s]-sigmatropische Umlagerungen

trans-Penta-2, 4-dienyl phenyl ether (trans- 1 ), on heating at 186° in a five-fold excess of N, N-diethylaniline, gave via a [3s, 3s] rearrangement 23% of 2-(1-vinyl-allyl)-phenol ( 2 ) and via a [5s, 5s] rearrangement 37% of trans-4-(penta-2, 4-dienyl)-phenol (trans- 3 ). The dimeric residue was formed from trans- 1 by diene synthesis. By working at high dilution, the formation of dimeric products was kept to a minimum. The inversion of the migrating pentadienyl residue during the rearrangement of trans- 1 to trans- 3 was proved by rearrangement of the methyl labelled ether trans, trans- 4 to the p-dienyl-phenol 8 (93%) (accompanied by only 7% of 9 ). trans- 5 gave the p-phenol 9 quantitatively. cis-Penta-2, 4-dienyl phenyl ether (cis- 1 ) was converted to 10 on heating, by a fast [1, 5s] H-migration. The above mentioned reactions of the type trans- 1 → trans- 3 show first order kinetics and are the first examples of [5s, 5s] sigmatropic rearrangements shown to go through a ten-membered transition state. The conformation of the activated complex is discussed in the light of the stereochemistry of the migrating penta-2, 4-dienyl group.     

Synthesis of (5R)- and (5S)-5-Methyl-5, 6-dihydrouridine Derivatives

The hydrogenation of 2′, 3′-O-isopropylidene-5-methyluridine (1) in water over 5% Rh/Al₂O₃ gave (5 R)- and (5 S)-5-methyl-5, 6-dihydrouridine (2) , separated as 5′-O-(p-tolylsulfonyl)- (3) and 5′-O-benzoyl- (5) derivatives by preparative TLC. on silica gel and ether/hexane developments. The diastereoisomeric differentiation at the C(5) chiral centre depends upon the reaction media and the nature of the protecting group attached to the ribosyl moiety. The synthesis of iodo derivatives (5 R)- and (5 S)- 4 is also described. The diastereoisomers 4 were converted into (5 R)- and (5 S)-2′, 3′,-O-isopropylidene-5-methyl-2, 5′-anhydro-5, 6-dihydrouridine (7) .     

5-(α-Fluorovinyl)tryptamines and 5-(α-Fluorovinyl)-3-(N-methyl-1′,2′,5′,6′,-tetrahydropyridin-3′- and -4′-yl)indoles—5-(α-Fluorovinyl)tryptamines

5-(α-Fluorovinyl)tryptamines 4a, 4b and 5-(α-fluorovinyl)-3-(N-methyl-1′,2′,5′,6′-tetrahydropyridin-3′- and -4′-yl) indoles 5a, 5b were synthesized using 5-(α-fluorovinyl)indole ( 7 ). The target compounds are bioisosteres of 5-carboxyamido substituted tryptamines and their tetrahydropyridyl analogs.     

A new synthesis of dibenzo[b,g][1,5]naphthyridine-6,12(5H,1H)dione (epindolidione)

A new convenient synthesis of dibenzo[b,g][1,5]naphthyridine-6,12(5H,11H)dione starting from N-phenylglycine ethyl ester is described. Ester condensation of N-phenylglycine ethyl ester with diethyl oxalate followed by reaction with aniline under acid catalysis gave a mixture of diethyl dianilinomaleate and diethyl dianilinofumarate in 54% yield. Upon heating this mixture in a high-boiling inert solvent, 3-anilino-2-ethoxycarbonyl-4-quinolone was obtained in 72% yield. Final ring closure of the quinolone derivative using polyphosphoric acid gave the epindolidione.     

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.     

Alkaline condensation of 9,10-phenanthrenedione with N,N-dialkylguanidines. A novel synthesis of 2′-(dialkylamino)spiro[9H-fluorene-9,4′-[4H]imidazol]-5′(3′H)ones

9,10-Phenanthrenedione was reacted with equimolar amounts of N,N-dimethylguanidine or creatine in 0.2 N potassium hydroxide in ethanol-water, 7:3 to obtain 2′-(dimethylamino)spiro-[9H-fluorene-9,4′-[4H]imidazol]-5′(3′H)one or N-(3′,5′-dihydro-5′-oxospiro[9H-fluorene-9,4′-[4H]imidazol]-2′-yl)-N-methylglycine, respectively. These products are the first derivatives of this ring system with 2′-amino substituents. Formation of these products accounts for the previously reported absence of fluorescence when 9,10-phenanthrenedione reacts with N,N-di-substituted guanidines.     

Stereoselective Synthesis and Diels-Alder Reactions of (Z)- and (E)-1,2-bis(Phenylthio)-1,3-Butadiene

Bromination of 3-phenylthio-2-sulfolene (2) with N-bromosuccinimide gave 2-bromo-3-phenylthio-2-sulfolene (3) which was converted mainly to 2,3-bis(phenylthio)-2-sulfolene (4) by treatment with sodium phenylthiolate. Thermal desulfonylation of 4 at different temperatures in the presence of a base (DBU) yielded stereoselectively the (Z)- and (E)-1,2-bis(phenylthio)-1,3-butadiene (6). These two geometric isomers could be thermally interconverted. The Diels-Alder reactions of 6 were also investigated. Only the (Z)-diene 6a could undergo the Diels-Alder reaction; the (E)-diene 6b was in situ converted to the Z isomer before undergoing (he Diels-Alder reaction. The reaction of 6a with N-phenylmaleimide gave the cycloaddition product 7 with complete endo selectivity, but under daylight or during chromatography it readily underwent a thioallylic rearrangement to yield 8 with inversion of configuration. The cycloaddition of 6a with methyl acrylate proceeded regiospecifically, but generating a mixture of endo and exo isomers. The endo/exo ratio could be increased by using ZnCl₂ as the catalyst.     

Reaction of N-[(α-acetoxy)-4-pyridylmethyl]-3,5-dimethylbenzamide with alkyl isocyanates

Reaction of N-(α-acetoxy)4-pyridylmethyl]-3,5-dimethylbenzamide 3 with methyl and ethyl isocyanates afforded 1,3-dimethyl and 1,3-diethyl-4-(3,5-dimethylbenzoylamino)-2-oxoimidazolidine-5-spiro-4′-[1′,4′-dihydro-1′-acetyl]pyridine 6a,b , respectively. However, the reaction of 3 with isopropyl, t-butyl and phenyl isocyanates gave the corresponding N,N′-diurea and the dimerization compound 8 . The structure of 6a was confirmed by crystal X-ray diffraction analysis.     

Synthesis and properties of 5-(1,2-dihaloethyl)-2′-deoxyuridines and related analogues

The regiospecific reaction of 5-vinyl-3′,5′-di-O-acetyl-2′-deoxyuridine ( 2 ) with HOX (X = Cl, Br, I) yielded the corresponding 5-(1-hydroxy-2-haloethyl)-3′,5′-di-O-acetyl-2′-deoxyuridines 3a-c . Alternatively, reaction of 2 with iodine monochloride in aqueous acetonitrile also afforded 5-(1-hydroxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3c ). Treatment of 5-(1-hydroxy-2-chloroethyl)- ( 3a ) and 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with DAST (Et₂NSF₃) in methylene chloride at -40° gave the respective 5-(1-fluoro-2-chloroethyl)- ( 6a , 74%) and 5-(1-fluoro-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6b , 65%). In contrast, 5-(1-fluoro-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6e ) could not be isolated due to its facile reaction with methanol, ethanol or water to yield the corresponding 5-(1-methoxy-2-iodoethyl)- ( 6c ), 5-(1-ethoxy-2-iodoethyl)- ( 6d ) and 5-(1-hydroxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3c ). Treatment of 5-(1-hydroxy-2-chloroethyl)- ( 3a ) and 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with thionyl chloride yielded the respective 5-(1,2-dichloroethyl)- ( 6f , 85%) and 5-(1-chloro-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6g , 50%), whereas a similar reaction employing the 5-(1-hydroxy-2-iodoethyl)- compound 3c afforded 5-(1-methoxy-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6c ), possibly via the unstable 5-(1-chloro-2-iodoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine intermediate 6h . The 5-(1-bromo-2-chloroethyl)- ( 6i ) and 5-(1,2-dibromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6j ) could not be isolated due to their facile conversion to the corresponding 5-(1-ethoxy-2-chloroethyl)- ( 6k ) and 5-(1-ethoxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 61 ). Reaction of 5-(1-hydroxy-2-bromoethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 3b ) with methanolic ammonia, to remove the 3′,5′-di-O-acetyl groups, gave 2,3-dihydro-3-hydroxy-5-(2′-deoxy-β-D-ribofuranosyl)-furano[2,3-d]pyrimidine-6(5H)-one ( 8 ). In contrast, a similar reaction of 5-(1-fluoro-2-chloroethyl)-3′,5′-di-O-acetyl-2′-deoxyuridine ( 6a ) yielded (E)-5-(2-chlorovinyl)-2′-deoxyuridine ( 1b , 23%) and 5-(2′-deoxy-β-D-ribofuranosyl)furano[2,3-d]pyrimidin-6(5H)-one ( 9 , 13%). The mechanisms of the substitution and elimination reactions observed for these 5-(1,2-dihaloethyl)-3′,5′-di-O-acetyl-2′-deoxyuridines are described.     

Synthesis of 1-substituted-2,3,4,9-tetrahydro-(2-oxopropyl)-1H-pyrido [3,4-b] indoles and their base-catalyzed rearrangements to N- [2-[2-(1-alkyl-3-oxobutenyl)-1H-indol-3-yl] ethyl]acetamides

The condensation of 1H-indole-3-ethanamides, 1 , with 2,4-pentanediones, 2 , gave enamines 3 . Acid catalyzed ring closure of 3 gave 1-(1-substituted-2,3,4,9-tetrahydro- (2-oxopropyl) -1H-pyrido [3,4-b] indoles 4 . Subsequent N-acetylation yielded 5 which sequentially produced 2,3-disubstituted indoles 6 and 7 resulting from C? N bond cleavage after treatment with sodium alkoxide in ethanol. Controlled catalytic hydrogenation of the latter gave saturated derivatives 8 and 9 .     

Favorskii Rearrangement in the Reaction of 3-(1-Adamantyl)-1-chloro-2-propanone with Amines

The reaction of 3-(1-adamantyl)-1-chloro-2-propanone with amines [diethylamine, (1-adamantyl)methylamine, p-toluidine, and piperidine] in diethyl ether at room temperature involves the Favorskii rearrangement and yields N,N-disubstituted amides of 3-(1-adamantyl)propanoic acid.     

Asymmetric Synthesis of (S)-5,5,5,5′,5′,5′,5′-Hexafluoroleucine

(S)-5,5,5,5′,5′,5′-Hexafluoroleucine ((S)- 13 ) of 81 % ee is prepared from hexafluoroacetone ( l ) and ethyl bromopyruvate (= ethyl 2-oxopropanoate) in 7 steps with an overall yield of 18% (Schemes 1 and 2). Key step in this sequence is the highly enantioselective reduction of the carbonyl group in α-keto ester 4 either by bakers' yeast (91 % ee) or by ‘catecholborane’ 6 utilizing an oxazaborolidine catalyst, yielding hydroxy ester (R)- 5 with 99% ee. The absolute configuration was determined by X-ray analysis of the HCl adduct (S,R)- 9b of (2S)-N-[(R)- l-phenylethyl]-5,5,5,5′,5′,5′-hexafluoroleucine ethyl ester.     

Synthesis and characterization of soluble polyimides derived from 2′,5′‐bis(3,4‐dicarboxyphenoxy)‐p‐terphenyl dianhydride

A novel bis(ether anhydride) monomer, 2′,5′‐bis(3,4‐dicarboxyphenoxy)‐p‐terphenyl dianhydride, was synthesized from the nitro displacement of 4‐nitrophthalonitrile by the phenoxide ion of 2′,5′‐dihydroxy‐p‐terphenyl, followed by alkaline hydrolysis of the intermediate bis(ether dinitrile) and cyclodehydration of the resulting bis(ether diacid). A series of new poly(ether imide)s bearing laterally attached p‐terphenyl groups were prepared from the bis(ether anhydride) with various aromatic diamines via a conventional two‐stage process that included ring‐opening polyaddition to form the poly(amic acid)s followed by thermal or chemical imidization to the poly(ether imide)s. The inherent viscosities of the poly(amic acid) precursors were in the range of 0.62–1.26 dL/g. Most of the poly(ether imide)s obtained from both routes were soluble in polar organic solvents, such as N,N‐dimethylacetamide. All the poly(ether imide)s could afford transparent, flexible, and strong films with high tensile strengths. The glass‐transition temperatures of these poly(ether imide)s were recorded as between 214 and 276 °C by DSC. The softening temperatures of all the poly(ether imide) films stayed in the 207–265 °C range according to thermomechanical analysis. For all the polymers significant decomposition did not occur below 500 °C in nitrogen or air atmosphere. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 1008–1017, 2004     

The reactions of tetrafluoroethylene oligomers: V. The reactions of perfluoro-3,4-dimethyl-4-ethylhexene-(2) with thionucleophiles and the chemical transformations of reaction products

The reactions of perfluoro-3,4-dimethyl-4-ethylhexene-(2) (1) with s-nucleophiles such as benzylthiol, allylthiol, phenylthiol and the chemical transformations of these reaction products were reported. 1 reacted with S-nucleophiles to give four types of isomeric products. At ?30～ ?60°C, in ether, kinetically controlled product 2 (a, b, c) were formed. Compound 2 might be converted directly into the thermodynamically stable products 3 (a, b,) in DMF-KF at r.t., At 100°C, 2 was converted to 4 (a, b, c) via intramolecular rearrangement. In KF-DMF at r.t., 4 was isomerized to 5 (a, b, c). 2a also reacted with another mole of thiol to give the corresponding disulfide 6 and hydrogen-containing olefin 7a as well as the disubstituted product 8a in DMF, but only give 3a and 9a in ether-Et₃N. The reaction of 2a with methyl alcohol gave only a small amounts of 3a and 10a. The reaction of 2b with dimethylamine was complex and 3b and 11 were obtained in low yield.     

Synthesis of pyridyloxadiazoles 1. Characterization and thermal rearrangement of an unexpected 1,2,4-oxadiazol-5(4H)one

The synthesis of pyridyloxadiazoles by the reaction of acid chlorides with 5-(2-pyrklyl)-tetrazole or 2-pyridineamidoxime was studied. Reaction of 2-pyridineamidoxime with N,N-dimethylcarbamyl chloride produced 3-(2-pyridyl)-4-N,N-dimethylaminocarbony 1-1,2,4-oxadi-azol-5(4H)one instead of the expected oxadiazole. The oxadiazolone underwent thermal rearrangement with expulsion of carbon dioxide to yield the desired 3-(2-pyridyl)-5-N,N-dimethylamino-1,2,4-oxadiazole.     

Synthesis of novel derivatives of 2-(azolylimino)thiazoline

Successive alkylation of 5-(3-phenylthioureido)-3H-imidazole-4-carboxamides with alkyl halides and chloroacetone gave (N-oxopropylimidazolyl)isothioureas, which were easily converted into derivatives of purine and imidazopyrazinone. In the case of ethyl 5-(3-phenylthioureido)-3H-imidazole-4-carboxylate, primary alkylation occurs at the N atom of the imidazole ring. Reactions of 5-(3-phenylthioureido)-3H-imidazole-4-carboxamides with haloketones afforded a number of 4-hydroxy-2-imidazolyliminothiazolidines and 2-imidazolylimino-Δ⁴-thiazolines.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2196–2204, October, 2004.