Synthesis of acyclic nucleoside analogs of 6-substituted 2-aminopurines and 2-amino-8-azapurines

Several new acyclonucleoside purine and 8-azapurine analogs have been prepared from 2-amino-4,6-dichloropyrimidine ( 1 ) and 3-amino-1,2-propanediol ( 2a ) and 4-amino-1-butanol ( 2b ), respectively, as the starting materials. The new target compounds are: 2-amino-6-chloro-9-(2,3-dihydroxypropyl)purine ( 6a ), 2-amino-6-chloro-9-(4-hydroxybutyl)purine ( 6b ), 2-amino-6-chloro-9-(2,3-dihydroxypropyl)-8-azapurine ( 7a ), 2-amino-6-chloro-9-(4-hydroxybutyl)-8-azapurine ( 7b ), 9-(2,3-dihydroxypropyl)-8-azaguanine ( 8a ), 9-(4-hydroxybutyl)-8-azaguanine ( 8b ), 9-(2,3-dihydroxypropyl)-8-azathioguanine ( 9a ), and 9-(4-hydroxybutyl)-8-azathioguanine ( 9b ). Also, the requisite intermediate pyrimidine derivatives, 2,5-diamino-4-(2,3-dihydroxypropylamino)-6-chloropyrimidine ( 5a ) and 2,5-diamino-4-(4-hydroxybutylamino)-6-chloropyrimidine ( 5b ) are novel.     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

A new type of deoxygenation of quinoxaline N-oxides

The reaction of 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4-oxide 3a or 2-[2-(p-bromobenzylidene)-1-methylhydrazino]-6-chloroquinoxaline 4-oxide 3b with dimethyl acetylenedicarboxylate under reflux in N,N-dimethylformamide resulted in deoxygenation to give 6-chloro-2-[2-(p-chlorobenzylidene)-1-methylhydrazino]quinoxaline 4a or 2-[2-(p-bromobenzilidene)-1-methylhydrazino]-6-chloroquinoxaline 4b , respectively, while the reaction of compound 3a or 3b with dimethyl acetylenedicarboxylate under reflux in dioxane precipitated dimethyl 8-chloro-4-[2-(p-chlorobenzyli-dene)-1-methylhydrazino]-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6a or dimethyl 4-[2-(p-bromobenzylidene)-1-methylhydrazino]-8-chloro-3aH-isoxazolo[2,3-a]quinoxaline-2,3-dicarboxylate 6b , respectively. Further refluxing of compound 6a or 6b in N,N-dimethylformamide provided compound 4a or 4b , respectively.     

Synthesis of 1-functionalized-6-hydroxy-4-methyl and 6,11-dihydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinones

Using 2-methoxy- and 2,5-dimethoxyacetophenones 8a and 8b as starting materials, 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ) and its 6-bromo derivative 7 were obtained via multistep sequences. Whereas Diels-Alder condensation of the former compound with homophthalic anhydride ( 22 ) led to a mixture of the two possible isomers: 1-chloro-11-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 23 ) and 1-chloro-6-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 24 ), this last tetracyclic chloroquinone was specifically obtained from 6-bromo-1-chloro-4-methylisoquinoline-5,8-quinone ( 7 ) and homophthalic anhydride. The 6,11-dihydroxy derivative was then prepared by ammonium nitrate oxidation or photochemically by cycloaddition of benzocyclobutenedione ( 28 ) and 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ). Chloro compounds were easily substituted by diamines to provide corresponding 1-amino substituted hydroxy tetracyclic quinones.     

Zur Synthese sulfonierter Derivate von 2,3-Dimethylanilin und 3,4-Dimethylanilin

On the Synthesis of Sulfonated Derivatives of 2,3-Dimethylaniline and 3,4-Dimethylaniline Baking the hydrogensulfate salt of 2,3-dimethylaniline ( 1 ) or of 3,4-dimethylaniline ( 2 ) led to 4-amino-2,3-dimethylbenzenesulfonic acid ( 4 ) and 2-amino-4,5-dimethylbenzenesulfonic acid ( 5 ), respectively (Scheme 1). The sulfonic acid 5 was also obtained by treatment of 2 with sulfuric acid or by reaction of 2 with amidosulfuric acid. 3-Amino-4,5-dimethylbenzenesulfonic acid ( 3 ) and 5-Amino-2,3-dimethylbenzenesulfonic acid ( 6 ) were prepared by sulfonation of 1,2-dimethyl-3-nitrobenzene ( 9 ) to 3,4-dimethyl-5-nitrobenzenesulfonic acid ( 11 ) and of 1,2-dimethyl-4-nitrobenzene ( 10 ) to 2,3-dimethyl-5-nitrobenzenesulfonic acid ( 12 ), respectively, with subsequent Béchamp reduction (Scheme 1). Preparations of 2-amino-3,4-dimethylbenzenesulfonic acid ( 7 ) and of 6-amino-2,3-dimethylbenzenesulfonic acid ( 8 ) were achieved by the sulfur dioxide treatment of the diazonium chlorides derived from 3,4-dimethyl-2-nitroaniline ( 24 ) and from 2,3-dimethyl-6-nitroaniline ( 31 ) to 3,4-dimethyl-2-nitrobenzenesulfonyl chloride ( 29 ) and 2,3-dimethyl-6-nitrobenzenesulfonyl chloride ( 32 ), respectively, followed by hydrolysis to 3,4-dimethyl-2-nitrobenzenesulfonic acid ( 30 ) and 2,3-dimethyl-6-nitrobenzenesulfonic acid ( 33 ), and final reduction (Scheme 3). Compound 7 was also synthesized by reaction of 4-chloro-2,3-dimethylaniline ( 23 ) with amidosulfuric acid to 2-amino-5-chloro-3,4-dimethylbenzenesulfonic acid ( 20 ) and subsequent hydrogenolysis (Scheme 2). 4′-Bromo-2′, 3′-dimethyl-acetanilide ( 13 ) and 4′-chloro-2′, 3′-dimethyl-acetanilide ( 14 ) on treatment with oleum yielded 5-acetylamino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 17 ) and 5-acetylamino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 18 ), respectively. Their structures were proven by hydrolysis to 5-amino-2-bromo-3,4-dimethylbenzenesulfonic acid ( 21 ) and 5-amino-2-chloro-3,4-dimethylbenzenesulfonic acid ( 22 ), followed by reductive dehalogenation to 3 .     

A computational study of the mechanism for the transmetalation of 2-trimethylstannylbuta-1,3-diene with SnCl4

Electronic structure calculations were performed at the B3LYP/6-31G level to identify the stationary structures on the potential energy surfaces for the transmetalation of 2-trimethylstannylbuta-1,3-diene with SnCl(4). The reaction pathways were characterized by locating the transition states on the intrinsic reaction coordinate. The calculations showed that the reaction between the reactant and SnCl(4), which generates 1-trichlorostannylbuta-2,3-diene via transmetalation, has a low energy barrier of 78.1 kJ.mol(-)(1). The following isomerization process is the rate-controlling step. It turned out that the isomerization process from 1-trichlorostannylbuta-2,3-diene to 2-trichloro-stannylbuta-1,3-diene via transmetalation with SnCl(4) is more energetically favorable than other possible isomerization processes.     

Reactions of 2-sulfanylethanol with mucochloric acid and its derivatives

Mucochloric acid reacted with 2-sulfanylethanol in the presence of triethylamine to give 3-chloro-5-hydroxy-4-(2-hydroxyethylsulfanyl)furan-2(5H)-one which underwent acid-catalyzed cyclization to 7-chloro-2,3,4a,6-tetrahydrofuro[2,3-b][1,4]oxathiin-6-one. Likewise, reactions of 5-alkoxy-3,4-dichlorofuran-2(5H)-ones with 2-sulfanylethanol in the presence of triethylamine involved replacement of chlorine in position 4 of the furan ring with formation of the corresponding 4-(2-hydroxyethylsulfanyl) derivatives. The reaction of mucochloric acid with 2-sulfanylethanol in excess aqueous potassium hydroxide resulted in the formation of an acyclic product, 3-(2-hydroxyethylsulfanyl)-2-chloroprop-2-enoic acid. The structure of 7-chloro-2,3,4a,6-tetrahydrofuro[2,3-b][1,4]oxathiin-6-one and 3-(2-hydroxyethylsulfanyl)-2-chloroprop-2-enoic acid was proved by X-ray analysis.     

Synthesis of pyrrolo[1,2-a]quinoxalines by 1,3-dipolar cycloaddition reaction. An additional reaction mechanism via an aziridine intermediate

The reaction of the 2-substituted 6-chloroquinoxaline 4-oxides 1a or 1b with 2-fold molar amount of methyl propiolate resulted in the 1,3-dipolar cycloaddition reaction to give 8-chloro-1,3-bismethoxycarbonyl-4-(piperidin-1-yl)pyrrolo[1,2-a]quinoxaline 4a or 8-chloro-1,3-bismethoxycarbonyl-4-(morpholin-4-yl)pyrrolo-[1,2-a]quinoxaline 4b , respectively. Compound 4a or 4b was transformed into 8-chloro-3-methoxycarbonyl-4-(piperidin-1-yl)pyrrolo[1,2-a]quinoxaline 5a or 8-chloro-3-methoxycarbonyl-4-(morpholin-4-yl)pyrrolo[1,2-a]-quinoxaline 5b , respectively. The structure of 4a,b was confirmed by the NOE measurement among the C₁ -H , C ₂-H and C ₉-H proton signals of 5a,b . An additional reaction mechanism was proposed for the ring transformation of isoxazolo[2,3-a]quinoxalines into pyrrolo[1,2-a]quinoxalines.     

Ring-opening reactions of 3-substituted 1-azabicyclo[1.1.0]butane with dichlorocarbene

Reaction of 3-ethyl-1-azabicyclo[1.1.0]butane ( 1a ) with chloroform-potassium tert-butoxide afforded a ring-opened product, 1,1-dichloro-2-aza-4-ethylpenta-1,4-diene ( 4a ), which was characterized via conversion to the corresponding N-substituted 5-chloro-1,2,3,4-tetrazole, Sa . Reaction of 3-phenyl-1-azabicyclo-[1.1.0]butane ( 1b ) with “Seyferth's reagent” (PhHgCCl₂Br) afforded 1,1-dichloro-2-aza-4-phenylpenta-1,4-diene ( 4b ), which also was characterized via conversion to a tetrazole derivative, i.e., 5b . Finally, the reaction of 1b with dichlorocarbene generated under phase transfer conditions (chloroform-sodium hydroxide-TEBA) was studied. At short reaction times (0.5 hour), the major reaction product was 4b . However, at longer reaction times (20–30 hours), two secondary products, 8 and 9 , were formed which resulted via subsequent dichlorocyclopropanation of 4b .     

Synthesis of fluorinated halonitrobenzenes and halonitrophenols using tetrafluoroethylene and buta-1,3-dienes as starting building blocks

The gas-phase copyrolysis of tetrafluoroethylene with buta-1,3-diene in a flow reactor at 495–505 °C produces 3,3,4,4-tetrafluorocyclohex-1-ene, which selectively converted to 1,2-difluorobenzene or 1-chloro-2,3-difluorobenzene. The latter can be converted to 2-chloro-3,4-difluoronitrobenzene, 2,3,4-trifluoronitrobenzene, 2,3-difluoro-6-nitrophenol, or 2-chloro-3-fluoro-4-nitrophenol via nitration, fluorodechlorination, and hydrolysis reactions.

     

Kinetics, products, and stereochemistry of the reaction of chlorine atoms with cis- and trans-2-butene in 10-700 Torr of N2 or N2/O2 diluent at 297 K

The reactions of Cl atoms with cis- and trans-2-butene have been studied using FTIR and GC analyses. The rate constant of the reaction was measured using the relative rate technique. Rate constants for the cis and trans isomers are indistinguishable over the pressure range 10-900 Torr of N2 or air and agree well with previous measurements at 760 Torr. Product yields for the reaction of cis-2-butene with Cl in N2 at 700 Torr are meso-2,3-dichlorobutane (47%), DL-2,3-dichlorobutane (18%), 3-chloro-1-butene (13%), cis-1-chloro-2-butene (13%), trans-1-chloro-2-butene (2%), and trans-2-butene (8%). The yields of these products depend on the total pressure. For trans-2-butene, the product yields are as follows: meso-2,3-dichlorobutane (48%), dl-2,3-dichlorobutane (17%), 3-chloro-1-butene (12%), cis-1-chloro-2-butene (2%), trans-1-chloro-2-butene (16%), and cis-2-butene (2%). The products are formed via addition, addition-elimination from a chemically activated adduct, and abstraction reactions. These reactions form (1) the stabilized 3-chloro-2-butyl radical, (2) the chemically activated 3-chloro-2-butyl radical, and (3) the methylallyl radical. These radicals subsequently react with Cl2 to form the products via a proposed chemical mechanism, which is discussed herein. This is the first detailed study of stereochemical effects on the products of a gas-phase Cl+olefin reaction. FTIR spectra (0.25 cm(-1) resolution) of meso- and DL-2,3-dichlorobutane are presented. The relative rate technique was used (at 900 Torr and 297 K) to measure: k(Cl + 3-chloro-1-butene) = (2.1 +/- 0.4) x 10(-10), k(Cl + 1-chloro-2-butene) = (2.2 +/- 0.4) x 10(-10), and k(Cl + 2,3-dichlorobutane) = (1.1 +/- 0.2) x 10(-11) cm3 molecule(-1) s(-1).     

新的酚型开链冠醚及由其衍生的二苯并冠醚的合成

将水杨醛与碱和氯甲基甲基醚反应, 再经过NaBH4还原, 即制得邻(甲氧基甲氧基)苯甲醇, 然后将其在DMF中与NaH和二(或三)甘醇二对甲苯磺酸酯反应, 得开链冠醚1a和1b。1a和1b经稀酸水解, 即脱保护而分别生成新的酚型开链冠醚2a和2b。用2a与二甘醇二对甲苯磺酸酯和NaH在DMF溶液中反应, 合成顺型二苯并-20-冠-6(3); 而2a与环氧氯丙烷在NaOH水溶液中反应, 则合成了17-羟基二苯并-18-冠-5(4)。     

Stereoselective Diels–Alder reactions of 3-phosphonopropenoyl derivatives of 1,3-oxazolidin-2-ones

Dienophiles of the general structure (EtO)₂P(O)CHCHCOX have been prepared, where X represents an oxazolidinone chiral auxiliary. Use of the (S)-4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one auxiliary gave Diels–Alder adducts with several cyclic and acyclic dienes. The crystal structures of the main cyclohexa-1,3-diene and 2,3-dimethylbutadiene adducts formed during reactions in the presence of dialkylaluminium halides are consistent with a reaction, which is stereoselectively endo with respect to the carbonyl group and occurs on the less hindered face of the dienophile when aluminium is chelated between the two carbonyl groups.     

3-nitrocoumarins as dienophiles in the Diels-Alder reaction in water. An approach to the synthesis of nitrotetrahydrobenzo[c]chromenones and dihydrodibenzo[b,d]furans

The [4 + 2] cycloadditions of 3-nitrocoumarin (1a), 6-chloro-3-nitrocoumarin (1b), and 6-, 7-, and 8-hydroxy-3-nitrocoumarins (1c, 5, and 6) with (E)-piperylene (7), isoprene (8), 2,3-dimethyl-1,3-butadiene (9), 2-methoxy-1,3-butadiene (10), 2,3-dimethoxy-1,3-butadiene (11), and cyclopentadiene (12) were investigated in aqueous medium, in organic solvent and under solventless conditions. The reactions performed in water occurred in heterogeneous phase but were faster than those executed in toluene or dichloroethane (DCE). 1a-c, 5, and 6 behaved as 2pi components in the Diels-Alder cycloadditions with 7-10 and 12, and exo adducts were preferentially or exclusively produced. Surprisingly 1a, behaved as a 4pi component in the cycloaddition in water with 11 and 4-substituted 3-nitrochromanones 20 and 21 were isolated. The cycloadditions of hydroxy-3-nitrocoumarins 1c, 5, and 6 with 1,3-diene 9 did not work in water or in organic solvent, but did work under solventless conditions. Nitrotetrahydrobenzo[c]chromenones 13-16, 24, and 25, originating from the normal electron-demand Diels-Alder reactions, were converted into dihydrodibenzo[b,d]furans 27-31 in water, via one-pot Nef-cyclodehydration reactions.     

硫杂冠醚的合成

冠醚化合物对金属离子的络合不仅具有较高的稳定性,而且更重要的是具有良好的选择性。当冠醚环中的氧原子部分或全部被氮或硫原子取代后,它们对碱金属、碱土金属的亲和性能降低,而对过渡金属离子的亲和能力相应提高。硫杂冠醚对亲硫的贵金属、重金属离子具有更强的络合能力和更高的选择性。1974     

Acyclic isoprenoid α,Β-enals in the Doebner and Knoevenagel reactions with monoethyl malonate

When acyclic isoprenoid ,-enals are condensed with monoethyl malonate in the presence of pyridine or 4-dimethylaminopyridine (Doebner reaction) or piperidine (Knoevenagel reaction), beside the esters of 2,4-alkadienic acids there are formed isomeric esters of the respective 3,5-alkadienic and 5-methylene-3-alkenic acids. The proportions of structural and geometric isomers depend on reaction conditions. Condensation of citral with monoethyl malonate is appreciably faster in the presence of secondary amine than of tertiary amine, but is accompanied by side products.See notes to Table 1.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 600–605, March, 1990.     

Synthesis of 4-Amino-substituted-6-hydroxy and 11-hydroxynaphtho[2,3-g]quinoline-5,12-diones,and the unexpected formation of disubstituted imidazo[4,5,l-i,j]naphtho[2,3-g]quinolin-7-ones

4-Chloroquinoline-5,8-dione ( 8a ) and 6-bromo-4-chloroquinoline-5,8-dione ( 8b ) were reacted with homophthalic anhydride to give tetracyclic compounds 10 and 11 respectively. The 6,11-dihydroxy derivative 12 was prepared in low yield by photochemical addition of benzocyclobutenedione to 4-chloroquinoline-5,8-dione ( 8a ) and in better yield through a Friedel-Crafts reaction of phthalic anhydride with 4-chloro-5,8-dimethoxyquinoline ( 7a ). Whereas 4-chloro-6-hydroxynaphtho[2,3-g]quinoline-5,12-dione ( 11 ) was substituted by amines in the usual way to the corresponding 4-amino-substituted derivatives, 4-chloro-11-hydroxynaph-tho[2,3-g]quinoline-5,12-dione ( 10 ) led to a mixture of 4-amino derivatives and the unexpected 2,6-disubstituted-imidazo[4,5,l-I-j]naphtho[2,3-g]quinolin-7-ones, 13a-b .     

PdI2-catalyzed coupling-cyclization reactions involving two different 2,3-allenols: an efficient synthesis of 4-(1',3'-dien-2'-yl)-2,5-dihydrofuran derivatives

Transition-metal-catalyzed dimeric coupling-cyclization reactions of two different 2,3-allenols afforded 4-(1',3'-dien-2'-yl)-2,5-dihydrofuran derivatives 3. 2-Substituted 2,3-allenols 1 cyclized to form the 2,5-dihydrofuran ring, whereas the 2-unsubstituted 2,3-allenols 2 provided the 1,3-diene unit at the 4-position. The reaction is proposed to proceed through an oxypalladation, insertion, and beta-hydroxide elimination process. The C=C double bond was formed with high E stereoselectivity by beta-hydroxide elimination.     

Reaction of substituted spiro[1,2,3,4-tetrahydronaphthalene-2,3′-(1′-pyrazolines)] with chlorinating reagents

In reaction of 4′-arylspiro[1,2,3,4-tetrahydronaphthalene-2,3′-(1′-pyrazolin)]-1-ones with N-chlorosuccinimide formed spirocyclic substituted 3-chloro-1-pyrazolines that lost nitrogen at heating transforming into spirocyclic chlorocyclopropanes. The reaction of the same pyrazolines with chlorine led to the formation of spirocyclic gem-dichlorocyclopropanes.     

Reaction of 2-(5-aminopyrazol-1-yl)quinoxaline 4-oxides with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 6 with ethyl 2-(ethoxymethylene)-2-cyanoacetate or (1-ethoxyethylidene)malononitrile gave 2-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7a or 2-(5-amino-4-cyano-3-methylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7b , respectively. The reaction of compound 7a or 7b with dimethyl acetylenedicarboxylate resulted in the 1,3-dipolar cycloaddition reaction and then ring transformation to afford 4-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8a or 4-(5-amino-4-cyano-3-methylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8b , respectively.