Synthesis of 3-aminopyrazolo[3,4-d]pyrimidine derivatives using N-bis(methylthio)methylene-p-toluenesulfonamide

N-Bis(methylthio)methylene-p-toluenesulfonamide ( 1 ) reacted with active methylene compounds such as malononitrile ( 2a ) and, cyanoacetamide ( 2b ) to give the corresponding 3-methylthio-3-p-toluenesulfonylami-nopropenenitrile derivatives 3a,b which were found to be convenient starting materials for the synthesis of 3,5-diaminopyrazole derivatives. Reaction of 3a and 3b with hydrazines gave the corresponding 3,5-diaminopyrazoles 4a-e , key intermediates for the synthesis of 3-aminopyrazolo[3,4-d]pyrimidine derivatives 5a-d .     

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.     

The cyclization of N,N′-bis[2-(dialkoxy)ethyl]-p-xylene-α,α′-diamine dihydrochloride to pyrido[3,4-g]isoquinoline and 3,8-phenanthroline

The ring closure of N,N′-bis[2-(dialkoxy)ethyl]-p-xylene-α,α′-diamine dihydrochloride in fuming sulfuric acid has been investigated and the cyclization products have been identified as the linear pyrido[3,4-g]isoquinoline as well as the previously reported angular 3,8-phenanthroline.     

C(6)N(7)-cyclized purines

By reaction of 6-[N-(2-hydroxyethyl)-N-methyl]aminopurine ( 2a ) and of the corresponding 3-hydroxypropyl derivative 2b with thionyl chloride a bridge to N(1) is formed yielding 5 and 6 , respectively, whereas from 6-[N-(4-hydroxybutyl)-N-methyl]aminopurine ( 2c ) the 4-chlorobutyl compound 4 is obtained, which cyclizes in alkaline medium to the C(6)-N(7) bridged compound 7 . A related cyclization to 11a–11f is observed when 6-chloropurines are reacted with 3-alkyl-1,3-oxazolidines or 3-methyl-1,3-thiazolidine.     

Reactions of Heterocumulenes with Organometallic Reagents: IX. Synthesis and Rearrangements of N-Allyl-and N-[2-(Vinyloxy)ethyl]-3-butenethioamides and -1-(methylsulfanyl)-3-buten-1-imines

Reactions of allyl and 2-(vinyloxy)ethyl isothiocyanates with alyylmagnesium bromide (THF-Et₂O, 20-30°C, 1-3 h) after hydrolysis or alkylation of adducts afforded respectively N-allyl- and N-[2-(vinyloxy)ethyl]-3-butenethioamides or N-allyl- and N-[2-(vinyloxy)ethyl]-1-(methylmercapto)-3-buten-1-imines. The reaction carried out in ethyl ether yielded instead of Nt-allyl-3-butenethioamide its isomer N-allyl-2-butenethioamide that cleanly isomerized in the system KOH-DMSOH₂O into N-(1-propenyl)-2-butenethioamide. N-[2-(vinyloxy)ethyl]-3-butenethioamide suffers a prototropic rearrangement into N-[2-(vinyloxy)ethyl]-2-butenethioamide only in the system     

Bis(α‐bromo ketones): Versatile Precursors for Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) and Bis(as‐triazino[3,4‐b][1,3,4]thiadiazines)

A synthesis of bis(α‐bromo ketones) 5a‐c and 6b,c was accomplished by the reaction of bis(acetophenones) 3a‐c and 4b,c with N‐bromosuccinimide in the presence of p‐toluenesulfonic acid (p‐TsOH). Treatment of 5a‐c and 6b,c with each of 4‐amino‐3‐mercapto‐1,2,4‐triazoles 9a,b and 4‐amino‐6‐phenyl‐3‐mercapto‐1,2,4‐triazin‐5(4H)‐ones 13 in refluxing ethanol afforded the novel bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 10a‐d and 11a‐c as well as bis(as‐triazino[3,4‐b][1,3,4]thiadiazines) 14a‐c and 15 , respectively, in good yields. Compounds 11b and 11c underwent NaBH₄ reduction in methanol to give the target 1,ω‐bis{4‐(6,7‐dihydro‐3‐substituted‐5H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl)phenoxy}butanes 12a and 12b in 42 and 46% yields, respectively.     

Dehydrochlorination of chloroform by N-methyl-N,N-bis(silatranylmethyl)amine

N,N-Bis(silatranylmethyl)methylamine 1 reacts with chloroform resulting in amine hydrochloride 2 and dichlorocarbene. The formation of the latter was proved by a cyclopropanation reaction and insertion into the Si-H bond. In the presence of cyclohexene, compound 2 and 7,7-dichlorobicyclo[4.1.0]heptane are the major reaction products. Compound 2 and 1-dichloromethylsilatrane were isolated upon the reaction of amine 1 with chloroform and 1-hydrosilantrane.     

Novel Synthesis of Isoquinoline Derivatives Derived from (Z)-4-(1,3-Diphenylpyrazol-4-yl)isochromene-1,3-dione

A series of isoquinoline derivatives were synthesized via the reaction of the (Z)-4-(1,3-diphenylpyrazol-4-yl)isochromene-1,3-dione with different hydrazides, primary amines, diamines, 2-aminothiophenol, 2-aminobenzoic acid, p-aminoacetophenone, and ethyl 2-amino-4,5,6,7-tetrahydrobenzo-[b]thiophene-3-carboxylate. All the synthesized compounds were characterized by infrared, ¹H NMR, and mass spectra besides the analytical data.     

Reaction of N-Heterocycles with Acetylenedicarboxylates in the Presence of N-Alkylisatins or Ninhydrin. Efficient Synthesis of Spiro Compounds

Summary. The 1,3-dipolar intermediates generated by addition of isoquinoline, to dialkyl acetylenedicaboxylates are trapped by N-alkylisatins to produce dialkyl 1,2-dihydro-2-oxo-1-alkylspiro[3H-indol-3,2′-[2H,11bH][1,3]oxazino[2,3-a]isoquinoline]-3′,4′-dicarboxylates in excellent yields. The reaction of isoquinoline, quinoline, or pyridine with dimethyl acetylenedicarboxylate in the presence of ninhydrin led to dimethyl 1,2-dihydro-1,3-dioxospiro[3H-indene-3,2′-[2H,11bH][1,3]oxazino[2,3-a]isoquinoline]-3′,4′-dicarboxylate, dimethyl 1,2-dihydro-1,3-dioxospiro[3H-indene-3,3′[3H,4aH][1,3]oxazino[3,2-a]quinoline]-1,2-dicarboxylate, or dimethyl 1,2-dihydro-1,3-dioxospiro[3H-indene-3,2′-[2H,9aH]pyrido[2,1-b][1,3]oxazino]-3,4-dicarboxylate.     

Reactions of pyridinium or isoquinolinium ketene dithioacetals with aromatic N-imines and S-imines

Reactions of ketene dithioacetals, 1-[1-substituted 2,2-bis(methylthio)ethenyl]pyridinium 1a-i or -isoquinolinium 2a,b iodides with aromatic N-imines, 1-aminopyridinium 3a-1,1 -aminoquinolinium ( 4 ), and 2-amino-isoquinolinium ( 5 ) mesitylene sulfonates gave the corresponding 2-methylthioimidazo[1,2-a]pyridines 9a-k , 2-methylthiopyrazolo[1,5-a]pyridines 11a-q , 2-methylthioimidazo[2,1-a]isoquinoline derivatives 10a,b and 2-methylthiopyrazolo[1,5-a]quinoline ( 12 ). The benzoyl compounds, 1-[1-benzoyl-2,2-bis(methylthio)ethenyl]-pyridinium iodides 1g,h,i reacted with N-imine 3a to give the 3-benzoyl-2-methylthioimidazo[1,2-a]pyridines 9h-k . The reaction of pyridinium ketene dithioacetals 1a,f,g (R¹ = COOE_t, COPh, and CN) with substituted pyridinium N-imines having an electron-withdrawing group on the pyridine ring afforded only the corresponding pyrazolo[1,5-a]pyridine derivatives 11j-r in good yields. Reactions of ketene dithioacetals with various S-imines are also described. Possible mechanisms for the formation of 9 and 11 are described.     

Products from furans. VI. Synthesis of dihydro-2-disubstituted-2H-pyran-3(4H)-ones,tetrahydro-3-(aminomethyl)-2-(p-methoxyphenyl)-2-methyl-2H-pyran-3-ol derivatives and 6-(p-methoxyphenyl -6-methyl-7-oxa-1,3-diazaspiro[4,5]decane-2,4-dione

Hydrogenolysis of 5,6-dihydro-6-(p-methoxyphenyl)-6-methyl-5-oxo-2H-pyran-2-yl ethyl carbonate yielded dihydro-2-(p-methoxyphenyl)-2-methyl-2H-pyran-3(4H)-one, 3 . Subsequently cyanohydrin 4 , derived from 3 , on reduction afforded 3-(aminomethyl)tetrahydro-2-(p-methoxyphenyl)-2-methyl-2H-pyran-3-ol, 5 . The synthesis of N-dimethyl,N-isopropyl,N-imidazolyl as well as N-oxazolinyl derivatives of 5 is presented. The synthesis of 6-(p-methoxyphenyl)-6-methyl-7-oxa-1,3-diazaspiro[4,5]decane-2,4-dione 10 , a spiro hydantoin prepared from ketone 3 is also reported.     

1,2-fused pyrimidines. V. Synthesis of 1-alkyl or phenyl-2H-dipyrido-[1,2-a:2′,3′-d]pyrimidine-2,5(1H)-diones

The reaction of 2-[(N-acyl, N-alkyl or phenyl)amino]-4H-pyrido[1,2-a]pyrimidin-4-ones 8a-g with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier reagent 1 (95°, 90 minutes) afforded 1-alkyl or phenyl-2H-dipyrido[1,2-a:2′,3′-d]pyrimidine-2,5(1H)^?diones, 3-alkyl substituted or not, 10a-g . The starting compounds 8 were prepared by treating 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones N-alkyl substituted 7a,b or N-phenyl substituted 4 with excess anhydrides (130°, 7 hours) when the 2-(alkylamino) derivatives 7 were used in the reaction, compounds 8 were obtained along with very small amounts of 3-acyl-2-(alkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones 9 .     

Synthesis of 2-(3-coumarinyl)pyrrolo[2,1-<Emphasis Type="Italic">a</Emphasis>]isoquinoline derivatives by the chichibabin reaction

2-(3-Coumarinyl)-5,5-dimethyl-5,6-dihydropyrrolo[2,1-a]isoquinolines were synthesized by the Chichibabin reaction of 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline with 3-bromoacetylcoumarin. Derivatives of benzo[f]isoquinoline and benzo[f]coumarin were obtained similarly.     

Design and synthesis of the 3′-aminocarbonylamino,aminothiocarbonylamino and N-(Hydroxy)guanidinyl derivatives of thymidine as potential anti-HIV agents

The 3′-substituted-3′-deoxythymidines 3a (urea), 3b (thiourea) and 3c [N-(hydroxy)guanidinyl)] were designed based on the known structure-activity correlations for the active anti-HIV agent, 3′-azido-3′-deoxythymidine (AZT). Hydrolysis of 3′-cyanamido-3′-deoxythymidine ( 2 ) with ammonium hydroxide in the presence of hydrogen peroxide afforded the 3′-urea analogue 3a , whereas reaction with hydrogen sulfide in methanol gave the 3′-thiourea derivative 3b. The 3′-[N-(hydroxy)guanidinyl] compound 3c was synthesized by reaction of the 3′-cyanamide 2 with hydroxylamine.     

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.     

Transformations of 2-(3-Hydroxy-3-methyl-1-butynyl)adamantan-2-ol >Catalyzed by Acids

Reaction of 2-(3-hydroxy-3-methyl-1-butynyl)adamantan-2-ol with acetonitrile under Ritter reaction conditions is accompanied by isomerization and partial hydration where the water addition to the triple bond occurs nonselectively. As a result of reaction carried out in the presence of 8 equiv of sulfuric acid a mixture was obtained of N ²-[4-(1-acetylamino-2-adamantyl)-2-methyl-3-butyn-2-yl]acetamide, N ³-[1-(1-acetylamino-2-adamantyl)-3-methyl-2-oxo-3-butyl]-acetamide, and N ³-[1-(1-acetylamino-2-adamantyl)-3-methyl-1-oxo-3-butyl]acetamide in ~10:3:2 ratio. In the presence of 2 equiv of the acid the mixture obtained consisted of N ²-[4-(1-acetylamino-2-adamantyl)-2-methyl-3-butyn-2-yl]acetamide, N ³-[1-(1-acetylamino-2-adamantyl)-3-methyl-2-oxo-3-butyl]acetamide, and 1-(1-acetylamino-2-adamantyl)-3-methyl-2-buten-1-one in the same ratio. In Rupe reaction conditions we obtained instead of the expected ,-unsaturated ketones a mixture of 1-(1-hydroxy-2-adamantyl)-3-hydroxy-3-methylbutan-1-one and 1-(1-hydroxy-2-adamantyl)-3-hydroxy-3-methylbutan-2-one in a 5:3 ratio.     

Mammalian alkaloids: Synthesis and O-methylation of (S)- and (R)-3′-hydroxycoclaurine and their N-methylated analogues with S-adenosyl-L-[methyl-14C]methionine in presence of mammalian catechol O-methyltransferase

O-Methylation of the optically active 3′-hydroxycoclaurines 3a and 3b and of the N-methylated analogs 5a,b with S-adenosyl-L -[methyl-¹⁴C]methionine in presence of mammalian COMT was investigated in vitro. The N-unsubstituted (1S)- and (1R )-isomers 3a and 3b , respectively, afforded almost equal amounts of the corresponding N-norreticuline 4 and N-nororientaline 19 , besides two unknown by-products (see Fig. and Table 1). The N-methylated (1S)-isoquinoline 5a , on the other hand, afforded largely (S)-orientaline ((S)- 19 ), while an almost equal mixture of (R)-reticuline ( 6b ) and (R)-orientaline ((R)- 19 ) was obtained from the (1R)-enantiomer 5b . The isoquinolines 3a,b and 5a,b were prepared by a Bischler-Napieralski cyclization yielding O-benzyl-protected isoquinoline 10 (Scheme 1). The optical resolution of 10 was accomplished with 2′-bromotartranilic acid. The N-methylated isoquinolines were prepared by N-formylation of 10a,b and reduction of the formamides 13a,b with diborane (→ 14a,b ). Deblocking of the benzyl-ether moieties of 10a,b and 14a,b was accomplished by catalytic hydrogenation in presence of HCl, affording directly 3a,b ·HCl and 5a,b ·HCl, respectively.     

Addition of trimethylsilyl azide and of “mixed anhydrides” to the N-C(3) σ-bond in 3-substituted-1-azabicyclo[1.1.0]butanes

Trimethylsilyl azide adds smoothly to the highly strained N-C(3) σ-bond in 3-ethyl-1-azabicyclo[1.1.0]-butane ( 1 ) to afford an adduct, 2 , that reacts in situ with a variety of electrophilic reagents (i.e., ethyl chloroformate, p-toluenesulfonyl chloride, benzoyl chloride, acetyl chloride, and oxalyl chloride) to afford the corresponding N-substituted-3-azido-3-ethylazetidines 3–7 , respectively in 62–72% yield. Similarly, 1 reacts regiospecifically with “mixed anhydrides” (i.e., p-toluenesulfonyl acetate, methanesulfonyl acetate, and benzoyl trifluoromethanesulfonate) to afford the corresponding adducts, 8–10 , respectively) in 38–68% yield. Reaction of p-toluenesulfonyl azide with 1-aza-3-phenylbicyclo[1.1.0]butane ( 12 ) produces two products: N-(p-toluenesulfonyl-3-azido-3-phenylazetidine ( 13 , 15%) and a dimeric product, N-(N'-p-toluenesulfonyl-3′-phenyl-3′-azetidinyl)-3-azido-3-phenylazetidine ( 14 , 28%). Ethyl chloroformate adds to the N-C(3) σ-bond in 1-aza-3-(bromomethyl)bicyclo[1.1.0]butane ( 15 ) to afford N-carboethoxy-3-(bromomethyl)-3-chloroazetidine ( 16 ) in 73% yield.     

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives 4 and 8 , respectively by 1,5-dipolar cyclization reactions of stabilized pyridinium N-ylides 3a-e or isoquinolinium N-ylide 7 is described. The starting N-ylides 3a-e and 7 are prepared by the reaction of the corresponding pyridinium salts 1a-e or isoquinolinium salts 6 with N-bis(methylthio)methylene-p-toluenesulfonamide (2) .     

Benzofuran systems. Regioselective bromination and some other reactions of 1-(3-benzofuranyl)-2-phenylethanones

1-[3-(2-Alkylbenzofuranyl)]-2-(3,5-dibromo-4-hydroxyphenyl)ethanones 5a,b and 1-[3-(2-alkylbenzofuranyl)-2-(3-bromo-4-methoxyphenyl)ethanones 3a,b were readily prepared by selective bromination of hydroxy 1a,b and methoxy 1c,d ethanones, respectively. A successful method of O-alkylamination of 5a with N-(2-chloroethyl)-N,N-diethylammonium chloride to 6a by a two-phase reaction under phase transfer conditions has been applied. Lithium aluminium hydride reduction of the carbonyl group of 1b to carbinol 4b was carried out in good yields.