A versatile synthesis of 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones

A mild and general strategy for the synthesis of 2-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones is described. The seven-membered lactam is prepared by intramolecular amide bond formation from the intermediate amino acid, which is obtained either by reductive alkylation of a variety of amines with N-Boc,N-Me-ortho-formyl-Phe and Phth-ortho-formyl-Phe, or by reductive amination of a variety of aldehydes with N-Boc-ortho-aminomethyl-Phe.     

Parallel synthesis of 3-amino-4H-quinolizin-4-ones, fused 3-amino-4H-pyrimidin-4-ones, and fused 3-amino-2H-pyran-2-ones

On the basis of the enaminone methodology, libraries of 3-amino-4H-quinolizin-4-ones, fused 3-amino-4H-pyrimidin-4-ones, and fused 3-amino-2H-pyran-2-ones were synthesized by the solid-phase and by the solution-phase parallel synthesis. The solution-phase approach turned out to be advantageous over the solid-phase approach. The solution-phase synthesis afforded, in most cases, analytically pure products in high yields, whereas the solid-phase approach gave products in poor yields and in low purity.     

A tandem one-pot, microwave-assisted synthesis of regiochemically differentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones

A one-pot, two-step synthesis of the title compounds employs a multicomponent Ugi condensation reaction, microwave irradiation, and Fe(0) as a reductant. Two pathways are accessible; both routes utilize bifunctional, o-nitro-substituted arenes leading to either C2, N4, C5 substitution (A) or C2, N4 substitution (B).     

Facile synthesis of 4-substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones by reductive cyclization of 2-chloro-N-(2-nitrobenzyl)acetamides

A facile and efficient method was developed for the synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones from 2-chloro-N-(2-nitrobenzyl)acetamides through a reductive cyclization using iron-ammonium chloride in ethanol–water in good yields. This method provides a simple approach to these benzodiazepine-3-ones which are of high value in the field of medicinal chemistry research.     

Organocatalyzed enantioselective synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylates

The organocatalyzed enantioselective synthesis of biologically active 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate derivatives was achieved using bifunctional cinchona alkaloids as the catalysts. Using quinine thiourea as the catalyst, the tandem Michael addition-cyclization reaction between 1,3-cyclohexanediones and alkylidenecyanoacetate derivatives gives the desired products in high yields (up to 92%) and good ee values (up to 82%).     

Regioselective alkylation of 2-alkyl-5,6,7,8-tetrahydro-3h-cycloheptimidazol-4-ones and 2-alkyl-3h-cycloheptimidazol-4-ones

Regioselective alkylation of 2-alkyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (1) and 2-alkyl-3H-cycloheptimidazol-4-one (2) was investigated. 3-[2'-(1-tert-Butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-5,6,7,8-tetrahydro-1H-cycloheptimidazol-4-one (6) was preferentially obtained under the conditions by using NaH in DMF or THF. On the other hand, 3-[2'-(1-tert-butyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-2-propyl-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (5), the synthetic intermediate compound of Pratosartan, was obtained selectively in the presence of n-Bu(4)NBr in toluene by using aqueous sodium hydroxide as a base. In this reaction, it was found that the concentration of the alkaline solution influences its regioselectivity. This selectivity was observed even for aldehyde and ester derivatives.     

Traceless solid-phase synthesis of 2-amino-5-alkylidene-thiazol-4-ones

2-Amino-5-alkylidene-thiazol-4-ones bearing two diversity points are prepared by a solid-phase strategy exploiting rhodanine as the starting material. Rhodanine is first loaded on bromo-Wang resin, subjected to Knovenagel condensation with aldehydes, and cleaved off the resin in a traceless manner by means of an amine.     

Organocatalyzed synthesis of 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles

2-Amino-8-oxo-tetrahydro-4H-chromene-3-carbonitriles were synthesized for the first time from a tandem Michael addition-cyclization reaction between cyclohexane-1,2-dione and benzylidenemalononitriles. An enantioselective synthesis of these compounds was achieved in moderate ee values (up to 63% ee) by using a cinchona alkaloid-derived thiourea catalyst.     

Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones

Uncatalyzed one-pot pseudo-four-component reaction of ethyl pyruvate, anilines, and aldehydes in n-hexane as solvent, under reflux, affords a variety of 3-amino-1,5-dihydro-2H-pyrrol-2-ones in high yield. n-Hexane is an excellent driving force in preparation of the desired products. These compounds have biological and pharmacological properties and are also used in medicinal chemistry. Use of a non-toxic and inexpensive solvent, simple and efficient synthesis, clean work-up, and high yields of the products are the advantages of this method. We report the first catalyst-free method for synthesis this class of compounds.     

A convenient synthesis of 3-amino-4-imino(thioxo)-imidazolidin-2-ones

Subsequent treatment of diethylphosphonopropyl α-aminonitriles with 1,1′-carbonyldiimidazole or 1,1′-carbonyl-di-(1,2,4-triazole) and hydrazines afforded substituted 3-amino-4-imino-imidazolidin-2-ones. Their acidic hydrolysis and their reactions with hydrogen sulfide are described.     

A general approach for the synthesis of 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones

Short stereoselective syntheses of both 5-substituted-4-amino-pyrrolidin-2-ones and 5-substituted-4-amino-3-pyrrolin-2-ones from natural α-amino acids are described.     

Combined solution-phase and solid-phase synthesis of 2-amino-7,8-dihydropteridin-6(5H)-ones

An efficient and general synthesis of substituted 2-amino-7,8-dihydropteridin-6(5H)-ones using a combination of solution-phase and solid-phase chemistry is described. Solution-phase chemistry was used to produce two pyrimidine regioisomers that were separated by flash column chromatography. Utilizing the desired regioisomer, solid-phase chemistry was used to effect the rapid construction of the substituted 2-amino-7,8-dihydropteridin-6(5H)-one system in high overall yield and purity.     

Asymmetric synthesis of trans-3-amino-4-alkylazetidin-2-ones from chiral N,N-dialkylhydrazones

Enantiopure N,N-dialkylhydrazones 3 smoothly react with N-benzyloxycarbonyl-N-benzyl glycine as an aminoketene precursor to afford trans-3-amino-4-alkylazetidin-2-ones 4 as single diasteromers. As an exception, hydrazone 3f (R = OBn) affords cis-(3R,4R)-4f under modified conditions. N-N Bond cleavage of cycloadducts 4 afforded free azetidinones 5 in high yields. [structure: see text]     

Efficient microwave-assisted synthesis of 4-amino-2-benzazepin-3-ones as conformationally restricted dipeptide mimetics

In this paper, we describe the synthesis of conformationally constrained dipeptide mimetic derivatives. Microwave flash heating was used in several synthetic steps providing the opportunity to perform the reactions in dramatically shortened time as well as to increase the obtained yields. The efficiency of the methodology makes it useful in order to prepare other dipeptides containing the 4-amino-tetrahydro-2-benzazepin-3-one motif.     

A base-catalyzed solution-phase parallel synthesis of substituted vinylic benzamides from 3-amino-2-cyclohexanones

An improved method for the synthesis of benzamides from 3-amino-2-cyclohexenones is presented. Using sodium hydride, a base-catalyzed N-benzoylation provided significantly higher yields (71-79%) for the reported compounds. This novel protocol was applied in the solution-phase parallel synthesis of a 12-member library of vinylic benzamide derivatives of 3-amino-2-cyclohexenones in 63-90% yield, using a Radley's Carousel Reaction Station.     

The synthesis of methyl 2-(benzyloxycarbonyl)amino-3-dimethylaminopropenoate. The synthesis of trisubstituted pyrroles, 3-amino-2H-pyran-2-ones,fused 2H-pyran-2-ones and 4H-pyridin-4-ones

Methyl 2-(benzyloxycarbonyl)aimno-3-dimemylaminopropenoate ( 2 ) was prepared from methyl N-(benzyloxycarbonyl)glycinate ( 1 ) and t-butoxybis(dimethylamino)methane, and used as a reagent for preparation of substituted 3-(benzyloxycarbonyl)amino-4H-quinolizin-4-ones 5 and 6 , ?2H-pyran-2-ones 17–19 , ?2H-1-benzopyran-2-ones 28–31 , and -naphthopyrans 32–35 , ?2H-pyrano[3,2-c]pyridine-2,5-dione 46 , -pyrano-[4,3-b]pyran-2,5-dione 47 , -pyrano[3,2-c]benzopyran-2,5-dione 48 , -pyrano[2,3-c]pyrazol-6-ones 49 and 50 , -pyrano[2,3-d]pyrirnidin-7-ones 51 and 52 derivatives. In the reaction of 2 with 1,3-diketones trisubsti tuted pyrroles 14–16 were formed. Selective removal of benzyloxycarbonyl group was achieved by cat alytic transfer hydrogenation with Pd/C in the presence of cyclohexene to afford free 3-amino compounds 7 , 8 , 20 , 36–38 and 53–57 in yields better than 80%.     

A new route for the synthesis of substituted 5-amino-4-cyanoimidazol-2-ones – precursors for the preparation of 3,6,7,9-tetrahydro-8H-purin-8-ones derivatives

5-Alkyl(aryl)amino-4-cyanoimidazol-2-ones were obtained on the basis of 2-alkoxycarbonylamino-3,3-dichloroacrylonitriles. They were then used for the synthesis of derivatives of 3,6,7,9-tetrahydro-8H-purin-8-ones.     

The synthesis of 1,3,4,5-tetrahydro-2,3-benzoxazepines and 1,2,4,5-tetrahydro-3,2-benzoxazepines

Condensation of o-bromomethylphenethyl bromide with potassium salt of N-hydroxyurethan afforded 3-earbethoxy-1,3,4,5-tetrahydro-2,3-benzoxazepine, which was hydrolyzed to 1,3,4,5-tetrahydro-2,3-benxoxazepine (III). The reaction of o-aeetoxymethylphenethyl bromide (VIb) with potassium salt of N-hydroxyurethan in DMF, gave a complex mixture, from which O-[2-(o-acetoxymethylphenyl)(ethyl]-N-earbethoxyhydroxylamine (VIIa) was separated. Subsequent desacetylation to VIIb and halogenation yielded O-[2-(o-bromomethylphenyl)ethyl]-N-carbethoxyhydroxylamine (VIIc). By treatment of VIIc with potassium hydroxide, 2-carbethoxy-1,2,4,5-tetrahydro-3,2-benzoxazepine (X) was obtained together with small amounts of 6,15-diearbethoxy-5,6,8,9,14,15,17, 18-octahy drodibe nzo[d,I]-1,8-dioxa-2,9-diazaeyclotetradec in e (XI). Hydrolysis of X with potassium hydroxide gave 1,2,4,5-tetrahydro-3,2-benzoxazepine (XII). N-Alkyl and N-acyl derivatives of III and XII were also prepared.