Preparation of 3-(2H-pyran-2-on-6-yl)indolizines and the diels-alder reactions with some olefinic and acetylenic dienophiles

3-(2H-Pyran-2-on-6-yl)indolizines 6a-d were prepared by 1,3-dipolar cycloaddition reactions of N-(2H-pyran-2-on-6-yl)methylpyridinium bromides 5a,b with dimethyl acetylenedicarboxylate (DMAD). All of the cycloaddition reactions of 6b with N-phenylmaleimide, p-benzoquinone, and DMAD took place at the 2-pyrone ring to give 3-substituted indolizines.     

Stereoselective total synthesis of (+)-strictifolione and (6R)-6[(E,4R,6R)-4,6-dihydro-10-phenyl-1-decenyl)-5,6-dihydro-2H-2-pyrone

The stereoselective total synthesis of two naturally occurring α-pyrone derivatives, (+)-strictifolione and (6R)-6[(E,4R,6R)-4,6-dihydroxy-10-phenyl-1-decanyl]-5,6-dihydro-2H-2-pyrone has been accomplished involving the Sharpless kinetic resolution and olefin cross-metathesis as the key reactions.     

6-取代苯并噻唑苯胺类化合物的合成

以2-氨基苯并噻唑类化合物为原料, 通过碱性条件下水解, 与苯甲酸类化合物在PPA(聚磷酸)条件下脱水环化, 部分化合物通过BBr₃去甲基化反应, 合成了一系列潜在的针对β-淀粉样蛋白的正电子放射性探针分子前体或作为参比的6-取代苯并噻唑苯胺类化合物, 并用¹H NMR, IR, EI/ESI-MS, HRMS, 元素分析等对其进行了表征. 同时测定比较了6种化合物与早老性痴呆(Alzheimer’s disease, AD)死者脑匀浆的亲和力强弱.     

Synthesis of 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones

The reactions of 1-substituted 2-nitro-3-phenylaminoprop-2-en-1-ones with cyanothioacetamide afforded the corresponding 6-substituted 3-cyano-5-nitropyridine-2(1H)-thiones, which were used for the synthesis of 6-substituted 3-cyano-2-methylthio-5-nitropyridines and 7-substituted 4-hydroxy-8-nitropyrido[2",3":4,5]thieno[2,3-b]pyridin-2(1H)-ones.     

Pyrimidine derivatives. VII. Nucleophilic reactions of 5-bromo-1-(bromoalkyl)-6-bromomethyl-2,4(1H,3H)-pyrimidinediones

The reactions of 1-(bromoalkyl)-5-bromo-6-bromomethyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1) with several nucleophiles were examined as follows: by reaction with sodium methoxide, 6-(bismethoxy)methyl-5-debrominated derivatives 2, 3 , and 4 were prepared; the corresponding di-substituted compounds (side chains in 1-and 6-positions) 5, 6, 7 , and 9 were obtained by treatment with silver nitrate, silver acetate, potassium thiocyanate, and potassium thioacetate; the reaction with thioacetamide and iso-butylamine gave bicyclic compounds [1,4]thiazino[4,3-c]- 11 , pyrazino[1,2-c]- 12 , and [1,4]diazepino[1,2-c]pyrimidinedione 13 , respectively; pyrrolidine, morpholine, and sodium azide afforded the corresponding 6-substituted compounds 14, 15 , and 16 .     

Claisen-Umlagerung von 2-Propinyl-(3-pyridyl)-und Allyl-(3-pyridyl)äthern

Claisen Rearrangement of 2-Propinyl (3-Pyridyl) and Allyl (3-Pyridyl) Ethers

1 Verbindungen vom Typ 1 werden mit Ausnahme von 17 und 25 als Äther benannt. Der systematische Name von 1 ist: 3-(2-Propinyl)oxy-pyridin.

2-Propinyl (3-pyridyl) ether ( 1 ), synthesized from the corresponding 3-pyridinol, was heated in DMF or decane at 208° in a sealed tube. In this way the furopyridines 2 and 3 were formed, and furthermore the pyranopyridine 4 if decane was used as solvent (Scheme 1). The same reactions took place with (2-methyl-3-pyridyl) 2-propinyl ether ( 14 ). In DMF only 15 , and in decane 16 as well as 15 were formed (Scheme 3). The rearrangement of the pyridine derivative 17 , which is substituted in both O-positions to the ether moiety, gave in both DMF and decane the diastereoisomeric tetracyclic compounds 18 and 19 . The same kind of reaction took place with 25 (Scheme 4). In the thermolysis of the allyl 3-pyridyl ether ( 27 ) cyclization was observed, too. The isolated product has the structure of the dihydrofuropyridine 28 (Scheme 6). The substituted allyl 3-pyridyl ether 30 reacted in the same way to the dihydrofuropyridine 31 (Scheme 6).     

Synthesis of 4-(2-acetoxyethoxymethyl)-6-methyl-1,2,4-triazin-3(4H)-one 1-oxide as thymidine analogue

Alkylation of the sodium salt and the trimethyl silylated derivatives of 6-methyl-1,2,4-triazin-3(4H)-one 1-oxide with chloromethoxyethyl acetate, n-hexyl chloride and benzyl bromide gave the 4-substituted products. However, attempts to achieve the ring closure of N⁴-(2-acetoxyethoxymethyl)thiosemicarbazide with bicarbonyl compounds to the corresponding as-triazines under different reaction conditions was not possible without disruption of the acetoxyethoxymethyl moiety. Although the as-triazine nucleoside analog II did not show antileukemic activity, this and other 4-alkylated as-triazine 1-oxides revealed good growth inhibitory effects against a representative spectrum of microorganisms.     

Thermolysis of N-allylic 1,2,4-triazoles

A number of 4-allylic substituted 3,5-diphenyl-4H-1,2,4-triazoles were thermolyzed at 315–320° in evacuated glass ampoules. The main reaction in the melt was rearrangement to the corresponding 1-substituted triazoles, which appeared to proceed via competing S_N2 and S_N2′ mechanisms. The allylic systems were observed to undergo [2,3]-allyl walk reactions between the 1- and 2-ring positions. Allyl to vinyl isomerization also took place. Substitution of the allylic moiety increased the rate of reaction but decreased the rate of isomerization of allylic to the vinylic substituted triazoles. The 4-vinyl substituted triazoles were inert under the reaction conditions. Some triazoles were converted into substituted pyridines. This was proposed to proceed via nitrogen extrusion and formation of a 1,3-dipolar intermediate (nitrile ylide) which added intramolecularly to the allyl moiety and subsequently aromatized to the pyridine.     

On 6-(thenoyl)-7,8-dichloro-4-oxo-4H-1-benzopyran-2-carboxylic acid

The annulation of the oxyacetic chain of thienylic acid into a γ-pyrone ring is described. The resulting 6-(2-thenoyl)-7,8-dichloro-4-oxo-4H-1-benzopyran-2-carboxylic acid retains almost 80% of the diuretic activity of the parent compound.     

Synthesis of α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetic acid derivatives

α-(Aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate, 3 and 8 , have been synthesized by catalytic hydrogenation of 6-cyanomethylene-9-methoxymethylpurine derivatives 2 and 7 which were obtained by the substitution of 6-chloro-9-(methoxymethyl)purine ( 1 ) with α-cyanoacetamide and ethyl cyanoacetate, respectively. Substitution of 3 and 8 with amines gave the corresponding N-substituted α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetamide and the ethyl acetate 4 and 10 . Reaction of 3 with piperidine gave 9-(methoxymethyl)-9H-purine-6-acetamide ( 5 ).     

Reaction of Ethyl 6-Alkyl(aryl)-4-chloromethyl-2-methylpyridine-3-carboxylates with Ammonia and Primary Amines

Ethyl 6-alkyl(aryl)-4-chloromethyl-2-methylpyridine-3-carboxylates react with ammonia andprimary amines to give 6-substituted 3-alkyl(aryl)-1-methyl-1'2-dihydropyrrolo[3'4-c]pyridin-7-ones.The reactions with 4-aminopyridine yield ethyl 6-alkyl(aryl)-2-methyl-4-(4-pyridylaminomethyl)pyridine-3-carboxylates.     

Synthesis of pyrimidino[4,5-b][1,5]benzodiazepin-2-ones and pyrimidino[1,6-a]benzimidazol-1-ones from 4-ethoxycarbonylamino-1H-1,5-benzodiazpine-3-carbonitrile via 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles

Reactions of 4-ethoxycarbonylamino-1H-1,5-benzodiazepine-3-carbonitrile (2) with aliphatic primary amines gave 1-substituted 4-(2-aminoanilino)pyrimidin-2(1H)-one-5-carbonitriles 3. Analogous reactions of 2 with aromatic primary amines afforded 2-(2′-anilino-1′-cyanovinyl)benzimidazoles 5 and 6. Upon treatment with triethylamine, 3 underwent intramolecular cyclization to give 3-substituted 5-aminopyrimidino[4,5-b]-[1,5]benzodiazepin-2(3H,11H)-ones 8 . Heating of 3 with p-toluenesulfonic acid in ethanol gave 2-substituted pyrimidino[1,6-a]benzimidazol-1(2H)one-4-carbonitriles 9 . Reactions of 2 with hydrazines were also described. Mechanistic pathways are proposed to account for the products.     

Synthesis of 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carbonitriles and -6-carboxylic acid esters

Dieckmann ring closure reactions of 4-[(2-cyanoethyl)substituted amino]-2-phenyl-5-pyrimidinecarboxylates (Ha-f) afforded several 5,6,7,8-tetrahydro-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitriles (IIIa-f). The open-chain intermediates (IIa-f) were prepared by dechloroamination of 5-carbethoxy-4-chloro-2-phenylpyrimidine (1a) with several 3-substituted amino- propionitriles. Alkylation of the sodium salt of 5,6,7,8-tetrahydro-8-methyl-5-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6- carbonitrile (IIIa) with methyl iodide in DMF resulted in methylation at C-6 to afford IV. Tosylation of IIIa in pyridine gave the corresponding tosyl ester (V) of the enolic form. Oxidative dehydrogenation at the 6,7-position resulted when IIIa reacted with thionyl chloride, affording 5,8-dihydro-8-methyl-5-oxo-2-phenylpyrido[2,3-d]pyrimidine-6- carbonitrile (VII). Dechloroamination of la or 5-carbethoxy-4-chloro-2-methylthiopyrimidine (Ib) with ethyl 3-ethylaminopropionate followed by Dieckmann cyclization of the resulting open-chain intermediates gave the corresponding ethyl 5,6,7,8-tetrahydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylates IX'a and IX'b, respectively. These exist predominately in the enol form and undergo alkylation and oxidation reactions similar to IIIa.     

A study of the acylation of 4-hydroxy-6-methyl-2-pyrone and 4 hy(lroxy-6-phenyl-2-pyrone

The acylation of 4-hydroxy-6-melhyl-2-pyrone (1) and 4-hydroxy-6-phenyl-2-pyrone (XXII) with aliphatic acid anhydrides, or with aliphatic acid chlorides in trifluoroacetic acid, has been found to product; first the corresponding ester, which then rearranges, partially or wholly, depending on the conditions and on the nature of the acyl moiety, to form the corresponding 3-acylpyrone. With aromatic acid chlorides in pyridine or in trichloroacetic acid only the corresponding ester was obtained. These esters, however, could be rearranged to the corresponding 3-acylpyrones with aluminum chloride. Acetoaeetylation of 1 and 4-hydroxycoumarin (XXIX) with diketene gave, in both cases, the C-acetoacetylated product.     

The synthesis and reactivity of polysilylacetylenes: Diels—Alder reactions to give bis (silyl) benzenes

Six bis(silyl)acetylenes (XMe²Si? C?C? SiMe₂X) with the following varied silicon substituents X were prepared: 1 (Me, Me); 2 (H, H); 3 (C1, H); 4 (CI, CI); 5 (MeO, H); 6 (MeO, MeO). While 1 and 2 may be prepared by the reaction of dilithio- or bis(bromomagnesium)-acetylide with the appropriate chlorosilane, similar reactions designed to give 3–6 yielded oligomers, XMe₂Si? (? C?C? SiMe₂)_n? X, 7, X=CI, MeO, as the major products, indicating that the acetylenic functionality on silicon activates the chlorosilane towards nucleophilic substitution. Compounds 3 and 4 were prepared by free radical chlorination of 2. Methanolysis of 3 and 4 gave quantitative yields of 5 and 6 respectively. Compounds 1–6 undergo a Diels–Alder reaction with α-pyrone to produce, after loss of carbon dioxide, bis(silyl)-substituted benzene derivatives. The order of reactivity has been determined to be: 4=6>3=5>1>2, indicating that chloro or alkoxy substituents favor the cycloaddition with 2- pyrone. The adducts formed by compounds 3–6 undergo an unusually facile hydrolysis or elimination to give 1,1,3,3-tetramethyl-1,3-disila-2-oxaindane.     

Synthesis and reactivity of 3-(2-chloroalkyl)-2,2-dihaloaziridines

3-(2-Chloroalkyl)-2,2-dihaloaziridines were synthesized via cycloaddition of dihalocarbenes to the CN double bond of β-chloroimines. Under the action of Lewis acids or HCl, N-C³ bond cleavage occurred, giving rise to N-substituted 2,4-dichloro-3,3-dimethylbutanamides, which were further converted to 3-chloropyrrolidin-2-ones under alkaline conditions. When 2,2-dichloro-3-(2-chloro-1,1-dimethylethyl)-1-phenylaziridine was reacted with sodium methoxide, aziridine ring opening with N-C² bond cleavage took place, leading to methyl 4-chloro-3,3-dimethyl-2-(phenylamino)butanoate.     

Synthese von 3-(2-Carboxy-4-Pyridyl)- und 3-(6-Carboxy-3-pyridyl)-DL-alanin

Synthesis of 3-(2-Carboxy-4-pyridyl)-and 3-(6-Carboxy-3-pyridyl)-DL-alanine As starting materials for potential photochemical approaches to betalaines C(R = COOH) and to muscaflavine F(R = COOH), β-(2-carboxy-4-pyridyl)- and β-(6(carboxy-3-pyridyl))-DL-alanine ( A and D with R = COOH or 4 and 11 ), respectively, were prepared (Scheme 1). The synthesis of 4 (= A, R = COOH) started with the 2-[(4-pyridyl)methyl]malonate 1 and proceeded via the N-oxide 2 , cyanation and hydrolysis (Scheme 2). Amino acid 11 was obtained from (3-pyridyl)methyl-bromide ( 6 ) via the malonate 7 by an analogous sequence of reactions (Scheme 3).     

Synthesis of 1-[2-Methyl-6(8)-R-quinolin-4-yl]thiosemicarbazides

1-(2-Methylquinolin-4-yl)thiocemicarbazides and S-(2-methylquinolin-4-yl)thiosemicarbazide hydrochlorides were synthesized by reaction of 6(8)-substituted 4-chloro-2-methylquinolines with thiosemicarbazide under different conditions. Alkaline hydrolysis of the hydrochlorides afforded substituted 1-(2-methylquinolin-4-yl)thiosemicarbazides.     

Synthesis of α-(aminomethylene)-9H-purine-6-acetic acid derivatives

α-(Aminornethylene)-9H-purine-6-acetamide ( 3a ) and the corresponding ethyl acetate 9 have been synthesized by catalytic hydrogenation of 6-cyanomethylenepurine derivatives 2 and 7 which were obtained by the substitution of 6-chloropurine derivatives with α-cyanoacetamide and ethyl cyanoacetate, respectively. Substitution of α-(aminomethylene)-9-(tetrahydrofuran)-9H-purine-6-acetamide ( 3b ) with amines gave the corresponding N-alkyl- and N-arylamines 5 , which were treated with acid to give N-substituted α-(aminomethylene)-9H-purine-6-acetamides 6 . Substitution of 9 with amines gave the corresponding N-alkyl- and N-aryl substituted amines 10 .     

The Michael-Type Addition Reaction: A Stereocontrolled Construction of a New Quaternary Chiral Center at C(2) of 2-(4-Hydroxybenzyl)cyclohexanone Derivatives

The Michael-type addition reaction was used as a convenient method for the stereocontrolled construction of a new quaternary C-center at position 2 of 2-substituted cyclohexanones (Scheme) with the aim to study the effect of an additional substituent at C(2) in a series of biologically active compounds bearing generally a 2-substituted cyclohexanone moiety. Thus, a new series of compounds consisting of a racemate (RS)- 12 and its enantiomers (S)- and (R)- 12 (ee ≥96% for both enantiomers) was obtained. The Michael adduct derivatives (S)-, (R)-, and (RS)- 12 were subjected to a biological screening using several non-related insect species.