Synthesis of Heterocycles from the Products of Anionic Arylation of Unsaturated Compounds. 7. Products of Haloarylation of Acrylic Acid and Its Esters in the Synthesis of Benzo[b]thiophene Derivatives

3-Chloro-2-chlorocarbonylbenzo[b]thiophenes were obtained on oxidation of Meerwein reaction products, viz. 3-aryl-2-halopropionic acids and their esters, with thionyl chloride in the presence of N-benzyl-N-methylmorpholinium chloride. Disubstituted thioureas were synthesized by the reaction of these compounds with ammonium thiocyanate and aromatic amines, and were cyclized by interaction with iodoacetic acid with the formation of 4-thiazolidinone derivatives. The same cyclization in the presence of aromatic aldehydes leads to the formation of the corresponding 5-arylidene-substituted 4-thiazolidinones.     

An Efficient Synthesis of Pyrazolyl‐1,2,3‐thiadiazoles via Hurd–Mori Reaction

An efficient synthetic strategy has been developed for the synthesis of pyrazolyl‐1,2,3‐thiadiazoles via Hurd–Mori cyclization reaction. The reaction of various pyrazolyl‐phenylethanones with semicarbazide hydrochloride in the presence of sodium acetate/methanol gave the corresponding semicarbazones ( 3a – i ). These semicarbazones were further reacted with thionyl chloride via the Hurd–Mori cyclization conditions to accomplish the title products ( 4a – i ). The present protocol favored for the formation of both pyrazolyl semicarbazone derivatives and pyrazolyl‐1,2,3‐thiadiazole derivatives by forming C─S, N─S, and C═N bonds in excellent yields with variety of substrates. The final compounds were characterized by analytical and spectral studies.     

Heterocyclization of Amidophenacylation Products of Uracil

When uracil is reacted with benzoylamino(chloro)acetophenone, we obtain two amidophenacylation products depending on the condensation conditions. The first product contains an amidophenacyl moiety at the N¹ center, and in the second product two such moieties are located at the N¹ and N³ centers of the uracil. Treatment of these accessible uracil derivatives with phosphorus oxychloride, thionyl chloride, or phosphorus pentasulfide leads to cyclization of the amidophenacyl side group, which is used to synthesize a number of modified pyrimidine bases with 2,5-diphenyloxazole or 2,5-diphenylthiazole residues.     

Partial Dehydrogenation of Saturated 4-Phenyl-1(2H)-phthalazinone Derivatives by Thionyl Chloride

cis-4a, 5,6,7,8,8a-Hexahydro-4-phenyl-1(2H)-phthalazinones (2) react with thionyl chloride in benzene to give tetrahydro derivatives (3); the corresponding reaction of methylene bridged derivatives (5) is also described.     

The Synthesis and Application of Novel Nitrating and Nitrosating Agents

Alcohols and phenols are efficiently nitrated with thionyl chloride nitrate or thionyl nitrate, even in the presence of an aromatic moiety. While thionyl chloride nitrate is suitable for nitration of primary OH-groups in carbohydrates, thionyl nitrate is reactive enough to react with secondary OH-groups as well. These reagents permit the highly selective nitration of the 5′-,2′5′- and 3′, 5′-OH-groups of ribonucleosides to produce either mono-or diprotected nitro derivatives in high yields. Carbon acids and the enol form of some ketones are efficiently nitrated with trifluoromethanesulfonyl nitrate/potassium tert-butoxide. Lutidine N-oxide (2,6-(CH₃)₂C₅H₃N O) was found to have a marked effect on nitration reactions. Similarly, thionyl chloride nitrite and thionyl nitrite exhibit an excellent capacity for nitrosation of the aforementioned substrates.     

Versatile, convenient synthesis of pyrimido[1,2,3-cd]purinediones

The alkylation of 3-substituted cycloalkylcarboxamido-6-aminouracil derivatives with 3-bromo-1-propanol followed by ring closure yields 1,3,8-trisubstituted xanthine derivatives bearing a polar hydroxyl group. Use of the more reactive 1,3-dibromopropane or homologous dibromoalkanes for the alkylation reaction results in simultaneous alkylation at N1 and the exocyclic amino group (N⁶) yielding imidazo-, pyrimido- and diazepino-pyrimidine derivatives. The pyrimidopyrimidine derivatives can subsequently be cyclised using hexamethyldisilazane at high temperature affording an easy, convenient and general access to tricyclic pyrimido[1,2,3-cd]purinediones. Alternatively, 3-substituted 6-amino-5-benzylideneaminouracil derivatives can be reacted with 1,3-dibromopropane followed by an oxidative cyclisation using thionyl chloride to obtain the desired tricyclic pyrimido[1,2,3-cd]purinediones, which are sterically fixed analogues of pharmacologically active purine derivatives.     

Synthesis and identification of 4-methyl-N-(4H-1,2,4-triazol-4-yl)-2-benzothiazolamine,an impurity in the synthesis of tricyclazole

The synthesis of 4-methyl-N-(4H-1,2,4-triazol-4-yl)-2-benzothiazolamine, 4 , a by-product in the synthesis of tricyclazole, 1 , by oxidative cyclization of the corresponding thiourea, 12 , with thionyl chloride, is described.     

Synthesis and selected reactions of 4-(diethoxyphosphorylmethyl)-3-furoic acid

Reduction of 4-(ethoxycarbonyl)-3-furoyl chloride with sodium borohydride in dioxane-DMF mixture leads to an ethyl 4-hydroxymethylfuran-3-carboxylate. The treatment of the latter with thionyl chloride at boiling yields the corresponding chloromethyl derivative. The obtained chloride reacts with one equivalent of sodium iodide in acetone at room temperature to form iodomethylfuran. Halomethylfurans synthesized are phosphorylated with sodium diethyl phosphite and triethyl phosphite to give ethyl 4-(diethoxyphosphorylmethyl)-3-carboxylate. The hydrolysis of this substance with one equivalent of potassium hydroxide in ethanol gives the corresponding furoic acid. Treating this substance in succession with ethyl chloroformate and sodium azide yields furoyl azide which while heating in toluene undergoes rearrangement to phosphorus-containing 3-furylisocyanate. Heating the latter with a mixture of acetic acid and acetic anhydride gives N-[4-(diethoxyphosphorylmethyl) furyl-3]acetamide. 4-(Diethoxyphosphorylmethyl)-3-furoic acid reacts with thionyl chloride to form the corresponding furoyl chloride. Its reduction with sodium borohydride in dioxane-DMF mixture leads to the phosphorylated 3-furylmethanol. Aminomethylation of its acetate with dimethylmethyleneiminium chloride in acetonitrile does not proceed at the ring. Instead of that the unstable ester of 3-(dimethylamino) propionic acid and the phosphorylated 3-furylmethanol are formed. In slightly basic medium free Mannich base decomposed to give the starting acetate.     

The preparation of 3-chlorobenzo[b] thiophene derivatives from cinnamie acids

The reaction of cinnamic acid derivatives with thionyl chloride and pyridine is a general procedure for the preparation of derivatives of 3-chlorobenzo[b] thiophene-2-carbonyl chloride from readily accessible starting materials. These compounds are easily converted to the corresponding acids, esters and amines.     

A Reinvestigation of the Dichlorination of Thymidine

The reaction of thymidine with thionyl chloride in HMPA, reported¹ to give pure 1-(3,5-dichloro-2,3,5-trideoxy-β-D-threo-pentofuranosyl)thymine, has been found to give a mixture of erythro and threo isomers. Upon reacting thymidine with thionyl chloride, according to the literature procedure,¹ a product was isolated which melted 138–141°C [reported¹ 138–140°C] and gave one spot in CHCl₃/ETOH (4:1) on Eastman silica gel sheets at R_f=0.6 [reported¹ one spot at R_f=0.7 on Baker silica gel sheets]. However, the TLC of the product in neat ethyl acetate or CHCl₃/MeOH (9:1) gave two spots. A sample was separated into pure components by flash chromatography².     

Nucleosides XII.1 Synthesis of 5‐Modified Isoguanosines and Reinvestigation of 5′‐Deoxy‐N3,5′‐cycloisoguanosine

Isoguanosine ( 3 ) underwent a coupling reaction with diaryl disulfides in the presence of tri‐n‐butylphosphine when its 6‐amino group was protected by N,N‐dimethylaminomethylidene. The synthesis of 5′‐deoxy‐N³,5′‐cycloisoguanosine ( 6 ) and its 2′,3′‐O‐isopropylidene derivative ( 11 ) were accomplished in excellent yields from isoguanosines ( 3 & 10 ) in the presence of triphenylphospine and carbon tetrachloride in pyridine. Chlorination at the 5′‐position of isoguanosine ( 3 ) with thionyl chloride followed by the aqueous base‐promoted cyclization afforded the same product 6 . The structures were elucidated by spectroscopic analysis including IR, UV, 1‐D and 2‐D NMR.     

Synthese von (Methylthio)penam-Derivaten durch Keten-Addition an 4,5-Dihydro-5-(methylthio)-1,3-thiazole

Synthesis of (Methylthio)penam Derivatives via Keten Addition onto 4,5-Dihydro-5-(methylthio)-1,3-thiazoles The 4,5-dihydro-5-(methylthio)-2-phenyl-1,3-thiazoles 3a and 3b , easily prepared from the corresponding 1,3-thiazol-5(4H)-thiones and MeLi, react with dichloroacetyl chloride ( 5a ) and acidoacetyl chloride ( 5b ) in the presence of Et₃N to give (methylthio)penam derivatives 6 (Table 1). The reaction mechanism is either a [2 + 2] cycloaddition of in situ generated ketene or a two-step reaction (Scheme 2). The structure of 6f has been confirmed by X-ray crystallography (Fig. 2). The relative configuration of 6a-e follow from comparison of their ¹H-NMR spectra with those of 6f (Fig. 1). The 6-azidopenams 6d and 6f have been reduced to aminopenams 8a and 8b , respectively. Acylation of 8a with phenacetyl chloride yields 9 (Scheme 4).     

3-(4-取代-哌嗪-1-甲基)-1,2,3,9-四氢咔唑-4-酮衍生物的合成与止吐活性研究

以1,3-环己二酮(1)为起始原料, 一个羰基与盐酸苯肼发生缩合反应生成1,3-环己二酮单苯腙(2), 2在ZnCl₂催化下通过分子内环合、重排反应得到1,2,3,9-四氢咔唑-4-酮(3), 3的甲基化物4在冰醋酸中经Mannich反应获得其3-二甲胺甲基物5, 5与哌嗪类化合物通过亲核取代反应合成了9个未见文献报道的3-(4-取代-哌嗪-1-甲基)-1,2,3,9-四氢咔唑-4-酮衍生物6a～6i. 所有合成的新化合物均经元素分析、红外光谱、质谱和核磁共振光谱证明其结构; 初步药理试验采用顺铂诱导的大鼠干呕模型研究了新化合物的止吐活性, 结果表明部分新化合物活性与昂丹司琼相当.     

Intramolecular cyclization of dialkyl[2-(5-chloro-2-hydroxyphenyl)-2-phenylethenyl]phosphine oxides by the action of thionyl chloride

An efficient procedure has been proposed for the synthesis of quasiphosphonium salts, 2,2-dialkyl-6-chloro-4-phenyl-2H-1,2-benzoxaphosphinin-2-onium chlorides, via cyclization of dialkyl[2-(5-chloro-2-hydroxyphenyl)-2-phenylethenyl]phosphine oxides under the action of thionyl chloride.     

Direct Transformation of Anthrone and Its Derivatives into Monothioanthraquinone S-Oxides

The reaction of anthrone with thionyl chloride in benzene yields 10-(chlorosulfinyl)anthrone, whilein DMF monothioanthraquinone S-oxide is formed; 4-substituted anthrones react with thionyl chloride in DMFin a similar way. The reaction of 4'5-dichloroanthrone with thionyl chloride results in dimerization of thesubstrate, formation of the corresponding bianthracenedione.     

Synthesis via pummerer intermediates. III. Rearrangements of 3-(methylsulfinyl)quinolinones, 3-(methylsulfinyl)cinnolinones, 3-(methylsulfinyl)chromanones and 3-(methylsulfinyl)chromones with acetic anhydride and with thionyl chloride

The reaction of 1-methyl-3-(methylsulfinyl)-4(1H)quinolinone ( 1 ) with acetic anhydride and thionyl chloride gave 3-[[(acetyloxy)methyl]thio]]-1-methyl-4(1H)quinolinone ( 2 ) and 3-[(chloromethyl)thio]-1-methyl-4(1H)quinolinone ( 3 ) respectively. 3-(Methylsulfinyl)-4(1H)cinnolinone ( 4 ) gave the corresponding products when treated under similar conditions. Treatment of 8-methoxy-3-(methylsulfinyl)-4H-1-benzopyran-4-one ( 11 ) with acetic anhydride and thionyl chloride gave bis addition vinyl Pummerer products 2,3-bis(acetyloxy)-2,3-dihydro-8-methoxy-3-(methylthio)-4H-1-benzopyran-4-one ( 12 ) and 2,3-dichloro-2,3-dihydro-8-methoxy-3-(methylthio)-4H-1-benzopyran-4-one ( 13 ), respectively.     

Stereospecific substitution of a hydroxy group by a chlorine atom in isomeric 2,3-disubstituted 3-hydroxytetrahydrothiophenes

The stereospecific synthesis of the three possible isomers of 4-amino-3-chloro-2-(4-methoxycarbonylbutyl)tetrahydrothiophene hydrohalides from the corresponding isomers of 4-amino-3-hydroxytetrahydrothiophene by the action of thionyl chloride was realized. Three isomers of 4-ureido-3-chloro-2-(4-methoxycarbonylbutyl)tetrahydrothiophene were obtained from the 3-chlorotetrahydrothiophene derivatives. The configurations of the isomeric compounds obtained were proved by ¹H and ¹³C NMR spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 327–333, March, 1991.     

Synthetic transformations of higher terpenoids: XVII. Intramolecular cyclization of N-furfuryl amides of the labdane series

16-(Benzylaminomethyl)lambertianic acid methyl ester reacts with 2-methylprop-2-enoyl chloride to give unsaturated amide which readily undergoes intramolecular [4 + 2]-cycloaddition with formation of terpenoid derivatives of 10-oxa-3-azatricyclo[5.2.1.0^1,5]decenone. Acetylation of lambertianic acid methyl ester with acetic anhydride occurs preferentially at the 2-position of the furan ring and is accompanied by migration of the exocyclic double bond. Reductive amination of 16-acetyl-15,16-epoxylabda-8(9),13,14-triene and subsequent reaction of the resulting amine with 2-methylprop-2-enoyl chloride give intramolecular cyclization products in high yield without isolation of intermediate furfurylacryloyl derivative. Reactions of methyl 16-(benzylaminomethyl)-15,16-epoxylabda-8(9),13,14- and -8(17),13,14-trien-18-oates with maleic anhydride lead to the formation of the corresponding 10-oxa-3-azatricyclo[5.2.1.0^1,5]dec-8-ene-6-carboxylic acid derivatives as mixtures of diastereoisomers.     

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.     

Facile synthesis of 2-(substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones

Interaction between 2,5-dichlorothiophene-3-carbonyl isothiocyanate, accessible via 2,5-dichlorothiophene-3-carbonyl chloride, and model heterocyclic amines produced the respective 2,5-dichloro-N-(substituted aminocarbonothioyl)thiophene-3-carboxamides. Upon heating, the deprotonated form of the latter underwent intramolecular cyclization to deliver the corresponding 2-(substituted amino)-4H-thieno[3,2-e]-1,3-thiazin-4-ones. The structures of these new bicyclic derivatives and their acyclic precursors are based on microanalytical and spectral (IR, MS, and NMR) data.