4- Chloro-2-substituted thieno

Benzo[e]thieno[3,2- ]thiepin-10(5Ef)-one 388 can be smoothly reduced with sodium borohydride to the corresponding alcohol, which forms the chloro substituted compound under standard treatment with thionyl chloride (1991CPB2564). Dihydro derivatives of pyrrolo-benzothiazepine 377 have been reported starting from ketone 373 by a carbonyl reduction, bromination and amination sequence (Scheme 76, Section 5.1.1 (1998JMC3763, 2002JMC344, 2004JMC143)). 

The synthesis of some new substituted thieno[2,3-Z>]thiophenes (369)-(372) has been achieved <93BCJ201l> in a one-pot reaction employing solid-liquid phase transfer catalysis (PTC) conditions (K2C03, benzene, tetrabutylammonium bromide catalyst) and starting from acetylacetone, CS2, and a-chloro compounds in 1 1 2 molar ratio. The reaction of acetylacetone and CS2 with ethyl chloroacetate, chloroacetonitrile, 2-(chloroacetylamino)thiazole, or chloroacetanilide was carried out under PTC conditions by stirring the reactants reaction times and temperatures were optimized. The corresponding thieno[2,3-6]thiophenes (369)-(372) were obtained in excellent yields (51-93%). 

Thieno[3,4-d][ 1,2,3]triazole, tetramethyl-synthesis, 6, 1015 Thieno[3,4-c][ 1,2,3]triazoles synthesis, 6, 1042 Thieno[3,4-d][ 1,2,3]triazoles reactions, 6, 1036 synthesis, 6, 1044 Thienyl radicals generation, 4, 832 Thiepane, 2-acetoxy-synthesis, 7, 574 Thiepane, 2-chloro-nucleophilic substitution, 7, 573 synthesis, 7, 574 Thiepane, 2-methyl-synthesis, 7, 573 Thiepane, 2-phenyl-synthesis, 7, 573 Thiepane, 3,3,6,6-tetramethyl-cycloaddition reactions, 7, 574 Thiepanes, 7, 547-592 applications, 7, 591... 

Substituted 3-hydroxythiophenes are convenient starting-points for the synthesis of the thieno[3,2-Mthiophene system. Shvedov et obtained 50% of 3-chloro-3-ethoxycarbonyl-5-methylthiophene-2-aldehyde (110) from 3-ethoxycarbonyl-4-hydroxy-2-methylthiophene (109) by Vilsmeier formylation at 100°. Reaction with thioglycolic ter formed 3-ethoxycarbonyl-5-methoxycarbonyl-2-methylthieno[3,2-6]-thiophene (111) [. (36)]. 

Thieno[3,2-c]pyridin-4-one (277) has been prepared by thermal cyclization of 2-thienyl-vinyl isocyanate (Scheme 73) (70BSB301). The derived chloro compound (278) can either be reduced by zinc-acetic acid to (260) or be readily converted into other derivatives by nucleophilic substitution of the halogen. The formation of 4-thiomethyl-6,7-dihydro-thieno[3,2-c]pyridine (280) by cyclization of the isothiocyanate (279) has also been reported (equation 23) (73GEP2318399). 

There are also few reports of the nitration of phenyl derivatives of large ring heterocycles. 7-Chloro-5-phenyl-l//-thieno[2,3- ]-l, 4-diazepin-2(3//)-one (92a) is nitrated to yield the 6-nitro derivative (92b) without phenyl substitution. 5-Phenyl-l-//-thieno[2,3-c]-l, 4-diazepin-2(3 )-one (91c) undergoes both nitration and chlorination to give 7-substituted products also without the formation of nitrophenyl derivatives (73M704, 73M709). 

Recently, the synthesis of 5-aryl-2-oxopyrrole derivative 210 as synthon for the highly substituted pyrrole 211 as starting compound for fused heterocycle 212 was published [56], Diethyl 6-bcnzyl-5-phenyl-6//-thieno[2,3-/ ]pyrrolc-2,4-dicarboxylatc 212 was prepared from ethyl l-benzyl-5-chloro-4-formyl-2-phcnyl-l //-pyrrolc-3-carboxylate 211 and ethyl 2-sulfanylacetate in refluxing ethanol (Scheme 41). 

A method used to prepare four of six possible thienopyridines (1992S528, 1997S949, 1998S1095) holds considerable promise. In particular, the synthesis of thieno[2,3-6]pyridine derivatives 31 and 32 involves the reaction of 2-chloro-3-(cyanomethyl)pyridine (33) and ethyl 2-chloro-3-pyridylacetate (34) with hetero-cumulenes, such as carbon disulfide and phenyl isothiocyanate. The reaction proceeds through the formation of the corresponding dianions 35 and 36 followed by cyclization through intramolecular nucleophilic substitution of the chlorine atom. 

Ring chlorination of 2-amino(or substituted amino)thieno[3,4-d]pyrim-idin-4(3//)-ones 370 (90EUP404356) and 5,7-dihydro-2-(2-methylanilino) thieno[3,4-c/]pyrimidin-4(3//)-one 372 (91MIP1) in boiling phosphoryl chloride gave the respective 4-chloro compounds 371 (90EUP404356) and 373 (91MIP1). The displacement of chlorine from both these compounds by a variety of nucleophiles was also reported. 

Scheme 45 Coupling-addition-nucleophilic aromatic substitution three-component synthesis of 4//-thiochromen-4-ones 82, 4/f-thiopyrano[2,3-i)]pyridin-4-ones 83, 2-chloro-4/f-thieno[2,3-b] thiopyran-4-ones 84, or 7//-benzo-[b]thieno[3,2-i)]thiopyran-7-ones 85...

The action of NaBH4 on 141 (X = X = Cl) gave 2-chloro-3,4-dihydro-thieno[3,4-d]pyrimidines 142, which were used for the synthesis of 2-substituted dihydrothieno[3,4-d]pyrimidines via nucleophilic substitution reactions (81JMC376). 

In the case of Y = C02Et, the reaction affords 5-hydroxy thienopyrimidines, which exist predominantly as the oxo form (118). Pyrimidines 119 starting compounds can be prepared by two methods. One of them involves substitution of the mercaptoacetic acid residue for the chlorine atom in 4-chloro-5-ethoxycarbonylpy-rimidines 120. Pyrimidines 119 are then cyclized in the presence of bases to thieno[2,3-<7]pyrimidin-5-ones 118 (1988JHC959, 1993INP13664). 

Preparation of thieno[2,3-b]pyrazines involves appropriate substituted pyrazines as intermediates. Possible alternative routes starting from thiophenes were not attempted as 2,3-diaminothiophene is only accessible with difficulty. Reaction of 2-chloro-3-cyanopyrazine (3) with a-mercaptocarbonyl compounds in the presence of sodium carbonate gave high yields of the 7-amino derivatives 4 and 5. 

Chloro-4-substituted-4/7-benzo-l-thia-2,4-diazine 1,1-dioxides 154 (R = alkyl, Ph R = H, Cl) undergo substitution of the chloride in the presence of amines to provide the 3-(aminoalkyl) derivatives 155 (R = COAr, NH2, NHCOAr) (Equation 26) <2006BMC650>. Compounds related to 154 react similarly with aryl carboxamides in the presence of base to provide the C-3 A-amido analogs of 155 <2006BMC650>. The 3-(bromomethyl)-3,4-dihydro-277-benzo-l-thia-2,4-diazine 1,1-dioxides 156 (R=H, Me, Cl) react with piperidines to afford the substitution products 157 (Equation 27) as do the related 3-(bromomethyl)-277-benzo-l-thia-2,4-diazine 1,1-dioxides <2005BML1185>. Similar displacements with piperazine nucleophiles on N-alkylated 277-thieno[3,4-( ]-l-thia-2,4-diazine-3(477)-one 1,1-dioxides have been reported <2000EJM751>. 

Pyridazine-fused Systems.—Robba and co-workers have extended their earlier work on thienopyrazines to more heavily fused systems. From benzo[6]thiophen derivatives such as (575)—(577), the benzo[Z>]thieno-[2,3-reaction with hydra-zine. Compounds (579) and (580) could by standard methods be transformed to the chloro-derivatives, which easily undergo nucleophilic substitution, whereby different substituents were introduced at the pyridazinic... 

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