Thieno pyridine-5 -ones

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

Thieno[3,2-c]pyridine-4(5H)-thione, 6,7-dihydro-synthesis, 4, 762 Thieno[2,3-c]pyridin-4-ones synthesis, 4, 1007, 1008 Thieno[2,3-c]pyridin-7-ones synthesis, 4, 1007 Thieno[3,2-c]pyridin-7-ones synthesis, 4, 1007... 

To a solution of 10 g of 2-N-methyl-aminoacetamido-3-o-chlorobenzoyl-5-ethylthiophene in 50 ml of pyridine are added 20 ml of benzene and 1.9 g of acetic acid. The resulting mixture is refluxed with stirring for 10 hours in a flask provided with a water-removing adaptor. The reaction mixture is concentrated, and the residue is extracted with chloroform. The chloroform layer is washed with water and then with a sodium hydrogen carbonate solution, then dried over magnesium sulfate. The chloroform is distilled off under reduced pressure, and toluene is added to the residue. Thus is precipitated white crystalline-5-o-chloropheny -7-ethyl-1 -methyi-1,2-dihydro-3H-thieno-[2,3-e] [ 1,4] diazepin-2-one, MP 105°C to 106°C. 

Oxidation (MnOj) of thieno[2,3-6]thiopyrylium perchlorate gave, inter alia, 2-formylthieno[2,3-Z>]thiophene (12%). Sinfilarly, thieno[3,2-hjthiopyrylium perchlorate afforded 2-formylthieno[3,2-6]thiophene (43%). > en the same perchlorates were oxidized by the CrOj-pyridine complex, the main products were 2/f-thieno[2,3-6]thiopyran-2-one and 2i/-thieno[3,2-6]thiopyran-2-one, respectively. ... 

Since isoquinolinones are known to be very potent inhibitors of poly(ADP-ribose)polymerase (PARP), thieno[3,4-( ]pyridin-4-ones have been studied for their potential as PARP inhibitors <1999BMC297>. Early studies indicate that the sulfur analogues also act as potent PARP inhibitors. Thienopyridine diazonium salts can be converted into heterocyclic dyes that are useful as disperse dyes for polyester fabrics <2005DP(64)223, 2006DP(70)60>. 

In one route, tidopidine (1) was assembled via Sn2 displacement of 2-chlorobenzyl chloride (9) with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (8). " The nucleophile 8 was synthesized by heating 2-thiophen-2-yl-ethylamine (6) with 1,3-dioxolane in the presence of concentrated hydrochloric acid. 1,3-Dioxolone gave better yields than with formaldehyde, paraformaldehyde and 1,3,5-ttioxane. The interesting transformation 6 —> 8 first involved the formation of the corresponding Mannich base 7, which then underwent a Pictet-Spengler type reaction to afford the ring-closure product 8. It was of interest to note that a possible intramolecular aminomethylation did not take place. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

Eloy and Deryckere have applied their synthesis of isocarbostyrils (69HCA1755) to the preparation of thieno[2,3-c]- and thieno[3.2-c]-pyridines (Scheme 65) (70BSB301). Thermal-cyclization of 3-thienylvinyl isocyanate prepared from the corresponding azide (269) by Curtius rearrangement yields thieno[2,3-c]pyridin-7-one (270), which is transformed to (259) following usual methods. 

Ames and Ribeira (75JCS(Pl)1390) described a method for the preparation of thieno[2,3-c]pyridin-7-ones (Scheme 68). The sodium salt of 3-bromothiophene-2-carboxylic acid reacts with carbanions in the presence of copper or copper(II) acetate to give condensation products (274) by displacement of bromide ion, often with simultaneous deacetylation. Cyclization of (274) provides a convenient route to thieno[2,3-c]pyridin-7-ones. Thieno[2,3-c]pyridin-4-ones and thieno[3,2-c]pyridin-7-ones have been prepared by Friedel-Crafts cyclization of AT-(2-thenyl)- and A-(3-thenyl)-glycine derivatives (81H(l6)127l). 

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). 

Thieno[3,2-fc]pyridines are obtained in 49-87% yield (74JPR169). Application of the Friedlander reaction to 3-amino-2-formylthiophene gives (261) in reasonable yield (Scheme 78) (75ACS(B)224,75 ACS(B)233). As in the case of the synthesis of furo[3,2- >]pyridines (Section 3.17.2.1.1(i)(d), Scheme 17), it was unnecessary to isolate the o-aminocarbonyl compounds. 6-Substituted 7-hydroxythieno[3,2-6]pyridin-5(4/7)-ones (e.g. 295) can be prepared by base-catalyzed cyclization of the amides (294), which were obtained in high yields from readily available 3-amino-2-alkoxycarbonylthiophenes (293 Scheme 79) (80JCR(S)6) for... 

Electrophilic substitution reactions of thieno[3,2-cf pyridine occur at position 7 (equation 38). With dimethyl sulfate in an alkaline medium, thieno[3,2-cf pyrimidin-4-one (347) yields an N-methyl derivative. 

Examples of the synthesis of thieno[2,3-Z>]pyridines according to method C are scarce. In this case, the synthesis of the starting 3-cyanopyridine-2(l //)-thione, its -alkylation, and cyclization of an intermediate occur as a multicomponent one-pot process. For example, the reaction of thioamides 28 with l-(4-morpho-lino)cyclohexene (29) in anhydrous ethanol followed by treatment with a twofold excess of KOH and then with a-bromo ketones produced thienoquinolines 30 (1997KGS1384). 

The one-pot Stille cross-coupling reaction of compound 256 produced all four isomeric thieno[3,2-c]naphthyridines (1994JHC11). The stepwise formation of the C(7)-C(7a) and C(4)-N(5) bonds of the thieno[3,2-c]pyridine system can be considered as a modification of the above-described approaches. For example, aldehyde 256 reacts with arene 265 to give 266 reduction of its nitro group is accompanied by cyclization to form thieno[3,2-c]isoquinoline A-oxide (267) (1990JHC1127). 

Methods based on the pyridine to thieno[3,2-c]pyridine transformation are less well developed. Most of the above-described procedures are based on the nucleophilic displacement of the substituent at position 4 of the pyridine ring with a sulfur-containing fragment followed by cyclization of the resulting product. For example, the reaction of 4-chloropyridines 286 with methyl thioglycolate produced 287 and 288 in one step as a result of the replacement of the chlorine atom and Thorpe or Thorpe Dieckmann cyclization (1987JHC85). 

The hydroxy group of l-(2-hydroxyethyl)thieno[3,4-d]pyrimidine-2,4(3//)-dione 344 was chlorinated with thionyl chloride in a mixture of pyridine and chloroform, or mesylated with methanesulfonyl chloride in pyridine. No ring chlorination was observed under these conditions. The resulting l-(2-chloro or 2-methanesulfonylethyl) derivative 365 was cyclized to l,2-dihydrooxazolo[2,3-6]thieno[3,4-d]pyrimidin-5-one 366 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (89H985). A similar transformation of 3-(2-hydroxyethyl)thieno[3,4-d]pyrimidine-2(l//),4-diones 333a,b into the 3-(2-chloroethyl) derivatives 367 with thionyl chloride occurred in chlo-... 

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