Thieno pyridine, synthesis

The preparation of selenolopyridazines is accomplished in the usual manner by condensation of diformylselenophenes with hydrazines. Both selenolo[2,3-cf]pyridazine (432) and selenolo[3,"4-tf]pyridazine (433) are obtained in this way (72BSF3453) as crystalline compounds with m.p. 158 and 153 °C, respectively. By strict analogy with the synthesis of boron containing furo- and thieno-pyridines (Sections 3.17.2.3.1, 3.17.3.3.1), boroxazoselenolo-pyridines (e.g. 434) and borazaroselenolopyridines (435,436) could be prepared by condensation of appropriately substituted formylselenophenoboronic acids and hydroxylamine or hydrazine <72IJS(A)(2)257>. 

Reviews have appeared dealing with the synthesis of 6i/-pyrido[4,3- ]-carbazoles, thieno-pyridines, and imidazo-pyridines (and their benzo-analogues) having a bridgehead nitrogen atom. ... 

Thieno[3,2-c]pyridazine-3-carboxylic acid synthesis, 4, 819-820 Thienopyridazines, 4, 1015 Thieno[2,3- hjpyridazines nitration, 4, 1016 synthesis, 4, 791, 1015 Thieno[3,2-c]pyridazines synthesis, 4, 1016 Thieno[3,4-d]pyridazines synthesis, 4, 1016 Thieno[2,3-6]pyridine, 4-amino-synthesis, 4, 1005... 

Thieno[2,3-6]pyridine, 6-amino-2,3,4,5-tetracyano-synthesis, 4, 805 Thieno[2,3-6]pyridine, 5-ethyl-nitration, 4, 1014... 

Thieno[2,3-c]pyridine, 2-amino-6-benzyl-3-ethoxycarbonyl-4,5,6,7-tetrahydro-biological activity, 4, 1015 Thieno[2,3-c]pyridine, 4,5,6,7-tetrahydro-biological activity, 4, 1015 Thieno[3,2-6]pyridine, 3-hydroxy-synthesis, 4, 1010... 

Thieno[2,3-6]pyridine-2-carboxylic acid, 3-amino-synthesis, 4, 1005... 

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... 

It has been shown that acetamidothiophenes 22 can be converted to either chlorothieno[2,3-h]pyridines 23 or chlorothieno[2,3-h]pyridinecarboxaldehydes 24 using POCI3 and DMF by appropriate choice of reaction conditions. However, unlike the acetanilides, initial ring formylation rather than side-chain formylation is believed to lead to the formation of the pyridine ring. These reactions have been extended to the synthesis of the isomeric thieno[3,2-I>]- and thieno[3,4-I>]pyridines, 25 and 26, from 3-acetamidothiophene and 3-acetamido-2,5-dimethylthiophene, respectively. 

A simple, efficient, and high-yielding synthesis of quinazolin-4-ylamines and thieno[3,2-d]pyridin-4-ylamines based on the condensation of appropriately functionalized N -(2-cyanophenyl)-N,N-dimethylformamidines and primary amines has been reported by Han and coworkers (Scheme 6.253) [440]. Optimization of the reaction parameters resulted in the use of acetonitrile/acetic acid as a solvent mixture and of 1.2 equivalents of the requisite amine. In general, microwave heating at 160 °C for 10 min provided excellent product yields. 

INAC reactions have also led to enantioselective syntheses of key intermediates in the synthesis of antibiotic l 3-Methylcarbapenem (724), to optically pure derivatives of tetrahydropyrano[2,3] cyclohexane (725a) to novel terahydro-isoxazolo-fused pyrano 2,3-/ quinolines (725b) and to a novel heterocyclic system, isoxazolo[3,4-d]thieno[2,3-b]pyridine (Scheme 2.229) (221). 

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

In 1972 Wright prepared 3-chlorothieno[3,2-6]thiophene-2-carbonyl chloride (94) in 11-13% yield by heating 3-(2-thienyl)acrylic acid, thionyl chloride, and pyridine, a method of synthesis of benzo[6]-thiophene-2-carbonyl chloride derivatives. " Methyl 3,5-dichloro-thieno[3,2-6]thiophene-2-carboxylate (95) and methyl 2-chloro-3-(5-chloro-2-thienyl)acrylate were also isolated. When fte reaction was carried out in refluxing toluene or chlorobenzene, the acid chloride (94)... 

A modification of the Pomeranz-Fritsch synthesis <1983JCXI3344> is used in the preparation of thieno[2,3- l-pyridine and its 2-substituted derivatives. An aryl aldehyde undergoes condensation with aminoacetaldehyde dimethyl acetal giving a Schiff base which cyclizes to form an imine product. The imine is treated with ethyl chloroformate followed by triethyl phosphate to form an intermediate carbonate-phosphonate, which then cyclizes to the thienopyr-idine product (Scheme 22) <2004S1935>. Very low product yields (2-17%) are obtained for alkyl- and phenyl-substituted thieno[2,3- ]pyridines however, the unsubstituted product and 2-halogenated derivatives give moderate yields (28-44%). 

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. 

Russian workers (74KGS58) carried out Vilsmeier reactions on 4,5-disubstituted 2-acylthienylamines and cyclized the resulting 3-formyl compounds with substances containing active methylene groups (Scheme 60). A versatile new synthesis of thieno[2,3-6]pyridines is also based on the Vilsmeier formylation of 2-acetamidothiophenes. Whereas with equimolar amounts of DMF and phosphorus oxychloride 3-formyl derivatives are obtained,... 

A further synthesis of thieno[2,3-6]pyridines (79JHC603) resembles quite closely the preparation of pyrrolo[2,3-fc]pyridines (76AP597). 2-Amino-3-cyanothiophenes (e.g. 268 Scheme 62) were reacted with ethyl aminocrotonate to give enamines, which were cyclized with sodium ethoxide yielding 4-aminothieno[2,3-5]pyridines. 

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. 

An efficient synthesis of thieno[2,3-c]pyridine starting from 4-vinylpyridine (275) has been described by Klemm and coworkers (Scheme 69) (68JHC883). Because 4-vinylpyridine and hydrogen sulfide under high-temperature conditions formed (259) only in very low yield, (275) was converted into benzyl pyridyl sulfide (276) prior to thermolysis. Thieno[2,3-c]pyridine is obtained as low-melting (m.p. 59-60 °C) yellow crystals. 

A simple two-step synthesis of 4-arylthieno[3,2-c]pyridine-6-carboxylic acids has recently been presented by Eweiss (Scheme 74) (B-81MI31703). The condensation of thiophene-2-carbaldehyde with an N -aroylated a-amino acid yields a thienylidene azlactone (281) which on treatment with AICI3 is converted to a thieno[3,2-c]pyridine (283). A nitrilium ion (282) resulting from a vinyl-oxygen fission is probably involved as an intermediate. Sandberg s method already mentioned in the previous section has also been applied to the synthesis of thieno[3,2-c]pyridines (Scheme 75). 

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... 

A convenient synthesis of thieno[3,2-6]pyridines using the enamine (299), prepared in high yield by the Michael addition of (293) to dimethyl acetylenedicarboxylate, has been described (equation 26) (78JCR(S)393). The cyclization to (300) is effected by sodium hydride in DMF. 

Two methods have been employed for the synthesis of thieno[3,2-fc]pyridine which use gas-phase pyrolysis techniques. Klemm and coworkers starting with 2-vinylpyridine prepared (261) in a manner (Scheme 81) (68JHC883) strictly analogous to the synthesis of thieno[2,3-c]pyridine (Scheme 69). Another convenient route to (261) consists of the... 

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