Intramolecular 4+2 cycloaddition of thieno[2,3-e][1,2,4]triazines: routes towards condensed thieno[2,3-b]pyridines

Synthetic approaches towards new condensed thienopyridine ring systems including furo[2,3-b]thieno[3,2-e]pyridines, bisthieno[2,3-b:3′,2′-e]pyridines, 5H-chromeno[2,3-b]thieno[3,2-e]pyridines, 5H-benzo(f)chromeno[2,3-b]thieno[3,2-e]pyridines have been achieved by application of intramolecular 4+2 cycloaddition reactions of suitably designed thieno[2,3-e][1,2,4]triazines tethered with alkene or alkyne terminals.     

Synthesis of substituted thiazolo[4,5-b]pyridines and other annulated heterocycles via SN2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions

A new combinatorial method for the preparation of substituted thiazolo[4,5-b]pyridines, which utilizes cyanoacetamide, heterocumulenes (isothiocyanates, carbon bisulfide), and ethyl-4-chloroacetoacetate in a new S_N2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions has been developed. The obtained thiazolo[4,5-b]pyridines were then used together with aldehydes and malononitrile in another Knoevenagel reaction→Michael reaction→hetero-Thorpe-Ziegler domino reaction for the synthesis of substituted 4,6-dihydro-5H-pyrano[2,3-d]thiazolo[4,5-b]pyridines.     

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines via microwave-activated inverse electron demand Diels-Alder reactions

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines have been synthesized from 1,2,4-triazines using the inverse electron Diels-Alder reaction. For this purpose, 3-methylsulfanyl-1,2,4-triazines were reacted with several nucleophiles allowing the formation of appropriately substituted alkynes to undergo the intramolecular inverse electron demand Diels-Alder reaction. Sealed-tube microwave activation of the cycloaddition reaction has proved to be very efficient and allowed shorter reaction times. This strategy enabled an efficient synthesis of 3-hydroxy-2,3-dihydrofuro[2,3-b]pyridines and 4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridines with several points of diversity on the bicyclic scaffold.     

Synthesis of enantiopure furo[2,3-b]pyrroles

A simple method for the preparation of enantiopure furo[2,3-b]pyrroles, a rare class of concave bicyclic nitrogen and oxygen heterocycle, in promising yield has been developed. The 3-substituted pyrrolidinediones prepared from (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (Garcinia acid) have been cyclized diastereo as well as enantioselectively to furo[2,3-b]pyrroles. The cyclization follows Baldwin’s rule.     

Chemistry of thienopyridines. VIII. Substitution products derived from thieno[2,3-b] pyridine 7-oxide

Thieno[2,3-b]pyridine (I) was concerted to the N-oxide (II, 53%) by means of hydrogen peroxide and acetic acid. Nitration of II in sulfuric acid gave 4-nitrothieno[2,3-b]pyridine 7-oxide (III, 50%), while nitration in acetic acid formed the isomeric 5-nitrothieno[2,3-b]pyridine 7-oxide (IV, 54%). Compounds III and IV were reduced to the corresponding 4- and 5-aminothieno[2,3-b]pyridines, respectively. Treatment of III with acetyl chloride gave 4-chlorothieno-[2,3-b]pyridine 7-oxide (XI, 81%), convertible in two steps to 4-(N-substituted amino)thieno-[2,3-b]pyridines (especially of the 4-dialkylaminoalkylamino type) for screening as potential antimalarial drugs. 4-Aminothieno[2,3-b]pyridine reacted with aromatic aldehydes to give Schiff's bases and other products. Mechanisms for some of the reactions are suggested. NMR spectral data are reported for various 4-substituted thieno[2,3-b]pyridine compounds.     

New method for the synthesis of substituted thieno[3,2-b]pyridines and 5H-pyrano[2,3-d]thieno[3,2-b]pyridines derived from them

A new highly selective method was developed for the synthesis of substituted thieno[3,2-b]-pyridines based on the domino reaction of monopotassium salt (rather than dipotassium one) of carbamoylcyanodithioacetic acid with ethyl 4-chloroacetoacetate. Substituted 5H-pyrano[2,3-d]-thieno[3,2-b]pyridines were synthesized based on these thieno[3,2-b]pyridines.     

Synthesis of condensed quinoxalines. Part II

A novel efficient synthesis of fluorescent, fused quinoxalines was achieved. 7-Triazolyl-1,4-dioxino[2,3-b]-quinoxalines were synthesized by the diazotisation of 7-amino-1,4-dioxino[2,3-b]quinoxaline and coupling with selected aromatic amines followed by air oxidation. Diazotised aryl amines were coupled with 7-amino-1,4-dioxino[2,3-b]quinoxalines followed by subsequent air oxidation afforded 1,4-dioxino[2,3-b]quinoxalino-[6,5-d]1,2,3-triazoles. 7-Amino-1,4-dioxino[2,3-b]quinoxaline was condensed with conjugated enol ethers followed by cyclization in dowtherm resulted in 1,4-dioxino[2,3-b]quinoxalino[6,5-b]pyridines.     

Reactivity of sarcosine and 1,3-thiazolidine-4-carboxylic acid towards salicylaldehyde-derived alkynes and allenes

The reaction of sarcosine and 1,3-thiazolidine-4-carboxylic acid with salicylaldehyde-derived alkynes and allenes opened the way to new chromeno[4,3-b]pyrrole and chromeno[2,3-b]pyrrole derivatives. Tetrahydro-chromeno[4,3-b]pyrroles were obtained from the reaction of these secondary amino acids with O-propargylsalicylaldehyde. Interestingly, sarcosine reacted with ethyl 4-(2-formylphenoxy)but-2-ynoate to give a monocyclic pyrrole resulting from rearrangement of the initially formed 1,3-dipolar cycloadduct. Decarboxylative condensation of ethyl 4-(2-formylphenoxy)but-2-ynoate with 1,3-thiazolidine-4-carboxylic acid afforded in a stereoselective fashion the expected chromeno-pyrrolo[1,2-c]thiazole, which structure was unambiguously established by X-ray crystallography. However, the 1H,3H-pyrrolo[1,2-c]thiazole resulting from the opening of the pyran ring was also isolated. The reaction with O-buta-2,3-dienyl salicylaldehyde afforded 3-methylene-hexahydrochromeno[4,3-b]pyrrole. O-Allenyl salicylaldehyde reacted with sarcosine and 1,3-thiazolidine-4-carboxylic acid to give a new type of chromeno-pyrroles. A mechanism proposal for the synthesis of these chromeno[2,3-b]pyrroles has been presented.     

Microwave enhanced Suzuki coupling: a diversity-oriented approach to the synthesis of highly functionalised 3-substituted-2-aryl/heteroaryl imidazo[4,5-b]pyridines

A modified approach for the synthesis of 3-substituted 2-aryl/heteroaryl imidazo[4,5-b]pyridines utilising palladium catalysed cross-coupling reactions under microwave enhanced conditions has been achieved. utilisation of (A-^taphos)₂PdCl₂-catalysed cross-coupling reactions enables rapid derivatization of this (imidazo[4,5-b]pyridines) pharmaceutically relevant core. This catalytic system is compatible with a broad spectrum of arylboronic acids—electron rich, electron poor, and heteroarylboronic acids.     

Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

A convenient approach to the synthesis of 2-(2-aminoethyl)pyrroles and their heterocyclization into hydrogenated pyrrolopyridines and related pyrroloindolizines

2-(2-Aminoethyl)pyrroles and 2-(2-succinimidoethyl)pyrroles were prepared from acetals of ethyl 4-oxoalkanoates via latent vinyl 1,4-dicarbonyl compounds as the key intermediates. The Pictet-Spengler condensation of 2-(2-aminoethyl)pyrroles with aromatic aldehydes gave 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines in good yields. 4,5,7,8,9,9a-Hexahydro-3H-pyrrolo[2,3-g]indolizines were prepared in a similar way starting from 2-(2-succinimidoethyl)pyrroles.     

Functional sulfur-containing compounds

The Thorpe-Ziegler intramolecular cyclization of 2-RCH₂S-, 2-RCH₂S(O)-, and 2-RCH₂SO₂-substituted nicotinic acid esters and nitriles (R is alkyl, aryl, and 2-thienyl) upon the action of potassium tert-butoxide has been studied. The reaction results in the formation of the corresponding 2-R-substituted 3-aminothieno[2,3-b]pyridines, 3-aminothieno[2,3-b]pyridine 1-oxides, and 3-aminothieno[2,3-b]pyridine 1,1-dioxides with the reaction taking place only in the case if R is aryl or 2-thienyl. Methyl esters of 2-RCH₂S-, 2-RCH₂S(O)-, and 2-RCH₂SO₂-substituted nicotinic acids also undergo the intramolecular cyclization of the Dieckmann type to form the corresponding 2-R-substituted 3-hydroxythieno[2,3-b]pyridines, thieno[2,3-b]pyridin-3(2H)-one 1-oxides, and thieno[2,3-b]pyridin-3(2H)-one 1,1-dioxides. Such a reaction takes place for all the R groups except when R = AlkCH₂S and AlkCH₂S(O).     

Synthesis of new condensed thieno[2,3-b]pyridines containing pyrimidine and imidazole rings

Two different convenient methods have been developed for the synthesis of condensed thieno[2,3-b]pyridines. The intramolecular cyclization of 3-amino-2-hydrazinocarbonyl-7,7-dimethyl-7,8-dihydo-5H-pyrano[3,4-e]-thieno[2,3-b]pyridine was carried out to give 7,7-dimethyl-2-oxo-1,2,6,7-tetrahydro-9H-pyrano[3′,4′-e]-imidazo[4″,5″∶2,3]thieno[5,4-b]pyridine, which is the first representative of a new heterocyclic system.     

A concise synthesis of functionalized 2,3-dihydrofuro[3,2-b], [3,2-c], and [2,3-b]pyridines

A strategy for the efficient and rapid one-pot synthesis of 2-aryl-2,3-dihydrofuro[3,2-b], [3,2-c], and [2,3-b]pyridines from readily available o-nitropicolines and aromatic aldehydes is described. The key transformation involves reaction of o-nitropicolines with aromatic aldehydes in the presence of TBAF and Hünig's base giving rise to functionalized products having molecular complexity suitable for further manipulation.     

Sc(OTf)3-catalyzed intramolecular aza-Prins cyclization for the synthesis of heterobicycles

The coupling of (E)- and (Z)-hex-3-ene-1,6-ditosylamide with various aldehydes in the presence of 10 mol % Sc(OTf)₃ gave the corresponding trans- and cis-fused 1,5-ditosyl-octahydro-1H-pyrrolo[3,2-c]pyridines, respectively, in good yields via intramolecular aza-Prins cyclization, whereas the coupling of (E)- and (Z)-N-(6-hydroxyhex-3-enyl)-4-methylbenzenesulfonamide afforded the corresponding trans- and cis-fused octahydro-1-tosylpyrano[4,3-b]pyrroles derivatives, respectively, via intramolecular Prins-cyclization.     

A facile synthesis of 2,3-disubstituted furo[2,3-b]pyridines

In a three-step sequence starting from readily available starting materials, 2,3-carbon disubstituted furo[2,3-b]pyridines can be accessed in good yields and purity. Furo[2,3-b]pyridines bearing ester, amide and ketone groups at the 2-position can be prepared with a variety of aryl and alkyl groups at the 3-position.     

Functionalized sulfur-containing compounds. 13. Synthesis of substituted 3-amino-2-(organylsulfinyl)-and-(organylsulfonyl)thieno[2,3-b]pyridines

A method for the synthesis of substituted 3-amino-2-(organylsulfinyl)thieno[2,3-b]pyridines by the Thorpe—Ziegler intramolecular cyclization of substituted 3-cyano-2-[(organyl-sulfinyl)methylthio]pyridines was proposed. 3-Amino-2-(organylsulfonyl)thieno[2,3-b]pyridines were obtained by reactions of substituted 3-cyanopyridine-2-thiones with chloromethyl organyl sulfones. The reaction intermediates 3-cyano-2-[(organylsulfonyl)methylthio]pyridines were transformed into 3-amino-2-(organylsulfonyl)thieno[2,3-b]pyridines. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 510–515, March, 2006.     

Synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines from 2,3-dihalopyridines, (hetero)arylalkynes,and Na2S. Further functionalizations

A simple and efficient three-step methodology is described for the first time for the synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines. The first step is a Sonogashira coupling from 3-bromo-2-chloropyridine or 2-bromo-3-chloropyridine with several (hetero)arylalkynes to obtain the corresponding 2- or 3-chloro(hetero)arylethynylpyridines. These were cyclized by treatment with Na₂S affording the expected 2-(hetero)arylthienopyridines. As an improvement, these reactions were also performed in one-pot, without the isolation of the Sonogashira product, giving the thienopyridines in similar or better yields, reducing significantly the reaction time after the addition of Na₂S. Further functionalizations were achieved in the thienopyridine system either by bromination in the thiophene ring or chlorination in the pyridine ring via a N-oxide intermediate, allowing metal-catalyzed coupling reactions and/or nucleophilic substitutions. The functionalization of some substituents is also possible and as an example a 1,3-diarylurea was obtained from the reaction of an aniline derivative with an arylisocyanate.     

Preparation of novel pyridine-fused tris-heterocycles; pyrido[4,3-e]pyrrolo-/pyrido[4,3-e]furano[2,3-c]pyridazines and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole

Three novel pyrido-fused tris-heterocycles have been prepared based on a Suzuki coupling and subsequent cyclisation approach. Pyrido[4,3-e]pyrrolo[2,3-c]pyridazine (3b, 77%) and pyrido[4,3-e]furano[2,3-c]pyridazine (5b, 76%) were obtained by intramolecular diazocoupling. Successful diazocoupling of furan (5b) is thus reported for the first time by NOBF₄ generation of the diazonium intermediate. N-TIPS-pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (TIPS-4b) was synthesised by thermal cyclisation of pyridyl nitrene in considerably higher yield (71%) than previously experienced from similar cyclisations, due to TIPS-activation.     

Reaction of thieno[2,3-b]pyridines with sodium hypochlorite: An unusual and stereoselective one-pot approach to dimeric pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridines

The oxidation of 3-aminothieno[2,3-b]pyridine-2-carboxamides with commercially available bleach leads to the formation of dimeric pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridines (7a,14a-diamino-7,14-bis(aryl)-7,7a,14,14a-tetrahydro-6H,13H-pyrido[3″″,2″″:4?,5?]thieno[2?,3?:4″,5″]pyrrolo-[3″,4″:3′,4′]pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridine-6,13-diones) in moderate yields (37–52%).