Application of directed metalation in synthesis. Part 8: Interesting example of chemoselectivity in the synthesis of thioaurones and hydroxy ketones and a novel anionic ortho-Fries rearrangement used as a tool in the synthesis of thienopyranones and thiafluorenones

Chemoselective synthesis of thioaurones or 3-hydroxy benzo[b]thiophen-2-aryl ketones, 1-hydroxy naphtho[2,1-b]thiophen-2-aryl ketones and chalcones from N,N-diethyl-ortho-methyl sulfanyl aryl amides were described. (Benzo[b]thiophen-2-yl) alkylates and (naphtho[2,1-b]thiophen-2-yl) alkylates undergo a novel anionic ortho-Fries rearrangement leading to (3-hydroxy benzo[b]thiophen-2-yl) and (1-hydroxy naphtho[2,1-b]thiophen-2-yl) alkyl ketones. The hydroxy ketones were used as intermediates in the synthesis of wide range of benzothienopyranones and thiafluorenones.     

Microwave-assisted synthesis of novel N-(4-phenylthiazol-2-yl)-benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides inspired by marine topsentines and nortopsentines

We report the synthesis of novel N-(4-phenylthiazol-2-yl)-substituted benzo[d]thiazole-, thiazolo[4,5-b]pyridine-, thiazolo[5,4-b]pyridine- and benzo[d]oxazole-2-carboximidamides, which were inspired by marine topsentines and nortopsentines. Condensation of 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt) with various ortho-halogenated anilines, aminopyridines and aminophenols gave the corresponding aryliminodithiazoles in good to excellent yields. Copper(I)-mediated or nucleophilic-assisted cyclization of aryliminodithiazoles furnished cyano-functionalized benzo[d]thiazoles, thiazolo[4,5-b]- and thiazolo[5,4-b]-pyridines and benzo[d]oxazoles. The latter were condensed with substituted 4-phenylthiazol-2-amines to furnish twenty seven new polyaromatic carboximidamides in moderate to good yields.     

Heck-like coupling and Pictet-Spengler reaction for the synthesis of benzothieno[3,2-c]quinolines

A series of 6-arylbenzothieno[3,2-c]quinolines were synthesised in three steps from benzo[b]thiophene. After a selective Heck-type coupling of benzo[b]thiophene with different o-nitroaryl bromides to obtain 2-(o-nitroaryl)benzo[b]thiophenes, corresponding 2-(benzo[b]thiophen-2-yl)anilines were involved in a Pictet-Spengler reaction to form the quinoline cycle.     

Facile synthesis of regio-isomeric naphthofurans and benzodifurans

Naphtho[1,2-b]furans 1a-f, naphtho[2,1-b]furans 2a-f, benzo[1,2-b:5,4-b′]difurans 3a-b, benzo[1,2-b:4,5-b′]difurans 4a-b, and benzo[1,2-b:4,3-b′]difurans 5a-b were synthesized by base-catalyzed cyclization reaction of the corresponding o-alkoxybenzoylarene derivatives. The o-alkoxybenzoylarenes were obtained from the etherification reaction of the o-hydroxybenzoylarenes, which were prepared either by the reaction of methoxyarenes with benzoyl chloride in the presence of aluminum chloride or by photo-Fries rearrangement of aryl benzoates.     

Efficient synthesis of 5-nitro-benzo[b]furans via 2-bromo-4-nitro-phenyl acetates

Acetylation/Sonogashira cross-coupling reaction/cyclization has been carried out in one-pot using a Na₂PdCl₄/2-(di-tert-butylphosphino)-N-phenylindole/CuI system in TMEDA to give 5-nitro-2-substituted benzo[b]furans in excellent yields. We also describe the extension of this method to 4-EWG-2-bromo-phenols obtaining 2,5-disubstituted-benzo[b]furans in good yields.     

Synthesis of pure stereoisomers of benzo[b]thienyl dehydrophenylalanines by Suzuki cross-coupling. Preliminary studies of antimicrobial activity

Several benzo[b]thienyldehydrophenylalanines were synthesized from pure stereoisomers of the methyl ester of N-(tert-butoxycarbonyl)-β-bromodehydrophenylalanine as an extension of our previously reported method for the synthesis of dehydrotryptophan analogues to dehydrophenylalanine derivatives. The latter were obtained in high yields by N-deprotection and bromination of N,N-bis-(tert-butoxycarbonyl)-(Z)-dehydrophenylalanine using TFA and NBS. This was carried out in two steps or in a one pot procedure resulting in different E/Z ratios. These compounds were coupled under Suzuki cross-coupling conditions [Pd(PPh₃)₄, Na₂CO₃, DME/H₂O] with several boronic benzo[b]thienyl acids in good to high yields maintaining the stereochemistry of the starting materials. The best yields were obtained when the boronic acid was in position 7 of the benzo[b]thiophene and with the E isomer of the brominated dehydrophenylalanine. In some cases it was possible to increase the lower yields by changing the Pd source to PdCl₂(PPh₃)₂. A model dipeptide was prepared coupling a benzo[b]thienyldehydrophenylalanine with the methyl ester of alanine. Preliminary antimicrobial studies were performed with both isomers of one of the β, β-diaryldehydroalanines obtained. The results show that the compounds are selective and very active (very low MICs) against Gram positive bacteria (B. cereus and B. subtilis) the Z-isomer being more active. The compounds are also active against Candida albicans presenting similar MICs.     

Novel synthesis of benzo[b]carbazoles

A new method was adopted for the synthesis of benzo[b]carbazoles by Claisen condensation followed by Fischer indole cyclization. Newly synthesized benzo[b]carbazoles were treated with ethanol amine in the presence of polyphosphoric acid which leads to the formation of pyrazino carbazoles. All the synthesized compounds were characterized by all spectral means.     

Multibromo-N-alkylcarbazoles: synthesis, characterization, and their benzo[b]thiophene derivatives

We present an efficient method for the selective bromination of N-alkylcarbazoles using N-bromosuccinimide (NBS) in THF. Four brominated N-alkylcarbazoles including 3-bromo-, 3,6-dibromo-, 1,3,6-tribromo- and 1,3,6,8-tetrabromo-carbazoles were prepared and identified by ¹H NMR spectroscopy. Subsequent cross-coupling of these carbazoles with benzo[b]thien-2-ylboronic acid gave the corresponding benzo[b]thien-2-yl functionalized carbazoles in good yields.     

Convenient synthesis of fused pyrano[3,2-h]- and furo[3,2-h]benzo[f]coumarins from naphthalene-2,3-diol

The treatment of 8-propargyloxy-benzo[f]coumarin with boron trifluoride diethyl etherate in N,N-dimethylformamide under reflux or MW irradiation resulted in pyrano[3,2-h]benzo[f]coumarin, while the furo[3,2-h]benzo[f]coumarin is received from the treatment with N-methylformamide under MW irradiation.     

An unexpected route toward the synthesis of spiro-benzo[b]acridine-furan derivatives

A facile and straightforward procedure for the synthesis of spiro-benzo[b]acridine-6,2′-furan derivatives via the reaction between benzo[b]acridine-6,11-dione, electron-deficient acetylenic compounds, and an isocyanide is described. The benzo[b]acridine-6,11-dione is obtained from the reaction between 2-(aminomethyl)aniline and 2-hydroxynaphthalene-1,4-dione via an unexpected reaction pathway. The products are synthesized in medium to high yields and no complicated purification is required.     

A facile synthesis of benzo[b][1,4]thiazepine derivatives by palladium acetate catalyzed reaction

The preparation of steroid/nonsteroid fused benzo[b][1,4]thiazepines and 2-arylsubstituted benzo[b][1,4]thiazepines is described from Pd(OAc)₂ catalyzed reaction of steroidal/nonsteroidal β-halovinyl aldehydes and 2-aminothiophenols in DMF under heating condition.     

Synthesis of 1,3-disubstituted benzo[c]thiophene analogs containing benzo[b]thiophene/benzo[b]pyrrole

The synthesis of 1,3-disubstituted benzo[c]thiophene analogs incorporating benzo[b]thiophene/benzo[b]pyrrole units is described.     

Synthesis and characterization of benzo[c]thiophene analogs incorporating benzo[b]thiophene/1-hexylindole/benzo[b]furan

Synthesis of 1,3-disubstituted benzo[c]thiophene analogs incorporating heterocycles such as benzo[b]thiophene/1-hexylindole/benzo[b]furan and thiophene units is described. Optical and electrochemical studies of the benzo[c]thiophene analogs are also reported.     

Synthesis and intramolecular cyclization of novel β,β-bis-(benzo[b]thienyl)dehydroalanine derivatives

The methyl ester of tert-butyloxycarbonyl-β,β-dibromodehydroalanine was obtained in a one-pot procedure from bis-(N-tert-butyloxycarbonyl)dehydroalanine. The former was reacted with several boronic benzo[b]thiophene acids under Suzuki cross coupling conditions, to give new β,β-bis-(benzo[b]thienyl)dehydroalanines in high yields. These compounds were cyclized to pyrrole derivatives by treatment with Pd(OAc)₂ and Cu(OAc)₂ in DMF.     

Recent advances in the synthesis of benzo[b]thiophene fused polycyclic derivatives: Strategies and reactions

Benzo[b]thiophene fused compounds with a unique active heterocyclic skeleton have wide applications in the fields of medicinal chemistry, organic synthesis, and organic functional materials, which resulted in rapid development of many efficient methods for the construction of benzo[b]thiophene-fused heterocycles in recent years. Among these methods, the domino reaction of benzo[b]thiophene derivatives is a practical and powerful synthetic route to access benzo[b]thiophene-fused heterocycles by virtue of the particularity of sulfur atom. This review summarizes the latest developments in the construction of benzo[b]thiophene-fused heterocycles by ring formation at the C2-C3-position of benzo[b]thiophene derivatives in the past decade. Additionally, this review is divided into four parts according to the four kinds of benzo[b]thiophene derivatives used, including thioaurone, thioisatin, substituted benzo[b]thiophene, and azadiene.     

2-Oxobenzo[h]chromene: a novel entry for the synthesis of functionalized angular polycyclic azaarenes

An efficient and short synthesis of (5,6-dihydrobenzo[h]pyrido[2,1-b]quinazolin-2-ylidene)acetonitriles, (5,6-dihydrobenzo[h]pyrazino[2,1-b]quinazolin-2-ylidene)acetonitriles and (5,6-dihydrobenzimidazo[1,2-b]benzo[f]isoquinolin-7-yl)acetonitriles in good yields is delineated through base catalyzed ring transformation of 4-(piperidin-1-yl)-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with 2-amino-pyridine, 2-aminopyrazine and (imidazo-2-yl)acetonitrile.     

Palladium-catalyzed amination and cyclization to heteroannellated indoles and carbazoles

New ortho-bromodiarylamines in the benzo[b]thiophene series were prepared by palladium-catalyzed amination, either in the benzene or in the thiophene ring. These were submitted to palladium-catalyzed cyclization, under different required conditions, to give several differently substituted thieno[3,2-c] or [2,3-b]carbazoles and indolo[3,2-b]benzo[b]thiophenes. This constitutes a novel synthetic route to both tetracyclic systems.     

Synthesis of new benzo[b]thieno fused ring systems via transition metal-mediated cyclisations

The compact synthesis of a new ring fused benzo[b]thieno derivative with an embedded nine-membered ring system via ring closing metathesis methodology is described. The preparation of the novel 11H-benzo[b]thieno[2,3-c]pyrrolo[2,3-a]indol-11-one via palladium-mediated oxidative cyclisation of benzo[b]thien-2-oyl indole derivatives is also reported.     

An efficient phosphine-free palladium coupling for the synthesis of new 2-arylbenzo[b]thiophenes

Straightforward and rapid access to 2-arylbenzo[b]thiophenes has been developed. It involved a catalytic coupling of 3-activated benzo[b]thiophenes with several aryl halides in the presence of a phosphine-free palladium system. In case of fragile functional groups such as aldehydes, a quaternary ammonium was used as an additive as with the other substrates, the coupling performed better and faster in the presence of a crown ether, the best one being DCH-18-C-6, with good yields and low reaction times. This method would provide a direct access to novel structures of biological interest.     

The first synthesis of the benzo[b]indolo[1,2-h][1,7]naphthyridine ring system

The first syntheses of representatives of the benzo[b]indolo[1,2-h][1,7]naphthyridine ring system have been accomplished using the Friedländer reaction.