Short diastereoselective synthesis of cis- and trans-hexahydropyrido[2,1-a]isoindole derivatives

A new and highly stereoselective access to 4,10b-trans or 4,10b-cis hexahydropyrido[2,1-a]isoindole derivatives is reported, both requiring an intramolecular Mannich-type reaction as key step. The cis diastereoisomer is obtained in three steps from a 2-alkyl benzaldehyde through the stereoselective formation of a 2,6-cis-disubstituted piperidine, while the trans stereomer is efficiently obtained, in a single step, if a 2-formyl benzoic acid is involved in the Mannich cyclization process.     

Stereoselective reductions of N-Boc-hexahydro-1H-indolin-5(6H)-ones

We report the divergent effects of a 3a-methyl and 3a-phenyl substituent on the chemoselectivity and stereoselectivity of reduction of the enamide moiety of N-Boc-hexahydro-1H-indolin-5(6H)-ones. Under ionic reduction conditions (triethylsilane/trifluoroacetic acid) the enamide group of 3a-methyl-N-Boc-hexahydro-1H-indolin-5(6H)-one was reduced to afford exclusively a cis ring-fused product. For the 3a-phenyl substituted analogue more forcing conditions (sodium cyanoborohydride at pH 2-2.5) were required and resulted in the selective reduction of the enamide group to give a trans ring-fused product as well as reduction of the ketone group.     

Stereoselective multigram-scale synthesis of cis- and trans-β-phenylproline derivatives

Efficient routes for the gram-scale preparation of the proline analogues that bear a phenyl substituent attached to the pyrrolidine β carbon (cis- and trans-β-phenylproline) have been developed. The cis derivative was synthesized from N-Boc-β-alanine in six steps and 78% overall yield. The generation of a vinyl triflate with full regiochemical control together with a high-yielding cross-coupling reaction and a completely stereoselective hydrogenation are at the basis of the high efficiency of the procedure. Epimerization of the cis β-phenylproline derivative with lithium bis(trimethylsilyl)amide provided access to the trans isomer.     

A convenient synthesis of benzofuro[3,2-c]isoquinolines and naphtho[1′,2′:4,5]furo[3,2-c]isoquinolines

A convenient method for the preparation of benzofuro[3,2-c]isoquinoline derivatives is described. The condensation reaction of methyl 2-(chloromethyl)-benzoate with substituted salicylonitriles 7a-c and intramolecular cyclization of the resulting substituted methyl 2-[(2-cyanobenzyl)oxy]benzoates 10a-c using potassium tert-butoxide results in the substituted benzofuro[3,2-c]isoquinolin-5(6H)-ones 1a-c. The same sequence of reactions starting from 2-(chloromethyl)benzonitrile and compounds 7a-c gave substituted 5-aminobenzofuro[3,2-c]isoquinolines 13a-c. In addition, this method is useful for the synthesis of other heterocycles. For example, using 1-cyano-2-naphthol 16, instead of the salicylonitriles 7a-c, gives naphtho[1′,2′:4,5]furo[3,2-c]isoquinolines.     

An expedient approach for the synthesis of pyrrolo[3,2-d]pyrimidines (9-deazaxanthines) and furo[3,2-d]pyrimidine via radical cyclization

A new efficient route for the synthesis of substituted 9-deazaxanthines in excellent yields via aza-Claisen rearrangement followed by radical cyclization has been achieved. This methodology has also been applied to the synthesis of furo[3,2-d]pyrimidine.     

De novo synthesis of teleocidin B analogs

Teleocidin B analogs have been synthesized in 24 steps and 1.9% overall yield. The key steps include aromatic Claisen rearrangement, intramolecular Heck reaction of a tetra-substituted alkene, and ruthenium (II) catalyzed indole cyclization. Teleocidin and the new analogs promote cell spreading on fibroblast cells that were treated with amino-Nogo, an inhibitor of cell spreading.     

Stereoselective synthesis of cis- and trans-3-fluoro-1-phenylcyclobutyl amine

A stereoselective approach to the synthesis of cis- and trans-3-fluoro-1-phenylcyclobutylamine has been developed. Excellent stereoselectivity was obtained by the reduction of the appropriately substituted cyclobutanone to give either cis- or trans-isomers of 3-hydroxyl-1-phenylcyclobutylamine, which was stereoselectively converted to the 3-fluoro derivative.     

Copper-catalyzed efficient synthesis of 5-arylindazolo[3,2-b]quinazolin-7(5H)-ones from 2-nitrobenzaldehydes

A novel and practical copper-catalyzed approach was developed for the preparation of 5-arylindazolo[3,2-b]quinazolin-7(5H)-ones. The 2-amino-N′-arylbenzohydrazideis easily prepared by a reaction of isatoic anhydride with arylhydrazine. Then, through a condensation/intramolecular cyclization reaction by 2-nitrobenzaldehydes in the present of CuI, the corresponding 5-arylindazolo[3,2-b]quinazolin-7(5H)-ones are produced in good yields.     

Stereoselective synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via intramolecular hetero-Diels-Alder reaction

The synthesis of 3a,7a-dihydro-3H,4H-furo[3,4-c]pyran-1-ones via an intramolecular hetero-Diels-Alder reaction of easily accessible α,β-unsaturated γ-ketoesters was investigated. The reaction was found to proceed in a highly stereoselective way leading to single, cis-configured product isomers. The same diastereomer is formed, independently of the configuration of the enone double bond of the precursor. The respective E- and Z-isomers react either through an endo-E-syn or an exo-Z-syn transition state.     

First total syntheses of the 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines annoretine and litebamine

We describe here the first total synthesis of the two natural 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines, annoretine and litebamine, from [2-(2-styrylphenyl)ethyl]methylcarbamic acid ethyl esters. The key steps were the Bischler-Napieralski cyclization to form the isoquinoline unit and photocyclization of the resulting 2-methyl-5-styryl-3,4-dihydro-2H-isoquinolin-1-ones to 2-methyl-3,4-dihydro-2H-naphtho[2,1-f]isoquinolin-1-ones.     

Synthesis and rearrangement of cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones: an access to cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones

2-Substituted-4a-hydroxy-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 2a-c were synthesized by an one-step cyclocondensation from the 5-substituted-2-amino-2-oxazolines 1a-c with ethyl 2-oxocyclohexanecarboxylate in ethanol at room temperature, and easily dehydrated to provide 2-substituted-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 3. In refluxing xylene, the reaction conducted with various ethyl 2-oxocycloalkanecarboxylates led to the two isomeric 2-substituted-8/9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones 3 and 2-substituted-5H-cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones 4. The structure of some compounds was unambiguously established using X-ray crystallography. According to results from the DSC analysis of compound 2a, formation of the thermodynamically stable pyrimidinones 4 could be related to an intramolecular rearrangement of kinetically controlled pyrimidinones 3.     

Pd-Mediated synthesis of 7H-benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid derivatives from indole-containing Baylis-Hillman adducts

We synthesized novel tetracyclic fused indole derivatives via the intramolecular Heck reaction of indole-containing Baylis-Hillman adducts in good to moderate yields.     

A novel construction of quino-fused tropone skeleton: first synthesis of 12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one derivatives

In the present investigation, the incorporation of both quinoline moiety and tropone ring in a molecule frame work in fused form leading to a series of structurally novel and biologically intriguing quinoline/tropone hybrids 12H-benzo[4,5]cyclohepta[1,2-b]quinolin-12-one derivatives has been first achieved through a simple, and economical two-step procedure, involving the one-pot synthesis of (E)-2-(arylvinyl)quinoline-3-carboxylic acids followed by intramolecular Friedel–Crafts acylation reaction using polyphosphoric acid (PPA).     

Regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones and 12H-benzopyrano[3,2-c][1]benzopyran-5-ones by radical cyclization

5-Hydroxy uracils or 4-hydroxy[1]benzopyran-2-ones were refluxed with 2-bromobenzyl bromides in acetone in the presence of anhydrous potassium carbonate to afford a number of 5-(2′-bromobenzyloxy) pyrimidine-2,4-dione (80-92%) or 4-(2′-bromobenzyloxy) benzopyran-7-ones (70-82%) respectively. These were then refluxed with tri-n-butyltin chloride and sodium cyanoborohydride in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) for 3-4 h to give 1H,3H,6H [2]benzopyrano[4,3-d]pyrimidine-2,4-diones (75-85%) or 12H-benzopyrano[3,2-c][1]benzopyran-5-ones (70-85%) respectively.     

First synthesis of 4-aminopyrido[2′,3′:4,5]furo[3,2-d]pyrimidines

This Letter describes for the first time the synthesis of pyrido[2′,3′:4,5]furo[3,2-d]pyrimidines substituted by a primary or secondary amino group on position 4 of the pyrimidine ring. Application of microwave irradiation technology allowed fast and convenient procedures.     

One-pot synthesis of fluorine containing 3-cyano/ethoxycarbonyl-2-methyl-benzo[b]furans

Fluoro-substituted 3-cyano-2-methyl-benzo[b]furans and ethyl 2-methyl-benzo[b]furan-3-carboxylates are conveniently prepared in a single step in good yield by the microwave induced tandem intramolecular Wittig and Claisen rearrangement reactions of the corresponding [(aryloxyacetyl) (cyano) methylene] triphenylphosphorane and [(aryloxyacetyl) (ethoxycarbonyl) methylene] triphenylphosphoranes, respectively.     

Galanthamine analogs: 6H-benzofuro[3a,3,2,-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine

The known cholinesterase inhibitory capability of the Amarylidaceae alkaloid galanthamine prompted preparation of analogs in which the position of the nitrogen within the azepine ring is altered. The analogs 6H-benzofuro[3a,3,2-e,f][1]benzazepine and 6H-benzofuro[3a,3,2-e,f][3]benzazepine were prepared in 19 and 2.5%, respectively, following Kametani and Shimizu approaches, respectively. The aniline derivative 6H-benzofuro[3a,3,2-e,f][1]benzazepine failed to undergo most of the reactions typical for galanthamine. Thus, it neither oxidized to the analogous narwedine, nor epimerized to the analogous epigalanthamine, nor reduced to the lycoramine analog, under the conditions used for galanthamine.     

Synthesis of 4H-[1,3]dithiolo[4,5-b]pyrroles through the reaction of benzoyl isothiocyanate and dialkyl acetylenedicarboxylates in the presence of Ph3P

Benzoyl isothiocyanate reacts with dialkyl acetylenedicarboxylates in the presence of triphenylphosphine in a mechanistically novel reaction to afford highly substituted dialkyl 2-(benzoylimino)-5-phenyl-4H-[1,3]dithiolo[4,5-b]pyrrole-4,6-dicarboxylates with double insertion of the isothiocyanate. The reaction proceeds via a carbon to nitrogen migration of an alkoxycarbonyl group.     

Montmorillonite KSF-catalyzed one-pot synthesis of hexahydro-1H-pyrrolo[3,2-c]quinoline derivatives

Aryl amines react with endocyclic ene-carbamates such as tert-butyl 2,3-dihydro-1H-1-pyrrolecarboxylate and tert-butyl 1,2,3,4-tetrahydro-1-pyridinecarboxylate, on the surface of montmorillonite KSF clay under mild conditions to afford the corresponding 3-aminopropylhexahydropyrrolo[3,2-c]quinoline or 4-aminobutyloctahydrobenzo[h][1,6]naphthyridine derivatives in excellent yields with moderate diastereoselectivity.     

A facile domino protocol for the stereoselective synthesis of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines

A facile protocol for the stereoselective construction of trans-2,3-dihydrobenzofurans and cis-5,6-dihydrofuro[2,3-d]pyrimidines from the reactions of 2,2′-sulfonylbis(1,3-diarylprop-2-en-1-ones) with cyclic 1,3-diketones, viz. cyclohexane-1,3-diones, barbituric acid, and 2-thioxodihydropyrimidine-4,6(1H,5H)-dione in the presence of DBU in ethanol is described. This transformation presumably occurs via domino Michael addition-proton exchange-annulation via intramolecular displacement sequence.