Concise and Free-Metal Access to Lactone-Annelated Pyrrolo[2,1-a]isoquinoline Derivatives via a 1,2-Rearrangement Step.

Here, An efficient approach to obtaining previously unknown furo[2',3':2,3]pyrrolo[2,1-a]isoquinoline derivatives from readily available 1-R-1-ethynyl-2-vinylisoquinolines is described. The reaction features a simple procedure, occurs in hexaflouroisopropanol and does not require elevated temperatures. It has been found that the addition of glacial acetic acid significantly increases the yields of the target spirolactone products. Using trifluoroethanol instead of hexaflouroisopropanol results in the formation of pyrido[2,1-a]isoquinolines.

Divergent and Nucleophile-Assisted Rearrangement in the Construction of Pyrrolo[2,1-b][3]benzazepine and Pyrido[2,1-a]isoquinoline Scaffolds.

Under microwave (MW) irradiation at 150 °C in toluene and in the presence of nucleophiles (DMAP, triphenylphosphine and tetrahydrothiophene) 1-substituted 1-ethynyl-2-vinyldi- and tetrahydroisoquinolines undergo [3,3]-sigmatropic rearrangement providing pyrrolo[2,1-b][3]benzazepines in good yields. The replacement of toluene with acetonitrile directs the rearrangement towards the formation of 7,11b-dihydro-6H-pyrido[2,1-a]isoquinolines.

Synthesis of Isomeric 3-Benzazecines Decorated with Endocyclic Allene Moiety and Exocyclic Conjugated Double Bond and Evaluation of Their Anticholinesterase Activity.

Transformations of 1-methoxymethylethynyl substituted isoquinolines triggered by terminal alkynes in alcohols were studied and new 3-benzazecine-containing compounds synthesized, such as 6-methoxymethyl-3-benzazecines incorporating an endocyclic C6-C8 allene fragment and the -ylidene derivatives 6-methoxymethylene-3-benzazecines. The reaction mechanisms were investigated and a preliminary in vitro screening of their potential inhibitory activities against human acetyl- and butyrylcholinesterases (AChE and BChE) and monoamine oxidases A and B (MAO-A and MAO-B) showed that the allene compounds were more potent than the corresponding -ylidene ones as selective AChE inhibitors. Among the allenes, 3e (R3 = CH2OMe) was found to be a competitive AChE inhibitor with a low micromolar inhibition constant value (Ki = 4.9 µM), equipotent with the corresponding 6-phenyl derivative 3n (R3 = Ph, Ki = 4.5 µM), but 90-fold more water-soluble.

Design of new anti-Alzheimer drugs: ring-expansion synthesis and synchrotron X-ray diffraction study of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa-hydro-azonino[5,6-b]indole-2,3-di-carboxyl-ate.

The title compound, C20H23FN2O4, is the product of a ring-expansion reaction from a seven-membered fluorinated hexa-hydro-azepine to a nine-membered azonine. The nine-membered azonine ring of the mol-ecule adopts a chair-boat conformation. The C=C and C-N bond lengths [1.366 (3) and 1.407 (3) Å, respectively] indicate the presence of conjugation within the enamine CH2-C=C-N-CH2 fragment. The substituent planes at the C=C double bond of this fragment are twisted by 16.0 (3)° as a result of steric effects. The amine N(Et) N atom has a trigonal-pyramidal configuration (sum of the bond angles = 346.3°). The inter-planar angle between the two carboxyl-ate substituents is 60.39 (8)°. In the crystal, mol-ecules form zigzag chains along [010] by inter-molecular N-H⋯O hydrogen-bonding inter-actions, which are further packed in stacks toward [100]. The title azonino-indole might be considered as a candidate for the design of new Alzheimer drugs.

Ring-expansion synthesis and crystal structure of dimethyl 4-ethyl-1,4,5,6,7,8-hexa-hydro-azonino[5,6-b]indole-2,3-di-carboxyl-ate.

The title compound, C20H24N2O4, is the product of a ring-expansion reaction from a seven-membered hexa-hydro-azepine to a nine-membered azonine. The azonine ring of the mol-ecule adopts a chair-boat conformation. In the crystal, mol-ecules are linked by bifurcated N-H⋯(O,O) hydrogen bonds, generating [010] zigzag chains. The title compound shows inhibitory activity against acetyl-cholinesterase and butyrylcholinesterase, and might be considered as a candidate for the design of new types of anti-Alzheimer's drugs.