Cascade Synthesis of New Indole-Containing Pentacyclic Scaffolds Mediated by Aryl and Iminyl Radicals.

A five-step approach, starting from simple 1,5-disubstituted indoles, has been implemented for the synthesis of diversely substituted indole-pyrido-indene pentacyclic compounds up to 54 % yield via domino radical-mediated processes in the presence of the radical reagents DLP/TTMSS and AIBN/TTMSS. Reactions proceeded with diverse key starting radical cyano-precursors strategically synthesized which were subsequently transformed into the target pentacyclic compounds through an aryl/iminyl radical-mediated domino reactions sequence. In addition to the routine spectroscopic techniques, the structure of radical precursors, as well as, the target pentacyclic products were unequivocally established by single crystal X-ray diffraction, confirming the effectiveness of the proposed synthetic sequence.

Experimental and theoretical study of the mechanism and rate constants of the sequential 5-exo-trig spirocyclization involving vinyl, aryl and N-alkoxyaminyl radicals.

In this research the sequential generation and cyclization of N-alkoxyaminyl radicals to produce 1-azaspiro[4.4]nonane, a prominent scaffold in organic and medicinal chemistry, was studied. Competition experiments in benzene at 80 °C with brominated oxime ethers using Bu3SnH as chain transfer and AIBN as the initiator generated vinyl or aryl radicals which were captured by oxime ethers, allowing approximate 5-exo-trig cyclization constants at 4.6 × 108 s-1 and 9.9 × 108 s-1 respectively to be established. Similar results were obtained by kinetic studies using the transition state theory (TST) from ab initio calculations with density functional theory (DFT) using the M06-2X, B3LYP, mPW1PW91 and TPSSh functionals in combination with the 6-311+G(d, p) basis set. Additionally, it was found that the 5-exo-trig cyclization of the N-alkoxyaminyl radical onto CC double bonds is a reversible process whose constants were determined to be in the range of 6.2 × 100 s-1 and 3.5 × 106 s-1 at 80 °C, depending on the nature of the substituents. The calculation of the radical stabilization energy (RSE) shows that the N-alkoxyaminyl radical is a very stable species and its reactivity in the addition on alkenes is governed by its nucleophilic character and the stability of the carbon-centered radical formed after cyclization. The reduction constant of the N-alkoxyaminyl radical with Bu3SnH in the gas phase at 80 °C was also estimated to be 3.4 × 100 M-1 s-1 through computational calculations. This information facilitates the rational planning of cascades and other methodologies applied to the construction of carbocyclic and aza-heterocyclic compounds.

Synthesis of 1-Azaspiro[4.4]nonane Derivatives Enabled by Domino Radical Bicyclization Involving Formation and Capture of Alkoxyaminyl Radicals.

The application of a domino radical bicyclization for the synthesis of compounds containing the 1-azaspiro[4.4]nonane skeleton in 11-67% yields as a mixture of diastereomers is described (trans configuration preference). This process involved formation and capture of alkoxyaminyl radicals. For this purpose, O-benzyl oxime ethers with a brominated or iodinated aromatic ring or a terminal alkynyl group and an alkenyl moiety were employed as starting materials. The bicyclization was initiated by 2,2'-azobisisobutyronitrile or triethylborane and promoted by Bu3SnH. The best results were obtained with O-benzyl oxime ethers containing an alkenyl moiety tethered to electron withdrawing groups or aryl substituents, whereas oxime radical precursor attached to methyl-substituted olefin precluded the capture of alkoxyaminyl radical, giving rise mainly to monocyclized product.

Design, synthesis and crystallographic study of novel indole-based cyano derivatives as key building blocks for heteropolycyclic compounds of major complexity.

A four-stage reaction sequence has been designed and developed for the synthesis of highly functionalized enolate esters as key building blocks for the synthesis of novel heteropolycyclic compounds of potential pharmaceutical value. The sequence starts with simple commercially available indoles and proceeds via 3-(indol-3-yl)-3-oxopropanenitriles, which react with 2-bromobenzaldehyde to form the corresponding chalcones; these are readily reduced to dihydrochalcones, which are in turn acylated to form the enolate esters. The compounds in this sequence have been characterized by IR and 1H and 13C NMR spectroscopy, by mass spectrometry and by elemental analysis. The molecular and supramolecular structures are reported for representative examples, namely (E)-3-(2-bromophenyl)-2-(1-methyl-1H-indole-3-carbonyl)acrylonitrile, C19H13BrN2O, (Ib), (2RS)-2-(2-bromobenzyl)-3-(1-methyl-1H-indol-3-yl)-3-oxopropanenitrile, C19H15BrN2O, (IIb), and (2RS)-3-(1-benzyl-1H-indol-3-yl)-2-(2-bromobenzyl)-3-oxopropanenitrile, C25H19BrN2O, (IIc), the latter two of which crystallize with Z' = 2, and (E)-1-(1-acetyl-1H-indol-3-yl)-3-(2-bromophenyl)-2-cyanoprop-1-en-1-yl acetate, C22H17BrN2O, (III), and (E)-1-(1-benzyl-1H-indol-3-yl)-3-(2-bromophenyl)-2-cyanoprop-1-en-1-yl benzoate, C32H23BrN2O, (IV). The structure of the related chalcone (E)-2-benzoyl-3-(2-bromophenyl)prop-2-enenitrile, (V), has been redetermined at 100 K, where it is monoclinic, as opposed to the triclinic form reported at ambient temperature.

2-[1'-(Benz-yloxy)spiro-[indane-1,2'-pyrrolidine]-5'-yl]aceto-nitrile.

In the title compound, C21H22N2O, the planes of the two six-membered rings make a dihedral angle of 89.51 (7)°. The pyrrolidine ring has a puckering amplitude q 2 = 0.418 (3) and a pseudo-rotation phase angle ϕ2 = -166.8 (5), adopting a twist conformation (T). The other five-membered ring has a puckering amplitude q 2 = 0.247 (2) and a pseudo-rotation phase angle ϕ2 = -173.7 (5), adopting an envelope conformation with the CH2 atom adjacent to the C atom common with the pyrrolidine ring as the flap. In the crystal, mol-ecules are linked via C-H⋯N, enclosing R (2) 2(20) rings, forming chains propagating along [100]. The aceto-nitrile group is disordered over two positions and was refined with a fixed occupancy ratio of 0.56:0.44.