Imidoyl Radicals for the Synthesis of Chromenoquinolines and Naphthyridines

The stability of imidoyl radicals prepared from 2-(2-alkenyloxy)-phenyl selenoimidates and 2-(2-allylamino)-phenyl selenoimidates and their intramolecular free radical cyclization through the slow addition of tri-N-butyltin hydride and AIBN to obtain 4-chromanones and 4-quinolones were studied. The extension of the methodology to N-phenyl substituted imidoyl selenoates produced tandem cyclizations of the imidoyl radical with the allyl substituent, followed for a second cyclization of the intermediate radical with the aromatic substituent to produce dihydro-chromenoquinolines or tetrahydro-dibenzonaphtyridines. Further oxidation with DDQ produced: 6H-chromeno [4,3,b] quinoline and 7-methyl-6H-chromenoquinoline from 2-alkenylamino-phenylbenzamide and 5,6-dihydro-dibenzo [b,h][1,6] naphthyridine and 5,6-dihydro-7-methyl-dibenzo [b,h][1,6] naphthyridine from 2-2-(alkylamino)-N-phenylbenzamides. The cyclization of 2-(N,N-di-prop-2.enylamino)-N-phenylnicotinamide selenoate obtained from 2-aminonicotinic acid, produced 5,6-dihidro-benzo[b]pyrido2,3-h] [1,6] naphthyridine.


Introduction
Chromanones, quinolones, chromenoquinolines and naphthyridines constitute important polycycles of pharmaceutic antibacterial compounds; they are also present in natural products.The search of new synthetic method for these heterocycles can contribute to the development of new and better pharmaceutic compounds.
In this work, we present the synthesis of chromanones and quinolones by a radical intramolecular cyclization of O-allyl or N-allyl phenyl selenoimidates, prepared from imidoyl chlorides.
The extension of this reaction to aromatic substituted selenoimidates gave chromenoquinolines and benzonaphtyridines through a tandem cyclization of the imidoyl radical and the allyl substituent followed of a second cyclization with the aromatic substituent and further oxidation of the dihydro or tetrahydro polycycles.
Uneyama et al. [5] obtained indoles from an intramolecular photochemical homolysis of azo compounds derived of imidoyl iodides to triple bonds and Zhang and Studer [6] published a review on the use of isonitriles as radical acceptors.
There are some examples of imidoyl radicals obtained from amides: Esker and Newcomb [7] prepared imidoyl radicals from secondary amides by reaction of the amide with phosgene to give an imidoyl chloride followed by reaction with the sodium salt of N-hydroxypyridine-2-thione which produced amidyl radicals by visible light initiation.These radicals were cyclized to form γ-lactams and N-acyl pyrimidines.Manley [8] and Zhong et al. [9] obtained imidoyl chlorides by the combination of oxalyl chloride and DMF, and Cunico and Pandey [10] obtained these compounds from amides and phosphorous pentachloride.
The transformation of imidoyl chlorides to selenoimidates or teluroimidates facilitates the handling of the imidoyl radicals; these compounds are prepared from imidoyl chlorides and phenylselenyl anions [11] or from the reaction of oxime sulfonates with organoaluminum selenoates [12].Bowman et al. [13] obtained phenyl-selenyl imidates from the reaction of aromatic ortho-alkenylamides with phosgene and phenyl selenide and Fujiwara et al. [11] made indoles from butyl-selenyl imidates prepared from selenium and isocyanates.
Bachi and Dennenmark published a short paper [14] on the cyclization of selenoimidates to obtain chromanones or chromenoquinolines from 2-allyloxy-Nalkylbenzamides or 2-allyloxy-N-phenylbenzamides as raw materials; they report imidoyl radicals as intermediates of the cyclization reactions, but the methodology for radical preparation is not reported.After these papers, they did not use this method.Rigby et al. [15] and Fujiwara et al. [11] also prepared and characterized some selenoimidates.
A recent review [16] reports various radical cyclizations of isocyanides, isothiocyanates, nitriles, and other C-N unsaturated bond systems.A variety of 5and 6-membered nitrogen-containing heterocycles were prepared via imidoyl or iminyl radical intermediates.International Journal of Organic Chemistry
These unstable compounds, solids at room temperature, were purified after basification using chromatography on basic alumina.Yields of 79% -75% were obtained.Their IR spectra and H 1 NMR spectra were the expected, as reported by Meese et al. [19].The phenylamide of 2-aminonicotinic acid (1i in Table 1), was prepared from 2-aminonicotinic acid through the formation of an oxathiazinone with thionyl chloride [20]; further treatment with sodium hydride in DMF-allyl bromide and finally with aniline.Extraction and chromatography produced 2-(N-allylamino)-N-phenyl nicotinamide.This compound was methylated with sodium hydride and methyl bromide to give 2(allyl(methyl)amino-N-phenyl nicotinamide

2-(allyl(methyl)amino-N-phenyl nicotinamide
Sodium phenyl selenides were prepared from diphenyl diselenide and sodium hydride in dry THF under dry nitrogen, an added to the imidoyl chlorides in the presence of dimethylformamide to get selenoimidates [21].Yields of these reactions (60% and 70%) were comparatively higher than the reported (20% -45%) (see Table 1).We did not find nitriles produced by fragmentation.In all cases, a small quantity of amide was recovered (see Table 1).We did not find nitriles produced by fragmentation recovered.

Amides substituents Yields
Two examples of the NMR 1 H spectra of benzamides and two of the imidoyl chlorides are shown: Benzamides International Journal of Organic Chemistry

Experimental
The raw materials and silica gel were acquired from Sigma Aldrich.DMF was dried with calcium hydride and dichloromethane with phosphorous pentoxide.1H J 0.9 J = 8.5 Hz).
2-Alkenyloxy-N-alkylbenzamides: Allyl or crotyl bromide were added to N-alkyl and N-aryl salicylamides in acetone and refluxed for 10 hours.Elimination of the inorganic salts and solvent evaporation produced the alkenyloxi-N-alkylbenzamide which was purified by column chromatography.
The solvent eliminated at reduced pressure and the product chromatographed in a silica gel column, using hexane-ethyl acetate 80:20.2-(N,N-di-prop-2-enylamine)-N-phenylnicotinamide: 4(1H)-oxo-pyrido-(2,3-d) oxathiazinone (1.5 g) in anhydrous DMF were made to react with 0.3 g (12.5 mmol of sodium hydride stirring for 1 hour.5 ml.(12.2 mmol) or allyl bromide were added to the anion and the mixture refluxed during 12 hs and poured in a suspension aniline (6 ml, 65.8 mmol)-water at 0˚C.After stirring 2 hours and maintained at 0˚C for 10 hours.The organic layer was separated from water and the aniline distilled at reduced pressure.The resulting product was purified by chromatography on a silica gel column.

Imidoyl radicals cyclization.
In a two necked flask fit with a condenser and nitrogen atmosphere, a 0.02 M solution of phenyl selenium imidate or imidoyl chloride (1 eq) in anhydrous toluene was bubbled with nitrogen in order to eliminate the oxygen. 1 eq. of tributiltin, and 0.025 eq of AIBN in toluene (15 ml) were placed in a sealed vial, under nitrogen.Theimidate solution was heated at 100˚C and the mixture of Bu 3 SnH-AIBN was slowly added during 2 hours.The mixture was refluxed 2 more hours.After cooling at room temperature, 20 ml of a 4 M aqueous solution of sodium hydroxide was added.After stirring 2 hrs, the organic layer was washed with water until pH 7, and dried with sodium sulfate.The residue of evaporation of the solvent at reduced presion was purified in a silica gel column, using hexane-ethyl acetate 93:7 as eluent.In a two necked flask fit with a condenser and nitrogen atmosphere, a 0.02 M