Quinoline RADICAL CYCLIZATION

Acylation of isoquinolines. A mixture of an isoquinoline and Bu,SnH reacts at — 78° with a 3-halopropionyl chloride in CH,C12 to give N-acyl-l,2-dihydroiso-quinolines in 80-95% yield (cf., 13, 10). These can undergo radical cyclization with BujSnH/AIBN to furnish benzoindolizidin-3-ones. 

As an example of alkylideneaminyl radical cyclization in quinoline synthesis, Forrester and colleagues reported the cyclization of (l,2,3,3-tetraphenylpropylideneaminooxy)acetic acid 91 by oxidation with KjSjOg (Scheme 43), and various heterocyclic compounds were prepared by this method. 

A novel radical cyclization of ketimine-enynes has recently been reported by Wang and coworkers [50]. The diradical intermediates were synthesized en route to quinolines 156, 157 and benzocarbazoles 160-163 (Scheme 28). 

The 2-isocyanostyrene derivatives have also been prepared by the Pudovik Reaction with a variety of aldehydes. In addition, a variant of the 5-exo-dig radical cyclization of 2-alkynylphenylisonitriles using thiols as both radical initiators and nucleophiles has been developed. Under these conditions, quinolines can be obtained by a potentially competitive 6-endo-dig radical cyclization. ... 

The sonochemistry of the other alkali metals is less explored. The use of ultrasound to produce colloidal Na has early origins and was found to greatly facilitate the production of the radical anion salt of 5,6-benzo-quinoline (225) and to give higher yields with greater control in the synthesis of phenylsodium (226). In addition, the use of an ultrasonic cleaning bath to promote the formation of other aromatic radical anions from chunk Na in undried solvents has been reported (227). Luche has recently studied the ultrasonic dispersion of potassium in toluene or xylene and its use for the cyclization of a, o-difunctionalized alkanes and for other reactions (228). 

Baylis-Hillman adducts such as 55 and 56 derived from 2-nitrobenzaldehydes were shown to function as useful precursors to functionalized (1H)-quinol-2-ones and quinolines. Treatment of 55 and 56 with iron and acetic acid at 110 °C afforded 57 and 58, respectively <02T3693>. A variety of other cyclization reactions utilized in the preparation of the quinoline scaffold were also reported. An iridium-catalyzed oxidative cyclization of 3-(2-aminophenyl)propanols afforded 1,2,3,4-tetrahydroquinolines <02OL2691>. The intramolecular cyclization of aryl radicals to prepare pyrrolo[3,2-c]quinolines was studied <02T1453>. Additionally, photocyclization reactions of /rans-o-aminocinnamoyl derivatives were reported to provide 2-quinolones and quinolines <02JHC61>. Enolizable quinone and mono- and diimide intermediates were shown to provide quinolines via a thermal 6jt-electrocyclization <02OL4265>. Quinoline derivatives were also prepared from nitrogen-tethered 2-methoxyphenols. The corresponding 2-methoxyphenols were subjected to a iodine(III)-mediated acetoxylation which was followed by an intramolecular Michael addition to afford the quinoline OAc O... 

Formation of pentacycle 55 was consistent with the radical addition-quinoline rearomatization-overoxidation sequence depicted below. Thus, the initially formed acyl radical L undergoes regioselective cyclization upon the 4-position of the quinoline ring to give the azacyclohexadienyl radical M, which is probably oxidized by hydrogen abstraction at the hands of the initiator AIBN <04AGE95>. A new hydrogen abstraction at the doubly... 

The reductive cyclization protocol was then applied to a suitably A-protected radical precursor to allow further access to the alkaloid calothrixin B. Satisfactorily, 2-indolylacyl radicals derived from A-(methoxymethyl) selenoester 57 underwent cyclization under TTMSS-AIBN conditions with an even higher efficiency than their A-methyl counterparts. The reaction nevertheless followed a different course as, after the radical addition and quinoline rearomatization, pentacyclic phenol 58, a fully aromatic tautomeric form of ketone P, was isolated in 90% yield. The same phenol 58 was isolated although in lower yields (50-70%) using either stannane-AIBN or AIBN-irradiation protocols. 

Interestingly, 7-azaindole is formed in the pyrolysis of nicotine at or above 800°. It was considered a free radical reaction and unusual as it involves a three-atom rather than a four atom side chain in the cyclization. Quinoline is also formed. The products were identified by gas chromatography. 

Intramolecular cyclizations of iodobenzenes tethered to pyridines via a two-carbon linkage yields quinolines and isoquinolines. Radical initiators are employed and yields as high as 98% are reported <030BC4047>. Pyridines substituted in the 2- and 3-positions gave complex mixtures in lower yields. 

With this substrate (28) the ring closure can be conveniently accomplished with either stannyl or sulfanyl radicals with no concomitant formation of the six-membered-cyclization quinoline product, which is present instead, or is predominantly formed, in all of the reaction mixtures obtained with group other than TMS. At the same time, both radical precursors, that is, stannane and thiol, can serve as nucleophiles for the intermediate indolenines 29 and 31, which are trapped to give the final substituted indoles 30 and 32 with high efficiency. 

Treatment of / ara-substituted benzylideneanilines 618 (R = Me, Cl or MeO) with phenylacetylene in the presence of diisopropyl peroxydicarbonate results in mixtures of 6-and 7-substituted 2,4-diphenylquinolines, 621 and 623. It is thought that the process is initiated by the formation of arylimidoyl radicals 619, which add to phenylacetylene to form the radicals 620. The latter cyclize to the 6-substituted quinolines by Route A. An alternative mode of cyclization (Route B) proceeds via the spiro-radicals 622, which eventually yield the 7-isomers. ... 

The complex 628 is converted into the benzo[methyl phenylpropiolate. Irradiation of mixtures of the co-iodoalkynes 630 (R = H, Me, Ph or PhCH2) and phenyl isocyanide produces cyclopentano[ ]quinolines by way of a radical addition to the isocyanide, followed by two cyclizations (equation 63). ... 

This way of rationalization is substantiated by the photolytic behavior of, -unsaturated aldehydes (478) (Scheme 162). Only in one of the five cases studied was 479 observed this result is in accordance with the difficult intramolecular addition of alkoxyl radicals in the Cy6/Cy7 case. Since thiyl cyclizations appear efficient even in the Cy6/Cy7 case one might expect to observe easy photocyclizations of unsaturated thiones also in this case the easy photochemical synthesis of quinolines from A -(o-styryl)thioamides appears to be an excellent illustration of this view. Here, the sulfur analog of 479 would be an intermediate. To complete the analogy, one may expect the converse P-scission reaction to be efficient with radicals that readily open such as oxyranylalkyl ones (see Section VIII.2) in this way an interesting macrolide synthesis was described by Carlson. Photolysis of epoxycyclanone (480)... 

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