Cyclizations Using Aryl Radicals

Atropisomers of ortko- and N-substituted o-iodoacrylamides, N-aUyl-N-o-iodoarylamides are stable at ambient temperature with a barrier of interconversion of approximately 20-30 kcal mol. Enantioenriched, axially chiral aryl iodides reacted at ambient temperature under reductive reaction conditions to provide the corresponding 5-exo cycUzation products. It has been shown by Curran that the axial chiraUty can be transferred into centrochirality, and hence 5-exo aryl radical cyclization occurs more rapidly than does racemization of the axially chiral aryl 

Various benzoselenophenes 106 were successfully prepared using the Sni reaction at selenium. Selenides 104, readily prepared from the corresponding epoxides, react under standard radical conditions by homolytic substitution at selenium to the heterocycles 105. Water elimination finally provides the benzoselenophenes 106 in high yields (Equation 13.17) [165, 166]. In analogy, Te-containing heterocycles can also be prepared [166, 167]. 

The homolytic substitution at trivalent phosphorus has recently been disclosed as a new method for the metal-free C-P bond formation. Oshima [168] has shown that in situ-generated tetraphenylbisphosphane (X = PPhj) (Equation 13.18) reacts under standard conditions with aryl radicals to afford, after oxidation, the corresponding aryl diphenylphosphane sulfides. 

More recently, Studer [169] has replaced Ph2P-PPh2 by the readily available tri-mefhyltindiphenylphosphane (X = SnMes) as radical acceptor (Equation 13.18). The reaction of various aryl hahdes under radical reaction conditions produced, after oxidation, the corresponding aryl diphenylphosphane oxides with good yields. 

TEMPO 2,2,6,6-tetramethylpiperidine-l-oxyl radical TMSCl trimethylchlorosilane 

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Scheme 13.19 Radical cyclizations using aryl radicals.

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... 

A similar strategy has been applied to the synthesis of kainoids and related compounds (eq 3). Both stoichiometric and catalytic amounts of cobalt reagents have been used in these and other cyclization studies. Several examples of these types of cyclizations have been published, including cyclizations using aryl halides as precursors to aryl radicals. ... 

There are many synthetic examples that use radical cyclization as a key step, and the radical precursor is not limited to iodides or bromides. In Pattenden s synthesis of pentalenene, conjugated selenyl ester 156 was treated with Bu3SnH and AIBN to give a 45% yield of tricyclic ketone 159. Loss of PhSe generated the acyl radical 157, which exists in equilibrium with the ketene radical 156. Radical cyclization via the latter intermediate leads to 159. Cyclization via aryl radicals is also possible. In Schultz s synthesis of hexahydro-phenanthren-2-one derivatives, " aryl bromide 160 was cyclized to 161 in 78% yield under standard conditions. Radical cascade reactions have become quite popular for the synthesis of polycyclic ring systems. In these reaction, polyenes are subjected to radical cyclization, generating tricyclic or even tetracyclic ring systems. 5 Chiral auxiliaries have been used effectively in radical cyclization reactions. ... 

The C-Se and C-Te bonds are formed by an internal homolytic substitution of vinyl or aryl radicals at selenium or tellurium with the preparation of selenophenes and tellurophenes, respectively. An example is shown below, where (TMSIsSiH was used in the cyclization of vinyl iodide 65 that affords... 

Germanes are also used for the reduction of various organic halides at ambient temperature under Et3B/C>2 initiation. For example, tri-2-furylgermane mediated radical cyclizations of aryl iodides proceed in good yields (Scheme 6, Eq. 6a) and are also possible with NaBH4 in the presence of a catalytic amount of triphenylgermane (Eq. 6b) [ 16]. 

The aryl radical cyclization has been successfully used for the preparation of substituted dihydrobenzo[Z)]indoline derivatives [59], An example is shown in Reaction (7.49). The diene 42 was preliminarly subjected to ring-closure metathesis using Grubbs catalyst and then treated with (TMS)3SiH and EtsB at -20 °C, in the presence of air, to provide the compound 43 with an excellent diastereoselectivity. 

Crich and Rumthao reported a new synthesis of carbazomycin B using a benzeneselenol-catalyzed, stannane-mediated addition of an aryl radical to the functionalized iodocarbamate 835, followed by cyclization and dehydrogenative aromatization (622). The iodocarbamate 835 required for the key radical reaction was obtained from the nitrophenol 784 (609) (see Scheme 5.85). lodination of 784, followed by acetylation, afforded 3,4-dimethyl-6-iodo-2-methoxy-5-nitrophenyl acetate 834. Reduction of 834 with iron and ferric chloride in acetic acid, followed by reaction with methyl chloroformate, led to the iodocarbamate 835. Reaction of 835 and diphenyl diselenide in refluxing benzene with tributyltin hydride and azobisisobutyronitrile (AIBN) gave the adduct 836 in 40% yield, along with 8% of the recovered substrate and 12% of the deiodinated carbamate 837. Treatment of 836 with phenylselenenyl bromide in dichloromethane afforded the phenylselenenyltetrahydrocarbazole 838. Oxidative... 

Formation of cyclized products, resulting from intramolecular attack of the intermediate aryl radical in the SrnI reaction on a second aromatic ring (i.e. intramolecular homolytic arylation) are rare and not synthetically useful.64-158-161... 

Although the bimolecular additions of aryl radicals to aromatic rings are not useful due to a lack of selectivity, the corresponding cyclizations are useful for constructing biaryl bonds. Equation (5) provides a generalized example of the Pschorr reaction.172 This cyclization of a diazonium salt is one of the classical methods for biaryl bond formation, and there are a variety of related reactions.138... 

Moreover, using the same starting materials, they have reported the regio- and stereoselective synthesis of enantiopure or racemic benzofused tricyclic (3-lactams such as benzocarbapenems and benzocarbacephems (III and IV, Fig. 17) via intramolecular aryl radical cyclization [287]. 

Beckwith and Storey have developed a tandem translocation and homolytic aromatic substitution sequence en route to spiro-oxindoles [95CC977]. Treatment of the bromoaniline derivative 122 with tin hydride at 160 °C generated the aryl radical 123 which underwent a 1,5-hydrogen atom transfer to give intermediate 124. Intramolecular homolytic aromatic substitution and aromatization gave the spiro-oxindole 125. Intramolecular aryl radical cyclization on to a pyrrole nucleus has been used to prepare spirocyclic heterocycles [95TL6743]. 

Reduction of the reaction time was achieved by the use of microwave dielectric heating in synthesis of 2-cyanobenzothiazoles from anilines and 4,5-dichloro-l,2,3-dithiazolium chloride [84,85]. Mn(OAc)3 promoted the radical-mediated cyclization of aryl- and benzoyl-thioformanilides. The re-... 

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