Radical cyclization thermal

In general, conjugation efficiency is highest with chains composed entirely of sp C-C bonds. However, these chains are flexible and thus conformation-ally inhomogeneous. In addition, they are unstable with respect to other photochemical (like cis-trans isomerization, [2 + 2]cyclization) or thermal processes (radical initiated or electrocyclizations). The chemical and conformational stability may be increased by rigidifying the carbon backbone. 

Bergman proposed that the reaction mechanism of the cyclization under thermal conditions (200 °C) involved the initial generation of a 1,4-benzenediyl diradical species known as para-benzyne (2). Bergman reported that when the reaction was carried out in a hydrocarbon solvent, such as 2,6,10,14-tetramethylpentadecane, benzene was formed as the final product. This suggests that the hydrocarbon solvent (RH) acts as a hydrogen atom donor to quench the diradical intermediate 2. This result hints at the radical nature of the mechanism operative in the Bergman cyclization. 

The rare [1,4] hydrogen transfer has been observed in radical cyclizations. With respect to [1,7] hydrogen shifts, the rules predict the thermal reaction to be antarafacial. Unlike the case of [1,3] shifts, the transition state is not too greatly strained, and such rearrangements have been reported, for example,... 

Fig. 19 The reaction energy profiles for thermal (on the left) and radical-anionic (on the right) C1-C6 and C1-C5 cyclizations of the parent enediyne computed at the B3LYP/ 6-31G level.

Thermal intramolecular [2 + 2]-cydoadditions of phenylsulfonyl-substituted allenes 33 gave 34 stereoselectively. An initial carbon-carbon bond formation occurred at the central allenic carbon and the proximal olefmic carbon. The resulting non-allylic radical 35 is unstable and cyclizes rapidly which may account for the high stereoselectivity [30]. 

The elimination of arenes is not limited to the radical cations of the carotenoids. Just as the neutral compounds themselves also tend to undergo (thermal) cyclization followed by arene loss, the protonated analogues, e.g. ion 82 generated by Cl or fast atom bombardment (FAB) mass spectrometry are prone to eliminate one or even two arene molecules as well (Scheme 26)270. 

Step 10 is a thermal cyclization reaction not requiring a catalyst. The participation of a radical intermediate in the rearrangement reaction was verified by radiotracer studies (94a). 

Early work was focused to establish the preference for exo- vs endo-mode of cyclization. However, the absence of an effective method for generation of alkyl and/or aryl substituted silyl radicals made this task difficult. The reaction of prototype alkanesilane I with thermally generated t-BuO radicals at 145 °C after 4 h afforded a 48 % yield of unreacted starting material and 19 % yield of a six-membered cyclic product (Scheme 6.1) [1]. Moreover, EPR studies of the same reaction recorded the spectra at temperatures between —30 and 0°C, which were identified as the superimposition of two species having allylic-type (2) and six-membered ring (3) structures, respectively [2]. At higher temperatures radical 2 predominates therefore, the low yield detected in the product studies could derive from the extensive t-BuO attack on the allylic hydrogens. 

The endo-mode of cyclization is found to be the preferred path also in the lower homologues. Reaction (6.2) shows the reactions of two silanes (8) with thermally generated t-BuO radicals to afford the five-membered ring in low yields via a 5-endo-trig cyclization [1], EPR spectra recorded from these two silanes with photogenerated t-BuO radicals are assigned to secondary alkyl radical intermediates formed by an intermolecular addition involving the expected silyl radical and the parent silane [2],... 

In Reaction (7.20) is reported the cyclization of a thermally unstable propar-gyl bromide cobalt complex mediated by Ph2SiH2 at room temperature and Et3B/02 as the radical initiator. However, a mixture of reduced and bromine atom-transfer products (1 1.8 ratio) are isolated due to the low hydrogen donation of the employed silane [31]. 

The cation-radical version of diene synthesis, in which the diene is in a strongly electron-deficient state, is characterized by an unusual high endoselectivity. In this case, endoselectivity is sig-nihcantly higher than that of thermal or photochemical initiation of a neutral molecule (cf. Mlcoch and Steckhan 1987). As follows from the charge diagram depicted in Scheme 7.21, when a cation-radical and neutral molecule approach each other, not only the C(l)-C(6) and C(4)-C(5) interactions are bonding (indeed, these interactions result in cyclization), but C(2)-C(7) and C(3)-C(8) interactions are also bonding. As a result, the endo product is formed. 

Intramolecular cyclization of o-diethynylbenzene gives us an opportunity to compare results of the thermal and cation-radical variants of the reaction. There are three possible modes of cyclization shown in Scheme 7.25. 

Although the 1,6 cyclization takes place in the thermal process, the cation-radical initiation leads to the 1,5 cyclization (Ramkumar et al. 1996). Chemical oxidation of o-diethynylbenzene bearing two terminal phenyl groups by tris(p-bromophenyl)ammoniumyl hexachloroantimonate as the catalytic oxidizing agent in the presence of oxygen yields 3-benzoyl-2-phenylindenone in 70% yield (Scheme 7.26). 

Turning from the intramolecular process to the intermolecular ones, we now extend our comparison of the thermal and cation-radical cyclizations. It is also interesting to take sonication into account as a route to initiate cyclizations. The reaction between 2-butenal A,A-dimethylhydrazone (a diene) and 5-hydroxy-l,4-naphthoquinone (a dienophile) gives such an opportunity. In toluene, at 20°C, the reaction follows as depicted in Scheme 7.28 (Nebois et al. 1996). 

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

Intramolecular cyclization of diphenylamines to carbazoles is one of the most versatile and practical methods. This has been achieved photochemically, thermally in the presence of elemental iodine at 350°C, or with platinum at 450-540°C, via free radicals with benzoyl peroxide in chloroform, or by using activated metals such as Raney nickel or palladium on charcoal. Most of these methods suffer from low to moderate yields, and, in some cases, harsh reaction conditions (8,480). 

It is the opinion of the present authors that isomerization of a tertiary alkyl radical to a primary radical as in the formation of II from I is improbable. The formation of IV is similarly unlikely. The cycliza-tion of V by intramolecular alkylation seems quite plausible however, equation 9 does not explain either the formation of V or its subsequent cyclization. The following mechanism has the advantages that, like the generally accepted free radical-initiated mechanisms, it postulates a chain reaction and that the intramolecular alkylation step is directly analogous to that proposed for thermal alkylation, namely addition of an alkyl radical to the double bond of the alkene (Frey and Hepp, 12). The method of formation of the chain initiator, R —, again is not critical since R —, merely starts the first cycle of the chain reaction it may be formed by decomposition of the isobutylene. 

Tin glycolates or o-diphenolates undergo photochemical or thermal radical cyclization (Equation (31)) to 1,3,2-dioxastannolanes or benzo-l,3,2-dioxastannolenes in high yields <86JOM(303)87>. 

A new stabilized phosphorus ylide 357 designed to undergo thermal tandem cyclization has been prepared. Upon flash vacuum pyrolysis at 850 °C, loss of PhsPO and Me radical results in tandem cyclization to give [l]ben-zothieno[3,2- ][l]benzothiophene 356 (Equation 7) <1998J(P1)3937>. 

Aryl-l,2-dihydro-3-nitro[l,8]naphthyridines have been obtained by the 6jt-thermal electrocyclization of l-(2-arylide-neamino-3-pyridyl)-2-nitroethylenes, obtained in situ from aromatic aldehydes and l-(2-amino-3-pyridyl)-2-nitroethylene in xylene <2002SC747>. 2-Chlorotetrahydro[l,8]naphthyridines have also been obtained from 2,6-dichloropyridines using a free radical xanthate-mediated cyclization <20040L3671>. 

The photoconversion of spiro[benzofuran-2,r-cyclohexa-3, 5 -diene]-2, 3(2//)-diones to dibenzofurans is recorded (81JCS(Pi)870). It was proposed that excitation of the dienone chromophore of the grisedienone (401) causes either concerted or radical ring opening to pairs of stereoisomeric dienylketenes. One member of each pair can undergo a thermal intramolecular va + tts cyclization to yield a /3-lactone subsequent loss of C02 would yield the products. 

Allyloxy)iodoarenes react with Sml2 to yield radical anions, which undergo thermal fragmentation. The resulting aryl radicals can cyclize to dihydrobenzofurans (Entries 8-10, Table 15.9). The radical obtained after cyclization can be reduced and treated with a proton source such as water or an alcohol to yield alkanes, or with carbonyl compounds to yield alcohols (Entry 10, Table 15.9). 

The highly strained double bond in methylenecyclopropane displays enhanced reactivity in cycloaddition reactions. In addition to normal [4+2] cycloaddition to 1,3-dienes (e.g. equation 13)32, methylenecyclopropane and its derivatives have a pronounced tendency to undergo thermal [2+2] cycloaddition reactions. For example, thermal dimerization of methylenecyclopropane in the gas phase results in formation of isomeric dispirooctanes 16 and 17 (equation 14)33. This unusual cyclization is considered to proceed via a stepwise radical mechanism involving the intermediacy of biradical 18 (equation 15)34. Equation 15 demonstrates that methylenecyclopropanes possessing substituents capable of stabilizing intermediate radicals undergo efficient [2+2] dimerization even... 

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