Cyclization pathway

Preparative routes to aziridines and 1-azirines are derived from cycloelimination processes in which one, and sometimes two, bonds are formed directly to the nitrogen atom (Scheme 1). For aziridines these include the two intramolecular cyclization pathways involving either nucleophilic displacement by the amine nitrogen (or nitrenium anion) on the /3-carbon (route a) or nucleophilic displacement by a /3-carbanionic centre on the amine nitrogen... 

To obtain information about the cyclization pathway, an analogous reaction was carried out with phenylhydrazine (in this case, positions 3 and 5 of the forming pyrazole are nonequivalent) (69ZOR1179). The only reaction product (yield 65%) appeared to be l-phenyl-5-methylpyrrazole (108). 

The cyclization pathway proposed (81UK1252) involves nucleophilic substitution of the hetero group (XR) by the formamide amino group to form either enyne formamide 157 or imine 158. 

The decomposition of 2-(2-phenylphenylsulfanyl)benzenesulfonyl chloride (5) at elevated temperatures leads to the formation of tribenzo[6,c/,/]thiepin(6) in 24% yield by an intramolecular cyclization pathway. Mechanistically, this thermolysis is comparable to the Pschorr reaction (cf. Houben-Weyl, Vol. 5/2b, p 420 Vol. 10/3, p 189) however, copper(I) chloride is now preferred as a catalyst, without any solvent.4 In the thermolysis of 5, 4-phenyldibenzothiophene (7) is formed as a byproduct in 14% yield. Octachloronaphthalene can also be employed as a catalyst however, the yield of 6 is somewhat lower (19%).4... 

The photochemically induced conversion of diarylamines into carbazoles is known to proceed via a similar cyclization pathway a dipolar dihydro-... 

Fig. 24 Relative energies for the transition states and radical products for the different cyclization pathways (benzannelated systems in parentheses).

In practice, reduction of 35 (—2.43 V vs SCE) in the presence of 3,5-dimethylphenol as a proton donor, tetra- -butylammonium hexafluorophos-phate as the supporting electrolyte, and DMF as the solvent, led to the y-hydroxy ester 40 and lactone 41 [22]. No sign of any material resulting from cyclization onto the alkene was detected. It was concluded that radical cyclization does not occur in this instance, and that the homogeneous electron transfer rate exceeds that of a 5-exo-trig radical cyclization, thereby implying the operation of either a radical anion or carbanion cyclization pathway. 

Fig. 21 Qualitative depiction of favorable cyclization pathways for representative peroxy radicals of methyl heteroaromatics (top, pyridine and bottom, furan). Cyclization for the alkylated six-membered heteroaromatics is driven by the thermodynamic stability of the resulting ring, while cyclization for the alkylated five-membered heteroaromatics is dictated by which pathway allows the generation of a stable allylic radical system.

A radical cyclization pathway to reduced pyrrolo[2,3-3]pyridines has been reported from 2-bromo-3-(2-aminoethyl)-pyridine and benzophenone in the presence of AIBN and tributyltin hydride (Equation 38) <20010L1009>. Both electron-donating and electron-withdrawing functional groups can be present on the pyridine ring since the radical has its unpaired electron localized in a cr-orbital. 

By contrast, for iodide 18 having the triple bond activated by a phenyl group, conversion to the cyclic organozinc species 25 occurred effectively and the latter could be efficiently functionalized, provided that traces of moisture were excluded by pre-treatment of zinc powder with Mel. The substituted benzylidene cyclopentanes 26 and 27 were respectively obtained after iodinolysis and palladium-catalyzed cross-coupling reaction with benzoyl chloride (equation 10). However, it could not be assessed whether the formation of organozinc 25 was attributable to an anionic or a radical cyclization pathway (or both) as, had iodide 26 been produced by a radical iodine atom-transfer, it would have been converted to 25 by reaction with metallic zinc due to the presence of the activating phenyl group21. 

Scheme 20 Different cyclization pathways of of the ketosulfone to etoricoxib.

A third possible pathway could yield indan through cyclononane intermediate. We know that cyclononane undergoes transannular dehydrocycli-zation over platinum-on-charcoal catalyst at 300°C, to perhydroindan and then to indan (38) but so far there is no evidence for the direct cyclization of n-nonane to cyclononane. Unfortunately, Il in and Usov used an acidic catalyst and we cannot separate the contributions of acid and metal catalysis to the two mechanisms. Experiments over nonacidic platinum catalysts could show the relative importances of the platinum metal in the two cyclization pathways. 

Each of the syntheses of seychellene summarized in Scheme 20 illustrates one of the two important methods for generating vinyl radicals. In the more common method, the cyclization of vinyl bromide (34) provides tricycle (35).93 Because of the strength of sjp- bonds to carbon, the only generally useful precursors of vinyl radicals in this standard tin hydride approach are bromides and iodides. Most vinyl radicals invert rapidly, and therefore the stereochemistry of the radical precursor is not important. The second method, illustrated by the conversion of (36) to (37),94 generates vinyl radicals by the addition of the tin radical to an alkyne.95-98 The overall transformation is a hydrostannylation, but a radical cyclization occurs between the addition of the stannyl radical and the hydrogen transfer. Concentration may be important in these reactions because direct hydrostannylation of die alkyne can compete with cyclization. Stork has demonstrated that the reversibility of the stannyl radical addition step confers great power on this method.93 For example, in the conversion of (38) to (39), the stannyl radical probably adds reversibly to all of the multiple bond sites. However, the radicals that are produced by additions to the alkene, or to the internal carbon of the alkyne, have no favorable cyclization pathways. Thus, all the product (39) derives from addition to the terminal alkyne carbon. Even when cyclic products might be derived from addition to the alkene, followed by cyclization to the alkyne, they often are not found because 0-stannyl alkyl radicals revert to alkenes so rapidly that they do not close. 

Oxidatively generated oxocarbenium ions have been used for intramolecular epoxide activation. Cascade reactions to form oligotetrahydrofuran products that demonstrated a strong preference for the exo-cyclization pathway were achieved in good yields when disubstituted epoxides were used as substrates. High stereoselectivity was observed in these reactions, with complementary diastereomers being formed from diastereomeric (g) epoxides.257... 

Davis (82) compared the conversion of n-octane at 1 atmosphere and 200 psig and found that the metal catalyzed dehycrocyclization selectivity, based upon the distribution of C8-aromatic isomers, was the same at both pressures. Thus, for the Pt or Pt-Sn catalyst the dominant metal catalyzed cyclization pathway to produce aromatics was a 1,6-ring closure provided the support did not have acidity to effect isomerizations. 

Davis (83) later proposed that both 1,5- and 1,6-cyclization pathways occurred with these catalysts however, at atmospheric pressure the 1,5-cyclization pathway led to coking whereas at higher pressures the 1,5-cyclization pathway led to the production of C8 isoalkanes through hydrogenolysis of the cyclopentanes that were formed through 1,5-cyclization. 

Aromatics may be formed by a bifunctional pathway when an acidic alumina support is used. Furthermore, it has been reported that the bifunctional pathway leads to aromatics at least 20 times faster than the metal only pathway (84). In addition, the bifunctional pathway is more selective for aromatics formation than the metal cyclization pathway (84). 

Irradiation of the / -(aryl)ethanesulfonamides 190 in the presence of DAIB-I2 provides access to the dihydrobenzothiazine dioxides 191 and 192 (Scheme 55) (OOJOC926). In these reactions, formation of the thiazine ring by the radical cyclization pathway to give 191 is followed by electrophilic iodination of the arene nucleus to give 192. 

In addition to these two problems in heptenyl radical cycliza-tions, competitive 1,5-hydrogen transfer may occur if there are accessible allylic hydrogens. Furthermore, in pentenyl radical cyclizations the formation of cyclobutane rings is very slow and the reverse reaction is greatly favored, whereas the formation of cyclopentane rings by 5-endo cyclization is disfavored. Therefore, despite the synthetic usefulness of radical cyclization processes, the cyclization pathway is mainly limited to 5-exo cyclization along with the much less efficient 6-exo and 6-endo cyclizations. 

One common way to modify tryptophan residues occurs through the addition of 2-hydroxy-5-nitrobenzyl bromide (HNB). Also known as Koshland s reagent (68), this compound first alkylates the 3-position of the ring and eventually leads to the formation of a product mixture through subsequent intramolecular cyclization pathways. Fig. 6c. This reagent exhibits good tryptophan selectivity, although some levels of... 

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