Intermediate Intramolecular free radical addition

At the same time, however, Hobson obtained only (Cy5) and no (Cy6) products from JV-chloro-iV-methylhept-4-enamine with silver salts. His conclusion, developed by further work, was that these products may arise from intramolecular free radical addition of aminyl radicals rather than from nitrenium intermediates. 

Detailed n.m.r. studies have been reported on some bicyclic uridine analogues reported last year by Chattopadhyaya s group, formed by intramolecular addition of free radicals to allyl ethers (see Vol. 25, p. 258).i66 The same group have described the preparation of the thymine nucleoside 134 by means of intramolecular free radical trapping by an allyl group tethered by a temporary silicon connection (Scheme 15). Similar sequences were used to make analogous compounds with the three-carbon branch at C-2 in a down position (D-ribo-), and at C-3 in the up orientation, but an attempt to make the compound with the C-2 up stereochemistry led to a tricyclic product after oxidation in which the intermediate bicyclic radical had attacked C-6 of the thymine ring. 167... 

The same group recently disclosed a related free radical process, namely an efficient one-pot sequence comprising a homolytic aromatic substitution followed by an ionic Homer-Wadsworth-Emmons olefination, for the production of a small library of a,/3-unsaturated oxindoles (Scheme 6.164) [311]. Suitable TEMPO-derived alkoxy-amine precursors were exposed to microwave irradiation in N,N-dimethylformam-ide for 2 min to generate an oxindole intermediate via a radical reaction pathway (intramolecular homolytic aromatic substitution). After the addition of potassium tert-butoxide base (1.2 equivalents) and a suitable aromatic aldehyde (10-20 equivalents), the mixture was further exposed to microwave irradiation at 180 °C for 6 min to provide the a,jS-unsaturated oxindoles in moderate to high overall yields. A number of related oxindoles were also prepared via the same one-pot radical/ionic pathway (Scheme 6.164). 

Sml2726 or Zn and MejSiCl,727 and by electrochemical728 and photochemical729 methods. Most of these methods have been used for intramolecular addition and most or all involve free radical intermediates. 

An intramolecular 2-alkylation was also observed in a sulfonyl free radical induced addition-cyclization <95SL763>. A key intermediate in a new synthesis of pallescensin A (a biologically active labdane diterpene) was prepared by a cationic cyclization reaction with a furan <95SYN1141>. The sonochemical Barbier reaction was extended to carboxylate salts. 2-Furanylketones 10 can be obtained by sonication of a mixture of furan, lithium carboxylate, an alkylchloride, and lithium in THF <95JOC8>. 

Many radical cations derived from cyclopropane (or cyclobutane) systems undergo bond formation with nucleophiles, typically neutralizing the positive charge and generating addition products via free-radical intermediates [140, 147). In one sense, these reactions are akin to the well known nucleophilic capture of carbocations, which is the second step of nucleophilic substitution via an Sn 1 mechanism. The capture of cyclopropane radical cations has the special feature that an sp -hybridized carbon center serves as an (intramolecular) leaving group, which changes the reaction, in essence, to a second-order substitution. Whereas the SnI reaction involves two electrons and an empty p-orbital and the Sn2 reaction occurs with redistribution of four electrons, the related radical cation reaction involves three electrons. 

As mentioned in an earlier section in this Report, free-radical carbon-carbon bond-forming processes are becoming increasingly important in synthesis, and this year they have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. Thus, Hart and his group have now applied their intramolecular tin hydride generated ot-acylamino radical to alkyne cyclization [viz. (97) - (98)] and to the synthesis of (-)-dehydrohastanecine (99), (+)-heliotridene (100), and (+)-hastanecine (101). In addition, free radical in mechanism is the photochemical cyclization of the -acylpyrrolidine (102) to the pyrrolizidene (103), a key intermediate in a synthesis of ( )-isoretronecanol (104). 

Likewise, photolysis of 4-pentynyl nitrite (156) (R = H) led Rieke to conclude that the alkoxyl radical (A ) (Scheme 71) did not undergo free radical intramolecular addition. In fact, Dupuy was indeed able to isolate, the y-butyrolactone (157) (although in very low yield), whose formation may be ascribed to the decomposition of a nitrosovinylic CyS intermediate. 

Barton and coworkers used free radical cyclization in the synthesis of tetracyclines (Scheme 105). Photolysis of 254 (X,Y = SR or OR) gives the corresponding radical, which cyclizes to the (Cy6) compound 255 in 80% yield when X,Y = SCH2CH2O. Quite remarkably, 255 is formed only in the cis form. Another completely stereoselective reaction toward the cis compound involving intramolecular addition to an acetylenic bond has been described by Pradhan and was discussed in Section IX.2 (Scheme 70). An analogous reductive cyclization (K, NH3) of ethynyl ketones has been used by Stork in the construction of a tricyclic intermediate for the synthesis of gibberellic acid. ... 

Free radical intramolecular additions, providing as they do an internal trap for the free radical in a fast and selective manner, have been one of the most popular tools used in recent years to demonstrate the occurrence of radical intermediates on the reaction pathway. 

---