Aminyl radicals synthesis

Scheme 3.26. Synthesis of pyrrozidine 3-105 by a domino radical cyclization via an aminyl radical.

The copper complexed aminyl radical cyclization has been used as a key step in a short total synthesis of ( )-gephyrotoxin 223AB (60). The alkenyl substituted ALchloropiperidine 59 was stereoselectively cyclized to construct the indolizidine ring system (Scheme 17) (86JOC5043). Tribu-... 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

Illustrative of the chemistry of the aminyl radical is a synthesis of the A -methyl derivative of the antibiotic (—)-anisomycin (73) [20]. It was obtained by treating (E )-5-alkenylamine 71 with -butyllithium at —78°C, followed by anodic oxidation at a constant current (17.5mA/cm") in a 100 1 mixture of tetrahydrofuran (THE) and hexamethyl-phosphor-ous-triamide (HMPA) containing 0.25 M lithium perchlorate at — 10°C. A 5-exo,trig cycli-zation of the metalated aminyl radical afforded pyrrolidine 72 as a single isomer in a 53% yield. A routine series of transformations converted 72 to the target structure 73. 

The history of C-H amination can be traced to the earliest work of Hofmann involving the reactivity of /V-bi omoamines. chemistry later recognized by Loffler and Freytag for its potential to facilitate pyrrolidine synthesis from simple acyclic precursors [11]. The intermediacy of both haloamine and aminyl radical in this stepwise oxidation reaction is now generally accepted, as is the hyper-reactivity of... 

Kim developed a new entry into A -heterocycles by radical cyclizations onto alkyl azides. Iodides, bromides and thionocarbonates (Scheme 28, Eq. 28.1) are suitable radical precursors. 5-Exo cyclizations afford 3,3-triazenyl radicals that lose N2 to furnish an aminyl radical [79]. Following this work, Kilburn has applied this strategy to the formation of spiro-heterocycles from methylenecyclopropanes [80]. Finally, this reaction was applied as a key step in a very elegant cascade synthesis of aspi-dospermidine developed by Murphy (Scheme 28, Eq. 28.2) [81]. 

The jV-chloro-compounds were the first to be employed as radical cyclization precursors in the synthesis of pyrrolidines and piperidines, as well as fused and bridged heterocyclic skeletons [7], Aminyl and amidyl radicals were thus generated and used in intramolecular additions. Higher yields and selectivities are obtained with the metal-complexed species. Some selected examples are reported in Table 4. Generally, a typical radical chain mechanism is involved (with chlorine atom transfer from 7V-chloro-compound). In the particular case of copper-cornplexed aminyl radical cyclization, a redox chain process operates (with fast chlorine ligand transfer from cupric chloride)... 

Much work has been devoted to the synthesis of the pyrrolidine and pyrrolidone systems by free radical methods. For pyrrolidine derivatives it is preferable to initiate the cyclization from an aminyl radical generated from Af-chloro- or N-sulfeny-lamine. - ... 

The indolizidine alkaloid swainsonine 412, a potential anticancer drug, has been the target of a number of syntheses. Pearson [99] started with 2,3-O-isopro-pylidene-D-erythronolactone 413, which afforded in three steps the allyUc alcohol 414. This compound was in turn submitted to Claisen-Johnson rearrangement and afforded ester 415. Selective dihydroxylation followed by functional group manipulations led to the target alkaloid (Scheme 6.68). An aminyl radical cycHza-tion was the key step in an ant venom alkaloid 416 synthesis [100]. The Claisen-Johnson rearrangement was used in the preparation of both side chains of this pyrroUdine alkaloid (Scheme 6.68). 

Similar results have been observed with heteroatomic radicals such as aminyl radical (in an example already discussed in Section VIII.3.A, Scheme 44, and more recently as an important step in the total synthesis of the alkaloid dendrobine ) and with the carboxamidyl radical. The intramolecular addition of thiyl radicals to cyclohexenes generally gives a mixture of the (Cy5) and (Cy6) products. In the same way, intramolecular addition to an unsaturated chain of a thiyl radical on a cyclohexane ring also gives a mixture of (Cy5) and (Cy6) products. This lack of selectivity is in accord with the behavior of unsaturated thiyl radicals discussed in Section VIII.4. An interesting exception of possible relevance to the biosynthetic route to cepham has been discussed in Section VIII.4.B (Scheme 58). The behavior of ethylenic aminothiols such as 107 under free radical initiation (Scheme 52, Section VIII.4.A) has been generalized to compounds such as 267, which affords 268 in 87% yield (Scheme 109). 

Intramolecular addition of aminyl radicals has been more extensively studied in order to obtain azabicyclic compounds. The first report (Scheme 122) was made in 1970 by Heusler, who devised an elegant synthesis of chloroazatwistanes (309) (two epimers in 80% yield) by irradiating the N-chloroamine (308) in trifluoroacetic acid. While he did not propose a mechanism, it appears that the origin of the product 309 is in accord with an... 

However, under suitable conditions, azides react with a variety of radicals and this is the basis of several useful synthetic procedures for the formation of carbon-nitrogen bonds. For instance, synthesis of azides by radical addition of an azidyl radical to alkenes (Scheme 8.3a) and by reaction of an alkyl radical with an azidating reagent (Scheme 8.3b) will be presented. The reduction of azides leading to aminyl radicals (Scheme 8.3c) and the addition of alkyl radicals to alkyl azides (Scheme 8.3d) will also be discussed. 

Beckwith [51] and Bowman [34] have developed the use of sulfenamides as precursors for aminyl and amidyl radicals. Bowman [36, 52, 53] and Newcomb [54] have applied the protocols to the synthesis of a range of nitrogen heterocycles. The best examples are given in Table 5. 

---