Aminyl-radical cyclization

The attacking radical need not always be at carbon. Amidyl radical are known and give cyclization reactions. Aminyl radical cyclizations have been reported. Oxygen radical can be generated under photochemical conditions, and they add to alkenes in a normal manner. ... 

The slow rate of cyclization and the unfavorable equilibrium may cause problems for aminyl radical cyclizations. However, most chain substituents should accelerate such cyclizations, and in so doing, shift... 

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-... 

Isomerization of free radicals, in particular, cyclization of aminyl radicals, cyclization and decyclization of oxygen-containing radicals, and decomposition of peroxyalkyl radicals to give epoxides 04UK1181. 

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)... 

An efficient methodology for the construction of pyrrolizidines and other polycyclic nitrogen heterocycles using a radical domino sequence has been revealed by Bowman and coworkers [46]. These authors employed sulfenamides as substrates, which easily form aminyl radicals by treatment with tributyltin hydride and AIBN. For instance, 3-101 smoothly underwent a twofold 5-exo-trig cyclization to give the tetracyclic pyrrolizidine product 3-105 in 90% yield (Scheme 3.26). As intermediates, the radicals 3-102 to 3-104 can be assumed. 

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

New cyclizations via photochemically generated aminyl radicals have been reported, including further examples of the Hofmann-Loeffler-Freytag reaction.313 Intramolecular addition of an aminyl radical, generated by photochemically induced nitrogen chlorine bond homoysis, is also accompanied by cyclization as illustrated by the conversion of the unsaturated N-chloroamide 378 to the pyrrolidine 379.314 Piperidine formation can also... 

Treatment of 329, the A-butyl-A-4-pentenyl analogue of 327, with trifluoroacetic acid and r-butylthiolate radicals (from r-butylthiol) under irradiation with visible light gives the aminyl radical 330, which cyclizes to the pyrrolidine 331 and a r-butylthiolate radical is regenerated (equation 115). It is believed that the process involves, at least partially,... 

A S-exo-trig cyclization of the metalated aminyl radical provided pyrrolidine (123) as a single isomer in a 53% yield. A routine series of transformations converted it to the target structure (124). 

Neutral aminyl radicals generated by anodic oxidation of lithium alkenyl amides undergo a stereoselective cyclization to cis-l-methyl-2,5-disubstituted pyrrolidines [249]. 

In contrast to the large body of kinetic data that is available on hexenyl radical cyclizations, relatively little is known about the cyclizations of azahexenyl analogs. Only very recently have the detailed studies of Newcomb permitted a complete analysis of a useful parent cyclization.173 As illustrated in equation (6), aminyl radical (55) cyclizes to (56) with a rate constant of about 3 x 103 s 1, but (56) reverts to (55) with a slightly greater rate constant of 7 x 103 s 1. That the cyclization of (55) is very slow, and that (55) is actually slightly preferred at equilibrium over (56), can be understood in terms of the above explanations for N—H bond strengths. 

To facilitate the cyclizations of nitrogen-centered radicals, one need only increase the electronegativity at nitrogen. This makes the radical more electrophilic (which accelerates the cyclization), and strengthens the forming bonds (which shifts the equilibrium to the cyclic product). Amminium radical cations are more well-behaved in cyclizations than aminyl radicals, and these radical cations can either be formed directly from ammonium salts, or by protonation of aminyl radicals (which are relatively weak bases and require strong acids for protonation). Metal-complexed aminyl radicals are highly reactive, and amidyl radicals are also useful.178... 

In contrast to aminyl radicals, alkoxyl (and acyloxy) radicals are highly reactive. As illustrated in equation (7), their cyclization reactions are extremely rapid and irreversible. However, the rapidity of such cyclizations does not guarantee success because alkoxyl radicals are also reactive in inter- and intramolecular hydrogen abstractions, and -fragmentations (see Section 4.2.S.2). This lack of selectivity may limit the use of alkoxyl radicals in cyclizations, but S-exo cyclizations are so rapid that they should succeed in many cases, and other types of cyclizations may also be possible. 

Halogenated purines. 8BrdAdo has been used to study some of the steps in the cyclization reaction that yields the purine cyclonucleosides/tides (Flyunt et al. 2000 Chatgilialoglu et al. 2003). Upon the reaction of eaq, the very reactive vinylic radical at C(8) is formed [reaction (238) k= 1.6 x 10 dm3 mol-1 s 1] which undergoes rapid H-abstraction from the hydroxymethyl group at C(5 ) [reaction (239)]. In neither of these reactions are radicals formed which strongly absorb in the accessible UV/Vis range. Upon addition of the C(5 ) radical to C(8) [reaction (239) k = 1.6 x 105 s-1], an aminyl radical is formed whose UV/Vis spectrum is... 

The electronic nature of a nitrogen centered radical, dictated by reaction conditions and/or the radical precursor employed, is crucial to the mode of reaction, to the ability to undergo efficient intramolecular cyclizations or intermolecular additions, and to the products isolated from the radical reaction. The types of radicals discussed in this review include neutral aminyl radicals, protonated aminyl radicals (aminium cation radicals), metal complexed aminyl radicals, and amidyl radicals. Sulfonamidyl and urethanyl radicals are known (71S1 78T3241), but they are not within the scope of this chapter. 

Intramolecular cyclizations of alkenylaminyl radicals produced from tetrazenes have been reported. The regioselectivity of cyclizations of aminyl radicals derived from N-3-butenyltetrazene (1), A-4-pentenyl tetrazene (2), and JV-5-hexenyl tetrazene (3) have been studied (78MI1). The position of the alkene moiety is important because other reaction pathways can compete with cyclization. 

The cyclization of aminyl radical 5, produced by decomposition of tetrazene 4 (Scheme 1), was investigated, and products were analyzed by GC/MS comparisons to authentic materials. The results are summarized in Table 1 (83JA7759). It is important to note that no piperidine products were detected and that a 1 1 ratio of cyclic-to-acylic disproportionation... 

Aminyl radicals also can be generated via electrochemical oxidation of amide bases or O-substituted hydroxylamines. Suginome has studied radical cyclizations involving oxidations of lithium alkenylamides as a route to ccs-l-methyl-2,5-disubstituted pyrrolidines (85TL6085). Electrolysis of lithium alkenylamide 17a, generated from the amine and butyllithium at - 78°C, led to the formation of 18a, exclusively cis, in 52% yield (Scheme 4). The reactions require 0.25 M UC104 in THF HMPA (30 1) as the supporting electrolyte. A variety of 2-substituted amines were studied. 

Cyclization of electrochemically generated aminyl radicals is more efficient when the species contains a phenyl-substituted double bond. Evidently, this facilitates cyclization relative to other reactions, and good yields of 5-unsubstituted, 5-alkyl, and 5-aryl-2-benzylpyrrolidines were obtained (Table II, entries 4-6) (91T747). Moderate yields of 4-substituted-2-benzylpyrrolidines also were obtained (entries 7-8). Again, the stereoselectivity was excellent for R2 = Ph, but it was only 3 1 for R2 = CHV... 

The apparent dichotomy between good yields of pyrrolidine products from anodic oxidation of lithium alkenylamides and the generally low reactivity of neutral aminyl radicals toward cyclization might be explained by the presence of lithium cations in the electrochemical reactions. The lithium cation has been shown to act as a Lewis acid in promoting aminyl... 

The rate constants determined in the kinetic studies described above were derived from relative rate constants. The rate constant for N-propylcyclobutylaminyl radical ring opening is the only absolute rate constant known for an aminyl radical. It is possible that this rate constant is only a minimum value and may be in error by up to a factor of 10. The rate constant for H-atom transfer from hydrogen donors to aminyl radicals and those for cyclization and ring opening of aminyl radicals all bear the uncertainty of this initial value. However, the ratios of rate constants... 

---