6-exo cyclization

Formation of five-membered heterocycles through radical methodologies has been investigated extensively. Inter-, intramolecular, and cascade reactions have been reported for the synthesis of heterocycles. In the case of intramolecular cyclizations, 5-exo pathway is the preferred mode of reactivity. Rate constant for the formation of pyrrolidine by radical ring closure has been reported [95AJC2047],... 

After the reaction reached completion, the solid product was filtered off and identified by NMR spectroscopy and X-ray crystallography. By analyzing the data, the unexpected formation of amide product 40 from benzaldehyde 37C and its corresponding intermediate 39C was revealed. This represented a new transformation pathway, for which only a few related systems have been reported [58-60]. Scheme 14 displays the proposed mechanistic formation of amide product 40, supported by density functional theory (DFT) calculations [61]. In the presence of triethylamine as catalyst, the key intermediate 39C was formed from nitroaldol (Henry) reaction of 2-cyanobenzaldehyde 37C and nitroethane 38. The nitroaldol adduct 39C then underwent internal cyclization (5-exo-dig) to give iminolactone 41,... 

Aside from 8, 7, 6-endo, and 8, 7, 6-exo Heck cyclizations, 5-exo Heck cyclization is also feasible, although 5-endo cyclization is not favored. Kurihara et al. revealed a 5-exo Heck cyclization in their synthesis of the indole analog of magallanesine [IOS]. As depicted in Scheme 39, 5-exo Heck cyclization converted substrate 224 into 225, the indole analog of magallanesine (226) in 28% yield. The intermediate of the vinylic substitution was a palladium enolate, which underwent a syn 3-hydride elimination after isomerization. 

It is important to note here that both of the 5-exo radical cyclizations (133—>132—>131, Scheme 27) must proceed in a cis fashion the transition state leading to a strained mms-fused bicy-clo[3.3.0]octane does not permit efficient overlap between the singly occupied molecular orbital (SOMO) of the radical and the lowest unoccupied molecular orbital (LUMO) of the alkene. The relative orientation of the two side chains in the monocyclic radical precursor 134 is thus very significant because it dictates the relationship between the two outer rings (i. e. syn or anti) in the tricyclic product. The cis-anti-cis ring fusion stereochemistry of hirsutene would arise naturally from a cyclization precursor with trans-disposed side chain appendages (see 134). 

Cram s open-chain model 229 Cram s rule 229, 233 Cram chelate model 229 Cram cyclic model 229 Cram-Felkin-Anh model 191,207, 236 f 246 cubane 12,318 cyanoacetic acid 636 f. cyanohydrin, protected 145, 150 f. cyclic carbonate protection 541 f., 657, 659 f., 666, 670 cyclization -,6-endo 734 -, 5-exo 733 f. 

Similar 5-exo cyclization procedures have been widely utilized by Evans in his total syntheses of complex natural compounds, such as the synthesis of ionomycin [12a] and polyether antibiotic X-206 [12b]. A 5-exo cyclization of a y-epoxy alcohol has also been observed under basic conditions [12c]. 

The procedure described above may be used for the generation and 5-exo cyclization of a variety of substituted 5-hexenyllithiums and, with appropriate modification, provides a general route to a variety of other olefinic7 and acetylenic8 organolithiums that cyclize upon warming.9... 

It should also be noted that the 5-exo-trig cyclization of achiral olefinic organolithiums has been found to proceed enantioselectively when conducted in the presence of a chiral ligand that serves to render the lithium atom stereogenic. Thus, for example, R) 1 -allyl-3-methylindolinc has been prepared in 86 % ee by cyclization of an achiral aryllithium in the presence of an equivalent of (-)-sparteine.15... 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic... 

Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two examples are shown in Reaction (80), where treatment of 100 with E3B, air, and (TMS)3SiH provided the tricycle 101 in excellent yields as a single diastereomer. Interestingly, the bulky silyl ether moiety is not required to achieve stereoselectivity in this process. 

With 6-alkenoic acids the intermediate radical partially cyclizes to a cyclopentyl-methyl radical in a 5-exo-trig cycHzation [139] (Eq. 6) [138 a, 140] (see also chap. 6). To prevent double bond migration with enoic acids the electrolyte has to be hindered to become alkaline by using a mercury cathode. Z-4-Enoic acids partially isomerize to -configurated products. Results from methyl and deuterium labelled carboxylic acids support an isomerization by way of a reversible ring closure to cyclopropyl-carbinyl radicals. The double bonds of Z-N-enoic acids with N > 5 fully retain their configuration [140]. 

When free radicals are added to 1,5- or 1,6-dienes, the initially formed radical (9) can add intramolecularly to the other bond, leading to a cyclic product (10). When the radical is generated from an precursor that gives vinyl radical 11, however, cyclization leads to 12, which is in equilibrium with cyclopropylcarbinyl radical 13 via a 5-exo-trig reaction. A 6-endo-trig reaction leads to 14, but unless there are perturbing substituent effects, however, cyclopropanation should be the major process. 

Scheme 1 5-exo Cyclization initiated by phosphinyl radical addition onto an alkyne... 

For 4-alkynylamines, IH in the presence of PdCl2(MeCN)2 proceeds by two competitive processes a major 5-Exo-Dig cyclization and a minor 6-Endo-Dig one (Eq. 4.70) [278]. 

An analogous catalytic system has been applied to the IH of y- and 5-allenic amines which cyclize smoothly in the 5-Exo-Trig or 6-Exo-Trig mode, giving vinylpyrrolidines and vinylpiperidines, respectively (Eq. 4.92) [313]. 

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