Cyclizations mechanistic studies

Detailed mechanistic studies by Fodor demonstrated the intermediacy of both imidoyl chlorides (6) and nitrilium salts (7) in Bischler-Napieralski reactions promoted by a variety of reagents such as PCI5, POCI3, and SOCh)/ For example, amide 1 reacts with POCI3 to afford imidoyl chloride 6. Upon heating, intermediate 6 is converted to nitrilium salt 7, which undergoes intramolecular electrophilic aromatic substitution to afford the dihydroisoquinoline 2. Fodor s studies showed that the imidoyl chloride and nitrilium salt intermediates could be generated under mild conditions and characterized spectroscopically. Fodor also found that the cyclization of the imidoyl chlorides is accelerated by the addition of Lewis acids (SnCU, ZnCh), which provides further evidence to support the intermediacy of nitrilium salts. ... 

Bischler has suggested that anilines undergo 1,4-addition followed by dehydration which would explain the inherent regioselectivity. Mechanistic studies suggest that the reaction involves the reversible formation of diazetidinium ions 7 and there irreversible cyclization to quinolines. ... 

A proposed simplified mechanism for the conjugate addition/aldol cyclization, as depicted in Scheme 2.25, is based on detailed mechanistic studies performed on related Rh-catalyzed enone conjugate additions [45]. A model accounting for the observed relative stereochemistry invokes the intermediacy of a (Z)-enolate and a Zimmerman-Traxler-type transition state as shown in 2-110 to give 2-111. 

The Nazarov cyclization of vinyl aryl ketones involves a disruption of the aromaticity, and therefore, the activation barrier is significantly higher than that of the divinyl ketones. Not surprisingly, the Lewis acid-catalyzed protocols [30] resulted only in decomposition to the enone derived from 46,47, and CO. Pleasingly, however, photolysis [31] readily delivered the desired annulation product 48 in 60 % yield. The photo-Nazarov cyclization reaction of aryl vinyl ketones was first reported by Smith and Agosta. Subsequent mechanistic studies by Leitich and Schaffner revealed the reaction mechanism to be a thermal electrocyclization induced by photolytic enone isomerization. The mildness of these reaction conditions and the selective activation of the enone functional group were key to the success of this reaction. 

Mechanistic studies of the nickel-catalyzed cyclization of butadiene have been carried out. The formation of various cyclic compounds catalyzed by nickel complexes is explained via the intermediacy of ir-allylic nickel complexes 11 and 12. 

Widenhoefer has also disclosed an interesting extension consisting of hydrosilylative cyclization of a diene catalyzed by palladium. High enantioselectivity (up to 95% ee) was achieved by using palladium catalysts with Ci-symmetric pyridine-oxazoline ligands351,364 and recent mechanistic studies have confirmed the involvement of an intramolecular carbometallation step.365... 

Catalytic cycles involving both alkyne hydrorhodation and silylrhodation are proposed.613 However, mechanistic studies performed on related hydrogen-mediated enyne reductive cyclizations (vide supra) suggest oxidative cyclization of the enyne followed by hydrosilylytic cleavage of the resulting metallacycle via cr-bond metathesis is also plausible (Scheme 27). 

Although detailed mechanistic studies are not reported, the postulated mechanism for the reductive cyclization of allenic carbonyl compounds involves entry into the catalytic cycle via silane oxidative addition. Allene silylrhodation then provides the cr-allylrhodium hydride A-18, which upon carbometallation of the appendant aldehyde gives rise to rhodium alkoxide B-14. Oxygen-hydrogen reductive elimination furnishes the hydrosilylation-cyclization product... 

Early mechanistic studies have indicated that the oxypalladation step in the Wacker process proceeds through an <37z/z-pathway,399 although recent deuterium-labeling experiments have shown the viability of a yy/z-mechanism involving insertion of a metal-coordinated oxygen into the alkene.400,401 For example, with excess chloride ion present, the Wacker-type cyclization of a deuterated phenol system occurred in a primarily //-pathway, whereas the oxypalladation step favored a yy/z-mode in the absence of excess chloride ion (Scheme 16). Thus, either mechanism may be operative under a given set of experimental conditions. 

The above intramolecular diene cyclizations are likely to proceed through a similar set of reactions as shown in Scheme 6.2 for the intermolecular variants. Thus, as depicted in Scheme 6.6, formation of the zirconacyclopropane at the less hindered terminal alkene (—> ii), generation of the tricyclic intermediate iii, Zr—Mg exchange through the intermediacy of zirconate iy and 3-H abstraction and Mg alkoxide elimination in v may lead to the formation of the observed product. Additional kinetic and mechanistic studies are required before a more detailed hypothesis can be put forward. 

Many of the allenic parent systems mentioned in Schemes 5.1-5.3 have been of interest in mechanistic studies. Thus, the Z-isomer of 27 can either cyclize by the Myers-Saito route to the aromatic diradical 339 or under the so-called Schmittel cyclization conditions to yield the fulvene diradical 338 (Scheme 5.51) [141], both processes being discussed thoroughly in Chapters 13 and 20. 

The reductive cyclization of readily available enol phosphates of 1,3-dicarbonyl compounds bearing pendant olefinic units has been explored [66,67]. The chemistry is exceptionally interesting, and provides a unique route to structures possessing a cyclopropyl unit which is suitable for structural elaboration. The reaction occurs in a manner wherein the phosphate-bearing carbon behaves like a carbene that adds to the pendant alkene to form a cyclopropane. While this provides a useful way of viewing the transformation, mechanistic studies indicate that a carbene is not an actual intermediate. Examples are portrayed in Table 11. 

The experimental mechanistic study of the anodic cyclization reactions requires values for the variation of the peak potential (Ep) in LSV with the sweep rate (v), the concentration of substrate (C) and the concentration of added base (B). The plots of dEp/dlogv, dEp/dlogC, and dEp/dlogB provide an effective tool for qualitative mechanistic analysis. The diagnostic criteria developed for discrimination between the various possible mechanisms [5] and adopted for oxidative cyclizations are presented in Table 1. 

A detailed mechanistic study of acid-catalysed monocyclization of 5,6-unsaturated epoxides, such as (66), has now provided compelling evidence for a pathway in which the oxirane C—O cleavage and the C—C bond formation are concerted. These experimental results are now further supported by theoretical evidence for a concerted mechanism of the oxirane cleavage and A-ring formation in epoxysqualene cyclisation, obtained at the RHF/6-31G and B3LYP/6-31 + G levels. The chemical pathway thus parallels the mechanism of the enzymatic cyclization that plays a role in the biosynthesis of isoprenoids. 

Scheme 33 Mechanistic studies on the PET-sensitized cyclization of geraniol.

For mechanistic studies of the rhodium-catalyzed cyclization of 4-alkenals to cyclopen-tanones, see (a) Campbell, R. E., Jr. ... 

For preliminary mechanistic studies of the rhodium-catalyzed cyclization of 4-alkynals... 

Most mechanistic studies " have utilized lV,Al-diphenylmethyl-amine. With this substrate in the absence of oxygen, photochemical cyclization to the observable 312 (R = H, R = Me) is followed by disproportionation to the carbazole and to a tetrahydrocarbazole believed to be... 

Avalos et al. (223,224) also found that simpler 2-aminothioisomiinchnones react with nitroalkenes to give dihydrothiophenes and other products, work that includes detailed MO calculations that rationalize both the reactivity of the thioisomilnch-nones and the observed regioselectivity (224). These same thioisomtinchnones (324) react with aryl aldehydes to provide p-lactams 325 following fragmentation and subsequent cyclization of the primary cycloadducts (225). Novel 1,2,4-triazines are produced when 324 is exposed to diethyl azodicarboxylate (226), and detailed synthetic and mechanistic studies have been reported for the reactions of 324 with alkynes (227) and chiral 1,2-diaza-l,3-butadienes (228). 

Figure 4.3. Design of a radical probe mechanistic study. Formation of the rearranged product implicates the intermediate 5-hexenyl radical that cyclized to cyclopentylmethyl.

Interestingly, it was also found that A -acetyl-A -arylnitrenium ions cyclize to form protonated benzoxazole derivatives (34). This reaction was found to have barriers of 4-11 kcal/mol in the gas phase. Although this finding has yet to be verified experimentally, it is significant in view of the fact that these nitrenium ions are frequently used in mechanistic studies of DNA damage. 

In a few cases, detailed mechanistic studies have shown that the cyclization step is rate limiting. 6-7 One method has been to demonstrate that the overall rate of reaction is a function of the nucleophilicity of the ZR group or of the formed ring size.5-6 However, the cyclization step need not be the rate-limiting step in all electrophilic heteroatom cyclizations.8 The uncertainty about which step is rate limiting complicates attempts to derive general rationales for predicting the stereochemical results of these reactions. 

However, Samsel and Kochi concluded from a detailed mechanistic study that a chain mechanism analogous to group transfer (rather than radical-cobalt coupling) was operative in the cyclization of hexenylcobalt compounds to cyclopentylmethyl isomers. E. G. Samsel and J. K. Kochi, J. Am. Chem. Soc., 1986,108, 4790. 

Hexenyl radical cyclizations are typically more rapid than higher homologs, and, unlike lower homologs, they are irreversible. Therefore, they are the most generally useful class of radical cyclizations. Thanks to intensive mechanistic study, they are also the most well understood. 

Several recent examples of metal-promoted cyclizations of perchlorocarbonyl compounds are presented in Scheme 28, and a full paper by Weinreb is recommended as an excellent source of references to prior work in this area (including mechanistic studies on the role of the metal).127 The first two examples illustrate that the choice of substrates can dictate the types of products that are formed the initially formed y-chloro esters are stable to subsequent ionic reactions, but the ris-y-chloro acids form lactones. Interestingly, Weinreb has shown that the metal can equilibrate the cis- and /rans-y-chloro esters by reversible chlorine atom transfer. The third example128 illustrates a general feature of the atom transfer method yields at high concentration are comparable to (and sometimes better than) those provided by using tin hydride at low concentrations. Indeed, in the third example, the three chlorines on the ester provided three opportunities for cyclization during the tin hydride reduction, but 40% of the product still failed to cyclize. (Unfortunately, the tin hydride concentration was not specified.)... 

Detailed mechanistic study on these intramolecular hydrosilylation of allylic O-silyl ethers 59 and allylic A -silylamincs 63 using deuterium labeling techniques shows that 5-endo cyclization giving 60 or 64 proceeds via a Chalk-Harrod type hydrometalation catalytic cycle, while 4-exo cyclization process yielding 61 or 65 includes a Seitz-Wrighton type silylmetalation mechanism89. 

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