Cyclizations of Alkynes: Revisiting Baldwin’s Rules for Ring Closure

Progress in the synthesis and transformations of alkylidenecyclopropanes and alkylidenecyclobutanes.

ion (H in reactions with 1,4-CHD and Cl in reactions Figure 50. Free energy diagram of the electrophilic 5-exo and 6-endo-dig cyclizations of the p-OMe-substituted alkyne diazonium salt calculated at the B3LYP/6-31G(d,p) level with CPCM (water) correction (kcal/mol). Dashed lines correspond to the deprotected substrate where the acyl group is removed. The 6-endo product in the latter case opens to the starting material upon optimization. Scheme 21. Cationic Version of the Myers−Saito Cyclization Isopropanol acts as both a nucleophile and a proton source. Figure 51. Interaction of p-benzyne with halide anions illustrates that zwitterionic cycloaromatization of enediynes is feasible. Scheme 22. Radical Reactivity in Myers−Saito Cyclization of Enyne Allenes in Nonpolar Solvents Chemical Reviews Review dx.doi.org/10.1021/cr4000682 | Chem. Rev. XXXX, XXX, XXX−XXX U with CCl4) proceeds at the σ-center, whereas the delocalized πradical is stabilized and reacts much slower. The pattern of reactivity changes in methanol where benzyl methyl ether is formed as the major product (38%), as expected for a polar pathway. Products expected from the radical pathways (2-phenyl ethanol, 10%, and 1,2-diphenyl ethane, 2%) are formed in small amounts. These experimental observations excluded pathways including slowly equilibrating or nonequilibrating intermediates from the possible mechanistic scenarios. The data suggested that products from both polar and free radical reaction pathways arise either from a single reactive intermediate or from a pair of rapidly equilibrating species. Interestingly, reaction in CD3OH (0.003 M of enyne allene, 100 °C) leads to a complete shift into the ionic mode; methyl-d3 benzyl ether is formed as the only detectable product in 70% yield (Figure 52). To understand this complex mechanistic scenario, Carpenter et al. analyzed the possible roles of diradical, zwitterionic, and cyclic allene forms of α,3-didehydrotoluene in a thorough mechanistic study. The authors pointed out that, due to the absence of direct orbital overlap between the σand π-radical centers, the contribution of zwitterionic resonance to the diradical wave function should be severely diminished. Their computational analysis suggested that the first excited state is zwitterionic but lies 30−40 kcal/mol (with ∼10 kcal/mol possible energy lowering due to the solvent polarity) above the diradical ground state. Because the reaction has zeroth order in methanol, methanol cannot be involved in the rate-limiting step (e.g., in a nucleophile-assisted cyclization). The key kinetic experiment found that ratio of these products changed linearly in response to changes in 1,4-CHD concentration. This result shows that the two methanol-derived products are not formed from a single intermediate. The lack of solvent polarity effects on the observed rates for the disappearance of enyne allene suggests that the partitioning between the diradical and zwitterionic pathways occurs after the rate-determining TS. Because the two paths have to diverge before the system arrives to p-benzyne to explain the above [CHD] effect, the authors interpreted this combination of experimental and computational data in favor of the unusual electronically nonadiabatic reaction in Figure 53. It involves a post-transition state bifurcation between the two alternative paths: one to the ground-state diradical, and the other to the excited-state zwitterion. Thermal reactions that form products in their excited states are rare and usually include reactants that contain either strained systems or weak bonds or both, for example, dioxetanes responsible for the firefly bioluminescence. Direct formation of excited states from a strain-free all-carbon reactant is a remarkable and unusual finding, which deserves a more extensive study. Further evidence for the generality of zwitterionic intermediates in the Myers−Saito reaction was presented by Shibuya and co-workers who reported that such products often dominate under polar conditions. Deuterium-labeling studies confirmed the presence of zwitterionic species in cycloaromatization of enyne allenes with push−pull disubstitution at the terminal carbon. Decarboxylative cycloaromatization of the analogous Arsubstituted enediyne also proceeds via initial base-catalyzed isomerization into enyne allene (Scheme 23). The allene cyclizes in methanol within ∼6 h at 37 °C to give exclusively the ionic products. Reaction in benzene follows the radical routes, which involve either intramolecular (without 1,4-CHD) or intermolecular trapping (with 1,4-CHD) via H-atom transfer. The ketone product can form either via a radical or via an ionic path, but its yield increases in the presence of molecular oxygen at the expense of the classic Myers−Saito product. An example of a zwitterionic product in cycloaromatization of “skipped” (aza)enediynes was reported by Kerwin and coworkers. These compounds rearrange to (aza)enyne allenes Figure 52. Solvent-mediated switch to ionic reactivity in Myers−Saito cyclization of enyne allenes in methanol. Blue and red structures correspond to the ionic and diradical pathways, respectively. Figure 53. Top panel: Diradical/zwitterion resonance in α,3didehydrotoluene would require mixing of states of different symmetry. Bottom panel: The nonadiabatic transition from the ground state PES (S0) of Myers−Saito reaction to the zwitterionic excited state (S1) suggested by Carpenter. Scheme 23. Products Derived from Aryl-Substituted α,3Didehydrotoluenes via Radical (Blue) or Ionic (Red) Pathways Chemical Reviews Review dx.doi.org/10.1021/cr4000682 | Chem. Rev. XXXX, XXX, XXX−XXX V that subsequently cyclized when stored in methanol. Only the products derived from the zwitterionic reaction pathway were detected (Figure 54). This difference from the all-carbon system is either due to the lower H-atom abstracting ability of the N-substituted diradical or due to the an alternative path initiated by methanol addition to the (aza)enyne allene. The significance of the diradical/zwitterion dichotomy expands beyond purely mechanistic aspects. The relatively high polarity of many biological settings often facilitates ionic reactivity. Polar mechanisms were suggested for the formation of products not consistent with simple radical chemistry in natural enediynes. An ionic mechanism was suggested to explain the formation of formal 1:1:1 adduct of thiol, NCS chromophore, and water from holo-NCS (complex of NCS chromophore and its carrier protein).Subsequently, Myers and co-workers revised the product’s structure and suggested an alternative mechanism via the rearrangement of an α,3dehydrotoluene diradical to an α,2-dehydrotoluene diradical (Figure 55). They suggested that nucleophilic epoxide opening in holo-NCS is disfavored by the lack of stabilization from the resulting oxyanion in the hydrophobic pocket of the protein. Instead, the intermolecular nucleophilic attack of the thiol leads to a protonation-assisted nucleophilic ring closure. The α,3-dehydrotoluene product of this transformation undergoes an epoxy “radical clock” ring-opening to give the α,2dehydrotoluene species where the zwitterionic form is stabilized by resonance with the adjacent oxygen. Substitution patterns that stabilize either positive or negative charges (or both) favor the zwitterionic products. In particular, the presence of electronegative elements assists in accommodating the negative charge, thus facilitating the zwitterionic path. There is increasing evidence that in enyne heteroallene, cyclizations proceed via a variety of pathways (diradical, zwitterionic, carbine, as shown in Figure 56). In particular, zwitterionic C2−C7 cyclizations are promoted by acceptors at the exocyclic carbon. For example, the Moore cyclization of enyne ketenes proceeds through a cyclic intermediate, which can often behave as zwitterion because the exocyclic oxygen atom can efficiently accommodate the negative charge (Figure 57). The zwitterions formed in the thermal “C2−C7” cyclization of enyne-isocyanates benefit from delocalization of the negative charge between the exocyclic oxygen and endocyclic nitrogen. However, breaking the relatively strong isocyanate C O bond requires considerably higher temperatures than breaking of the respective CC and CNR bonds in the cyclizations of analogous allenes and keteneimines/carbodiimides. Only in the presence of excess of H-atom donor at 230 °C was the product of formal H-abstraction, 3-phenyl-2(1H)quinoline, produced in 47% along with a small amount of chlorinated compound (Scheme 24). Change from Ph to 2-MeOPh at the alkyne terminus led to benzofuro[3,2-c]quinolin-6(5H)-one in 11% yield and the Nmethylated adduct in 9% yield. The yield of the major product improved to 53% in the presence of 1.1 equiv of dimethylphenylsilyl chloride, which can intercept the oxyanion. Both the Me-group transfer and the dramatic effect of the Figure 54. The zwitterionic cyclization product of aza-enyne allenes is stabilized by endocyclic hyperconjugation and exocyclic π-conjugation. Figure 55. Revised mechanism for formation of formal thiol/water addition product after the holo-NCS activation by a thiol. Figure 56. A variety of cyclization pathways are available to enyne heteroallene due to the effects of incorporated heteroatom. Figure 57. Top: The zwitterionic resonance in the Moore C2−C7 cyclization product. Bottom: Selected products derived from trapping the zwitterionic Moore product formed from substituted enyne ketenes. Scheme 24. “C2−C7” Cyclization of Enyne-isocyanates Proceeds at Relatively High Temperatures Chemical Reviews Review dx.doi.org/10.1021/cr4000682 | Chem. Rev. XXXX, XXX, XXX−XXX W oxyanion trap additive strongly suggest the intermediacy of zwitterionic species (Scheme 25). In a similar way, the formation of pyrrolo quinolones from dimethylamino substituted enyne carbodiimides reported by Wang and co-workers also stems from a polar pathway.

Concerted reactions that produce diradicals and zwitterions: electronic, steric, conformational, and kinetic control of cycloaromatization processes.

Recent advances in sulfur- and phosphorous-centered radical reactions for the formation of S–C and P–C bonds

This work reexamined the stereoelectronic basis for the “favored attack trajectories” regarding the nucleophilic and radical cyclizations of alkynes. In contrast to the original Baldwin rules, the acute attack angle of a nucleophile leading to the proposed endo-dig preference for the formation of small cycles is less favorable stereoelectronically than the alternative obtuse trajectory leading to the formation of exo-dig products. For smaller cycles, this intrinsic stereoelectronic preference can be masked by the greater thermodynamic stability of the less strained endo-products. Unbiased comparison of competing cyclization attacks has been accomplished via dissection of the activation barrier into the intrinsic barrier and thermodynamic component via Marcus theory. Intrinsic barriers of thermoneutral reactions strongly favor exo-dig closures, in full accord with the greater magnitude of two-electron bond forming interactions for the obtuse trajectory. This analysis agrees very well with experimental obse...

Rules for anionic and radical ring closure of alkynes.

Despite being predicted to be stereoelectronically favorable by the Baldwin rules, efficient formation of a C−C bond through a 5-endo-dig radical cyclization remained unknown for more than 40 years This work reports a remarkable increase in the efficiency of this process upon β-Ts substitution, which led to the development of an expedient approach to densely functionalized cyclic 1,3-dienes Good qualitative agreement between the increased efficiency and stereoselectivity for the 5-endo-dig cyclization of Ts-substituted vinyl radicals and the results of density functional theory analysis further confirms the utility of computational methods in the design of new radical processes Although reactions of Br atoms generated through photochemical Ts−Br bond homolysis lead to the formation of cyclic dibromide side products, the yields of target bromosulfones in the photochemically induced reactions can be increased by recycling the dibromide byproduct into the target bromosulfones through a sequence of additio

Jason N. Abrams

Papers

In search of efficient 5-endo-dig cyclization of a carbon-centered radical: 40 years from a prediction to another success for the Baldwin rules.

Palladium(II)-catalyzed enyne cyclization strategies toward the podophyllotoxin ring system