Rana K. Mohamed

Concerted Reactions That Produce Diradicals and Zwitterions: Electronic, Steric, Conformational, and Kinetic Control of Cycloaromatization Processes

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.

Polyaromatic ribbon/benzofuran fusion via consecutive endo cyclizations of enediynes.

The Sonogashira/5-endo-dig/6-endo-dig cascade fuses a polycyclic aromatic backbone to the electron-rich furan subunit. The transformation proceeds in modest yields as a one-pot reaction. Efficiency of the full cascade is increased by removal of base prior to the addition of gold catalyst. Under these conditions, conversion to the full cascade products is achieved in nearly quantitative yields without purification of the intermediate products. Extension of the cascade toward triynes opens access to benzofuran-fused chrysene derivatives.

Alkenes as alkyne equivalents in radical cascades terminated by fragmentations: overcoming stereoelectronic restrictions on ring expansions for the preparation of expanded polyaromatics.

Chemoselective interaction of aromatic enynes with Bu3Sn radicals can be harnessed for selective cascade transformations, yielding either Sn-substituted naphthalenes or Sn-indenes. Depending on the substitution at the alkene terminus, the initial regioselective 5-exo-trig cyclizations can be intercepted at the 5-exo stage via either hydrogen atom abstraction or C-S bond scission or allowed to proceed further to the formal 6-endo products via homoallylic ring expansion. Aromatization of the latter occurs via β-C-C bond scission, which is facilitated by 2c,3e through-bond interactions, a new stereoelectronic effect in radical chemistry. The combination of formal 6-endo-trig cyclization with stereoelectronically optimized fragmentation allows the use of alkenes as synthetic equivalents of alkynes and opens a convenient route to α-Sn-substituted naphthalenes, a unique launching platform for the preparation of extended polyaromatics.

Drawing from a Pool of Radicals for the Design of Selective Enyne Cyclizations

Despite the possibility of intermolecular attack at four different locations, the Bu3Sn-mediated radical cyclization of aromatic enynes is surprisingly selective. The observed reaction path originates from the least stable of the equilibrating pool of isomeric radicals produced by intermolecular Bu3Sn attack at the π-bonds of substrates. The radical pool components are kinetically self-sorted via 5-exo-trig closure, the fastest of the four possible cyclizations. The resulting Sn-substituted indenes are capable of further transformations in reactions with electrophiles.

The Missing C1–C5 Cycloaromatization Reaction: Triplet State Antiaromaticity Relief and Self-Terminating Photorelease of Formaldehyde for Synthesis of Fulvenes from Enynes

The last missing example of the four archetypical cycloaromatizations of enediynes and enynes was discovered by combining a twisted alkene excited state with a new self-terminating path for intramolecular conversion of diradicals into closed-shell products. Photoexcitation of aromatic enynes to a twisted alkene triplet state creates a unique stereoelectronic situation, which is facilitated by the relief of excited state antiaromaticity of the benzene ring. This enables the usually unfavorable 5-endo-trig cyclization and merges it with 5-exo-dig closure. The 1,4-diradical product of the C1-C5 cyclization undergoes internal H atom transfer that is coupled with the fragmentation of an exocyclic C-C bond. This sequence provides efficient access to benzofulvenes from enynes and expands the utility of self-terminating aromatizing enyne cascades to photochemical reactions. The key feature of this self-terminating reaction is that, despite the involvement of radical species in the key cyclization step, no external radical sources or quenchers are needed to provide the products. In these cascades, both radical centers are formed transiently and converted to the closed-shell products via intramolecular H-transfer and C-C bond fragmentation. Furthermore, incorporating C-C bond cleavage into the photochemical self-terminating cyclizations of enynes opens a new way for the use of alkenes as alkyne equivalents in organic synthesis.

The Baldwin rules: revised and extended

The Baldwin rules constitute one of the clearest examples of the success which can be obtained through the application of stereoelectronic concepts to reaction design. With thousands of examples, the predictive power of these rules is inarguable. However, time has revealed a number of exceptions and gray areas within these rules, leading to extensions and revisions. In this review, we will present an overview of how subsequent studies of ring closure have clashed with several of Baldwins predictions, leading to the revision of some classes of ring closure (alkyne cyclizations, electrophilic closures, etc.). We also discuss for which the original rules were vague (epoxides) or absent (promoted cyclizations), and the evidence revealed since Baldwins work that has allowed for a better understanding of these ambiguities. With the concise summation of these amendments, this review aims to present an overview of the understanding of cyclization reactions to date. WIREs Comput Mol Sci 2016, 6:487–514. doi: 10.1002/wcms.1261

Rerouting Radical Cascades: Intercepting the Homoallyl Ring Expansion in Enyne Cyclizations via C–S Scission

The switch from 5-exo- to 6-endo-trig selectivity in the radical cyclization of aromatic enynes was probed via the combination of experimental and computational methods. This transformation occurs by kinetic self-sorting of the mixture of four equilibrating radicals via 5-exo-trig cyclization, followed by homoallyl (3-exo-trig/fragmentation) ring expansion to afford the benzylic radical necessary for the final aromatizing C-C bond fragmentation. The interception of the intermediate 5-exo-trig product via β-scission of a properly positioned weak C-S bond provides direct mechanistic evidence for the 5-exo cyclization/ring expansion sequence. The overall cascade uses alkenes as synthetic equivalents of alkynes for the convenient and mild synthesis of Bu3Sn-functionalized naphthalenes.

Alkynes as Linchpins for the Additive Annulation of Biphenyls: Convergent Construction of Functionalized Fused Helicenes

A new approach to fused helicenes is reported, where varied substituents are readily incorporated in the extended aromatic frame. From the alkynyl precursor, the final helical compounds are obtained under mild conditions in a two-step process, in which the final C-C bond is formed via a photochemical cyclization/ dehydroiodination sequence. The distortion of the π-system from planarity leads to unusual packing in the solid state. Computational analysis reveals that substituent incorporation perturbs geometries and electronic structures of these nonplanar aromatics.

A CO2 Cloak for the Cyanide Dagger

The fleeting stability of the cyanoformate ion formed from CO2 and cyanide has implications for plant enzymology and CO2 sequestration. [Also see Report by Murphy et al.] In the ever-expanding universe of compounds prepared to date, it is remarkable that a two-carbon ion with an apparently simple electronic structure could have eluded structural characterization until now. It is especially notable because this ion is formed from carbon dioxide (CO2) and cyanide (CN−), each with a rich chemical history. On page 75 of this issue, Murphy et al. (1) report trapping the elusive cyanoformate ion as a crystalline salt with a bulky and unreactive cation. Their crystallographic and spectroscopic analysis along with quantum-mechanical calculations reveal a seemingly ordinary carbon-carbon (C−C) bond with the length of ∼1.5 Å, yet cyanoformate balances on the brink of fragmentation in nonpolar environments and its C−C bond breaks in more polar solvents.