Metalloenediynes:  Ligand Field Control of Thermal Bergman Cyclization Reactions

Abstract

We report the preparation and thermal reactivities of unique Cu(I) and Cu(II) metalloenediyne complexes of the flexible 1,8-bis(pyridine-3-oxy)oct-4-ene-2,6-diyne ligand (bpod, 1). The thermal reactivities of these metalloenediynes are intimately modulated by metal oxidation state. Using differential scanning calorimetry (DSC), we demonstrate that the [Cu(bpod) 2 ] + complex (2) undergoes Bergman cyclization at 203 °C, whereas the Cu(II) analogue ( 3) is substantially more reactive and cyclizes at 121 °C. Similar results are also observed for mixed ligand [Cu(bpod)(pyridine) 2 ] +/2+ analogues 4 (194 °C) and 5 (116 °C), suggesting that both complexes of a given oxidation state have comparable structures. The Cu(bpod)Cl 2 compound (6) exhibits a cyclization temperature (152 °C) midway between the those of Cu(I) and Cu(II) complexes, which can be explained by the propensity for cis-CuN 2 Cl 2 structures to exhibit dihedral angle distortion. The oxidationstate-dependent thermal reactivity is unprecedented and reflects the influence of the ligand field geometry on the barrier to enediyne cyclization. On the basis of X-ray structures of Cu(pyridine) 4 + complexes, 2 and 4 are proposed to be tetrahedral. In contrast, the electronic absorption spectra of 3 and 5 each show a broad envelope that can be Gaussian resolved into three ligand field transitions characteristic of a Cu(II) center in a tetragonaloctahedral environment. This structural assignment is confirmed by the EPR spin Hamiltonian parameters (g | /A | (cm) ) 134 (3), 138 ( 5)) and is consistent with crystallographically characterized Cu(pyridine) 4 X 2 structures. Molecular mechanics calculations have independently derived comparable tetrahedral and tetragonal structures for 2 and 3, respectively, and determined the average alkyne termini separation to be 〈a〉 ) 4.0 Å for 2 and 3.6 Å for 3. Thus, the tetrahedral geometries of the copper centers in 2 and 4 increase the distance between alkyne termini relative to the tetragonal Cu(II) geometries of 3 and 5, and are therefore responsible for the increase in the thermal cyclization temperatures. The DSC and spectroscopic data for 6 support these conclusions, as the latter suggests a distorted four-coordinate structure in the solid state, and a six-coordinate geometry in solution, which gives rise to an intermediate Bergman cyclization temperature. Overall, our results emphasize the utility of newly emerging metalloenediyne complexes for controlling thermal Bergman cyclization reactions and provide insights into designing novel, pharmacologically useful metalloenediyne compounds.

Unique Metal‐Diyne, ‐Enyne, and ‐Enediyne Complexes: Part of the Remarkably Diverse World of Metal‐Alkyne Chemistry

“…Subsequent complexation with Cu(II) or Zn(II) generates macrocyclic complexes that exhibit cyclization temperatures by DSC, which are sensitive to the structure of metal site. The more rigid macrocyles containing Cu(II) or Zn(II) tend toward more planar-tetragonal structures based on correlation to previous studies (552,553) and undergo reaction between 120 and 140 C in the solid state. As the size of the macrocle increases, the Zn(II) derivative adopts a more distorted geometry, increasing the cyclization temperature to $160 C, while the Cu(II) structure remains planar-tetragonal.…”

“…29). Despite the apparent clarity of mechanism, the Buchwald study reported one negative result; the Hg 2þ compound did not The notion that metal geometry could be responsible for the disparate reactivities of the tetrahedral d 10 Hg 2þ versus square-planar d 8 Pd 2þ and Pt 2þ compounds was presented and demonstrated in four subsequent studies; two involving the 1,2-bis(diphenylphosphinoethynyl)benzene enediyne ligand with various d 10 metals (550,551), and two describing a previously unreported bis(pyridyl) enediyne where the bond between the two rings (e.g., Scheme 86) was removed to allow for enhanced conformational flexibility and response to changes in metal geometry (552,553). The bis(pyridyl) enediyne analogues also show a pronounced reactivity based on the geometry of the metal.…”

Vinylic tellurides as precursors in a stereoselective and convergent route to Z-enynes and Z-trisubstituted enediynes

“…10 In addition, Z-enediyne systems can be used in the synthesis of aromatic compounds via a Bergmann cyclization, especially when the reaction is promoted by transition metal complexes. 11 The advantage of the method proposed by us consists in the easy access to differently substituted Z-enediynes by the apropriate combination of the R group of the vinylic telluride and the R 1 group of the bromo-alkyne. Application of the above experimental conditions to the coupling of Z-telluroenynes and bromoacetylenes led to the Z-enediynes in good isolated yields ( Table 2).…”

Geometric and Electronic Control of Thermal Bergman Cyclization

“…Although the temperature decrease is modest, it is consistent with trends observed in other metal binding enediyne ligands as a function of ligand rigidity. 88,119,122 The Cu(II) complex of tact1:1, 88, exhibits a Bergman cyclization temperature of 121°C. The cyclization temperature is nearly identical to those reported for other [Cu(N) 4 ] 2+ metalloenediyne constructs whose tetragonal X···Cu(N 4 )···X structures have been characterized by EPR, ligand field region electronic absorption spectroscopy, and molecular mechanics calculations.…”