Iron(0)‐Mediated Stereoselective (3+2)‐Cycloaddition of Thiochalcones via a Diradical Intermediate

Abstract Reactions of α,β‐unsaturated aromatic thioketones 1 (thiochalcones) with Fe3(CO)12 leading to η4‐1‐thia‐1,3‐diene iron tricarbonyl complexes 2, [FeFe] hydrogenase mimics 3, and the thiopyrane adduct 4 are described. Obtained products have been characterized by X‐ray crystallography and by computational methods. Completely regio‐ and diastereoselective formation of the five‐membered ring system in products 3, containing four stereogenic centers, can be explained by an unprecedented, stepwise (3+2)‐cycloaddition of two thiochalcone molecules mediated by Fe3(CO)12. Quantum chemical calculations aimed at elucidation of the reaction mechanism, suggest that the formal (3+2)‐cycloaddition proceeds via sequential intramolecular radical transfer events upon homolytic cleavage of one carbon‐sulfur bond leading to a diradical intermediate.


.1 General information
Thiochalcones 1a-e were synthesized by treatment of corresponding chalcones with Lawesson's reagent in accordance with established literature procedures starting from the corresponding ketones and aldehydes, [1] triiron dodecarbonyl was prepared from iron pentacarbonyl following a known protocol. [2] Syntheses of complexes 2a-e, 3a-e and 4 were performed under N2 atmosphere by using standard Schlenk technique. Tetrahydrofuran used in all reactions was dried and deoxygenated over Na metal. Solvents used for column chromatography were distilled before the usage. All other solvents as well as commercially available compounds were purchased (Sigma-Aldrich, Acros, TCI, Alfa Aesar, abcr) and used as received without further purification. Geduran Si 60 (0.063-0.200 mm) was used as the stationary phase for column chromatography; TLC monitoring was performed on TLC Silica gel 60 F254.
Decomposition points were determined with APOTEC apparatus and are uncorrected. NMR spectra were recorded with Bruker 600 MHz and 400 MHz spectrometers (Avance III) using dried and deoxygenated CDCl3 as solvent. IR spectra were measured with a Tensor 27 FT-IR spectrometer. DIP-EI mass spectrometry (70 eV) was performed with a Finnigan MAT SSQ 710. Elemental analysis was performed using an Euro Vector EA3000 element analyser. For single crystal X-Ray diffraction a Nonius KappaCCD diffractometer was used.
Cyclic voltammetry for complexes 3a-e was accomplished with a three-electrode setup (working electrode: glassy carbon (d = 1.6 mm); reference electrode: Ag/Ag + in acetonitrile; counter electrode: Pt To ensure oxygen-free conditions, solution and headspace were purged with N2 while opening the system, during the runs only the headspace was purged. The cyclic voltammograms were referenced against the ferrocenium/ferrocene (Fc + /Fc) couple.

Computational details
In order to elucidate the reaction mechanism underlying the selective formation of the cycloadduct (3a), shown in Scheme 2 and Scheme S1, a suite of quantum chemical methods has been utilized. Initially, two rotamers of 1a the E (EA and EB) and the Z (ZA and ZB) isomers of the free thiochalcones (Ar 1 = thiophenyl, Ar 2 = phenyl, see Figure S1) were fully optimized at the DF-HF+DF-MP2 [4] /cc-pVTZ [5] (cc-pVTZ/JKFIT+cc-pVTZ/C) level of theory using PSI4 1.2.1, [6] followed by a vibrational analysis to confirm that a minimum on the 3N-6 dimensional potential energy (hyper-)surface (PES) was obtained.
Subsequently, the energy of EA, EB, ZA and ZB was recalculated within these optimized structures by LNO-CCSD(T) [7] and using the cc-pVQZ [5] basis set as implemented in the program MRCC. [8] Figure S1. Relative Gibbs energies of 1a (G in kJ mol -1 ), i.e., two rotamers of E (EA and EB) and Z (ZA and ZB) isomers within the fully optimized equilibrium structures, obtained at the DF-MP2/cc-pVTZ level of theory. The electronic energy contribution was subsequently obtained at the LNO-CCSD(T)/cc-pVQZ level of theory.
In the following, two molecules of thiochalcone are coordinated to the [Fe2(CO)6] fragment forming the respective adduct (A), while all combinations of EA, EB, ZA and ZB were considered, see Table S1 (left) exemplarily for A(EAEA). In addition to the ten possible combinations of the four isomers, coordination in a parallel as well as in an antiparallel fashion is conceivable. However, in the present study, we focused exclusively on adducts obtained by parallel coordination as the following reaction is highly unlikely to proceed starting from the antiparallel adducts, due to an unfavorable stereochemistry, i.e.
regarding the required carbon-carbon bond formation (C2-C3') among the two thioketones. All ten (parallel coordinated) adducts were optimized using the TPSSh [9] hybrid functional and the def2-TZVPP [10] basis set as implemented in ORCA 4.1.1 and 4.2.1, [11] while the resolution of identity approach was applied, using the respective def2/J auxiliary basis and the RIJCOSX [12] approximation for the Coulomb and exchange integrals, to reduce the computational demand. Furthermore, D3 dispersion correction with Becke-Johnson damping (D3BJ) [13] was added to account for (attractive) long-range interactions among the coordinated thioketones. A subsequent frequency analysis confirmed the presence of minima on the PES. For the adduct A(EAEA), resulting from coordination of the most stable isolated thioketone (EA, Figure S1), the structural and electronic properties were additionally calculated within the equilibrated triplet ground state structure. Table S1. Relative Gibbs energies of the adducts (G in kJ mol -1 , A), formed upon coordination of the [Fe2(CO)6] fragment by two molecules of 1a (EA, EB, ZA and ZB), respectively, and of the resulting products (P). All values are obtained for the closed-shell singlet ground state, triplet energies in parenthesis, and given with respect to A(EAEA) and P(EAEA), respectively. Selectively formed stereocenters (1, 2, 3 and 6) of the possible products are labeled; incorrectly formed centers are highlighted in red. Originating from these ten adducts, 16 products (P) are conceivable. These products are not symmetric with one thioketone contributing three and the other thioketone contributing two carbon atoms to the formed cyclopentene moiety. Thus, the products are denoted accordingly: Firstly, the thioketone contributing three carbon atoms; secondly, the thioketone contributing two carbon atoms, e.g. P(EBZB) vs. P(ZBEB). The structural and electronic properties of these product structures, resulting from a formal (3+2) cycloaddition, were obtained at the same level of theory as described previously for the adducts.
However, three of the constructed products, namely P(EAZA), P(ZAEA) and P(ZAZA), relax in already covered product states, thus a total number of 13 products is obtained. From these 13 products, merely two species -P(EAEA) and P(ZBEA)feature the correct stereochemistry of all four chiral carbon atoms as observed experimentally, see Table S1 (right). These two products only differ with respect to the torsion of the thiophenyl (Ar 1 ) and the phenyl (Ar 2 ) groups. Furthermore, P(EAEA), as obtained from the adduct A(EAEA) resulting from coordination of the most stable 1a isomer (EA, Figure S1), was optimized within triplet multiplicity, followed by a vibrational analysis. These computational results clearly show that both A(EAEA) and P(EAEA) are closed-shell singlet species.
In order to determine the reaction mechanism leading to the (3+2)-cycloproduct, the minimum energy path (MEP) along the reaction coordinate from the adduct to the respective product was approximated by the climbing image nudge elastic band (CI-NEB) method. [14] Based on the previously calculated thermodynamic properties of the free thiochalcones, their adducts and their respective products, the most plausible reaction coordinate connects EA, via the adduct A(EAEA) to the final product P(EAEA).
In order to estimate the influence of solvent stabilization along the closed-shell singlet reaction coordinate, single point calculations (closed-shell singlet) including the tetrahydrofuran solvent by the SMD continuum model [15] were performed ( Figure   are illustrated in red. All energies are calculated at the TPSSh/def2-SVP level of theory. respective adducts at a reduced level of theory. Therefore, MEPs within the singlet multiplicity (closedshell) were obtained by a locally developed program package [16] using the CI-NEB method and Grimme's semi-empirical GFN-xTB package. [17] The resulting PESs reveal that for the formation of P(EAEA)  activation energies (EA in kJ mol -1 ) are indicated.

Structure Determinations
The intensity data for the compounds were collected on a Nonius KappaCCD diffractometer using graphite-monochromated Mo-K radiation. Data were corrected for Lorentz and polarization effects; absorption was taken into account on a semi-empirical basis using multiple-scans. [18] The structures were solved by direct methods (SHELXS [19] ) and refined by full-matrix least squares techniques against SHELXL-2018. [20] All hydrogen atoms of the compound 2d and the hydrogen atoms bonded to the carbon atoms C1 to C4 of 1c, 3a, 4 and C3 of 2e were located by difference Fourier synthesis and refined isotropically. All other hydrogen atoms were included at calculated positions with fixed thermal parameters.
The crystal of 3d, and 3e contains large voids, filled with disordered solvent molecules. The size of the voids are (475, and 292) Å 3 /unit cell, respectively. Their contribution to the structure factors was secured by back-Fourier transformation using the SQUEEZE routine of the program PLATON [21] resulting in (215, and 80) electrons/unit cell, respectively. All non-hydrogen atoms were refined anisotropically. [21] 2 Molecular structures Crystallographic data as well as structure solution and refinement details are summarized in Table S2.
XP (SIEMENS Analytical X-ray Instruments, Inc.) was used for structure representations.           Figure   to the reduction process of Fe I Fe I to Fe I Fe 0 similar to their reported analogue complexes. [22] It can be noticed from Figure S12 that complex 3d shows a more negative reduction potential in comparison to complexes 3a-c and 3e. This indicates that the electron density of the iron core of 3d is higher than those of 3a-c and 3e, as consistent with the IR data. On initiating the electrochemical scan in the anodic direction of complexes 3d and 3e, two quasi-reversible anodic events at E1/2 = 0.07 V and 0.22 V for complex 3d and at E1/2 = 0.08 V and 0.23 V for complex 3e were observed. These oxidation peaks are corresponding to one-electron transfer of the ferrocene ligands.