Article Cite This: J. Org. Chem. 2018, 83, 964−972
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Mechanism and cis/trans Selectivity of Vinylogous Nazarov-type [6π] Photocyclizations† Stefan Pusch,‡ Andreas Tröster,§ Daniel Lefrancois,∥ Pooria Farahani,⊥ Andreas Dreuw,∥ Thorsten Bach,§ and Till Opatz*,‡ ‡
Institute of Organic Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10−14, 55128 Mainz, Germany Department Chemie and Catalysis Research Center (CRC), Technical University Munich, Lichtenbergstrasse 4, 85747 Garching, Germany ∥ Interdisciplinary Center for Scientific Computing, Ruprecht-Karls University, Im Neuenheimer Feld 205A, 69120 Heidelberg, Germany ⊥ Instituto de Química, Departamento de Química Fundamental, Universidade de São Paulo, C. P. 05508-000, São Paulo, SP Brazil §
S Supporting Information *
ABSTRACT: Vinylogous Nazarov-type cyclizations yield seven-membered rings from butadienyl vinyl ketones via a photochemical [6π] photocyclization followed by subsequent isomerization steps. The mechanism of this recently developed method was investigated using unrestricted DFT, SF-TDDFT, and CASSCF/NEVPT2 calculations, suggesting three different pathways that lead either to pure trans, pure cis, or mixed cis/trans configured products. Singlet biradicals or zwitterions occur as intermediates. The computational results are supported by deuterium-labeling experiments.
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INTRODUCTION
Scheme 1. One-Pot Photoisomerization/Pyrrole Synthesis/ [6π] Photocyclization
The Nazarov cyclization is an established method for the preparation of cyclopentenone derivatives and has found numerous applications in preparative organic chemistry.1 In contrast, methods for the preparation of seven-membered carbocycles are still scarce and mainly include cycloadditions, metatheses, or ring enlargements instead of electrocyclization approaches.2 Recently, the first example of a vinylogous Nazarov-type photocyclization yielding seven-membered rings was discovered by our group during the investigation of a onepot pyrrole synthesis (Scheme 1).3 The reaction proceeds via (i) a photochemical rearrangement4 of isoxazoles 1 to azirines 2, (ii) a cobalt(II)-catalyzed condensation reaction forming pyrroles 3, and (iii) a [6π] photocyclization yielding the cycloheptadienones 4.5 Curiously, only the trans product was observed for the phenyl derivative 4a, whereas cis/trans mixtures were obtained for furanyl and thienyl compounds 4b,c, an experimental finding that could not be rationalized at that time. The aim of the present work is to investigate the underlying mechanism and the origin of the different diastereoselectivities in the cyclization of 3 to 4 caused by subtle changes in the molecular structure. © 2017 American Chemical Society
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RESULTS AND DISCUSSION Initially, simplified model substrates 5a,b were chosen for a computational study of the cyclization mechanism (Scheme 2). A plausible reaction mechanism would include the photoexcitation of 5a,b, followed by a ring closure to a singlet Received: November 24, 2017 Published: December 22, 2017 964
DOI: 10.1021/acs.joc.7b02982 J. Org. Chem. 2018, 83, 964−972
Article
The Journal of Organic Chemistry
by irradiation with visible light (λ = 419 nm) using thioxanthone as a triplet sensitizer (Scheme 3).
Scheme 2. Model Substrates for the [6π] Photocyclization and Putative Reaction Mechanism
Scheme 3. Triplet-Sensitized Photocyclization
biradical or zwitterion 6a,b and eventually a concerted hydrogen shift, yielding 7a,b. Spin-unrestricted DFT calculations were performed using the range-separated (long-range-corrected) hybrid functional ωB97XD in combination with the augmented polarized 6311+G(2d,p) triple-ζ basis set and IEFPCM solvation for dichloromethane. This combination will simply be referred to as “UDFT” in the following text. The calculations were checked for consistency among the choices for functional (compared with B3LYP, B3LYP-D3BJ, and M06-2X), basis set [6-31+G(d), 6-311+G(2d,p), def2-TZVPP], and solvation model (IEFPCM, SMD); the respective tables can be found in the Supporting Information. As predicted by the Woodward−Hoffmann rules6 for a [6π] conrotatory electrocyclic ring closure,7 the cyclizations are photochemically allowed via the T1 states but thermally forbidden via the S0 states (Figure 1). Within the Dewar−
This result, taken together with the fact that the cyclization using UV light (λ = 300 nm) was already shown to be slowed down by trans-piperylene in our previous publication,3 strongly suggests a cyclization via a triplet pathway (at least partially). TDDFT and CASSCF calculations (see the Supporting Information) suggest that 5a is initially excited to S2(π,π*), yielding an S1(n,π*) state after internal conversion. An intersystem crossing (ISC) from S1(n,π*) to T1(π,π*) should then be possible as judged by the spin−orbit coupling constants. On the contrary, the excited singlet state order is inverted for 5b, i.e., most molecules are directly excited to S1, which can be characterized as a (π,π*) state. An ISC from S1(π,π*) to T1(π,π*) is not very efficient; therefore, it is probable that the cyclization of 5b might proceed via the S1 state with a low activation barrier via a conical intersection (CI).9 Spin-flip time-dependent DFT (SF-TDDFT) calculations10 were performed to prototypically study the anticipated S1/S0 minimum energy conical intersection (MECI) along the cyclization 5b → 6b.11 This technique was successfully used for the investigation of MECIs in previous works.12 In general, exchange−correlation functionals with large amounts of nonlocal Hartree−Fock exchange are required within SFTDDFT.10,13 Therefore, a relaxed scan of the S1 potential energy surface was performed at the SF-TD-BHHLYP/631+G(d) level of theory (Figure 3). Additionally, a MECI search along the reaction coordinate yielded a corresponding geometry at r = 1.66 Å, exhibiting an S1−S0 energy gap of only 4.81 × 10−6 hartree (0.003 kcal mol−1).
Figure 1. Energy profile for the photocyclization/H shift (UDFT).
Zimmerman model, transition states 5a,b → 6a,b represent 6π electron Möbius-aromatic systems (Figure 2).8 In contrast, the
Figure 2. Schematic orbital basis set for the cyclization 5a,b → 6a,b with an odd number of phase changes.
concerted suprafacial H shifts are allowed via the S0but not via the T1states, as they formally involve six electrons and no phase change in the orbital basis set. Experimentally, the photocyclization of substrate 3a (prepared by a stepwise procedure) to trans-4a can be induced
Figure 3. S1-optimized cyclization reaction coordinate of 5b → 6b [SF-TD-BHHLYP/6-31+G(d)]. The structure at the entry point of the CI seam (right) as well as the MECI (left) are shown in the insets. 965
DOI: 10.1021/acs.joc.7b02982 J. Org. Chem. 2018, 83, 964−972
Article
The Journal of Organic Chemistry As the bond-forming carbon atoms approach each other, the ground-state singlet energy (S0) rises until it becomes degenerate with T1 and S1 at r = 2.05 Å. When the CI is entered at r = 2.05 Å, 5b already has the correct geometry for the cyclization. At this point, excited molecules of 5b enter a 3N − 8 dimensional14 degenerate CI space, and ultrafast nonradiative decay into S0 can occur as well as efficient ISC from S1 into T1 or vice versa. The missing points from r = 2.0 to 1.66 Å are due to the CI space. Bond formation is the only significant change of the molecular structure when going through the CI. Now the molecules are back in the electronic ground state and end in the geometry of 6b. While the S0 cyclization energy barrier amounts to 54.3 kcal mol−1, the corresponding barrier for S1 is only 3.23 kcal mol−1. Cyclization via the S1 channel can thus be seen as a possible reaction pathway for the cyclization of 5b.15 For molecules that undergo ISC at the CI due to the near-degeneracy of S1 and T1, bond formation will also take place in the triplet state and its population will return back to the electronic ground state by ISC, which, based on the computed surfaces, may be the ratelimiting step. Interestingly, the ground state of phenyl-derived intermediate 6a is a singlet biradical16 according to UDFT calculations (which were accompanied by strong spin contamination: ⟨Ŝ2⟩ = 0.9939, after annihilation 0.5036). On the other hand, the ground state of furanyl-derived intermediate 6b is predicted to be a zwitterion. To check for potential multiconfigurational character with ab initio methods,17 we performed single-point calculations and reoptimizations at the CASSCF(14,n)/def2TZVPP level of theory (n = 13 or 12 for X = CHCH or O, respectively) with COSMO solvation for dichloromethane, including the whole π system of the corresponding intermediates. Indeed, significant singlet biradical character was found for 6a (Figure 4), whereas 6b seems to be a pure zwitterion containing a “oxocarbenium” moiety (Figure 5).
Figure 5. Contour plots (isovalue = 0.08) of the seventh (left) and eighth (right) orbitals from the active space of singlet 6b (CASSCF). Wave function composition (active space occupation pattern): 83.4% [222222200000] and
