trans Selectivity of Vinylogous Nazarov-type [6Ï

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Mechanism and cis/trans Selectivity of Vinylogous Nazarov-Type [6#] Photocyclizations Stefan Pusch, Andreas Tröster, Daniel Lefrancois, Pooria Farahani, Andreas Dreuw, Thorsten Bach, and Till Opatz J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02982 • Publication Date (Web): 22 Dec 2017 Downloaded from http://pubs.acs.org on December 22, 2017

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The Journal of Organic Chemistry

Mechanism and cis/trans Selectivity of Vinylogous NazarovType [6π] Photocyclizations

Stefan Pusch,† Andreas Tröster,‡ Daniel Lefrancois,§ Pooria Farahani,ǁ 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 ǁ

Instituto de Química, Departamento de Química Fundamental, Universidade de São Paulo, C. P.

05508-000, São Paulo, SP, Brazil

Dedicated to Professor Albert Padwa on the occasion of his 80th anniversary

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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract Graphic

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, SFTDDFT, 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 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 sevenmembered rings was discovered by our group during the investigation of a one-pot pyrrole synthesis (Scheme 1).3

Scheme 1. One-Pot Photoisomerization / Pyrrole Synthesis / [6π] Photocyclization

The reaction proceeds via (1st) a photochemical rearrangement4 of isoxazoles 1 to azirines 2, (2nd) a cobalt(II)-catalyzed condensation reaction forming pyrroles 3, and (3rd) 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.

Results and Discussion Initially, simplified model substrates 5a,b were chosen for a computational study of the cyclization mechanism (Scheme 2).

Scheme 2. Model Substrates for the [6π] Photocyclization and Putative Reaction Mechanism

A plausible reaction mechanism would include the photoexcitation of 5a,b, followed by a ring closure to a singlet 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. The calculations were checked for consistency among the choice of functional (comparing with B3LYP, B3LYP-D3BJ, and M06-2X), basis set (6-31+G(d), 6-311+G(2d,p), def2-TZVPP), as well as solvation model (IEFPCM, SMD); the respective tables can be found in the Supporting Information.


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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–Zimmerman model, transition states 5a,b→6a,b represent 6π electron Möbius-aromatic systems (Figure 2).8 In contrast, the concerted suprafacial H shifts are allowed via the S0 – but not via the T1 – states, as they formally involve six electrons and no phase change in the orbital basis set.

Figure 1. Energy profile for the photocyclization/H shift (UDFT).

Figure 2. Schematic orbital basis set for the cyclization 5a,b→6a,b with an odd number of phase changes.



Experimentally, the photocyclization of substrate 3a (prepared by a step-wise procedure) to trans-4a can be induced by irradiation with visible light (λ = 419 nm) using thioxanthone as a triplet sensitizer (Scheme 3).

Scheme 3. Triplet-Sensitized Photocyclization

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 a 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, exchangecorrelation functionals with large amounts of non-local Hartree-Fock exchange are required within SF-TDDFT.10,13 Therefore, a relaxed scan of the S1 potential energy surface was ACS Paragon Plus Environment

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performed at the SF-TD-BHHLYP/6-31+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 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.

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 dimensional,14 degenerate CI space and ultra-fast non-radiative decay into S0 can occur as well as efficient ISC from S1 into T1 or vice versa. The missing points from r = 2.0 Å 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 which 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 rate-limiting step. Interestingly, the ground state of phenyl-derived intermediate 6a is a singlet-biradical16 according to UDFT calculations (which were accompanied with 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)/def2-TZVPP 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 4. Contour plots (isovalue = 0.08) of the 7th (left) and 8th (right) orbitals from the active space of singlet-6a (CASSCF). Wavefunction composition (active space occupation pattern): 39.7% [2222221100000], 22.9% [...20...], 14.7% [...02...], other configurations < 1.9%.


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Figure 5. Contour plots (isovalue = 0.08) of the 7th (left) and 8th (right) orbitals from the active space of singlet-6b (CASSCF). Wavefunction composition (active space occupation pattern): 83.4% [222222200000], other configurations < 0.7%.

Satisfyingly, these pictures correspond well to the positions where significant spin density can be found for the UDFT solution (Figure 6).

Figure 6. Contour plot (isovalue = 0.02) of the spin density of 6a (spin-contaminated “singlet”, UDFT).

The UDFT- and CASSCF-optimized geometries are reasonably similar to each other. We observed a significant bending of the carbonyl oxygen for the furanyl-derived intermediate 6b, but not for intermediate 6a in the S0 states (see the Supporting Information). We hypothesized that this could lead to a tendency towards NH proton abstraction by the “enolate” oxygen



especially for the furanyl-derived intermediate 6b leading to tautomer 8b (Figure 7). Again, the isomerization of 6a,b to 8a,b is a thermally allowed and photochemically forbidden process.

Figure 7. Energy profile for the tautomerization/H shift (UDFT).

Intermediates 8a,b might also undergo a concerted thermally allowed H shift (involving 14 electrons in total), but this process seems unlikely as the activation barriers are significantly higher with ∆G‡ = 20.3 kcal mol–1 (a) and especially 29.8 kcal mol–1 (b). More plausible would be a further tautomerism of “enols” 8a,b via a stepwise (probably acid/base promoted) protonation/deprotonation pathway, eventually leading to the final products 7a,b. Comparing the transition states for transformations 6→7 and 6→8, it is evident that the preferred pathways are 6a→7a (∆∆G‡ = 0.45 kcal mol–1) and 6b→8b (∆∆G‡ = 8.8 kcal mol–1), respectively. Using the Curtin-Hammett principle, the resulting Boltzmann ratios for 6→7/6→8 are 68 : 32 (a) and 0 : 100 (b). Therefore, the [1,6] suprafacial H shift is favored for the phenyl derivative whereas the tautomerization is favored for the furanyl derivative (Figure 8).18


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Figure 8. Final energy profile (UDFT).

Consequently, transition state optimizations were performed for the two crucial competing steps for the “real” substrates (10a,b→trans-4a,b vs. 10a,b→11a,b, Scheme 4).

Scheme 4. Competing [1,6] H Shift and Tautomerization in the Cyclization of 10a,b to 4a,b

Here, the preference for one of the two pathways is even more pronounced than for the model substrates (Table 1).

Table 1. Relative Free Activation Enthalpies ∆∆G‡ = ∆G‡(10→trans-4) – ∆G‡(10→11) and Corresponding Ratios (10→trans-4/10→11) at 25 °C (UDFT) ∆∆G‡ / kcal mol–1

Ratio

a (X = CHCH)

(–)4.23

99.9 : 0.1

b (X = O)

(+)8.74

0.0 : 100.0



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One alternative explanation of the observed diastereoselectivity would be a subsequent cis/transisomerization of 4a,b, e.g. via photochemical acyl cleavage and radical recombination, after the inital formation of 4a,b from 3a,b. In this case, however, the formation of cis- and trans-4a with a ratio of approximately 1 : 1 (instead of pure trans-4a) would be predicted from the relative Gibbs free enthalpies of the two diastereomers (Table 2).

Table 2. Relative Free Enthalpies ∆G = G(trans-4) – G(cis-4) and Corresponding Ratios (trans-4/cis-4) at 25 °C (UDFT) ∆∆G‡ / kcal mol–1

Ratio

a (X = CHCH)

(+)0.67

24 : 76

b (X = O)

(+)0.33

36 : 64

Additionally, no cis/trans-isomerization could be observed as judged by HPLC/ESI-MS if pure cis- or trans-4b were irradiated at λ = 300 nm in dichloromethane. If on the other hand a protonation/deprotonation sequence is assumed for the direct formation of 4b from intermediate enol 11b yielding a mixture by product-development control, the calculated cis/trans ratio correlates well with the experimental finding of 22 : 78. Therefore, trans-4a seems to be formed from 3a by a light-induced cyclization followed by a concerted suprafacial [1,6] H shift, whereas 3b yields a cis/trans-mixture of 4b via a sequence of photocylization and tautomerizations. In accordance with our proposed mechanism, the one-pot reaction of deuterium-labeled isoxazole 1a-d5 gave pure pyrrole 4a-d5 with one deuterium α to the carbonyl group (Scheme 5). Furthermore, an equimolar mixture of 1a-d0 and 1a-d5 under the same reaction conditions yielded only 4a-d0 and 4a-d5. No crossover with formation of 4a-d1 or 4a-d4 could be observed, as expected for a selective intramolecular hydrogen shift. In contrast, furanyl compound 1b-d3 was mainly transformed into cis/trans-pyrroles 4b-d2 with little deuterium label in the α-position. ACS Paragon Plus Environment

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Therefore, an intermolecular hydrogen shift mechanism must apply here, probably with inclusion of acetylacetone or water molecules acting as proton sources for the enol intermediate discussed above.

Scheme 5. Deuterium Labeling Experiments

Curiously, upon irradiation of biphenyl derivative 12 the formation of cis-13 (from a photochemical [4π] Nazarov cyclization) and of cycloheptadienone cis-14 was observed, while the corresponding isomer trans-14 could not be detected (Scheme 6).



Scheme 6. Photocyclization of a Biphenyl-Derived Enone

NMR spectra of cis-14 had to be recorded at 100 °C, as this compound was near the coalescence point at room temperature, hampering the assignment (see the Supporting Information). The cis-fusion is supported by a small coupling constant of approximately 5.0 Hz between the corresponding hydrogen nuclei. Again, we chose a simplified computational model (Figure 9) for an initial investigation.

Figure 9. Mechanistic model of the [6π] photocyclization (UDFT).

The ground state of intermediate 16 is identified as a singlet biradical – and not as a zwitterion – by UDFT and DMRG-CASSCF(14,14)/def2-TZVPP/COSMO calculations (see the Supporting Information).19 Unlike above, the conformation of reactant 15 is not locked by an intramolecular NH···O hydrogen bond as in 3a,b (Figure 10). Thus, the enone β carbon atom in


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15 is closer to the opposite ortho carbon atom of the phenyl ring (arbitrarily termed the “6position” in the following), whereas in 3a it is closer to the phenyl’s “2-position”. Consequently, we found two transition states for a cyclization in the triplet state with cyclization on the 2- and 6-position (Figure 11), with the latter being energetically lower (∆∆G‡ = 1.82 kcal mol–1, corresponding to a ratio of 95.6 : 4.4).

Figure 10. Conformations of enones 3a,b (top) and 15 (bottom) with corresponding distances in Å (singlet ground states, UDFT).

Figure 11. Transition states (15→16) for a cyclization via T1 on the 2- and 6-position (left and middle, respectively) with vibrations along the reaction coordinate (UDFT) and Dewar– Zimmerman model for 15→16 (right). ACS Paragon Plus Environment


No similar low-energy cyclization via the 6-position could be found for 5a→6a via relaxed surface scans. The preference for a cyclization onto the 6-position (Figure 12) is even more pronounced in the “real” starting material 12 (∆∆G‡ = 3.51 kcal mol–1, yielding a ratio of 99.7 : 0.3).

Figure 12. Transition states for a cyclization via T1 on the 2-position (12→18, left) and 6position (12→19, right, UDFT).

However, a suprafacial [1,6] H shift would only be possible in intermediate 18 (derived from cyclization on the 2-position), but not in bowl-shaped intermediate 19 (after cyclization on the 6-position). As the latter pathway seems to be highly preferred, intermediate 19 must isomerize to the final product 14 via a protonation/deprotonation (or a free-radical) pathway. For product 14, the cis isomer is indeed favored with ∆G = 5.23 kcal mol–1 compared to the trans isomer, resulting in a cis/trans ratio of 100.0 : 0.0, in agreement with the experimental findings.

Conclusion A mechanistic rationale for the different diastereoselectivities in vinylogous Nazarov-type photocyclizations was developed. The mechanism was investigated by unrestricted DFT, SF-


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TDDFT, and CASSCF calculations. Three different pathways are suggested: (1) Cyclization on the 2-position of a phenyl ring, yielding a singlet-biradical intermediate, which forms pure transproduct after a fast suprafacial [1,6] H shift (3a→4a). (2) Cyclization on a furan ring and generation of a zwitterionic intermediate which tautomerizes to an enol, giving a cis/trans mixture after further isomerizations (3b→4b). (3) Cyclization on the 6-position of a phenyl ring forming a singlet-biradical intermediate, which yields pure cis-product due to a geometrically impossible suprafacial [1,6] H shift and product-development control (12→14). The proposed mechanism, showing the large impact of subtle structural variations on the observed diastereoselectivities, is supported by deuterium labeling experiments.

Experimental Section General Information Anhydrous dichloromethane was distilled from CaH2 and diethyl ether was distilled from sodium/benzophenone under nitrogen. Solvents were degassed using freeze-pump-thaw cycles or by nitrogen bubbling and an ultrasonic bath. CDCl3 was stored over alumina (Brockmann activity grade I). (2H5)Benzaldehyde,20 (2H3)furan-2-carbaldehyde,21 and cyclohex-1-en-1-yllithium22 were prepared according to known procedures. All other reagents were purchased from commercial suppliers and used without further purification. Photochemical reactions were performed in quartz tubes using a multilamp reactor equipped with a circular array of 16 lamps (λmax ca. 419 nm and 300 nm), a magnetic stirrer and a cooling fan. TLC was carried out on silica gel 60 F254 plates (UV visualization). Preparative normal-phase chromatography was performed on silica gel (35–70 µm). Preparative reversed-phase chromatography was carried out using an ACE5-C18PFP column (pore size: 5 µm, length: 15 cm, diameter: 30 mm) using a total flow rate of 37.5 mL min–1. Melting points were determined in open capillary tubes. NMR spectra were



recorded with 300 MHz, 400 MHz and 600 MHz instruments using standard pulse sequences. The chemical shifts are given in ppm (downfield relative to TMS) and were referenced to the residual solvent signal (CHCl3: δH = 7.26 ppm, CDCl3: δC = 77.16 ppm, CHCl2CDCl2: δH = 6.00 ppm, CDCl2CDCl2: δC = 73.78 ppm). IR spectra were recorded using a diamond ATR unit; wavenumbers are given in cm–1. ESI-MS and ESI-HRMS spectra (given: m/z values) were recorded using an ion trap and a Q-ToF instrument with dual source and suitable external calibrant, respectively. Triplet Sensitization A solution of pyrrole 3a3 (22.7 mg, 73.8 µmol, 1.00 equiv) and thioxanthen-9-one (7.84 mg, 37.0 µmol, 0.50 equiv) in acetonitrile (5 mL, c = 15 mmol/L) was degassed and irradiated (λ = 419 nm) for 35 min at room temperature. Removal of the solvent in vacuo and purification by flash column chromatography (3 : 1 hexane/ethyl acetate) yielded pyrrole trans-4a (22.5 mg, 73.2 µmol, 99%) as a colorless solid. The analytical data are identical to those already published.3 Photoisomerization Experiment A solution of pure cis- or trans-4b (8.9 mg, 30 µmol, 1.0 equiv),3 acetylacetone (3.1 µL, 3.0 mg, 30 µmol, 1.0 equiv), and cobalt(II) acetylacetonate (0.8 mg, 3 µmol, 0.1 equiv) in dry degassed dichloromethane (1.5 mL) was irradiated (λ = 300 nm) for 30 min at room temperature. No isomerization of cis- or trans-4b or vice versa could be detected via HPLC/ESI-MS (see the Supporting Information). 5-(Cyclohex-1-en-1-yl)-3-(2H5)phenyl-1,2-oxazole (1a-d5) Preparation applying the general procedure by Fokin and co-workers:23 To a solution of hydroxylamine hydrochloride (1.78 g, 25.6 mmol, 1.05 equiv) and (2H5)benzaldehyde (2.71 g, 24.4 mmol, 1.00 equiv) in tert-butanol/water (1 : 1, 100 mL) was added NaOH (1.02 g, 25.6 mmol, 1.05 equiv) and the mixture was stirred at room temperature for 30 min. ChloramineACS Paragon Plus Environment

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T trihydrate (7.21 g, 25.6 mmol, 1.05 equiv) was added in small portions over a period of 5 min. 1-Ethynylcyclohexene (3.01 mL, 2.72 g, 25.6 mmol, 1.05 equiv), copper sulfate pentahydrate (183 mg, 0.732 mmol, 0.03 equiv), and copper wire (140 mg) were added. The mixture was stirred at room temperature over night and poured into water (100 mL). Diluted aqueous NH4OH (20 mL) was added and the mixture was extracted with dichloromethane (3 × 80 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. Purification by flash column chromatography (99 : 1 → 80 : 20 cyclohexane/ethyl acetate) yielded the title compound (2.87 g, 12.5 mmol, 51%) as a slightly yellow crystalline solid: Rf 0.63 (5 : 1 cyclohexane/ethyl acetate). Mp: 83.6–84.7 °C. IR (ATR): 2933, 1576, 1429, 1340, 920, 801. 1H NMR, COSY (400 MHz, CDCl3): δ 6.66 (tt, J = 4.0, 1.8 Hz, 1H, H-2’), 6.38 (s, 1H, H-4), 2.42– 2.36 (m, 2H, H-6’), 2.30–2.22 (m, 2H, H-3’), 1.83–1.73 (m, 2H, H-5’), 1.73–1.65 (m, 2H, H-4’). 13

C NMR, HSQC, HMBC (101 MHz, CDCl3): δ 171.7 (C-5), 162.5 (C-3), 130.3 (C-2’), 129.4 (t,

J = 23.9 Hz, C-4’’), 129.4 (C-1’’), 128.4 (t, J = 24.5 Hz, C-3’’/5’’), 126.4 (t, J = 24.5 Hz, C2’’/6’’), 125.5 (C-3’), 96.3 (C-4), 25.5 (C-3’), 25.3 (C-6’), 22.2 (C-5’), 21.8 (C-4’). MS (ESI): m/z 231.2 (100%) [M + H]+, 253.2 (5.4%) [M + Na]+. HRMS (ESI-TOF) m/z [M + H]+ calcd for C151H112H5NO+ 231.1546, found 231.1545. No peak corresponding to 1a-d4 could be detected via HPLC/ESI-MS. Based on integration of the 1H NMR resonances at δ 7.81 (H-2’’), 7.45 (H-3’’), and 7.43 (H-4’’) from the three 1a-d4 isomers, the degree of deuteration can be estimated to 99.7% (2-pos.), 99.6% (3-pos.), and 99.8% (4-pos.). rel-(8aR,12aR)-5-Acetyl-6-methyl(1,2,3,4,8a-2H5)-8a,9,10,11,12,12ahexahydrodibenzo[3,4:5,6]cyclohepta[1,2-b]pyrrol-8(7H)-one (trans-4a-d5) A solution of isoxazole 1a-d5 (87.5 mg, 380 µmol, 1.00 equiv), acetylacetone (46.8 µL, 45.7 µg, 456 µmol, 1.20 equiv), and cobalt(II) acetylacetonate (9.8 mg, 38 µmol, 0.10 equiv) in dry



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dichloromethane (15 mL) was degassed and irradiated (λ = 300 nm) for 12 h at room temperature. Removal of the solvent in vacuo and purification by flash column chromatography (99 : 1 → 62 : 38 cyclohexane/ethyl acetate) yielded the title compound (112.9 mg, 361.4 µmol, 95%) as a colorless solid: Rf 0.34 (3 : 1 cyclohexane/ethyl acetate). Mp: 211.7–212.8 °C. IR (ATR): 3255, 2928, 1621, 1434, 754; 1H NMR, COSY, NOESY (400 MHz, CDCl3): δ 10.35 (br s, 1H, NH), 3.19 (dd, J = 12.3, 3.4 Hz, 1H, H-12a), 2.50 (s, 3H, CH3-6), 2.30–2.27 (m, 2H, H-8a, Ha-9), 2.25 (s, 3H, COCH3), 2.15–2.10 (m, 1H, Ha-12), 2.02–1.83 (m, 3H) + 1.42–1.33 (m, 3H) (Hb-9, Hab-10, Hab-11, Hb-12). 13C NMR, HSQC, HMBC (101 MHz, CDCl3): δ 198.0 (COCH3), 197.3 (C-8), 141.1 (C-12b), 140.3 (C-6), 133.0 (C-4a), 130.8 (t, J = 22.1 Hz, C-4), 130.3 (C-4b), 128.3 (C-7a), 127.3 (t, J = 23.3 Hz, C-2), 126.1 (t, J = 23.7 Hz, C-3), 125.3 (t, J = 22.8 Hz, C-1), 122.3 (C-5), 56.2 (t, J = 18.9 Hz, C-8a), 40.4 (C-12a), 31.6 (C-9), 31.2 (COCH3), 29.9 (C-12), 25.61 + 25.55 (C-10, C-11), 13.7 (CH3-6). MS (ESI): m/z 313.5 (100%) [M + H]+, 335.3 (43.5%) [M + Na]+. HRMS (ESI-TOF) m/z [M + H]+ calcd for C201H172H5NO2+ 313.1964, found 313.1966. No peak corresponding to 4a-d4 could be detected via HPLC/ESI-MS. Crossover Experiment A solution of isoxazole 1a-d0 (41.0 mg, 182 µmol, 0.50 equiv), 1a-d5 (41.9 mg, 182 µmol, 0.50 equiv),

acetylacetone

(44.8 µL,

43.7 µg,

437 µmol,

1.20 equiv),

and

cobalt(II)

acetylacetonate (9.3 mg, 36 µmol, 0.10 equiv) in dry dichloromethane (15 mL) was degassed and irradiated (λ = 300 nm, 16 × W) for 12 h at room temperature. Removal of the solvent in vacuo and purification by flash column chromatography (99 : 1 → 62 : 38 cyclohexane/ethyl acetate) yielded a 1 : 1 mixture of pyrroles trans-4a-d0 and -d5 [100.8 mg, 325.3 µmol (combined, using average molar mass), 89%] as a colorless solid: Rf 0.34 (3 : 1 cyclohexane/ethyl acetate). 1H NMR (400 MHz, CDCl3): δ 10.51 (br s, 1H), 7.47 (br d, J = 7.5 Hz, 0.5H), 7.31 (td, J = 7.5, ACS Paragon Plus Environment

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1.6 Hz, 0.5H), 7.25 (td, J = 7.5, 1.4 Hz, 0.5H), 7.16 (dd, J = 7.5, 1.6 Hz, 0.5H), 3.25–3.15 (m, 1H), 2.51 (s, 3H), 2.38–2.27 (m, 1H), 2.25 (s, 3H), 2.16–2.08 (m, 1H), 2.04–1.81 (m, 3H), 1.54– 1.31 (m, 3H). MS (ESI): m/z 308.7 (100%) [4a-d0 + H]+, 313.4 (91.5%) [4a-d5 + H]+, 330.3 (39.0%) [4a-d0 + Na]+, 335.2 (29.4%) [4a-d5 + Na]+. No peak corresponding to 4a-d4 could be detected via HPLC/ESI-MS (4a-d1 would overlap with the 13C isotope peak of 4a-d0). 5-(Cyclohex-1-en-1-yl)-3-[(2H3)furan-2-yl]-1,2-oxazole (1b-d3) Preparation applying the general procedure by Fokin and co-workers:23 To a solution of hydroxylamine hydrochloride (834 mg, 12.0 mmol, 1.33 equiv) and (2H3)furan-2-carbaldehyde (approx. 9.0 mmol) in tert-butanol/water (1 : 1, 50 mL) was added NaOH (480 mg, 12.0 mmol, 1.33 equiv) and the mixture was stirred at room temperature for 30 min. Chloramine-T trihydrate (3.38 g, 12.0 mmol, 1.33 equiv) was added in small portions over a period of 5 min. 1Ethynylcyclohexene (1.41 mL, 1.27 g, 12.0 mmol, 1.33 equiv), copper sulfate pentahydrate (85 mg, 0.34 mmol, 0.038 equiv), and copper wire (29 mg) were added. The mixture was stirred at room temperature over night and poured into water (50 mL). Diluted aqueous NH4OH (10 mL) was added and the mixture was extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. Purification by flash column chromatography (98 : 2 → 85 : 15 cyclohexane/ethyl acetate) yielded the title compound (562 mg, 2.58 mmol, 29%) as a slightly yellow crystalline solid: Rf 0.60 (5 : 1 cyclohexane/ethyl acetate). Mp: 53.7–54.3 °C. IR (ATR): 2932, 1599, 1435, 911, 781. 1H NMR, COSY (300 MHz, CDCl3): δ 6.64 (tt, J = 4.0, 1.8 Hz, 1H, H-2’), 6.31 (s, 1H, H-4), 2.39–2.32 (m, 2H, H-6’), 2.28– 2.20 (m, 2H, H-3’), 1.80–1.72 (m, 2H, H-5’), 1.72–1.63 (m, 2H, H-4’).

13

C NMR (75 MHz,

CDCl3): δ 171.4 (C-5), 154.9 (C-3), 144.6 (C-2’’), 143.4 (t, J = 31.0 Hz, C-5’’), 130.7 (C-2’), 125.2 (C-1’), 111.3 (t, J = 26.9 Hz, C-4’’), 109.7 (t, J = 27.1 Hz, C-3’’), 95.8 (C-4), 25.5 (C-3’),



25.2 (C-6’), 22.1 (C-5’), 21.8 (C-4’). MS (ESI): m/z 219.2 (100%) [M + H]+, 241.1 (13.1%) [M + Na]+. HRMS (ESI-TOF) m/z [M + H]+ calcd for C131H112H3NO2 219.1213, found 219.1212. No peak corresponding to 1b-d2 could be detected via HPLC/ESI-MS. Based on integration of the 1H NMR resonances at δ 7.53 (H-5’’), 6.87 (H-3’’), and 6.50 (H-4’’) from the three 1b-d2 isomers, the degree of deuteration can be estimated to 99.4% (3-pos.), 99.4% (4-pos.), and 99.4% (5-pos.). rel-(3bR,7aS)-11-Acetyl-10-methyl(2,3-2H2)-3b,5,6,7,7a,9hexahydrobenzo[5,6]furo[2’,3’:3,4]cyclohepta[1,2-b]pyrrol-8(4H)-one (cis-4b-d2) and rel-(3bR,7aR)-11-acetyl-10-methyl(2,3-2H2)-3b,5,6,7,7a,9hexahydrobenzo[5,6]furo[2’,3’:3,4]cyclohepta[1,2-b]pyrrol-8(4H)-one (trans-4b-d2) A solution of isoxazole 1b-d3 (82.9 mg, 380 µmol, 1.00 equiv), acetylacetone (46.8 µL, 45.7 µg, 456 µmol, 1.20 equiv), and cobalt(II) acetylacetonate (9.8 mg, 38 µmol, 0.10 equiv) in dry dichloromethane (15 mL) was degassed and irradiated (λ = 300 nm) for 12 h at room temperature. Removal of the solvent in vacuo and purification by flash column chromatography (99 : 1 → 62 : 38 cyclohexane/ethyl acetate) yielded a mixture of the title compounds (77.0 mg, 257 µmol, 68%, molar ratio cis-4b-d2/trans-4b-d2 = 76 : 24 based on integration of the UV trace from HPLC; minor byproducts: cis-/trans-4b-d3, see below) as a colorless solid. Preparative HPLC (42 : 58 acetonitrile/water) affored pyrroles cis-4b-d2 (47.1 mg, 157 µmol, 41%; minor byproduct: cis-4b-d3, see below) and trans-4b-d2 (14.9 mg, 49.8 µmol, 13%; minor byproduct: trans-4b-d3, see below) as colorless solids. Analytical data for cis-4b-d2: Rf 0.24 (3 : 1 cyclohexane/ethyl acetate). Mp: 194.1– 195.2 °C. IR (ATR): 3264, 2933, 1598, 1543, 1417. 1H NMR, COSY, NOESY (400 MHz, CDCl3): δ 10.59 (br s, 1H, NH), 3.26–3.09 (m, 1H, H-3b), 2.97–2.81 (m, 1H, H-7a), 2.47 (s, 3H, COCH3), 2.44 (s, 3H, CH3-10), 2.25–1.44 (m, 8H, Hab-4, Hab-5, Hab-6, Hab-7). 2H NMR (92 MHz, ACS Paragon Plus Environment

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CDCl3): δ 7.44 (1D, D-2), 6.48 (1D, D-3). 13C NMR, HSQC, HMBC (101 MHz, CDCl3): δ 199.2 (COCH3), 191.4 (br, C-8), 144.5 (C-11b), 141.2 (t, J = 30.0 Hz, C-2), 139.5 (C-10), 125.5 (br, C8a), 124.5 (br, C-3a), 121.4 (C-11), 120.5 (C-11a), 113.0 (t, J = 25.5 Hz, C-3), 52.1 (br, C-7a), 34.1 (br, C-3b), 31.5 (COCH3), 28.8 (br) + 26.5 (br) + 24.5 (br, 2C) (C-4, C-5, C-6, C-7), 13.1 (CH3-10). MS (ESI): m/z 300.3 (100%) [M + H]+, 322.2 (22.1%) [M + Na]+. HRMS (ESI-TOF) m/z [M + H]+ calcd for C181H182H2NO3+ 300.1569, found 300.1562. Based on integration of the 2H NMR resonance at δ 2.86 (D-7a, cis-4b-d3), the ratio cis-4bd2/cis-4b-d3 can be estimated to 94 : 6. Accordingly, an ESI-MS peak of m/z 301.1 (25.0%) is observed (expected 13C isotope peak intensity for [M + H]+ of 4b-d2: 19.5%). Analytical data for trans-4b-d2: Rf 0.26 (3 : 1 cyclohexane/ethyl acetate). Mp: 202.0– 202.9 °C. IR (ATR): 3270, 2931, 1596, 1544, 1413. 1H NMR, COSY, NOESY (400 MHz, CDCl3): δ 9.86 (br s, 1H, NH), 2.81 (td, J = 12.5, 4.5 Hz, 1H, H-3b), 2.54–2.39 (m, 1H, Ha-7), 2.48 (s, 3H, CH3-10), 2.44 (s, 3H, COCH3), 2.39–2.24 (m, 2H, Ha-4, H-7a), 1.93–1.85 (m, 1H) + 1.41–1.23 (m, 3H) (Hab-5, Hab-6), 1.73–1.62 (m, 1H, Hb-4). 2H NMR (92 MHz, CDCl3): δ 7.45 (1D, D-2), 6.53 (1D, D-3).

13

C NMR, HSQC, HMBC (101 MHz, CDCl3): δ 198.0 (COCH3),

192.3 (C-8), 144.4 (C-11b), 141.2 (t, J = 31.2 Hz, C-2), 140.0 (C-10), 126.8 (C-3a), 126.6 (C-8a), 20.5 (C-11), 120.0 (C-11a), 110.7 (t, J = 25.0 Hz, C-3), 51.2 (C-7a), 33.1 (C-3b), 31.9 (C-4), 31.0 (COCH3), 28.4 (C-7), 25.5 + 25.4 (C-5, C-6), 13.8 (CH3-10). MS (ESI): m/z 300.5 (100%) [M + H]+, 322.3 (27.9%) [M + Na]+. HRMS (ESI-TOF) m/z [M + H]+ calcd for C181H182H2NO3+ 300.1569, found 300.1563. Based on integration of the 2H NMR resonance at δ 2.30 (D-7a, trans-4b-d3), the ratio trans-4b-d2/trans-4b-d3 can be estimated to 85 : 15. Accordingly, an ESI-MS peak of m/z 301.2 (33.5%) is observed (expected 13C isotope peak intensity for [M + H]+ of 4b-d2: 19.5%).



Biphenyl-2-yl(cyclohex-1-en-1-yl)methanone (12) To a solution of biphenyl-2-carbaldehyde (405.0 mg, 2.223 mmol, 1.00 equiv) in dry diethyl ether (40 mL) was added cyclohex-1-en-1-yllithium (0.89 M solution in diethyl ether; 10.0 mL, 890 µmol, 4.00 equiv) and the mixture was stirred for 1 h at room temperature. The reaction was quenched by addition of aqueous phosphate buffer (pH = 7, 20 mL) and saturated NH4Cl (20 mL). The mixture was extracted with diethyl ether (3 × 20 mL), the combined organic layers were dried (Na2SO4), and the solvent was removed in vacuo. The resulting clear yellow oil was dissolved in dichloromethane (40 mL), NaHCO3 (560.3 mg, 6.669 mmol, 3.00 equiv) and DessMartin periodinane (1.131 g, 2.668 mmol, 1.20 equiv) were added, and the mixture was stirred for 2 h at room temperature. Aqueous saturated NaHCO3/Na2S2O3 (1 : 1, 40 mL) was added and the mixture was stirred for 30 min. The mixture was extracted with dichloromethane (3 × 30 mL), the combined organic layers were dried (Na2SO4), and the solvent was removed in vacuo. Purification by flash column chromatography (99 : 1 → 82 : 18 cyclohexane/ethyl acetate) yielded the title compound (523.3 mg, 1.995 mmol, 90%) as a clear yellow oil: Rf 0.62 (10 : 1 cyclohexane/ethyl acetate). IR (ATR): 2930, 1647, 1636, 1280, 744, 698. 1H NMR, COSY, NOESY (400 MHz, CDCl3): δ 7.57–7.47 (m, 1H, H-5’), 7.46–7.38 (m, 3H, H-3’, H-4’, H-6’), 7.36–7.31 (m, 2H, H-3’’/5’’), 7.31–7.25 (m, 1H, H-4’’), 7.25–7.20 (m, 2H, H-2’’/6’’), 6.16 (tt, J = 4.0, 1.6 Hz, 1H, H-2), 2.14–2.07 (m, 2H, Hab-6), 1.92–1.84 (m, 2H, Hab-3]), 1.43–1.28 (m, 4H, Hab-4, Hab-5).

13

C NMR, HSQC, HMBC (101 MHz, CDCl3): δ 200.8 (CO), 145.1 (C-2), 141.4

(C-1’’), 141.0 (C-1’), 139.94 + 139.92 (C-1, C-2’), 129.9 (C-5’), 129.5 + 127.21 (C-4’, C-6’), 128.8 (C-2’’/6’’), 128.6 (C-3’), 128.5 (C-3’’/5’’), 127.24 (C-4’’), 26.1 (C-3), 23.3 (C-6), 21.9 (C5), 21.5 (C-4). MS (ESI): m/z 263.3 (100%) [M + H]+, 285.2 (23.3%) [M + Na]+. HRMS (ESITOF) m/z [M + H]+ calcd for C19H19O+ 263.1436, found 263.1444.


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rel-(4aR,9aS)-8-Phenyl-1,2,3,4,4a,9a-hexahydro-9H-fluoren-9-one (cis-13) and rel(4bR,8aS)-4b,5,6,7,8,8a-hexahydro-9H-tribenzo[a,c,e][7]annulen-9-one (cis-14) A solution of enone 12 (496.5 mg, 1.893 mmol) in dry dichloromethane (60 mL) was degassed and irradiated (λ = 300 nm) for 15 h at room temperature. Removal of the solvent in vacuo and purification by flash column chromatography (99 : 1 → 78 : 12 cyclohexane/ethyl acetate) yielded a mixture of the title compounds (409.5 mg, 1.561 mmol, 82%, molar ratio cis-13/cis-14 ~ 1 : 1 based on 1H NMR integration) as a clear yellow oil. Preparative HPLC (60 : 40 acetonitrile/water) yielded cyclopentenone cis-13 (137.5 mg, 0.5241 mmol, 28%) and cyclopentadienone cis-14 (158.1 mg, 0.6026 mmol, 32%) as clear colorless oils. Analytical data for cis-13: Rf 0.62 (10 : 1 cyclohexane/ethyl acetate). IR (ATR): 2931, 1715, 760, 698. 1H NMR, COSY, NOESY (400 MHz, CDCl3): δ 7.58 (app-t, J = 7.5 Hz, 1H, H6), 7.50–7.36 (m, 6H, H-5, H-2’/6’, H-3’/5’, H-4’), 7.30–7.26 (m, 1H, H-7), 3.38 (d-app-t, J = 9.7, 6.6 Hz, 1H, H-4a), 2.80 (app-td, J = 7.0, 4.0 Hz, 1H, H-9a), 2.22–2.10 (m, 2H, Ha-1, Hb-4), 1.75–1.63 (m, 1H, Hb-1), 1.63–1.51 (m, 2H, Hb-2, Ha-3), 1.46–1.31 (m, 1H, Hb-3), 1.26–1.11 (m, 2H, Ha-2, Ha-4);

13

C NMR, HSQC, HMBC (101 MHz, CDCl3): δ 206.4 (CO), 159.5 (C-4b),

141.7 (C-8), 138.2 (C-1’), 133.6 (C-6), 131.8 (C-8a), 129.5 (C-2’/6’), 129.4 (C-7), 127.9 (C3’/5’), 124.0 (C-5), 49.3 (C-9a), 38.7 (C-4a), 32.6 (C-4), 23.2 (C-3), 23.1 (C-1), 22.6 (C-2). MS (ESI): m/z 263.3 (100%) [M + H]+, 285.2 (26.8%) [M + Na]+. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H19O+ 263.1436, found 263.1447. Analytical data for cis-14: Rf 0.62 (10 : 1 cyclohexane/ethyl acetate). IR (ATR): 2932, 1669, 1445, 758, 742. 1H NMR, COSY (400 MHz, CDCl2CDCl2, 373 K): δ 7.64–7.57 (m, 2H) + 7.53–7.33 (m, 6H) (H-1, H-2, H-3, H-4, H-10, H-11, H-12, H-13), 3.26 (d-app-t, J = 9.4, 4.9 Hz, 1H, H-4b), 3.11 (app-q, J = 5.1 Hz, 1H, H-8a), 2.14–1.81 (m, 4H, Ha-5, Ha-6, Hab-8), 1.77–1.66 (m, 1H, Hb-5), 1.66–1.43 (m, 3H, Hb-6, Hab-7).

13

C NMR, HSQC, HMBC (101 MHz,



CDCl2CDCl2, 373 K): δ 208.1 (CO), 142.0 (C-4a), 141.0 + 138.8 + 138.3 (C-9a, C-13a, C-13b), 131.3 + 130.3 + 128.8 + 127.9 + 127.5 + 127.2 (2C) (C-1, C-2, C-3, C-10, C-11, C-12, C-13), 128.4 (C-4), 57.9 (C-8a), 43.1 (C-4b), 29.3 (C-8), 27.1 (C-5), 25.2 (C-6), 23.3 (C-7). MS (ESI): m/z 263.3 (100%) [M + H]+, 285.2 (25.7%) [M + Na]+. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H18NaO+ 285.1255, found 285.1254. Computational Chemistry DFT and TDDFT calculations were performed using Gaussian 09, Rev. D.0124 with tight SCF and geometry optimization convergence criteria and an ultrafine integration grid. The B3LYP,25 M06-2X,26 and ωB97XD27 functionals were used in conjunction with the 6-31+G(d),28 6311+G(2d,p),28 and def2-TZVPP29 basis sets. IEFPCM30 and SMD31 solvation models for dichloromethane were employed. The D3BJ empirical dispersion correction was used.32 Transition state optimizations were conducted with the Berny algorithm (after a QST3 search or relaxed surface scan). All stationary points were confirmed as local minima or first-order saddle points by calculation of the full exact hessian (yielding no or exactly one imaginary frequency, respectively). Transition states were checked by inspection of the vibration along the reaction coordinate and by intrinsic reaction coordinate (IRC) calculations. SF-TDDFT10 calculations were performed using Q-Chem 4.433 employing the BHHLYP functional34 and the 6-31+G(d)28 basis set. For the scan, the distance r between the bond forming atoms was constrained and all other parameters were allowed to relax freely. MECI optimzation was performed using a branching-plane updating method with out-projecting of the coupling vector from the Hessian and using cartesian coordinates. CASSCF/NEVPT235 and DMRG-CASSCF19 calculations were performed using Orca 3.0.3–4.0.1.236 with tight SCF and geometry optimization convergence criteria. The def2-


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TZVPP29 basis set was used in conjunction with the corresponding “C” fitting set for the RI approximation. The COSMO solvation model37 for dichloromethane was used.

Associated Content Computational Chemistry, HPLC/ESI-MS, and NMR Spectra (PDF). XYZ Coordinates (ZIP).

Author Information Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

Acknowledgements We thank Prof. Kendall N. Houk (University of California, Los Angeles), Prof. Jürgen Gauss (Mainz), as well as Dr. Filippo Lipparini (Mainz) for helpful discussions and the Zentrum für Datenverarbeitung (Mainz) for access to the MOGON supercomputer. S.P. is grateful for a scholarship from the Fonds der Chemischen Industrie. P.F. is grateful to the Fundação de Amparo à Pesquisado Estado de São Paulo (FAPESP) for financial support under the 2015/02314-8 project number. We are indebted to Prof. em. Paul Margaretha (University of Hamburg) for the initial idea for this study.

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This method utilizes a ms = +1 triplet state as reference and creates ms = 0 singlet and

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N = number of atoms per molecule.

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However, excited molecules at the conical intersection also have the possibility to return

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An alternative explanation would be a slow ISC of T1-6b to S0-6b – compared to a fast

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factor). Formation of 7b directly from T1-6b could then occur via a dissociation/recombination mechanism, also leading to a thermodynamic cis/trans mixture. However, CASSCF calculations (see the Supporting Information) suggest that an ISC at the MECI geometry should be feasible. (19)

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