Modular access to functionalized 5–8–5 fused ring systems via a photoinduced cycloisomerization reaction

A photoinduced isomerization reaction enables stereocontrolled access to a range of fused 5–8–5 ring systems.


Materials and Methods
Unless otherwise stated, reactions were conducted in oven-dried glassware under an atmosphere of molecular nitrogen (N 2 ) using anhydrous solvents. Tetrahydrofuran (THF), acetonitrile (MeCN), dichloromethane (CH 2 Cl 2 ), diethyl ether (Et 2 O), toluene, benzene, and triethylamine (Et 3 N) were dried by passage through activated alumina using a solvent purification system. n-Butanol was distilled from CaH 2 prior to use. TMSCl was distilled directly before use. N-tert-butylbenzenesulfinimidoyl chloride was prepared by a modification of a reported procedure 1 and used as a 2 M solution in benzene (see, pg. S13). All other commercial reagents were used as received.
Usually one representative reaction and yield of the product is described in detail; isolated yields reported in Table 1 and Table 2 are the average yields obtained from duplicate experiments. Photochemical reactions were performed using a Rayonet RPR-100 photoreactor equipped with 24 W UV-lamps centered at 350 nm. Reaction temperatures were controlled using a temperature modulator. Column chromatography was conducted on silica gel 60 (240-400 mesh) purchased from VWR. Thin layer chromatography (TLC) was performed using pre-coated, glass-backed plates (SiO 2 , 60 PF254, 0.25 mm) and visualized by exposure to UV light (254 nm) or by anisaldehyde, ceric ammonium molybdate, and potassium permanganate staining. 1 H NMR spectra were recorded at 400 MHz or 600 MHz and are reported relative to deuterated solvent signals. Data for 1 H NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz), and integration. Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), qunitet (quint), multiplet (m), broad (br), apparent (app), and combinations thereof. 13 C NMR spectra were recorded at 100 or 150 MHz. Data for 13 C NMR spectra are reported in order of carbon multiplicity (C = quaternary, CH = methine, CH 2 = methylene, CH 3 = methyl) and chemical shift. Carbon multiplicity was established by DEPT135 and/or HMQC experiments. Reported melting points of solids are uncorrected. IR spectra were recorded on an FT-IR spectrometer and are reported in terms of frequency (cm -1 ). Mass spectra were collected on an LCT spectrometer utilizing either electrospray (ESI) or direct analysis in real time (DART) ionization techniques.
The crude residue prepared above was dissolved in acetone (17 mL) and NaI (4.05 g, 27.0 mmol) was added in a single portion. The resulting suspension was warmed to 70 °C and stirred for 18 h. The reaction mixture was then cooled to rt and concentrated under reduced pressure. The resulting solid was digested in water (50 mL) and extracted with Et 2 O (4 x 30 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (SiO 2 , hexanes) to afford S11 (1.60 g, 7.20 mmol, 83% overall yield from S10) as a 2-(3,3-dimethylpent-4-yn-1-yl)furan (S12): Following a modification of the procedure reported for S1, a solution of furan (0.6 mL, 8.0 mmol) in THF (4 mL) was cooled to -78 °C. A solution of n-BuLi (2.9 mL, 5.2 mmol, 1.8 M in THF) was added drop wise via syringe. The resulting solution was warmed to 0 °C. After 4 h, S11 (444 mg, 2.00 mmol) was added via syringe. The reaction mixture was warmed to rt over 15 min and then heated to 42 °C. After 32 h, the reaction was cooled to rt and treated with water (10 mL, caution: exothermic). The resulting slurry was extracted with Et 2 O (3 x 10 mL). The combined organic extracts were washed with water (10 S8 mL) and brine (10 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO 2 ; hexanes) to afford S12 (240 mg, 1.47 mmol, 73% yield) as a yellow oil: 1 H NMR (400 MHz, CDCl 3 ) δ 7.30 (dd, J = 0.7, 1.8, 1H), 6.28 (dd, J = 1.9, 3.1, 1H), 6. (E)-2-(5-iodo-3,3-dimethylpent-4-en-1-yl)furan (S13): A solution of S12 (130 mg, 0.80 mmol) in THF (2 mL) was added drop wise to a stirred suspension of ZrCp 2 HCl (227 mg, 0.88 mmol) in THF (2 mL) at rt. After 1 h, the reaction mixture was cooled to -78 °C and a solution of I 2 (230 mg, 0.90 mmol) in THF (2 mL) was added drop wise via syringe over 10 min. The reaction was maintained at -78 °C for 30 min and then treated with wet Et 2 O (15 mL, 1% H 2 O by volume). The resulting slurry was warmed to rt and treated with saturated aq. Na 2 S 2 O 3 (5 mL). The organic layer was separated and washed with water (5 mL) and brine (5 mL). The combined organics were dried over MgSO 4 , filtered, and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO 2 ; hexanes) to afford S13 (130 mg, 0.44 mmol, 55% yield) as a Photoprecursor 12i: Following a modification of the procedure reported by Mauduit, 11 n-BuLi (0.2 mL, 0.4 mmol, 2.1 M in THF) was added drop wise via syringe to a solution of S13 (120 mg, 0.41 mmol) in THF (1 mL) at -78 °C. After 5 min, a solution of 3methoxycyclopent-2-enone (50 mg, 0.5 mmol) in THF (0.3 mL) was added drop wise over 30 min. The reaction mixture then allowed to warm to -30 °C and maintained for 3 h. A solution of 5% aq. H 2 SO 4 (0.5 mL) was added at -30 °C and then the reaction was allowed to warm to rt over 30 min. The resulting slurry was extracted with Et 2 O (3 x 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO 2 ; 9:1 hexanes/acetone) to afford 12i (48 mg, 0.2 mmol, 48% yield) as a yellow oil: 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (d, J = 1.2, 1H), 6.47 (d, J = 16.1, 1H), 6.27-6.22 (m, 2H), 6.00 (s, 1H), 5 Gram-scale preparation of 3: A solution of 4 (1.00 g, 4.62 mmol) in n-BuOH (77 mL) was added to a 250 mL quartz round-bottom flask. The reaction mixture was exposed to UV light (hv = 350 nm) at 35 °C in a Rayonet photoreactor. After 55 h, the reaction was removed from the photoreactor, cooled to rt, and Et 3 N (0.7 mL, 5 mmol) was added via syringe. The resulting solution as warmed to 100 °C in a pre-heated oil bath. After 6 h, the reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (neutralized SiO 2 ; 2:1 hexanes/EtOAc) to afford 3 (610 mg, 2.82 mmol, 61% yield) as a yellow solid: mp = 50-51 °C; 1 H NMR (400 MHz, CDCl 3 ) δ 6.08 (d, J = 5.9, 1H), 5.86 (dd, J = 5.9, 1.8, 1H), 5 Cyclobutane 5: A solution of photosubstrate 4 (1.00 g, 4.62 mmol) in MeCN (77 mL) was added to a quartz flask. The reaction mixture was exposed to UV light (hv = 350 nm) at 35 °C in a Rayonet photoreactor. After 21 h, the reaction was removed from the photoreactor and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (neutralized SiO 2 ; 7:2 hexanes/EtOAc) to afford 5 ( Cope-rearrangement product 6: An analytic sample was prepared by charging an NMR tube with a degassed solution of 5 (6.5 mg, 0.03 mmol) in toluene-d 8 (0.5 mL) and heating the reaction mixture to 100 °C for 1.5 h. NMR spectra were collected from the crude reaction mixture: 1 H NMR (600 MHz, toluene-d 8  Preparation of 5-8-5 ring system derivatives 13a-j. General Procedure. A solution of photosubstrate (1 equiv) in MeCN (60 mM) was added to a quartz flask and exposed to UV light (hv = 350 nm) at 35 °C in a Rayonet photoreactor for the indicated amount of time. The reaction was removed from the photoreactor, cooled to rt, and Et 3 N (1.1 equiv) was added via syringe. The resulting solution was warmed to 80 °C or 100 °C in a pre-heated oil bath for the specified amount of time. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting crude products were purified by flash chromatography using neutralized silica gel. 13 Product 13a: Following the general procedure, 13a was synthesized from 12a (96 mg, 0.42 mmol). The reaction mixture was irradiated at 35 °C for 7.5 h. Following addition of Et 3 N, the resulting solution was heated to 80 °C for 2 h. The resulting crude residue was purified by flash chromatography ( Product 13e: Following a variation of the general procedure employing n-BuOH in place of MeCN, 13e was synthesized from 12e (115 mg, 0.50 mmol). The reaction mixture was irradiated at 35 °C for 12 h. Following addition of Et 3 N, the resulting solution was heated to 100 °C for 1 h. The resulting crude residue was purified by flash chromatography (neutralized SiO 2 ; 9:1 hexanes/acetone) to afford 13e (65 mg, 0.28 mmol, 57% yield) as Diastereomer S14: Following a variation of the general procedure employing n-BuOH in place of MeCN, S14 was synthesized from 12g (61.0 mg, 0.23 mmol). The reaction mixture was irradiated at 35 °C for 20 h. Following addition of Et 3 N, the resulting solution was heated to 100 °C for 2 h. The resulting crude residue was purified by flash chromatography (neutralized SiO 2 ; 9:1 Hexanes/EtOAc) to afford S14 (16 mg, 0.06 mmol, Product 13j: Following the general procedure, 13j was synthesized from 12j (182 mg, 0.78 mmol). The reaction mixture was irradiated at 35 °C for 6 h. Following addition of Et 3 N, the resulting solution was heated to 100 °C for 1 h. The resulting crude residue was purified by flash chromatography (neutralized SiO 2 ; 1:1 hexanes/EtOAc) to afford 13i (116 mg, 0.50 mmol, 64% combined yield, 1.3:1 mixture of diastereomers) as a white foam: 1 H NMR (600 MHz, CDCl 3 ) major diastereomer, δ 5.84 (dd, J = 5.9, 1.9, 1H), 4.61 (br s, 1H), 2.55 (s, 1H); minor diastereomer, δ 5.91 (dd, J = 5.9, 1.9, 1H), 4 Silyl enol ether 14: CuI (2.04 g, 10.7 mmol) was added to a flame-dried flask in a glove box. The flask was sealed, removed from the glove box, and THF (68 mL) was added via syringe. The resulting slurry was cooled to 0 °C and a solution of MeLi (13.5 mL, 21.6 mmol, 1.6 M in THF) was added drop wise over 15 min. The resulting solution was cooled to -78 °C. A solution of 3 14 (1.16 mg, 5.35 mmol) and TMSCl (6.7 mL, 27 mmol) in THF (37 mL) was prepared in a separate flask and then added drop wise to the cooled mixture of Me 2 CuLi over 1.5 h using an addition funnel. The resulting solution was maintained at -78 °C for 5 h, then the reaction was rapidly poured into a stirred suspension of Florisil (24 g) suspended in hexanes (220 mL) and Et 3 N (24 mL). 15 The resulting slurry was stirred at 0 °C for 1 h, then filtered. The filter cake was vigorously washed with hexanes (3 x 25 mL). The combined filtrate was filtered again to remove precipitate and concentrated under reduced pressure to afford 14 (1.59 g, 5.22 mmol, 98% yield) as a brown oil in >95% purity. This sensitive intermediate 16  Dieneone 16: A solution of unpurified silyl enol ether 14 (375 mg, 1.23 mmol) in CH 2 Cl 2 (6 mL) was added drop wise over 25 min to a solution of BCl 3 (2.5 mL, 2.5 mmol, 1.0 M in heptane) in CH 2 Cl 2 (6 mL) maintained at -78 °C. After 30 min, Et 3 N (35 mL) followed by MeOH (35 mL) was added via syringe at -78 °C. The reaction mixture was warmed to rt and concentrated under reduced pressure. The resulting oil was diluted with CH 2 Cl 2 (15 mL) and washed with H 2 O (20 mL). The aqueous layer was then extracted with CH 2 Cl 2 (4 x 10 mL). The combined organic extracts were dried over MgSO 4 , filtered, and concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography (SiO 2 ; 6:1 hexanes/acetone) to afford 16 (170 mg, 0.73 mmol, 60% yield) as a yellow solid: mp = 110-111 °C ; Preparation of N-tert-butylbenzenesulfinimidoyl chloride: Following a modification of the procedure reported by Mukiayama, 1 S-phenylthioacetate (2.0 mL, 15 mmol) was added drop wise to a solution N,Ndichloro-2-methylpropan-2-amine (2.69 g, 19 mmol) in benzene (6.5 mL) at rt. The resulting yellow solution was warmed to 80 o C during which time gas evolution occurred and the solution became red. After 2 h, the reaction mixture was concentrated under reduced pressure with care to minimize exposure to atmosphere. The resulting orange residue (3.85 g, 15 mmol, 100% yield) was analyzed for purity using 1 H NMR (>95% purity) and then digested in benzene (7.5 mL) to make a 2 M solution. The resultant orange solution was stable for ca. 1 week when stored under an N 2 atmosphere at rt: 1 H NMR (400 MHz, C 6 D 6 ) δ 7.92-7.88 (m, 2H), 6.94-6.90 (m, 3H), 1.38 (s, 9H). All other characterization data was identical to previously reported values. 1 IMPORTANT: In early iterations of our chemistry we attempted to use commercially available N-tertbutylbenzenesulfinimidoyl chloride. This material resulted in low yield of the resultant photoproducts 12 and invariably arrived in low purity (ca. 50% purity by 1 H NMR). The use of oxidant prepared as described above was critical to achieve the yields reported in this manuscript. Procedure & Analysis: An NMR tube was charged with a solution of E-4 (6.5 mg, 0.04 mmol) in CD 3 CN (0.45 mL). A 1 H NMR spectra of the reaction mixture was obtained under ambient conditions (panel A, above). The reaction mixture was then exposed to 350 nm UV-light at 35 o C in a Rayonet photoreactor. The reaction mixture was analyzed by 1 H NMR in five-minute intervals. Equilibrium was established after 10 min (panel B).
Results were compared to 1 H NMR spectra of independently prepared Z-4 (panel C) in CD 3 CN. We observed an equilibrium ratio of 2.3:1 under these conditions.

1 H NMR Experiment:
Photoequilibration of (Z)-4 Procedure & Analysis: An NMR tube was charged with a solution of Z-4 (6.5 mg, 0.04 mmol) in CD 3 CN (0.45 mL). A 1 H NMR spectra of the reaction mixture was obtained under ambient conditions (panel B, above). The reaction mixture was then exposed to 350 nm UV-light at 35 o C in a Rayonet photoreactor. The unpurified reaction was analyzed by NMR after 30 min (panel C) and 8 h (panel D). Results were compared to 1 H NMR spectra of purified E-4 (panel A) and 5 (panel E) in CD 3 CN, respectively. We observed that Z-4 readily equilibrated to a 2:1 mixture of E/Z-4 within 30 min. During this time we also observed formation of 5. The resulting equilibrium mixture of 4 slowly reacted to form 5 over the course of 8 h. This reaction proved to be highly stereoselective as product 5 was the only diastereomer observed. Procedure & Analysis: An NMR tube was charged with a solution of 5 (6.5 mg, 0.04 mmol) and Nbenzylbenzamide (8.5 mg, 0.04 mmol, internal standard) in CD 3 CN (0.45 mL). A 1 H NMR spectra of the reaction mixture was obtained under ambient conditions (time = 0, 100% 5). The reaction mixture was then exposed to 350 nm UV-light at 35 o C in a Rayonet. Photodecomposition was determined by integration of 5 relative to an N-benzylbenzamide as an internal standard at various time points over a 24 period (see above). We determined a half-life (t 1/2 ) of 18.2 h for 5 under these reaction conditions.

Photochemical reaction setup and analysis of quartz vs. Pyrex glassware.
Pictures of reaction setup in the Rayonet are provided below. Reactions described in Tables 1 and 2 were carried out in quartz flasks as described in the manuscript; however, the use of quartz is not required. As shown in Table S1, Pyrex glassware affords identical results (+/-3% yield, experiments repeated in duplicate) for the photoisomerization of substrate 4 to rearranged cyclooctadiene 3.

A B C
Reaction setup -gram scale