Divergent reaction pathways in gold-catalyzed cycloisomerization of 1,5-enynes containing a cyclopropane ring: dramatic ortho substituent and temperature effects

Gold-catalyzed cycloisomerization of 1,5-enynes containing a cyclopropane ring provides access to cyclobutane-fused 1,4-cyclohexadiene, 1,3-cyclohexadiene, tricyclic cyclobutene and biscyclopropane derivatives.

The substrates 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k, 1l, 1m, 1n, 1o, 1p, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m and 2n were synthesized according to Scheme S2. The corresponding iodide was synthesized according to the previously reported procedures. [2] The compound s-3 was synthesized according to the previously reported procedure: [3] To a 500 mL flame and vacuum dried three-neck flask was added compound s-1 (20.3 mL, 240 mmol) and 100 mL THF under Ar, then n-BuLi (2.5 M, 97 mL, 240 mmol) was added slowly at -78 o C. After the addition was complete, the reaction mixture was allowed to stir at -78 o C for 2 h. TMSCl (33 mL, 240 mmol) was added to the flask slowly at -78 o C. The reaction mixture was allowed to stir at -78 o C for 2 h, and then warmed to rt gradually. After 5 h, the reaction was quenched with water. The reaction mixture was extracted with Et 2 O, and the combined organic phase was dried over anhydrous sodium sulfate. The crude product was purified by vacuum distillation, and the product s-3 (100 mbar, 80 o C fraction) was obtained as a colorless oil (23.0 g, yield = 69%).

Synthesis of compound s-4:
To a 250 mL flame and vacuum dried three-neck flask was added compound s-3 (21.36 g, 154.5 mmol) and 100 mL Et 2 O under Ar, then n-BuLi (1.6 M, 100 mL, 160 mmol). After the addition was complete, the reaction mixture was allowed to stir at rt for 14 h. Allyl bromide (14.0 mL, 160 mmol) was added slowly to the reaction mixture to maintain gentle reflux.
After the addition was complete, the reaction mixture was warmed to rt. The reaction was quenched with water and the reaction mixture was extracted with Et 2 O, and the combined organic phase was dried over anhydrous sodium sulfate. The product s-4 was purified by vacuum distillation (50 mbar, 90-100 o C) and the desired product was afforded as a colorless oil (17.2 g, yield = 63%).

S5
Synthesis of compound 1f: To a 50 mL flask was added s-4a (850 mg, 4.5 mmol) and K 2 CO 3 (700 mg, 5.0 mmol) and 2.5 mL methanol, the reaction mixture was allowed to stir at rt for 2 hours.
Then p-Ph-PhI (1.12 g, 4.0 mmol) and 10 mL TEA (triethylamine) were added into the reaction system, respectively. The reaction mixture was solidified by liquid N 2 , and then evacuated and backfilled with Ar for 3 times. Pd(PPh 3 ) 2 Cl 2 (70 mg, 0.01 mmol) and CuI (38 mg, 0.02 mmol) were added under Ar. The reaction mixture was allowed to stir at rt overnight. The product was purified by column chromatography using PE as an eluent. The corresponding product 1f was afforded as a colorless oil (1.053 g, yield = 91%). The substrate 2o was synthesized according to Scheme S3.
Synthesis of compound s-5: To a 50 mL flask was added s-4a (5.35 g, 30 mmol), THF (20 mL) and TBAF3H 2 O (11.025 g, 35 mmol), the reaction mixture was allowed to stir at rt overnight. The reaction mixture was filtered through a short pad of silica gel using n-pentane as an eluent. The product was purified by distillation under ambient pressure, and the 60 o C fraction was collected as mixtures of THF, DCM and s-5 (4.315 g, yield = 72%, determined by 1 H NMR). The mixture was used in the next step without further purification.
Synthesis of compound 2o: To a 100 mL flask was added NaI (1.09 g), then the flask was flame and vacuum dried and s-5 (mixtures of DCM and THF, 1.5 g, 7.5 mmol) was added and then THF (20 mL) and n-BuLi (2.5 M, 3.25 mL, 8.0 mmol) were added at -78 o C. The reaction mixture was allowed to stir at -78 o C for 2.5 h. BnBr (1.10 mL, 9.0 mmol) was added and the reaction mixture was allowed to stir at 60 o C with an oil bath overnight. The product was purified by column chromatography using PE as an eluent. Product 2o was afforded as a colorless oil (0.863 g, yield = 59%). The substrates 2p and 2q were synthesized according to Scheme S4.
Synthesis of compound s-4d: To a 250 mL flame and vacuum dried three neck flask was added s- 3 (16.22 g, 118 mmol) and Et 2 O (50 mL), then n-BuLi (50 mL, 125 mmol) was added at 0 o C. The reaction mixture was warmed to rt and allowed to stir at rt overnight. (E)-1-bromobut-2-ene (19 g, 125 mmol) was added slowly at 0 o C. The reaction was quenched with H 2 O and the crude product was purified by vacuum distillation. The product s-4d (50 mbar, 100-120 o C fraction) was afforded as a colorless oil (10.053 g, yield = 44%, mixtures of three compounds).
Synthesis of compounds 2p and 2q: To a 50 mL flask was added s-4d (1.00 g, 5 mmol) and K 2 CO 3 (1.00 g, 7.2 mmol) and 2.5 mL methanol, the reaction mixture was allowed to stir at rt for 2 hours. Then 2-iodo-naphthalene (1.27 g, 5.0 mmol) and 10 mL TEA (triethylamine) were added. The reaction mixture was solidified by liquid N 2 , then evacuated and backfilled with Ar for 3 times.

Representative procedure for the gold(I) catalyzed cascade reactions of substrates 1:
To a 25 mL flame and vacuum dried Schlenk tube was added substrate 1a (37 mg, 0.2 mmol), the reaction tube was evacuated and backfilled with Ar.
[JohnPhosAuMeCN]SbF 6 (3.5 mg, 3 mol%) was dissolved in 2.0 mL DCM, and the air was bubbled out with Ar. Then the catalyst solution was added to the Schlenk tube at 0 o C. The reaction mixture was allowed to stir at 0 o C and the reaction S7 was quenched with DMS (dimethyl sulfide) when the reaction was complete. The product was purified by column chromatography using PE as an eluent. The product 3a was afforded as a colorless oil (34 mg, yield = 92%).
Representative procedure for the gold(I) catalyzed cascade reactions of substrates 2 leading to

4:
To a 25 mL flame and vacuum dried Schlenk tube was added substrate 2a (
Compound s-7a was synthesized according to the previously reported procedure: [1] To a 100 mL flask was added s-6 (1.66 g, 10 mmol), K 2 CO 3 (1.38 g, 10 mmol) and 4 mL MeOH, the reaction mixture was allowed to stir at rt for 1 h. 1-iodo-naphthalene (2.54 g, 10 mmol) and 15 mL TEA (triethylamine) were added. The reaction mixture was solidified by liquid nitrogen, then evacuated and backfilled with Ar for 3 times. Pd(PPh 3 ) 2 Cl 2 (100 mg, 0.014 mmol) and CuI (59 mg, 0.031 mmol) were added under Ar. The reaction mixture was allowed to stir at rt overnight. The compound s-7a was purified by column chromatography using PE as an eluent (1.418 g, yield = 64%).
Synthesis of compound s-8a: To a 100 mL flame and vacuum dried flask was added MePPh 3 I (4.04 g, 10 mmol), then the flask was evacuated and backfilled with Ar. THF (20 mL) was added, and then n-BuLi (2.5 M, 4 mL, 10 mmol) was added slowly at -78 o C. After 20 min., s-7a (1.10 g) dissolved in 10 mL THF was added slowly. The reaction mixture was warmed to rt gradually, and allowed to stir at rt for 6 h. The product was purified by column chromatography using PE as an eluent. The compound s-8a was afforded as a colorless oil (880 mg, yield = 81%).

S9
Synthesis of compound s-10a: To a 50 mL flask was added s-9a (914 mg, 3.87 mmol) and 10 mL DMSO, then 1.4 g IBX was added. The reaction mixture was allowed to stir at rt overnight. The product was purified by column chromatography (eluent: PE/EA = 20/1). The product was afforded as a colorless oil (624 mg, yield = 69%).
Synthesis of compound [D 2 ]-2b: To a 100 mL flame and vacuum dried flask was added CD 3 PPh 3 I (2.04 g, 5 mmol), then the flask was evacuated and backfilled with Ar. THF (20 mL) was added, and then n-BuLi (2.5 M, 2.0 mL, 5 mmol) was added slowly at -78 o C. After 20 min., s-10a (624 mg, 2.66 mmol) dissolved in 10 mL dry THF was added to the flask. The reaction mixture was allowed to warm to rt gradually and stirred at rt for 6 hours. The product [D 2 ]-2b was purified by column chromatography using PE as an eluent. The product was afforded as colorless oil (578 mg The deuterium labeling compound [D 2 ]-1a was synthesized according to Scheme S7.
Synthesis of compound s-9c: To a 100 mL flame and vacuum dried flask was added compound s-2 (7.11 g, 50 mmol), then the flask was evacuated and backfilled with Ar. THF (40 mL) was added and then n-BuLi (2.5 M, 20.0 mL, 50 mmol) was added slowly at -78 o C. The reaction mixture was allowed to stir at rt for 1.0 hour, then cooled to -78 o C. Epoxyethane dissolved in THF was added slowly until the color of reaction mixture disappeared. After 20 min., the reaction was quenched with saturated NH 4 Cl solution. The product was purified by silica gel column chromatography (eluent: PE/EA = 10/1 to 4/1). The product was afforded as a colorless oil (7.018 g, yield = 75%).
Synthesis of compound s-10c: To a 100 mL flask was added compound s-9c (3.969 g, 21.3 mmol), then 7.16 g IBX was added. The reaction mixture was allowed to stir at rt overnight. The product was purified by silica gel column chromatography (eluent: PE/EA = 30/1). The product was afforded as a colorless oil (3.625 g, yield = 92%).

Synthesis of compound [D 2 ]-1a:
To a 50 mL flame and vacuum dried flask was added CD 3 PPh 3 I (4.5 g, 11 mmol), then the flask was evacuated and backfilled with Ar. THF (20 mL) was added, and then n-BuLi (2.5 M, 4.4.0 mL, 11 mmol) was added slowly at -78 o C. After 20 min., s-10c (1.84 g, 10 mmol) dissolved in 10 mL dry THF was added to the flask. The reaction mixture was allowed to warm to rt gradually and stirred at rt for 6 hours. The product was purified by silica gel column chromatography using PE as an eluent. The product was afforded as a colorless oil (1.5 g, yield = 82%). The deuterium labeling compound [D 2 ]-1a' was synthesized according to Scheme S8. The deuterated allyl bromide was prepared according to the previously reported procedure. [4] Synthesis of compound [D 2 ]-1a': To a 100 L flame and vacuum dried flask was added compound s-2 (1.42 g, 10 mmol) and 20 mL THF under Ar, then n-BuLi (2.5M, 4.5 mL, 11.25 mmol) was added slowly at rt. The deuterated allyl bromide (Et 2 O solution) was added slowly until the brown color of the reaction mixture disappeared. Compound [D 2 ]-1a' and the compound s-2 can not be separated by silica gel column chromatography. The product was purified by GPC (gel permeation chromatography). The product was afforded as a colorless oil (0.105 g, yield = 6%). S12

Optimization of the Reaction Conditions.
Ph Catalyst temperature, solvent, 12 h Ph 1a 3a  We screened various reaction conditions to find out the optimal reaction conditions for the gold catalyzed cycloisomerization of compound 1a. We found that the product 3a can be obtained in 82% yield using PPh 3 AuCl/AgSbF 6 as catalyst (  (Table SI- 1, entry 4). When the temperature was lowered to -20 o C, the desired product was obtained in 35% yield and the compound 1a can be recovered quantitatively (Table SI- 1, entry 5). When the reaction was conducted at 0 o C and the solvent was degassed with Ar, the desired product can be obtained in 92% yield, and the unidentified byproduct could not be detected (

S13
The primary ligand effect was not obvious. Electron-deficient P(OAr) 3 ligand was not effective for our reaction. PPh 3 , P(p-F-Ph) 3 , and P(p-CF 3 -Ph) 3 gave similar result, indicating that electronic effect in the ligand was not obvious. Poor yield was obtained with electron-rich P(t-Bu) 3

S-A
The formation of product 3 was suggested to obtain through the reaction pathway Cycle II depicted in Scheme 7 in the main text of article. Actually, we initially investigated three possible routes to generate 3 as shown in Scheme S9 (Path a, Path b and Path c). The Path b was ruled out based on both the deuterium labeling experiment and theoretical calculations, since this reaction route was conflicted to the deuterium labeling experiment's results and the intermediate S-B could not be located theoretically. Both Path a and Path c were in consistence with the deuterium labeling experiment's results. However, the intermediate S-A in Path a could not be located theoretically, probably due to the steric hindrance between the ligand and the aryl group. Thus, the Path a was also ruled out. The most possible reaction route Path c is proposed as the Cycle II in Scheme 7. S167 12. Another mechanism for the formation of products 5b and 6b through intermediate 4b'