Rhodium-Catalyzed Synthesis of 2,3-Disubstituted Indoles from β,β-Disubstituted Stryryl Azides

Rhodium carboxylate complexes catalyze the cascade reaction to yield 2,3-disubstituted indoles as single regioisomers.

styrene, which was submitted to the subsequent Fe-mediated nitro-group reduction without further purification.
To a solution of nitro-substituted styrene (prepared from 4.0 mmol of ortho-nitrobenzylphophonate) in 20 mL of AcOH and 20 mL of EtOH was added 1.8 g of Fe powder (32 mmol). The resultant mixture was allowd to reflux at 80 °C overnight. After cooled down to ambient temperature, the resulting mixture was filtrated with a pad of Celite. The filtrate was diluted with 50 mL of water and washed with 3 × 10 mL dichloromethane. The resulting organic phase was washed with 40 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated in vacuo. Purification of the reaction mixture using MPLC afforded the product

C.
General Procedure for the Azidation Reaction. Following the procedure of Tor and co-workers, 7 the aniline group was transformed into an azide (s5). Yields were not optimized.
To a solution of aniline (3 mmol) in 5 mL of CH 2 Cl 2 was added subsequently 24 mg of CuSO 4 , 1.2 mL of Et 3 N, freshly prepared triflyl azide (9 mmol) in 15 mL of CH 2 Cl 2 , 1 mL of water and 2 mL of MeOH. The resulting mixture was allowed to react at room temperature overnight. Then, the reaction mixture was taken up by 15 mL dichloromethane, neutralized with a saturated aq. soln. of NaHCO 3 and washed with 3 × 10 mL of CH 2 Cl 2 . The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated in vacuo. Purification of the reaction mixture using MPLC afforded the product.
14f Styryl Azide 14f. The general procedure for azidation was followed using 0.31 g of aniline s20 (

III. Preparation of Substrates using a Suzuki Reaction.
General Procedure for the Arylboronic Acid Pinacol Ester Syntheses.

C.
General Procedure for the Suzuki Reaction.
Following the procedure of Driver and co-workers, 8 was aniline s6 treated with vinyl triflate s7 in the presence of (dppf)PdCl 2 to produce the desired aniline (s8). Yields were not optimized.
To a mixture of 0.919 g of boronic ether s6 (3.2 mmol), 0.261 g of (dppf)PdCl 2 (0.32 mmol) in 40 mL 1,4dioxane was added 8 mL of a 3M solution of NaOH in water followed by 1.36 g of crude triflate s7 (5.12 mmol). The resultant mixture was heated to 80 °C. After 12 h, the mixture was cooled to room temperature and filtrated through a pad of Celite. The filtrate was diluted with 20 mL saturated NH 4 Cl and extracted with an additional 2 × 30 mL of CH 2 Cl 2 . The combined organic phases were washed with 1 × 30 mL of brine. The resulting organic phase was dried over Na 2 SO 4 , and was concentrated in vacuo. Purification via MPLC afforded the product.
Following the procedure of Tor and co-workers, 7 the aniline group was transformed into an azide (s5). Yields were not optimized.
To a solution of aniline (3 mmol) in 5 mL of CH 2 Cl 2 was added subsequently 24 mg of CuSO 4 , 1.2 mL of Et 3 N, freshly prepared triflyl azide (9 mmol) in 15 mL of CH 2 Cl 2 , 1 mL of water and 2 mL of MeOH. The resulting mixture was allowed to react at room temperature overnight. Then, the reaction mixture was taken up by 15 mL dichloromethane, neutralized with a saturated aq. soln. of NaHCO 3 and washed with 3 × 10 mL of CH 2 Cl 2 . The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated in vacuo. Purification of the reaction mixture using MPLC afforded the product. Styryl Azide 14e. 9 The general procedure for azidation was followed using 0.65 g of aniline s30 (

IV. Development of Rhodium-Catalyzed Migration Reaction.
A. General Procedure for the Screening of Catalysts to Promote the Migration.
To a mixture of 0.026 g of aryl azide 8 (0.1 mmol), 0-100 % w/w of crushed 4 Å mol sieves, and metal salt (0 -5 mol %) in Schlenk tube was added 0.50 mL of solvent. The resulting mixture was heated and, after 16 h, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo. The resulting solid (oil) was dissolved in 1.5 mL of CDCl 3 and 0.007 mL of dibromomethane (0.1 mmol) was added. The areas of the C-H peak on the carbon 6 position in 9 and carbon 10 in 10 were compared to the area of CH 2 Br 2 to derive a yield.

B. Optimized General Procedure.
To a mixture of 0.026 g of aryl azide 5 (0.1 mmol), 100 % w/w of crushed 4 Å mol sieves, and metal salt (Rh 2 (esp) 4 or Rh 2 (hpfb) 4 , 5 mol %) in Schlenk tube was added 0.50 mL of PhMe. The resulting mixture was heated at 70 °C for 16 h, then, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo to afford analytically pure indole. In some cases, purification by MPLC is required.

E.
Effect of Ring Size on Rhodium-Catalyzed Migration.

General Procedure for the Optimization of Conditions to Promote the Migration.
To a mixture of 0.1 mmol of aryl azide 17c (0.1 mmol), 0-100 % w/w of crushed 4 Å mol sieves, and metal salt (0 -5 mol %) in Schlenk tube was added 0.50 mL of solvent. The resulting mixture was heated and, after 16 h, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo. The resulting solid (oil) was dissolved in 1.5 mL of CDCl 3 and 0.007 mL of dibromomethane (0.1 mmol) was added. The areas of the C-H peak on the carbon 13 position in 17c and carbon 13 in 18c were compared to the area of CH 2 Br 2 to derive a yield.

Optimized Procedure for Ring Expansion.
To a mixture of 0.026 g of aryl azide 17 (0.1 mmol), 100 % w/w of crushed 4 Å mol sieves, and metal salt (Rh 2 (O 2 CC 7 H 15 ) 4 , 5 mol %) in Schlenk tube was added 0.50 mL of PhMe. The resulting mixture was heated at  80 °C for 16 h, then, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo to afford analytically pure indole.

Scope and Limitations of Ring Expansion.
18a Indole 18a. 11 The general procedure was followed using 0.035 g of styryl azide 17a (0.189 mmol) and 0. Indole 18d. The general procedure was followed using 0.046 g of styryl azide 17d (0.203 mmol) and 0.008 g of Rh 2 (O 2 CC 7 H 15 ) 4 (0.010 mmol) in 0.6 mL of PhMe. Analysis of the reaction progress using 1 H NMR spectroscopy revealed that 18% of indole 18d formed and 35% starting of aryl azide 17d remained.

V. Mechanistic Experiments
A.

Synthesis of Aryl Azides 27.
Styrene s31. To a solution of 10.4 g of the phosphonium salt (19.3 mmol) in 100 mL of THF at -78 °C, was added 8.5 mL of n-BuLi (2.5 M in hexanes, 21.2 mmol) dropwise. After stirring for 1 h at -78 °C, the mixture was warmed to room temperature and stirred additional half an hour. Then 2.65 g of 2-nitrobenzaldehyde (17.5 mmol) was added, and the mixture was heated to reflux. After 16 h, the reaction mixture was diluted with 50 mL of water and extracted with CH 2 Cl 2 (3 × 30 mL). The resulting organic phase was washed with 60 mL of brine and dried over Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuo to afford styrene s31, which was carried on to the subsequent Fe-mediated reduction without any additional purification.
Aniline s32. To a solution of nitro-substituted styrene s31 in 40 mL of AcOH and 40 mL of EtOH was added 8.6 g of Fe powder (154.4 mmol). The resultant mixture was heated to reflux at 80 °C. After 16 h, the reaction mixture was cooled down to ambient temperature. Once cool, the resulting mixture was filtered through a pad of Celite. The filtrate was diluted with 80 mL of water and washed with 3 × 30 mL of dichloromethane. The resulting organic phase was washed with 50 mL of brine and dried over Na 2 SO 4 . The resulting mixture was filtered, and the filtrate was concentrated in vacuo. Purification by MPLC (10:1 hexanes:EtOAc) afforded the product as a yellow viscous oil as an 67:33 mixture of E-and Z-isomers (1.37 g, 24%, two steps): Spectral data for the major (E) isomer: 1 H NMR (  Aryl Azide 27a. To a solution of 0.82 g of aniline s32 (2.7 mmol) in 5 mL of CH 2 Cl 2 was added subsequently 24 mg of CuSO 4 , 1.2 mL of Et 3 N, freshly prepared triflyl azide (9 mmol) in 15 mL of CH 2 Cl 2 , 1 mL of water and 2 mL of MeOH. The resulting mixture was stirred at room temperature. After 16 h,, the reaction mixture was diluted with 15 mL of CH 2 Cl 2 , and the resulting mixture was neutralized by the addition of a saturated aq. soln. of NaHCO 3 . Once pH 7 was reached, the resulting mixture was washed with 3 × 10 mL of CH 2 Cl 2 . The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated After stirring for 1 h at -78 °C, the mixture was warmed to room temperature and stirred additional half an hour. Then 2.69 g of 2-nitrobenzaldehyde (19.1 mmol) was added, and the mixture was heated to reflux. After 16 h, the reaction mixture was diluted with 50 mL of water and extracted with CH 2 Cl 2 (3 × 30 mL). The resulting organic phase was washed with 60 mL of brine and dried over Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuo to afford styrene s35, which was carried on to the subsequent Fe-mediated reduction without any additional purification.
Aniline s34. To a solution of nitro-substituted styrene s33 in 40 mL of AcOH and 40 mL of EtOH was added 8.6 g of Fe powder (152.8 mmol). The resultant mixture was heated to reflux at 80 °C. After 16 h, the reaction mixture was cooled down to ambient temperature. Once cool, the resulting mixture was filtered through a pad of Celite. The filtrate was diluted with 80 mL of water and washed with 3 × 30 mL of dichloromethane. The resulting organic phase was washed with 50 mL of brine and dried over Na 2 SO 4 . The resulting mixture was Aryl Azide 27b. To a solution of 1.2 g of aniline s34 (3.8 mmol) in 5 mL of CH 2 Cl 2 was added subsequently 32 mg of CuSO 4 , 1.6 mL of Et 3 N, freshly prepared triflyl azide (12 mmol) in 15 mL of CH 2 Cl 2 , 1 mL of water and 2 mL of MeOH. The resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was diluted with 15 mL of CH 2 Cl 2 , and the resulting mixture was neutralized by the addition of a saturated aq. soln. of NaHCO 3 . Once pH 7 was reached, the resulting mixture was washed with 3 × 10 mL of CH 2 Cl 2 . The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated in vacuo. Purification by MPLC (100:1 hexane:EtOAc) afforded the product as a yellow solid as an 1:1 mixture of E-and Z-isomers (  Styrene s35. To a solution of 9.6 g of the phosphonium salt (16.4 mmol) in 60 mL of THF at -78 °C, was added 7.2 mL of n-BuLi (2.5 M in hexanes, 18.1 mmol) dropwise. After stirring for 1 h at -78 °C, the mixture was warmed to room temperature and stirred additional half an hour. Then 2.48 g of 2-nitrobenzaldehyde (16.4 mmol) was added, and the mixture was heated to reflux. After 16 h, the reaction mixture was diluted with 50 mL of water and extracted with CH 2 Cl 2 (3 × 30 mL). The resulting organic phase was washed with 60 mL of brine and dried over Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuo to afford styrene s33, which was carried on to the subsequent Fe-mediated reduction without any additional purification.
Aniline s36. To a solution of nitro-substituted styrene s35 in 30 mL of AcOH and 30 mL of EtOH was added 7.3 g of Fe powder (131.2 mmol). The resultant mixture was heated to reflux at 80 °C. After 16 h, the reaction SI1-34 mixture was cooled down to ambient temperature. Once cool, the resulting mixture was filtered through a pad of Celite. The filtrate was diluted with 70 mL of water and washed with 3 × 30 mL of dichloromethane. The resulting organic phase was washed with 50 mL of brine and dried over Na 2 SO 4 . The resulting mixture was filtered, and the filtrate was concentrated in vacuo. Purification by MPLC (10:1 hexanes:EtOAc) afforded the product as a yellow solid (602 mg, 11%, two steps); Spectral data for the major isomer: 1 H NMR ( (1.6 mmol) in 5 mL of CH 2 Cl 2 was added subsequently 16 mg of CuSO 4 , 0.8 mL of Et 3 N, freshly prepared triflyl azide (6 mmol) in 15 mL of CH 2 Cl 2 , 1 mL of water and 2 mL of MeOH. The resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was diluted with 15 mL of CH 2 Cl 2 , and the resulting mixture was neutralized by the addition of a saturated aq. soln. of NaHCO 3 . Once pH 7 was reached, the resulting mixture was washed with 3 × 10 mL of CH 2 Cl 2 . The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated in vacuo. Purification by MPLC (100:1 hexane:EtOAc) afforded the product as a pale solid (0.26 g, 43%). Spectral data for E-and Z isomer mixture  Styrene s37. To a solution of 8.5 g of the phosphonium salt (15.7 mmol) in 50 mL of THF at -78 °C, was added 6.9 mL of n-BuLi (2.5 M in hexanes, 17.3 mmol) dropwise. After stirring for 1 h at -78 °C, the mixture was warmed to room temperature and stirred additional half an hour. Then 2.4 g of 2-nitrobenzaldehyde (15.7 mmol) was added, and the mixture was heated to reflux. After 16 h, the reaction mixture was diluted with 50 mL of water and extracted with CH 2 Cl 2 (3 × 30 mL). The resulting organic phase was washed with 60 mL of brine and dried over Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuo to afford styrene s37, which was carried on to the subsequent Fe-mediated reduction without any additional purification.

SI1-35
Aniline s38. To a solution of nitro-substituted styrene s37 in 40 mL of AcOH and 40 mL of EtOH was added 7.1 g of Fe powder (125.6 mmol). The resultant mixture was heated to reflux at 80 °C. After 16 h, the reaction mixture was cooled down to ambient temperature. Once cool, the resulting mixture was filtered through a pad of Celite. The filtrate was diluted with 80 mL of water and washed with 3 × 30 mL of dichloromethane. The resulting organic phase was washed with 50 mL of brine and dried over Na 2 SO 4 . The resulting mixture was filtered, and the filtrate was concentrated in vacuo. Purification by MPLC (10:1 hexanes:EtOAc) afforded the product as a pale solid (1024 mg, 21%, two steps); Spectral data for the major isomer: 1 H NMR (500 MHz, CDCl 3 ) δ 7.12 -7.36 (m, 9H), 6.98 -7.04 (m, 1H), 6.81 -6.84 (m, 1H), 6.77 -6.78 (m, 1H), 6.66 -6.68 (m, 1H), 6.50 -6.56 (m, 1H), 3.76 (br, 2H); spectral data for both the E-and Z-isomer: 13  Aryl Azide 27d. To a solution of 0.90 g of aniline s38 (3.0 mmol) in 5 mL of CH 2 Cl 2 was added subsequently 24 mg of CuSO 4 , 1.2 mL of Et 3 N, freshly prepared triflyl azide (9 mmol) in 15 mL of CH 2 Cl 2 , 1 mL of water and 2 mL of MeOH. The resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was diluted with 15 mL of CH 2 Cl 2 , and the resulting mixture was neutralized by the addition of a saturated aq. soln. of NaHCO 3 . Once pH 7 was reached, the resulting mixture was washed with 3 × 10 mL of CH 2 Cl 2 . The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated  Styrene s39. To a solution of 3.46 g of the phosphonium salt (6 mmol) in 60 mL of THF at -78 °C, was added 2.4 mL of n-BuLi (2.5 M in hexanes, 6 mmol) dropwise. After stirring for 1 h at -78 °C, the mixture was warmed to room temperature and stirred additional half an hour. Then 0.91 g of 2-nitrobenzaldehyde (6 mmol) was added, and the mixture was heated to reflux. After 16 h, the reaction mixture was diluted with 50 mL of water and extracted with CH 2 Cl 2 (3 × 30 mL). The resulting organic phase was washed with 60 mL of brine and dried over Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuo to afford styrene s31, which was carried on to the subsequent Fe-mediated reduction without any additional purification.
Aniline s40. To a solution of nitro-substituted styrene s39 in 15 mL of AcOH and 15 mL of EtOH was added 2.7 g of Fe powder (48 mmol). The resultant mixture was heated to reflux at 80 °C. After 16 h, the reaction mixture was cooled down to ambient temperature. Once cool, the resulting mixture was filtered through a pad of Celite. The filtrate was diluted with 20 mL of water and washed with 3 × 10 mL of dichloromethane. The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . The resulting mixture was filtered, and the filtrate was concentrated in vacuo. Purification by MPLC (10:1 hexanes:EtOAc) afforded the product as a yellow solid ( Aryl Azide 27e. To a solution of 0.17 g of aniline s40 (0.5 mmol) in 5 mL of CH 2 Cl 2 was added subsequently 6 mg of CuSO 4 , 0.3 mL of Et 3 N, freshly prepared triflyl azide (2 mmol) in 5 mL of CH 2 Cl 2 , 1 mL of water and 2 mL of MeOH. The resulting mixture was stirred at room temperature. After 16 h, the reaction mixture was diluted with 10 mL of CH 2 Cl 2 , and the resulting mixture was neutralized by the addition of a saturated aq. soln. of NaHCO 3 . Once pH 7 was reached, the resulting mixture was washed with 3 × 10 mL of CH 2 Cl 2 . The resulting organic phase was washed with 20 mL of brine and dried over Na 2 SO 4 . After filtration, the filtrate was concentrated

B. Syntheses of 2,3-Diarylindoles
2-Phenyl-3-arylindoles were synthesized from alkynyltrifluoroacetanilide s41 following the method reported by Cacchi and co-workers. 15 Indole 28b. 15 To a solution of 0.59 g of acetylene (2.0 mmol) in 15 mL of MeCN was added subsequently 1.43 g of Cs 2 CO 3 , 0.1 mol of Pd(PPh 3 ) 4 (5 mol %), 1.14 g of 4-tert-butyliodobenzene (4.4 mmol). The resulting mixture was stirred at 100 °C until complete conversion (2h). After this time, the reaction mixture was cooled to room temperature, diluted with 30 mL of water and extracted with CH 2 Cl 2 (3 × 20 mL). The resulting organic phase was washed with 60 mL of brine and dried over Na 2 SO 4 . Purification by MPLC (30:1 hexane:EtOAc) afforded the product 28b as a yellow solid (0.59 g, 91%). The spectral data matched that reported by Cacchi and co-workers:

Intramolecular Competition Experiments.
To a mixture of 0.023 g of aryl azide 27a (0.07 mmol), 0.023 g of crushed 4 Å mol sieves, and 0.004 g of Rh 2 (O 2 CC 3 F 7 ) 4 (0.004 mol) in Schlenk tube was added 0.50 mL of PhMe. The resulting mixture was heated at 80 °C, after 16 h, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo to afford 0.021 g of a mixture of 28a and 29a (78:22). The resulting solid was dissolved in 1.5 mL of CDCl 3 . The areas of the C-H peak on the methoxy position were compared to derive a ratio (78:22). The products were identified by comparison with published 1 H NMR spectra of 28a. 17 To a mixture of 0.058 g of aryl azide 27b (0.16 mmol), 0.058 g of crushed 4 Å mol sieves, and 0.009 g of Rh 2 (O 2 CC 3 F 7 ) 4 (0.008 mol) in Schlenk tube was added 0.50 mL of PhMe. The resulting mixture was heated at 80 °C, after 16 h, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo to afford 0.053 g of a mixture of 28b and 29b (73:27). The resulting solid was dissolved in 1.5 mL of CDCl 3 . The areas of the C-H peak on the aromatic region were compared to derive a ratio (73:27). The products were identified by comparison with 1 H NMR spectra of 28b.
To a mixture of 0.060 g of aryl azide 27c (0.16 mmol), 0.060 g of crushed 4 Å mol sieves, and 0.009 g of Rh 2 (O 2 CC 3 F 7 ) 4 (0.008 mol) in Schlenk tube was added 0.50 mL of PhMe. The resulting mixture was heated at 80 °C, after 16 h, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo to afford 0.054 g of a mixture of 28c and 29c (60:40). The resulting solid was dissolved in 1.5 mL of CDCl 3 . The areas of the C-H peak on the aromatic region were compared to derive a ratio (60:40). The products were identified by comparison with 1 H NMR spectra of 28c.

SI1-40
To a mixture of 0.043 g of aryl azide 27d (0.13 mmol), 0.043 g of crushed 4 Å mol sieves, and 0.007 g of Rh 2 (O 2 CC 3 F 7 ) 4 (0.006 mol) in Schlenk tube was added 0.50 mL of PhMe. The resulting mixture was heated at 80 °C, after 16 h, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo to afford 0.039 g of a mixture of 28d and 29d (34:66). The resulting solid was dissolved in 1.5 mL of CDCl 3 . The areas of the C-H peak on the aromatic region were compared to derive a ratio (34:66). The products were identified by comparison with 1 H NMR spectra of 28d.
To a mixture of 0.040 g of aryl azide 27e (0.11 mmol), 0.040 g of crushed 4 Å mol sieves, and 0.006 g of Rh 2 (O 2 CC 3 F 7 ) 4 (0.005 mol) in Schlenk tube was added 0.50 mL of PhMe. The resulting mixture was heated at 80 °C, after 16 h, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo to afford 0.032 g of a mixture of 28e and 29e (21:79). The resulting solid was dissolved in 1.5 mL of CDCl 3 . The areas of the C-H peak on the aromatic region were compared to derive a ratio (21:79). The products were identified by comparison with 1 H NMR spectra of 28e.

D. Correlation of Product Ratio with Hammett Plot.
The log of the product ratios were correlated with Hammett σ-values to ascertain the existence of any linear free energy relationships.

D. Examination of Rates of Reaction of E-and Z-Isomers.
To a mixture of 0.043 g of aryl azide 8 (0.16 mmol), 0.043 g of crushed 4 Å mol sieves, and 0.009 g of Rh 2 (O 2 CC 3 F 7 ) 4 (0.008 mol) in Schlenk tube was added 0.60 mL of PhMe. The resulting mixture was heated at 70 °C, after 30 min, the heterogenous mixture was filtered through a short pad of Al 2 O 3 . The filtrate was concentrated in vacuo. The resulting solid (oil) was dissolved in 1.5 mL of CDCl 3 . The areas of the C-H peak on the carbon 9 in starting material aryl azide 8 was compared to derive a E:Z ratio.