SUPPORTING INFORMATION. in the Synthesis of Fluorenones and ortho-arylated. Benzonitriles

Transcription

1 SUPPRTING INFRMATIN Carbon-Hydrogen Bond Functionalization Approach in the Synthesis of Fluorenones and ortho-arylated Benzonitriles Dmitry Shabashov, Jesús R. Molina Maldonado and lafs Daugulis* Department of Chemistry, University of Houston, Houston, TX TABLE F CNTENTS Complete reference 12 General considerations Experimental part NMR spectra S2 S2 S3 S13 S1

2 REFERENCE 12 Plobeck, N.; Delorme, D.; Wei, Z.-Y.; Yang, H.; Zhou, F.; Schwarz, P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt, R.; Yue, S. Y.; Walpole, C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.; St-nge, S.; Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts, E. J. Med. Chem. 2000, 43, GENERAL CNSIDERATINS Reactions were performed without special precautions in 2-dram screw-cap vials. Flash chromatography was performed on 60 Å silica gel. The 1 H and 13 C NMR spectra were recorded using TMS or solvent peak as a standard. Melting points are uncorrected. Chemicals were used as received. 4-t-Butyliodobenzene, 4-chloroiodobenzene, 3-chloroiodobenzene, 3,5- dimethyliodobenzene, 3-trifluoromethoxyiodobenzene, 4-trifluoromethyliodobenzene, 4- bromoiodobenzene, and ethyl 4-iodobenzoate are commercially available. Procedure for silver acetate preparation has been reported before. 1 The following starting materials are known: N- cyclohexyl-3-methylbenzamide, 2 3-bromo-N-cyclohexylbenzamide, 3 N-cyclohexylbenzamide, 4 2-chloro-N-cyclohexylbenzamide, 5 3-methyl-N-propylbenzamide, 6 4-t-butyl-N-propylbenzamide. 7 1 Shabashov, D.; Daugulis,. rg. Lett. 2006, 8, Kimachi, T.; Takemoto, Y. J. rg. Chem. 2001, 66, Kang, D. H.; Joo, T. Y.; Chavasiri, W.; Jang, D.. Tetrahedron Lett. 2006, 48, Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, Gorecka, A.; Leplawy, M.; Zabrocki, J.; Zwierzak, A. Synthesis 1978, Possanzini, M.; Di Palo, V. Chromatographia 1990, 29, Kunishima, M.; Yoshimura, K.; Morigaki, H.; Kawamata, R.; Terao, K.; Tani, S. J. Am. Chem. Soc. 2001, 123, S2

3 EXPERIMENTAL PART 2-Methoxy-N-propylbenzamide: 2-Methoxybenzoic acid (2.0 g, 13.1 mmol) was suspended in thionyl chloride (10 ml) and vigorously refluxed for min. Excess of thionyl chloride was distilled off and residue was dried under vacuum to give a yellow oil. Acid chloride was dissolved in dry dichloromethane (25 ml) followed by addition of n-propylamine (2.5 ml, 30.2 mmol). The resulting mixture was stirred overnight. After that, the reaction mixture was washed with 1M HCl solution, saturated NaHC 3 solution, and organic layer was dried over MgS 4. Evaporation of solvent gave 2.41 g (95%) of colorless oil, R f =0.14 (EtAc/hexanes 1/4). 1 H NMR (300 MHz, CDCl 3, ppm) δ 8.22 (dd, 1H, J= 7.7, 1.9 Hz) 7.88 (br s, 1H) (m, 1H) (m, 1H) 6.97 (d, 1H, J= 8.5 Hz) 3.97 (s, 3H) (m, 2H) (m, 2H) 0.99 (t, 3H, J= 7.4 Hz). 13 C NMR (75 MHz, CDCl 3, ppm) δ 165.2, 157.4, 132.5, 132.3, 121.9, 121.3, 111.3, 55.9, 41.4, 22.9, FT-IR (neat, cm -1 ) υ 3406, Anal. calcd. for C 11 H 15 N 2 : C 68.37, H 7.82, N Found: C 67.83, H 7.86, N General procedure for synthesis of benzonitriles: Benzamide (1 equiv), Pd(Ac) 2 (5 mol%), AgAc ( equiv), and aryl iodide (3-4 equiv) were dissolved in trifluoroacetic acid (0.5 ml) and heated at 120 o C for 0.5-4h. The reaction mixture was cooled to room temperature and trifluoroacetic anhydride (TFAA, equiv.) was added. The vial was placed in oil bath ( o C) for 1-3h. The conversion was monitored by GC. After completion of reaction, ether was added to reaction mixture followed by filtration through a pad of Celite. Filtrate was washed twice with aqueous NaHC 3. rganic layer was dried over MgS 4. Solvent was removed by evaporation in vacuum and residue was purified by flash chromatography. S3

4 CN Cl 2-(4-Chlorophenyl)-5-methylbenzonitrile: N-Cyclohexyl-3-methylbenzamide (152 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (140 mg, 0.84 mmol), and 4- chloroiodobenzene (501 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 1h at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (200 µl, 1.4 mmol) was added and reaction mixture was heated for 1h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/17) and recrystallization from hexanes gave 130 mg (65%) of a crystalline material, mp o C (hexanes), R f =0.36 (EtAc/hexanes 1/10). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.57 (d, 1H, J= 1.4 Hz) (m, 5H) 7.37 (d, 1H, J= 8.0 Hz) 2.43 (s, 3H). 13 C NMR (75 MHz, CDCl 3, ppm) δ 141.7, 138.4, 136.8, 135.0, 134.3, 134.0, 130.2, 130.0, 129.2, 118.7, 111.3, FT-IR (neat, cm -1 ) υ Anal. calcd. for C 14 H 10 ClN: C 73.85, H 4.43, N Found: C 73.74, H 4.49, N (3,5-Dimethylphenyl)-5-methylbenzonitrile: N-Cyclohexyl-3-methylbenzamide (152 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and 3,5- dimethyliodobenzene (487 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 30 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 1.5h at 90 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/15 to 1/10) followed by preparative HPLC (EtAc/hexanes 1/15) gave 83 mg (54%) of crystalline material, mp o C (hexanes), S4

5 R f =0.34 (EtAc/hexanes 1/10). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.54 (s, 1H) (m, 2H) 7.14 (s, 2H) 7.06 (s, 1H) 2.41 (s, 3H) 2.38 (s, 6H). 13 C NMR (75 MHz, CDCl 3, ppm) δ 143.3, 138.4, 137.6, 134.1, 133.7, 130.3, 130.1, 126.8, 119.0, 111.4, 21.5, ne carbon signal could not be detected. FT-IR (neat, cm -1 ) υ Anal. calcd. for C 16 H 15 N: C 86.84, H 6.83, N Found: C 86.57, H 6.92, N ,3,7-Trimethylfluoren-9-one byproduct was isolated by preparative HPLC (EtAc/hexanes 1/15) as a yellow crystalline material (42 mg, 27%). Spectral properties are identical with the compound obtained from 3-methyl-N-propylbenzamide (Table 2, entry 2). 2-(4-Ethoxycarbonylphenyl)-5-methylbenzonitrile: N-Cyclohexyl-3-methylbenzamide (152 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and ethyl 4- iodobenzoate (580 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 40 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 1.5h at 90 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/9 to 1/7) gave 135 mg (73%) of crystalline material, mp o C (EtAc/hexanes), R f =0.42 (EtAc/hexanes 1/4). 1 H NMR (300 MHz, CDCl 3, ppm) δ (m, 2H) (m, 3H) (m, 2H) 4.14 (q, 2H, J=7.2 Hz) 2.45 (s, 3H) 1.42 (t, 3H, J= 7.2 Hz). 13 C NMR (75 MHz, CDCl 3, ppm) δ 166.3, 142.6, 141.8, 138.7, 134.3, 134.0, 130.8, , , 129.0, 118.6, 111.4, 61.3, 20.9, FT-IR (neat, cm -1 ) υ 2224, Anal. calcd. for C 17 H 15 N 2 : C 76.96, H 5.70, N Found: C 77.10, H 5.72, N S5

6 5-Bromo-2-(4-ethoxycarbonylphenyl)-benzonitrile: 3-Bromo-N-cyclohexylbenzamide (197 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and ethyl 4- iodobenzoate (580 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 2h at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 2h at 90 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/8) gave 130 mg (56%) of crystalline material, mp o C (EtAc/hexanes), R f =0.40 (EtAc/hexanes 1/4). 1 H NMR (300 MHz, CDCl 3, ppm) δ (m, 2H) 7.92 (d, 1H, J=2.1 Hz) 7.81 (dd, 1H, J=8.4, 2.1 Hz) (m, 2H) 7.42 (d, 1H, J=8.4 Hz) 4.42 (q, 2H, J=7.1 Hz) 1.42 (t, 3H, J= 7.1 Hz). 13 C NMR (75 MHz, CDCl 3, ppm) δ 166.2, 143.5, 141.4, , , 131.6, 131.3, 130.3, 128.8, 122.2, 117.1, 113.3, 61.5, FT-IR (neat, cm -1 ) υ 2227, Anal. calcd. for C 16 H 12 BrN 2 : C 58.20, H 3.66, N Found: C 58.42, H 3.65, N Bromo-2-(3-chlorophenyl)-benzonitrile: 3-Bromo-N-cyclohexylbenzamide (197 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and 3- chloroiodobenzene (501 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 2h at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (200 µl, 1.4 mmol) was added and reaction mixture was heated for 1h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/19 to 1/15) gave 148 mg (72%) of crystalline material, mp S6

7 o C (EtAc/hexanes), R f =0.37 (EtAc/hexanes 1/10). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.91 (d, 1H, J=2.1 Hz) 7.79 (dd, 1H, J=8.4, 2.1 Hz) (m, 1H) (m, 3H) 7.38 (d, 1H, J=8.4 Hz). 13 C NMR (75 MHz, CDCl 3, ppm) δ 143.0, 138.9, 136.4, 136.3, 135.1, 131.6, 130.4, 129.4, 128.9, 127.1, 122.1, 117.0, FT-IR (neat, cm -1 ) υ Anal. calcd. for C 13 H 7 BrClN: C 53.37, H 2.41, N Found: C 53.44, H 2.39, N Chloro-2-(4-trifluoromethylphenyl)-benzonitrile: 2-Chloro-N-cyclohexylbenzamide (166 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and 4- trifluoromethyliodobenzene (571 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 4h at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (200 µl, 1.4 mmol) was added and reaction mixture was heated for 1h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/10) gave 166 mg (84%) of crystalline material, mp o C (EtAc/hexanes), R f =0.22 (EtAc/hexanes 1/10). 1 H NMR (300 MHz, CDCl 3, ppm) δ (m, 2H) (m, 2H) (m, 2H) 7.41 (dd, 1H, J=7.2, 1.7 Hz). 13 C NMR (75 MHz, CDCl 3, ppm) δ 146.6, 141.3, 138.7, 133.6, (q, J C- F=32.5 Hz), 129.5, 128.4, (q, J C-F =5.3 Hz), (q, J C-F =273.7 Hz), 115.2, Signal for one carbon could not be detected. FT-IR (neat, cm -1 ) υ Anal. calcd. for C 14 H 7 ClF 3 N: C 59.70, H 2.50, N Found: C 59.80, H 2.51, N ,6-Bis-(3-trifluoromethoxyphenyl)-benzonitrile: N-Cyclohexylbenzamide (142 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (269 mg, 1.61 mmol), and 3- S7

8 trifluoromethoxyiodobenzene (806 mg, 2.8 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 3h at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (200 µl, 1.4 mmol) was added and reaction mixture was heated for 3h at 90 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/16 to 1/11) gave 188 mg (63%) of crystalline material, mp o C (hexanes), R f =0.30 (EtAc/hexanes 1/10). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.72 (t, 1H, J=7.8 Hz) (m, 6H) 7.42 (s, 2H) (m, 2H). 13 C NMR (75 MHz, CDCl 3, ppm) δ 149.6, 145.6, 140.5, 132.9, 130.4, 129.6, 127.7, 121.9, 121.4, (q, J C-F =258.3 Hz) 117.2, FT-IR (neat, cm -1 ) υ Anal. calcd. for C 21 H 11 F 6 N 2 : C 59.58, H 2.62, N Found: C 59.76, H 2.59, N General procedure for synthesis of fluorenones: Benzamide (1 equiv), Pd(Ac) 2 (5 mol%), AgAc ( equiv), and aryl iodide (3-4 equiv) were dissolved in trifluoroacetic acid (0.5 ml) and heated at 120 o C for 0.5-1h. The reaction mixture was cooled to room temperature and trifluoroacetic anhydride (TFAA, equiv.) was added. The vial was placed in oil bath (110 o C) for 1-4.5h. The conversion was monitored by GC. After completion of reaction, ether or dichloromethane was added to reaction mixture and the reaction mixture was filtered through a pad of Celite. Filtrate was washed twice with aqueous NaHC 3. rganic layer was dried over MgS 4. Solvent was removed by evaporation in vacuum and residue was purified by flash chromatography. 7-Methyl-2-trifluoromethylfluoren-9-one: 3-Methyl-N-propylbenzamide (124 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (140 mg, 0.84 mmol), and 4- trifluoromethyliodobenzene (571 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting S8

9 solution was heated for 40 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 4.5h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/17 to 1/13) gave 137 mg (75%) of yellow crystalline material, mp o C (EtAc/hexanes), R f =0.41 (EtAc/hexanes 1/10). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.89 (s, 1H) 7.73 (d, 1H, J=7.9 Hz) 7.57 (d, 1H, J=7.9 Hz) 7.52 (s, 1H) 7.47 (d, 1H, J=7.7 Hz) 7.34 (d, 1H, J=7.7 Hz) 2.41 (s, 3H). 13 C NMR (75 MHz, CDCl 3, ppm) δ 192.5, 147.9, 140.9, 140.7, 135.8, 134.9, (q, J C-F =5.3 Hz) (q, J C- F=32.8 Hz) 125.6, (q, J C-F =271.5Hz) , , 121.1, 120.3, FT-IR (neat, cm -1 ) υ Anal. calcd. for C 15 H 9 F 3 : C 68.70, H Found: C 68.44, H ,3,7-Trimethylfluoren-9-one: 8 3-Methyl-N-propylbenzamide (124 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (140 mg, 0.84 mmol), and 3,5-dimethyliodobenzene (487 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 40 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (200 µl, 1.4 mmol) was added and reaction mixture was heated for 1h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/16 to 1/11) gave 123 mg (79%) of yellow crystalline material, R f =0.50 (EtAc/hexanes 1/10). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.42 (s, 1H) 7.35 (d, 1H, J=7.6 Hz) 7.24 (d, 1H, J=7.6 Hz; signal partially overlaps with solvent peak) 7.12 (s, 1H) 6.81 (s, 1H) 2.57 (s, 3H) 2.37 (s, 3H) 2.36 (s, 3H). 8 Reim, S.; Lau, M.; Langer, P. Tetrahedron Lett. 2006, 47, 6903 S9

10 7-Ethoxycarbonyl-1-methoxyfluoren-9-one: 2-Methoxy-N-propylbenzamide (135 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and ethyl 4- iodobenzoate (580 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 40 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 1h at 110 o C. Dichloromethane (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (CH 2 Cl 2 followed by CH 2 Cl 2 /EtAc 20/1 to 10/1) gave 131 mg (66%) of yellow crystalline material, mp o C (CH 2 Cl 2 /hexanes), R f =0.34 (CH 2 Cl 2 ). 1 H NMR (300 MHz, CDCl 3, ppm) δ 8.29 (d, 1H, J=1.3 Hz) 8.19 (dd, 1H, J=7.8, 1.6 Hz) 7.58 (d, 1H, J=7.8 Hz) (m, 1H) 7.21 (d, 1H, J=7.3 Hz) 6.91 (d, 1H, J=8.6 Hz) 4.40 (q, 2H, J=7.2 Hz) 4.01 (s, 3H) 1.42 (t, 3H, J=7.2 Hz). 13 C NMR (75 MHz, CDCl 3, ppm) δ 190.6, 165.9, 158.9, 147.4, 145.7, 137.1, 135.7, 135.0, 132.0, 125.1, 121.3, 120.2, 114.6, 113.9, 61.4, 56.3, FT-IR (neat, cm -1 ) υ Me Br 2-Bromo-8-methoxyfluoren-9-one: 2-Methoxy-N-propylbenzamide (135 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and 4-bromoiodobenzene (594 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 30 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 1h at 110 o C. Dichloromethane (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (CH 2 Cl 2 /hexanes 2/1 to 5/1) followed by recrystallization from acetone-hexanes S10

11 gave 125 mg (62%) of yellow crystalline material, mp o C (acetone/hexanes), R f =0.43 (CH 2 Cl 2 /hexanes 5/1). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.76 (d, 1H, J=1.7 Hz) 7.58 (dd, 1H, J=7.7, 1.7 Hz) (m, 1H) 7.37 (d, 1H, J=7.8 Hz) 7.12 (d, 1H, J=7.4 Hz) 6.86 (d, 1H, J=8.5 Hz) 3.99 (s, 3H). 13 C NMR (75 MHz, CDCl 3, ppm) δ 190.3, 158.8, 145.9, 142.0, 137.3, , , 127.4, 123.3, 121.8, 120.1, 113.7, 113.2, FT-IR (neat, cm -1 ) υ Anal. calcd. for C 14 H 9 Br 2 : C 58.16, H Found: C 58.11, H tert-Butyl-1-methoxyfluoren-9-one: 2-Methoxy-N-propylbenzamide (135 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and 4-t-butyliodobenzene (546 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). The solution was heated for 30 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 1h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/7 to 1/4) gave 116 mg (62%) of yellow crystalline material, mp o C (EtAc/hexanes), R f =0.65 (EtAc/hexanes 1/1). 1 H NMR (300 MHz, CDCl 3, ppm) δ 7.70 (d, 1H, J=1.8 Hz) 7.48 (dd, 1H, J=7.8, 1.8 Hz) (m, 2H) 7.10 (d, 1H, J=7.3 Hz) 6.81 (d, 1H, J=8.4 Hz) 3.99 (s, 3H) 1.34 (s, 9H). 13 C NMR (75 MHz, CDCl 3, ppm) δ 192.3, 158.6, 153.2, 146.9, 140.8, 136.8, 134.9, 130.9, 121.3, 120.8, 120.1, 113.0, 112.9, 56.1, 35.3, FT-IR (neat, cm -1 ) υ Anal. calcd. for C 18 H 18 2 : C 81.17, H Found: C 81.08, H S11

12 6-tert-Butyl-2-chloro-8-(4-chlorophenyl)-fluoren-9-one: 4-t-Butyl-N-propylbenzamide (153 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (269 mg, 1.61 mmol), and 4- chloroiodobenzene (668 mg, 2.8 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 1h at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (300 µl, 2.1 mmol) was added and reaction mixture was heated for 3h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/7 to 1/3) gave 170 mg (64%) of yellow crystalline material, mp o C (EtAc/hexanes), R f =0.29 (CH 2 Cl 2 /hexanes 1/4). 1 H NMR (300 MHz, CDCl 3, ppm) δ (m, 3H) (m, 5H) 7.17 (d, 1H, J=1.7 Hz) 1.40 (s, 9H). 13 C NMR (75 MHz, CDCl 3, ppm) δ 191.3, 159.3, 145.2, 142.0, 141.2, 136.5, 136.3, 135.3, 134.6, 134.0, 130.7, 128.7, 128.4, 127.5, 124.5, 121.2, 117.2, 35.8, FT-IR (neat, cm -1 ) υ Anal. calcd. for C 23 H 18 Cl 2 : C 72.45, H Found: C 72.71, H Benzonitrile formation from isopropyl benzamide N-Isopropyl-3-methylbenzamide (124 mg, 0.7 mmol), Pd(Ac) 2 (7.8 mg, mmol), AgAc (152 mg, 0.91 mmol), and 4-chloroiodobenzene (501 mg, 2.1 mmol) were dissolved in TFA (0.5 ml). Resulting solution was heated for 40 min at 120 o C. After cooling to room temperature, trifluoroacetic anhydride (200 µl, 1.4 mmol) was added and reaction mixture was heated for 1h at 110 o C. Ether (5 ml) was added to reaction mixture followed by work-up as described in general procedure. Purification by flash chromatography (EtAc/hexanes 1/8 to 1/5) gave 147 mg of an 8:1 mixture of 2-(4-chlorophenyl)-5-methylbenzonitrile and 2-chloro-7- methylfluorenone (NMR analysis by comparison with authentic products). S12

13 NMR DATA Me N H Entry 3, Table 2, SM PPM S13

14 Me N H Entry 3, Table 2, SM PPM S14

15 CN Cl Entry 1, Table 1, PR PPM S15

16 CN Cl Entry 1, Table 1, PR PPM S16

17 CN Entry 2, Table 1, PR PPM S17

18 CN Entry 2, Table 1, PR PPM S18

19 CN Entry 3, Table 1, PR PPM S19

20 CN Entry 3, Table 1, PR PPM S20

21 CN Br Entry 4, Table 1, PR PPM S21

22 CN Br Entry 4, Table 1, PR PPM S22

23 CN Cl Br Entry 5, Table 1, PR PPM S23

24 CN Cl Br Entry 5, Table 1, PR PPM S24

25 Cl CN CF3 Entry 6, Table 1, PR PPM S25

26 Cl CN CF 3 Entry 6, Table 1, PR PPM S26

27 CF3 CF3 CN Entry 7, Table 1, PR PPM S27

28 CF3 CF3 CN Entry 7, Table 1, PR PPM S28

29 CF3 Entry 1, Table 2, PR PPM S29

30 CF3 Entry 1, Table 2, PR PPM S30

31 Entry 2, Table 2, PR PPM S31

32 Me Entry 3, Table 2, PR PPM S32

33 Me Entry 3, Table 2, PR PPM S33

34 Me Br Entry 4, Table 2, PR PPM S34

35 Me Br Entry 4, Table 2, PR PPM S35

36 Me Entry 5, Table 2, PR PPM S36

37 Me Entry 5, Table 2, PR PPM S37

38 Cl Cl Entry 6, Table 2, PR PPM S38

39 Cl Cl Entry 6, Table 2, PR PPM S39