HETEROCYCLES

Paper | Special issue | Vol. 82, No. 2, 2011, pp. 1617-1631
Received, 16th September, 2010, Accepted, 5th November, 2010, Published online, 18th November, 2010.
DOI: 10.3987/COM-10-S(E)125

■ Synthesis of 2- and 3-Indolylpyrroles via 1,3-Dipolar Cycloadditions of Münchnones and Nitroalkenes

Justin M. Lopchuk and Gordon W. Gribble*

6128 Burke Laboratory, Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, U.S.A.

Abstract

A series of 2- and 3-indolylpyrroles were generated via 1,3-dipolar cycloadditions between (2-nitrovinyl)indoles and symmetrical and unsymmetrical 1,3-oxazolium-5-olates (münchnones).

INTRODUCTION
Methods for the synthesis of biheteroaryl compounds are of great importance due to the broad applicability and privileged nature1 of these structures, which include natural products,2 pharmaceuticals,3 and materials such as polymers4 and dyes.5 Naturally occurring biheteroaryl structures exist as unfused2 or fused systems, examples of which are shown in Figure 1.2

Currently, the most common way to synthesize these heterocycles is with transition metal catalyzed cross-coupling.6 While these methods are rapidly improving, the direct cross-coupling of two heteroaryl moieties remains a challenge.7 Few other methods exist for providing convenient access to simple unfused indolylpyrrole core structures. Mohanakrishnan and coworkers recently disclosed a cycloaddition method based on tosylmethylisocyanide (TosMIC) which allows access to protected indolylpyrrole structures.8 Our laboratory has long been interested in the use of 1,3-oxazolium-5-olates (münchnones) for the synthesis of both fused heteroaromatics9 and caged systems.10 The 1,3-dipolar cycloaddition of münchnones and nitroalkenes provides an orthogonal and transition metal-free methodology that allows flexible access to these structures. As an extension of our work with 2- and 3- nitroindoles,9 we endeavored to examine various 2- and 3-(2-nitrovinyl)indoles as substrates for 1,3-dipolar cycloadditions with symmetrical and unsymmetrical münchnones.

RESULTS AND DISCUSSION
The münchnone precursors were prepared as previously reported9 and the cyclized münchnones were generated in situ (Scheme 1) with N,N’-diisopropylcarbodiimide (DIPC).

In lieu of the conventional Henry reaction approach, 3-(2-nitrovinyl)indoles 12 and 13 were synthesized directly from indoles 9 and 10 by an addition-elimination reaction of 1-(dimethylamino)-2-nitroethylene11 (Scheme 2). However, the attempted synthesis of 14 using this route failed, presumably because 1-(phenylsulfonyl)indole 11 is too electron-deficient to undergo the requisite initial Michael addition reaction.

Compound 14 was instead prepared by N-protection of indole-3-carboxaldehyde12 followed by condensation with nitromethane in a standard Henry reaction13 (Scheme 3).

The unprotected and methyl–protected 2-(2-nitrovinyl)indoles were generated in four and five steps, respectively, from commercially available indole-2-carboxylic acid through a sequence of esterification,14 reduction,15 oxidation,15 protection16 (for the N-methyl derivative), and condensation with nitromethane17 (Scheme 4). Attempted generation of 20 from 19 with methyl iodide or dimethyl sulfate did not yield an appreciable amount of the desired product.

Instead, 1-(phenylsulfonyl)indole derivative 21 was generated (Scheme 5) from indole via N-protection,18 C2-lithiation (quenching with DMF),19 and condensation with nitromethane.17

With the nitroalkenes in hand, their reactivity with münchnones 5-8 was investigated. Gratifyingly, 3-(2-nitrovinyl)indoles 12-14 reacted smoothly with symmetrical münchnones 5 and 6 to give the corresponding pyrrole products 24-29 in good yields (Table 1). It is proposed that the 1,3-dipolar cycloadditions proceed though a bicyclic adduct which expels carbon dioxide and eliminates nitrous acid to give the substituted N-benzyl-3-indolylpyrroles (Scheme 6).9 The protecting group on the indole (or lack thereof) seemingly had no effect on the reaction.

In a similar manner, 2-(2-nitrovinyl)indoles 19-21 were allowed to react with symmetrical münchnones 5 and 6. The corresponding 3-pyrrol-2-ylindoles were obtained in high yield and again, the various protecting groups on the starting indoles had no effect on the outcome of the reaction (Table 2).

With the success of münchnones 5 and 6, we turned our attention to unsymmetrical münchnones 7 and 8 and tested them under the same reaction conditions. The reaction of münchnone 7 with 3-(2-nitrovinyl)indoles 12-14 gave the expected pyrrole products in moderate to good yield with reasonably good regioselectivity (Table 3). The protecting group on the indole nitrogen did appear to alter the reaction; phenylsulfonyl deriviative 14 was optimal and yielded the major product in an 88:12 ratio and in 71% overall yield. However, münchnone 8 gave substantially different results (Table 3). In each case, 8 was both less reactive (lower yielding) and less regioselective. Phenylsulfonyl deriviative 14 still provided the highest yielding reaction (65%) but was completely nonselective, giving essentially a 1:1 mixture of isomers.

Once again, 2-(2-nitrovinyl)indoles 19-21 proved more reactive then their isomeric counterparts. The reactions with münchnone 7 proceeded in good to excellent yield with good regioselectivity (Table 4). While phenylsulfonyl indole 21 gave the best yield, it also showed the lowest selectivity of the group. Methyl–protected indole 20 exhibited a 9:1 selectivity with a 76% yield. As expected, münchnone 8 was less reactive in all cases; however, the selectivity was reasonably good in each case. Most surprisingly, N-methylindole 20 afforded the opposite major product then what was expected based on the other results in this study. The reason for this change is unknown and currently under investigation. As has mostly been the case, N-phenylsulfonylindole 21 gave optimal results with a ratio of 91:9 in 78% yield.

In summary, we report a reaction protocol that allows access to a variety of substituted 2- and 3-indolyl pyrroles in moderate to high yields. In the case of unsymmetrical münchnones, the regioselectivity varies substantially from being completely nonselective to where the major products are obtained in a 9:1 ratio. Extensions of this methodology to other heterocyclic systems as well as mechanistic and computational studies designed to rationalize both the reactivity and regioselectivity are currently underway and will be reported in due course.

EXPERIMENTAL
General: 1H NMR (300 MHz), 13C NMR (75 MHz), and NOE experiments were performed on a Varian Unity spectrometer. Chemical shifts are reported in ppm with the solvent signal used as an internal reference (CDCl3, 7.26 ppm). Coupling constants are reported in Hz and peak splittings are listed as broad singlet (br s), singlet (s), doublet (d), doublet of doublets (dd), triplet (t), or multiplet (m). Tetrahydrofuran (THF) was obtained by distillation from sodium benzophenone ketyl immediately prior to use. All other commercial reagents were used as received.

3-(2-Nitrovinyl)-1H-indole11 (12): A round bottom flask was charged with 1-(dimethylamino)-2-nitroethylene (1.06 g, 9.1 mmol, 1.2 eq.) and CH2Cl2 (25 mL). The flask was cooled to 0 °C. Trifluoroacetic acid (2.02 g, 17.7 mmol, 2.3 eq.) was added slowly, followed by a solution of indole (2.00 g, 7.6 mmol, 1.0 eq.) in CH2Cl2 (15 mL). The resulting solution was stirred at 0 °C for 65 min then poured into ice water (100 mL) and the layers separated. The aqueous layer was extracted with CH2Cl2 (2 x 60 mL) and the combined organic extracts were washed with saturated aqueous NaHCO3 (1 x 60 mL), brine (1 x 60 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel (30% EtOAc in hexanes) to give 12 as a light brown solid (1.32 g, 92%). 1H NMR (CDCl3) δ 8.74 (br s, 1H), 8.30 (d, 1H, J = 13.4 Hz), 7.83-7.78 (m, 2H), 7.68 (d, 1H, J = 2.9 Hz), 7.50-7.46 (m, 1H), 7.39-7.32 (m, 2H).

1-Methyl-3-(2-nitrovinyl)-1H-indole11 (13): A round bottom flask was charged with 1-(dimethylamino)-2-nitroethylene (2.12 g, 18.2 mmol, 1.2 eq.) and CH2Cl2 (50 mL). The flask was cooled to 0 °C. Trifluoroacetic acid (4.04 g, 35.4 mmol, 2.3 eq.) was added slowly, followed by a solution of 1-methylindole (2.00 g, 15.2 mmol, 1.0 eq.) in CH2Cl2 (30 mL). The resulting solution was stirred at 0 °C for 45 min then poured into ice water (150 mL) and the layers separated. The aqueous layer was extracted with CH2Cl2 (2 x 100 mL) and the combined organic extracts were washed with saturated aqueous NaHCO3 (1 x 100 mL), brine (1 x 100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel (30% EtOAc in hexanes) to give 13 as an orange solid (2.43 g, 79%). 1H NMR (CDCl3) δ 8.25 (d, 1H, J = 13.4 Hz), 7.78-7.73 (m, 2H), 7.52 (s, 1H), 7.42-7.31 (m, 3H), 3.87 (s, 3H).

3-(2-Nitrovinyl)-1-(phenylsulfonyl)-1H-indole20 (14): A round bottom flask was charged with ammonium acetate (2.14 g, 27.8 mmol, 2.4 eq.), nitromethane (4.87 g, 79.8 mmol, 6.9 eq.), and acetic acid (25 mL). 1-(phenylsulfonyl)indole-3-carboxaldehyde (3.30 g, 11.6 mmol, 1 eq.) was added and the mixture was heated to 100 °C for 6 h, cooled to room temperature, and stirred overnight. The reaction mixture was poured into distilled water (100 mL) and 2M NaOH was added with stirring until the pH = 7. The aqueous solution was extracted with EtOAc (4 x 50 mL); the combined organic extracts were washed with brine (1 x 50 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel (30% EtOAc in hexanes) to give 14 as a tan solid (3.58 g, 94%). 1H NMR (CDCl3) δ 8.15 (s, 1H), 8.05-7.94 (m, 2H), 7.77-7.37 (m, 9H).

Representative procedure for the synthesis of 19-21: A round bottom flask was charged with indole-2-carboxaldehyde (1.0 g, 6.89 mmol, 1.0 eq.), nitromethane (1.5 g, 24.6 mmol, 3.6 eq), and methanol (25 mL). The flask was cooled to 0 °C (ice bath) and 50% aqueous sodium hydroxide (7.5 mL) was added slowly dropwise with vigorous stirring. After 90 min, an ice-water mixture (25 mL) was added. The resulting mixture was poured slowly into ice cold 20% aqueous HCl (150 mL) under stirring. After 5 min, the crude 19 which precipitated was collected by vacuum filtration over sintered glass and dried in air.

2-(2-Nitrovinyl)-1H-indole17 (19): The crude product was purified by flash chromatography over silica gel (30% EtOAc in hexanes) to give 19 as a light brown solid (1.13 g, 87%). 1H NMR (CDCl3) δ 8.31 (br s, 1H), 8.05 (d, 1H, J = 13.4 Hz), 7.66 (d, 1H, J = 8.1 Hz), 7.50 (d, 1H, J = 13.7 Hz), 7.42-7.32 (m, 2H), 7.20-7.15 (m, 1H), 7.07 (s, 1H).

1-Methyl-2-(2-nitrovinyl)-1H-indole21 (20): The crude product was purified by flash chromatography over silica gel (30% EtOAc in hexanes) to give 20 as an orange solid (1.17 g, 84%). 1H NMR (CDCl3) δ 8.17 (d, 1H, J = 13.4 Hz), 7.71-7.63 (m, 2H), 7.35 (d, 2H, J = 5.6 Hz), 7.19-7.13 (m, 1H), 7.10 (s, 1H), 3.88 (s, 3H).

2-(2-Nitrovinyl)-1-(phenylsulfonyl)-1H-indole (21): The crude product was purified by flash chromatography over silica gel (30% EtOAc in hexanes) to give 21 as a yellow solid (0.91 g, 87%). 1H NMR (CDCl3) δ 8.81 (d, 1H, J = 13.4 Hz), 8.26 (d, 1H, J = 8.6 Hz), 7.76 (d, 1H, J = 9.5 Hz), 7.59-7.26 (m, 8H), 7.11 (s, 1H); HRMS (ESI+) m/z calculated for C16H13N2O4S (MH+) 329.0596, found 329.0602.

Representative procedure for the reaction of nitroalkenes and münchnones (24-41): A round bottom flask was charged with the 3-(2-nitrovinyl)indole (94 mg, 0.50 mmol, 1 eq.), münchnone precursor 1 (518 mg, 1.5 mmol, 3 eq.) and THF (20 mL). DIPC (233 µL, 1.5 mmol, 3 eq.) was added and the mixture was heated to reflux under nitrogen for 18-24 h. Once TLC indicated complete consumption of the nitroalkene, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified directly by flash chromatography over silica gel (1:3 CH2Cl2:hexanes) to yield pure 24.

3-(1-Benzyl-2,5-diphenyl-1H-pyrrol-3-yl)-1H-indole (24): White solid, 78% yield; 1H NMR (CDCl3) δ 7.87 (d, 2H, J = 7.1 Hz), 7.52-7.11 (m, 16H), 6.81 (s, 1H), 6.76 (d, 2H, J = 7.6 Hz), 6.70 (s, 1H), 5.20 (s, 2H); 13C NMR (CDCl3) δ 139.7, 136.2, 135.7, 133.9, 133.8, 132.3, 132.1, 131.6, 131.1, 129.3, 129.1, 129.0, 128.9, 128.7, 128.5, 128.5, 128.0, 127.6, 127.2, 127.0, 126.3, 122.0, 120.6, 119.7, 117.0, 112.2, 111.2, 110.4, 48.8; HRMS (ESI+) m/z calculated for C31H25N2 (MH+) 425.2018, found 425.2026.

3-(1-Benzyl-2,5-diphenyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (25): White solid, 62% yield; 1H NMR (CDCl3) δ 7.79 (d, 1H, J = 7.8 Hz), 7.48 (d, 2H, J = 6.8 Hz), 7.38-7.06 (m, 15H), 6.75-6.72 (m, 3H), 6.57 (s, 1H), 5.18 (s, 2H), 3.64 (s, 3H); 13C NMR (CDCl3) δ 139.7, 137.0, 135.6, 134.0, 133.8, 132.1, 131.5, 129.3, 128.6, 128.4, 128.4, 127.7, 127.5, 127.2, 126.9, 126.7, 126.3, 121.5, 120.8, 119.1, 110.7, 110.5, 109.2, 74.0, 48.8, 32.9; HRMS (ESI+) m/z calculated for C32H27N2 (MH+) 439.2174, found 439.2172.

3-(1-Benzyl-2,5-diphenyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (26): Light orange solid, 81% yield; 1H NMR (CDCl3) δ 8.05 (d, 1H, J = 8.3 Hz), 7.78 (d, 1H, J = 7.8 Hz), 7.67 (d, 2H, J = 7.8 Hz), 7.52-7.17 (m, 18H), 7.13 (s, 1H), 6.77-6.74 (m, 3H), 5.22 (s, 2H), 13C NMR (CDCl3) δ 139.3, 138.3, 136.0, 135.4, 133.7, 133.5, 132.9, 131.4, 131.2, 129.4, 129.3, 128.8, 128.7, 128.6, 127.9, 127.4, 127.2, 124.8, 123.5, 123.0, 121.3, 118.9, 114.5, 113.9, 110.1, 48.9; HRMS (ESI+) m/z calculated for C37H29N2O2S (MH+) 565.1950, found 565.1942.

3-(1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-1H-indole (27): Light yellow solid, 84% yield; 1H NMR (CDCl3) δ 8.07 (br s, 1H), 7.80 (d, 1H, J = 7.8 Hz), 7.41-7.14 (m, 7H), 7.00 (d, 2H, J = 7.6 Hz), 6.23 (s, 1H), 5.13 (s, 2H), 2.26 (s, 6H); 13C NMR (CDCl3) δ 138.9, 136.4, 129.0, 127.7, 127.3, 126.0, 122.1, 121.6, 120.7, 119.6, 113.5, 113.3, 111.2, 107.6, 47.3, 12.6, 11.4; HRMS (ESI+) m/z calculated for C21H21N2 (MH+) 301.1705, found 301.1703.

3-(1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (28): Yellow solid, 75% yield; 1H NMR (CDCl3) δ 7.82 (d, 1H, J = 7.8 Hz), 7.39-7.26 (m, 5H), 7.18 (t, 1H, J = 6.8 Hz), 7.15-7.01 (m, 3H) 6.24 (s, 1H), 5.15 (s, 2H)3.84 (s, 3H), 2.28 (s, 6H); 13C NMR (CDCl3) δ 138.9, 137.1, 129.0, 128.1, 127.6, 127.3, 126.4, 126.0, 124.5, 121.7, 120.9, 119.1, 113.4, 112.0, 109.3, 107.6, 47.3, 33.0, 12.6, 11.5; HRMS (ESI+) m/z calculated for C22H23N2 (MH+) 315.1861, found 315.1856.

3-(1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (29): Orange solid, 68% yield; 1H NMR (CDCl3) δ 8.09 (d, 2H, J = 8.3 Hz), 7.96-7.90 (m, 3H), 7.74 (d, 2H, J = 7.8 Hz), 7.54-7.25 (m, 6H), 6.98 (d, 2H, J = 8.0 Hz), 6.19 (s, 1H), 5.12 (s, 2H), 2.23 (s, 6H); 13C NMR (CDCl3) δ 138.4, 138.3, 135.6, 133.9, 131.6, 129.4, 129.1, 128.4, 127.7, 127.0, 125.9, 125.4, 123.5, 122.2, 121.4, 120.0, 113.9, 111.0, 107.1, 47.3, 12.6, 11.4; HRMS (ESI+) m/z calculated for C27H25N2O2S (MH+) 441.1637, found 441.1631.

2-(1-Benzyl-2,5-diphenyl-1H-pyrrol-3-yl)-1H-indole (30): White solid, 92% yield; 1H NMR (CDCl3) δ 7.73 (br s, 1H), 7.56-7.36 (m, 11H), 7.20-7.07 (m, 6H), 6.77-6.75 (m, 3H), 6.47 (s, 1H), 5.12 (s, 2H); 13C NMR (CDCl3) δ 139.1, 136.3, 136.0, 134.7, 133.3, 132.9, 131.9, 131.6, 129.4, 129.3, 129.1, 129.0, 128.8, 128.6, 127.8, 127.2, 126.2, 121.2, 120.0, 119.9, 115.6, 110.5, 108.3, 98.7, 48.7; HRMS (ESI+) m/z calculated for C31H25N2 (MH+) 425.2018, found 425.2018.

2-(1-Benzyl-2,5-diphenyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (31): Pale yellow solid, 90% yield; 1H NMR (CDCl3) δ 7.53-7.03 (m, 17H), 6.72 (d, 2H, J = 7.8 Hz), 6.49 (s, 1H), 6.34 (s, 1H), 5.23 (s, 2H), 3.44 (s, 3H); 13C NMR (CDCl3) δ 139.2, 132.0, 130.7, 130.0, 129.4, 129.0, 128.7, 128.6, 128.5, 128.4, 127.7, 127.6, 127.1, 126.2, 120.7, 120.1, 119.4, 112.1, 109.4, 101.7, 49.1, 30.9; HRMS (ESI+) m/z calculated for C32H27N2 (MH+) 439.2174, found 439.2176.

2-(1-Benzyl-2,5-diphenyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (32): White solid, 94% yield; 1H NMR (CDCl3) δ 8.32 (d, 1H, J = 8.3 Hz), 7.62 (d, 2H, J = 9.5 Hz), 7.51-7.11 (m, 17H), 6.95 (dd, 2H, J = 1.5, 8.1 Hz), 6.75-6.72 (m, 2H), 6.51 (s, 1H), 6.25 (s, 1H), 5.20 (s, 2H); 13C NMR (CDCl3) δ 139.6, 139.1, 137.9, 136.8, 136.3, 135.2, 133.5, 133.4, 132.2, 130.9, 130.4, 129.4, 129.0, 128.7, 128.5, 128.2, 127.7, 127.5, 127.2, 126.4, 124.2, 123.8, 120.5, 116.0, 114.1, 113.9, 113.0, 49.1; HRMS (ESI+) m/z calculated for C37H29N2O2S (MH+) 565.1950, found 565.1945.

2-(1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-1H-indole (33): White solid, 92% yield; 1H NMR (CDCl3) δ 8.11 (br s, 1H), 7.64 (d, 1H, J = 6.6 Hz), 7.40-7.30 (m, 4H), 7.20-7.14 (m, 2H), 7.00 (d, 2H, J = 7.6 Hz), 6.49 (s, 1H), 6.19 (s, 1H), 5.12 (s, 2H), 2.41 (s, 3H), 2.25 (s, 3H); 13C NMR (CDCl3) δ 138.2, 136.0, 135.7, 130.0, 129.1, 128.7, 127.5, 126.1, 125.9, 121.0, 119.9, 119.9, 112.7, 110.5, 105.1, 98.5, 47.2, 25.7, 12.6, 11.7; HRMS (ESI+) m/z calculated for C21H21N2 (MH+) 301.1705, found 301.1706.

2-(1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (34): Pale yellow solid, 70% yield; 1H NMR (CDCl3) δ 7.66 (d, 1H, J = 7.8 Hz), 7.42-7.15 (m, 6H), 7.03 (d, 2H, J = 7.3 Hz), 6.45 (s, 1H), 6.10 (s, 1H), 5.15 (s, 2H), 3.78 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H); 13C NMR (CDCl3) δ 138.4, 137.8, 129.1, 128.6, 128.1, 127.7, 127.5, 125.9, 120.8, 120.0, 119.5, 111.6, 109.4, 108.0, 101.0, 47.4, 31.0, 12.6, 11.3; HRMS (ESI+) m/z calculated for C22H23N2 (MH+) 315.1861, found 315.1864.

2-(1-Benzyl-2,5-dimethyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (35): Light orange solid, 86% yield; 1H NMR (CDCl3) δ 8.39 (d, 1H, J = 8.3), 7.50-7.07 (m, 13H), 6.40 (s, 1H), 6.09 (s, 1H), 5.08 (s, 2H), 2.26 (s, 3H), 1.92 (s, 3H); 13C NMR (CDCl3) δ 138.8, 138.4, 138.1, 138.0, 133.4, 130.9, 129.1, 128.7, 127.5, 127.1, 127.0, 126.1, 124.1, 124.1, 120.3, 116.5, 112.4, 111.1, 110.1, 47.4, 12.6, 11.1; HRMS (ESI+) m/z calculated for C27H25N2O2S (MH+) 441.1637, found 441.1641.

3-(1-Benzyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)-1H-indole (36a): White solid, 51% (obtained as the major isomer – 77:23 ratio of 36a:36b); 1H NMR (CDCl3) δ 7.80 (d, 1H, J = 7.6 Hz), 7.45-7.08 (m, 11H), 7.00 (d, 2H, J = 7.1 Hz), 6.69 (d, 1H, J = 2.4 Hz), 6.49 (s, 1H), 5.09 (s, 2H), 2.27 (s, 3H); 13C NMR (CDCl3) δ 139.4, 136.2, 133.9, 131.4, 129.1, 129.0, 128.9, 128.7, 128.5, 127.3, 127.1, 126.0, 122.3, 121.9, 121.9, 120.7, 119.6, 115.3, 112.6, 111.2, 108.4, 47.9, 12.8; HRMS (EI+) m/z calculated for C26H22N2 (M+) 362.17830, found 362.17707.

3-(1-Benzyl-2-methyl-5-phenyl-1H-pyrrol-3-yl)-1H-indole (36b): Clear oil, 20% (obtained as the major isomer – 63:37 ratio of 36b:36a); 1H NMR (CDCl3) δ 8.09 (s, 1H), 7.85 (d, 1H, J = 7.8), 7.43-7.06 (m, 14H), 6.62 (s, 1H), 5.26 (s, 2H), 2.26 (s, 3H); 13C NMR (CDCl3) δ 139.3, 136.4, 134.4, 129.0, 128.9, 128.9, 128.7, 127.3, 127.3, 127.0, 126.0, 122.3, 121.9, 121.8, 120.7, 119.8, 115.1, 113.0, 111.3, 109.7, 48.3, 11.7; HRMS (EI+) m/z calculated for C26H22N2 (M+) 362.17830, found 362.17743.

3-(1-Benzyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (37a): Orange solid, 86% (obtained as the major isomer – 74:26 ratio of 37a:37b); 1H NMR (CDCl3) δ 7.73 (d, 1H, J = 8.1 Hz), 7.41-7.18 (m, 9H), 7.09 (t, 2H, J = 6.8 Hz), 7.00 (d, 2H, J = 7.6), 6.59 (s, 1H), 6.45 (s, 1H), 5.08 (s, 2H), 3.65 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3) δ 139.5, 137.0, 134.0, 131.3, 129.0, 128.9, 128.5, 127.3, 127.1, 126.6, 126.0, 121.4, 120.9, 119.0, 115.4, 111.2, 109.2, 108.5, 47.9, 32.8, 12.8; HRMS (ESI+) m/z calculated for C27H25N2 (MH+) 377.2018, found 377.2021.

3-(1-Benzyl-2-methyl-5-phenyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (37b): Orange oil, 39% (obtained as the major isomer – 56:44 ratio of 37b:37a); 1H NMR (CDCl3) δ 7.91 (d, 1H, J = 7.8 Hz), 7.50-7.12 (m, 14H), 6.67 (s, 1H), 5.31 (s, 2H), 3.87 (s, 3H), 2.32 (s, 3H); 13C NMR (CDCl3) δ 139.4, 137.1, 134.3, 131.4, 129.2, 128.9, 128.7, 127.2, 126.9, 126.5, 126.0, 121.8, 120.8, 119.3, 115.3, 111.1, 109.8, 109.4, 48.3, 33.0, 11.7; HRMS (ESI+) m/z calculated for C27H25N2 (MH+) 377.2018, found 377.2021.

3-(1-Benzyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (38a): Pale orange solid, 71% (obtained as the major isomer – 88:12 ratio of 38a:38b); 1H NMR (CDCl3) δ 8.02 (d, 1H, J = 8.3 Hz), 7.67 (d, 2H, J = 7.8 Hz), 7.50-7.19 (m, 13H), 7.08 (s, 1H), 6.96 (d, 2H, J = 7.1 Hz), 6.39 (s, 1H), 5.07 (s, 2H), 2.24 (s, 3H); 13C NMR (CDCl3) δ 138.9, 138.3, 135.4, 133.7, 133.1, 131.7, 131.2, 129.7, 129.3, 129.1, 129.0, 128.7, 127.9, 127.3, 127.0, 126.0, 124.7, 123.6, 122.8, 121.3, 119.4, 113.8, 112.8, 108.2, 48.0, 12.8; HRMS (ESI+) m/z calculated for C32H27N2O2S (MH+) 503.1793, found 503.1789.

3-(1-Benzyl-2-methyl-5-phenyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (38b): Orange solid, 65% (obtained as the major isomer – 51:49 ratio of 38b:38a); 1H NMR (CDCl3) δ 8.10 (d, 2H, J = 8.3 Hz), 7.94 (d, 2H, J = 7.6 Hz), 7.77 (d, 2H, J = 7.6 Hz), 7.66 (d, 2H, J = 7.6 Hz), 7.54-7.18 (m, 10H), 7.04 (d, 2H, J = 7.1 Hz), 6.55 (s, 1H), 5.24 (s, 2H), 2.24 (s, 3H); 13C NMR (CDCl3) δ 138.9, 138.3, 135.4, 133.6, 133.0, 131.4, 131.3, 129.7, 129.3, 129.1, 129.0, 128.7, 127.9, 127.3, 127.0, 125.9, 124.6, 123.4, 122.5, 121.3, 119.4, 113.8, 112.7, 108.2, 48.0, 11.7; HRMS (ESI+) m/z calculated for C32H27N2O2S (MH+) 503.1793, found 503.1795.

2-(1-Benzyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)-1H-indole (39a): Off-white solid, 89% (obtained as the major isomer – 87:13 ratio of 39a:39b); 1H NMR (CDCl3) δ 7.68 (br s, 1H), 7.53-7.25 (m, 8H), 7.15-7.03 (m, 3H), 6.94 (d, 2H, J = 7.1 Hz), 6.43 (s, 1H), 6.40 (d, 1H, J = 1.7 Hz), 4.98 (s, 2H), 2.24 (s, 3H); 13C NMR (CDCl3) δ 138.8, 135.9, 135.1, 133.1, 131.6, 130.2, 130.1, 129.2, 129.1, 129.0, 128.9, 128.8, 127.4, 125.9, 125.9, 120.9, 119.8, 119.7, 114.0, 110.4, 106.4, 98.3, 47.7, 12.7; HRMS (ESI+) m/z calculated for C26H23N2 (MH+) 363.1861, found 363.1862.

2-(1-Benzyl-2-methyl-5-phenyl-1H-pyrrol-3-yl)-1H-indole (39b): Off-white solid, 62% (obtained as the major isomer – 74:26 ratio of 39b:39a); 1H NMR (CDCl3) δ 8.16 (br s, 1H), 7.64 (d, 2H, J = 7.1 Hz), 7.38-7.02 (m, 12H), 6.54-6.52 (m, 2H), 5.23 (s, 2H), 2.41 (s, 3H); 13C NMR (CDCl3) δ 138.7, 136.1, 135.1, 133.3, 131.6, 129.9, 129.2, 129.1, 129.0, 128.9, 128.8, 127.6, 127.5, 125.9, 125.9, 121.3, 120.1, 119.8, 114.3, 110.6, 107.1, 99.0, 48.2, 11.9; HRMS (ESI+) m/z calculated for C26H23N2 (MH+) 363.1861, found 363.1859.

2-(1-Benzyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (40a): Yellow solid, 76% (obtained as the major isomer – 90:10 ratio of 40a:40b); 1H NMR (CDCl3) δ 7.55 (d, 1H, J = 7.8 Hz), 7.39-6.99 (m, 13H), 6.34 (s, 1H), 6.23 (s, 1H), 5.15 (s, 2H), 3.40 (s, 3H), 2.23 (s, 3H); 13C NMR (CDCl3) δ 139.0, 137.6, 132.9, 130.5, 129.8, 129.1, 129.1, 128.8, 128.6, 128.6, 127.5, 127.4, 125.9, 120.6, 120.0, 119.3, 113.5, 110.1, 109.4, 101.5, 48.1, 30.8, 12.8; HRMS (ESI+) m/z calculated for C27H25N2 (MH+) 377.2018, found 377.2019.

2-(1-Benzyl-2-methyl-5-phenyl-1H-pyrrol-3-yl)-1-methyl-1H-indole (40b): Yellow oil, 45% (obtained as the minor isomer – 30:70 ratio of 40b:40a); 1H NMR (CDCl3) δ 7.66 (d, 1H, J = 7.6 Hz), 7.40-7.00 (m, 13H), 6.49 (s, 1H), 6.44 (s, 1H), 5.26 (s, 2H), 3.80 (s, 3H), 2.24 (s, 3H); 13C NMR (CDCl3) δ 138.9, 137.6, 132.8, 130.5, 129.8, 129.1, 129.0, 128.8, 128.7, 128.6, 127.5, 127.4, 125.9, 120.9, 120.1, 119.6, 113.4, 110.1, 109.5, 101.3, 48.4, 31.0, 11.5; HRMS (ESI+) m/z calculated for C27H25N2 (MH+) 377.2018, found 377.2018.

2-(1-Benzyl-5-methyl-2-phenyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (41a): Tan solid, 95% (obtained as the major isomer – 79:21 ratio of 41a:41b); 1H NMR (CDCl3) δ 8.26 (d, 1H, J = 8.5 Hz), 7.63-7.12 (m, 13H), 7.02-6.97 (m, 5H), 6.28 (s, 1H), 6.23 (s, 1H), 5.09 (s, 2H), 2.24 (s, 3H); 13C NMR (CDCl3) δ 139.6, 138.9, 137.8, 137.5, 134.2, 133.5, 132.5, 130.8, 129.1, 129.0, 129.0, 128.9, 128.8, 128.8, 128.3, 127.4, 127.2, 127.1, 124.1, 123.8, 120.5, 116.0, 113.0, 111.7, 48.1, 12.8; HRMS (ESI+) m/z calculated for C32H27N2O2S (MH+) 503.1793, found 503.1801.

2-(1-Benzyl-2-methyl-5-phenyl-1H-pyrrol-3-yl)-1-(phenylsulfonyl)-1H-indole (41b): Tan solid, 78% (obtained as the major isomer – 91:9 ratio of 41b:41a); 1H NMR (CDCl3) δ 8.40 (d, 1H, J = 8.1 Hz), 7.53-7.10 (m, 18H), 6.49 (s, 1H), 6.39 (s, 1H), 5.22 (s, 2H), 1.97 (s, 3H); 13C NMR (CDCl3) δ 138.8, 138.8, 138.1, 137.4, 133.5, 131.5, 130.8, 129.1, 129.1, 128.9, 128.9, 128.7, 128.7, 128.3, 127.5, 127.3, 127.1, 126.1, 124.3, 124.1, 120.4, 116.5, 112.6, 112.2, 48.3, 11.5; HRMS (ESI+) m/z calculated for C32H27N2O2S (MH+) 503.1793, found 503.1797.

ACKNOWLEDGEMENTS
This work was supported by the Donors of the Petroleum Research Fund (PRF), administered by the American Chemical Society, and by Wyeth.

References

1. M. E. Welsch, S. A. Snyder, and B. R. Stockwell, Curr. Op. Chem. Bio., 2010, 14, 347; CrossRef D. A. Horton, G. T. Bourne, and M. L. Smythe, Chem. Rev., 2003, 103, 893. CrossRef
2. K. C. Nicolaou and J. S. Chen, Pure Appl. Chem., 2008, 80, 727; CrossRef G. M. Cragg, P. G. Grothaus, and D. J. Newman, Chem. Rev., 2009, 109, 3012; CrossRef A. J. Kochanowska-Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489. CrossRef
3. F. Rodrigues de Sa Alves, E. J. Barreiro, and C. Fraga, Mini-Rev. Med. Chem., 2009, 9, 782. CrossRef
4. A. C Grimsdale, K. L. Chan, R. E. Martin, P. G. Jokisz, and A. B. Holmes, Chem. Rev., 2009, 109, 897. CrossRef
5. E. Barni, P. Savarino, and G. Viscardi, Trends in Het. Chem., 1991, 2, 27; A. Loudet and K. Burgess. Chem. Rev., 2007, 107, 4891. CrossRef
6. J. S. Carey, D. Laffan, C. Thomson, and M. T. Williams, Org. Biomol. Chem., 2006, 4, 2337. CrossRef
7. V. F. Slagt, A. H. M. de Vries, J. G. de Vries, and R. M. Kellogg, Org. Process Res. Dev., 2010, 14, 30. CrossRef
8. R. Balamurugan, R. Sureshbabu, G. G. Rajeshwaran, and A. K. Mohanakrishnan, Synth. Comm., 2009, 39, 531. CrossRef
9. G. W. Gribble, E. T. Pelkey, W. M. Simon, and H. A. Trujillo, Tetrahedron, 2000, 56, 10133; CrossRef G. W. Gribble, E. T. Pelkey, and F. L. Switzer, Synlett, 1998, 1061. CrossRef
10. G. W. Gribble, W. R. Sponholtz III, F. L. Switzer, F. J. D’Amato, and M. P. Byrn, Chem. Comm., 1997, 11, 993. CrossRef
11. S. Mahboobi, G. Grothus, and W. Meindl, Arch. der Pharm., 1994, 327, 105. CrossRef
12. G. W. Gribble, J. Jiang, and Y. Liu, J. Org. Chem., 2002, 67, 1001. CrossRef
13. A. Cote, V. N. G. Lindsay, and A. B. Charette, Org. Lett., 2007, 9, 85. CrossRef
14. M. D. Ganton and M. A. Kerr, Org. Lett., 2005, 7, 4777. CrossRef
15. J. Waser, B. Gaspar, H. Nambu, and E. M. Carreira, J. Am. Chem. Soc., 2006, 128, 11693. CrossRef
16. O. Ottoni, R. Cruz, and R. Alves, Tetrahedron, 1998, 54, 13915. CrossRef
17. J. Harley-Mason and E. H. Pavel, J. Chem. Soc., 1963, 2565.
18. H. L. Fraser and G. W. Gribble, Can. J. Chem., 2001, 79, 1515. CrossRef
19. M. G. Saulnier and G. W. Gribble, J. Org. Chem., 1982, 47, 757. CrossRef
20. S. Cassel, B. Casenave, G. Deleris, L. Latxague, and P. Rollin, Tetrahedron, 1998, 8515. CrossRef
21. N. S. Narasimhan, R. S. Kusurkar, and D. D. Dhavale, Indian J. Chem., Sect A, 1983, 1004