Synthesis of 2-BMIDA Indoles via Heteroannulation: Applications in Drug Scaffold and Natural Product Synthesis

A Pd-catalyzed heteroannulation approach for the synthesis of C2 borylated indoles is reported. The process allows access to highly functionalized 2-borylated indole scaffolds with complete control of regioselectivity. The utility of the process is demonstrated in the synthesis of borylated sulfa drugs and in the concise synthesis of the Aspidosperma alkaloid Goniomitine.


General procedure C: For example, synthesis of Compound 38
To a flame-dried 250 mL round bottom flask, ((but-3-yn-1-yloxy)methyl)benzene (6.63 g, 41.4 mmol, 1.0 equiv.) was dissolved in THF (124 mL, 0.33 M) and cooled to 0 °C. To this solution was added EtMgBr (22.6 mL, 49.7 mmol, 2.2 M in Et2O, 1.2 equiv.) dropwise and the resulting suspension was stirred at 0 °C for 10 minutes before the ice bath was removed and stirring was continued for a further 30 minutes.
In a separate, flame-dried 500 mL round bottom flask, B(OMe)3 (9.23 mL, 82.8 mmol, 2.0 equiv.) was dissolved in THF (100 mL, 0.82 M) and cooled to -78 °C. To this cold solution was added, via cannula, the above Grignard suspension over approximately 10 minutes. After complete addition, the reaction mixture was stirred at -78 °C for one hour before removing the dry ice/acetone bath and stirring for a further two hours as it warmed to room temperature. The flask was unstoppered and N-methyliminodiacetic acid (12.2 g, 82.8 mmol, 2.0 equiv.) was added followed by DMSO (50 mL). The flask was placed on a rotary evaporator with the water bath set at 60 °C to remove the majority of the volatiles. The flask contents were then distilled under high vacuum (<0.5 mbar, 80 °C) to remove remaining DMSO to leave a gum-like residue. To this was added 1:1 brine/H2O (300 mL) and this was extracted with 3:2 EtOAc/acetone (2 x 300 mL). The organic layers were combined, washed with water (50 mL), dried over Na2SO4, filtered, and concentrated to a residue that was purified by flash column chromatography (silica gel, 0-25% MeCN in DCM) to give an off-white solid which was then triturated from EtOAc and hexane to give the product as a fluffy white solid (7.80 g, 60%).   trace  2  40  5  3  60  42  4 100 50

S10
1,4-Dinitrobenzene in DMSO-d6 (0.05 M, 1 mL) was added to the crude product and an aliquot was analysed by 1 H NMR.

Compound S8
A mixture of 2,3-dimethoxyaniline (157 mg, 1.02 mmol, 1.00 equiv.) in Et2O (6.8 mL, 0.15 M) and sat. aq. Na2CO3 (2 mL) was stirred vigorously in the dark at room temperature. A solution of ICl (271 mg, 1.67 mmol, 1.63 equiv.) in Et2O (2 mL) was added in one portion and the mixture was stirred for 3 h at room temperature. The layers were separated, and the organic extract was washed successively with sat. aq. Na2S2O3 (10 mL) and sat. aq. NaHCO3 (10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated to a residue

S13
that was purified by flash column chromatography (silica gel, 2.5-5% acetone in hexane) to give the product as a pale yellow oil which solidified on standing (146 mg, 51%). 1

Compound S20
A solution of 4-methyl-2-iodoaniline (1.17 g, 5.00 mmol, 1.00 equiv.) and Et3N (767 µL, 5.50 mmol, 1.10 equiv.) in DCM (16.7 mL, 0.33 M) was cooled to 0 °C. AcCl (945 µL, 13.0 mmol, 2.60 equiv.) was added dropwise and the mixture was allowed to warm to room temperature and stir for 68 h. Methanol (10 mL) was added and the mixture was stirred for 10 min before water (20 mL) was added. The layers were separated, and the aqueous layer was extracted with DCM (20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give a residue that was purified by flash column chromatography (silica gel, 20-40% EtOAc in hexanes) to give the product as a pale yellow solid (1.03 g, 75%). 1

Products from Table 1, Scheme 2, and Scheme 3 Compound 1b
A solution of 2-iodoaniline (21.9 g, 100 mmol, 1.00 equiv.) and Et3N (30.7 mL, 220 mmol, 2.20 equiv.) in DCM (250 mL) was cooled to 0 °C. Ac2O (11.3 mL, 120 mmol, 1.20 equiv.) was added. The reaction mixture was then warmed to a gentle reflux for 18 h. The mixture was allowed to cool to room temperature before addition of sat. aq. NaHCO3 (200 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic extracts were then dried over Na2SO4, filtered, and concentrated to a residue that was purified by flash column chromatography (silica gel, 20-80% EtOAc in hexane) to give the product as a white solid (23.1 g, 88%). 1

Compound 11
Prepared according to General Procedure A using Pd(dppf)Cl2

S33
25% MeCN in DCM) gave an off-white solid which was triturated from EtOAc and hexane to give the product as a fluffy white solid (7.80 g, 60%). 1

Compound 39
Prepared using General Procedure A using Pd(dppf)Cl2 (707 mg, 966 µmol, 5 mol%), 38 (6.09 g, 19.3 mmol, 1.0 equiv.), NaOAc (3.96 g, 48.3 mmol, 2.5 equiv.) and 2-iodoaniline (5.08 g, 23.2 mmol, 1.2 equiv.). Flash column chromatography (silica gel, 6-30% MeCN in DCM) gave the product as a brown solid (7.08 g, 90%). 1  Compound 40 a) Compound S29. A flame-dried round-bottom flask was charged with i-Pr2NH (9.95 mL, 71.0 mmol, 1.30 equiv.) and THF (250 mL, 0.28 M) and cooled to 0 °C. To the stirred solution was added n-BuLi (2.43 M in hexanes, 27.0 mL, 65.6 mmol, 1.20 equiv.) via syringe, and the solution was stirred at 0 °C for 30 min. A solution of 1-benzyl-2-piperidinone (10.3 g, 54.6 mmol, 1.0 equiv.) in THF (100 mL, 0.54 M) was added, resulting in a bright yellow coloured solution. This was stirred at 0 °C for 10 min before being allowed to warm to room temperature where it was stirred for a further 30 min. The mixture was then cooled to -78 °C. Ethyl iodide (5.71 mL, 71.0 mmol, 1.30 equiv.) was added via syringe over several minutes and the reaction mixture was stirred at this temperature for a further 30 min before being allowed to warm to room temperature and stir for 1 h. Sat. aq. NH4Cl (100 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to a residue that was purified by flash column chromatography (10-30% EtOAc in hexane) to give the product as a colourless oil (11.56 g, 97%). 1  ) in THF (10 mL) was then added via syringe then the reaction mixture was allowed to warm to room temperature and stir overnight. The mixture was quenched with sat. aq. NH4Cl (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to a residue that was purified by flash column chromatography (silica gel, 10-20% ethyl acetate in hexane) to give the product as a colourless oil (1.50 g, 61%). 1  Compound 42 a) Compound S31. A mixture of 41 (526 mg, 1.07 mmol, 1 equiv.) and Pd/C (10 wt%, 114 mg, 107 µmol, 10 mol%) in EtOAc (11 mL, 0.1 M) was stirred vigorously as it was sparged with a balloon of H2. The mixture was then stirred at room temperature under balloon pressure of H2 for 3.5 h. The reaction mixture was then filtered through a plug of celite, and the cake washed with MeOH (3 x 10 mL). The filtrate was concentrated to a residue that was purified by flash column chromatography (silica gel, 10-30% EtOAc in hexane) to give the product as a light pink oil (527 mg, 89%). 1   After complete addition, the reaction mixture was allowed to warm to room temperature, stirred for 1 h. The mixture was quenched with sat. aq. Rochelle's salt (10 mL) then stirred overnight at room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to a residue that was purified by flash column chromatography (silica gel, 5-40% EtOAc in hexane) to give the product as a colourless gum (76 mg, 55%). 1  S36 c) Compound 42. A mixture of S30 (73.0 mg, 0.15 mmol, 1.00 equiv.) and Pd(OH)2 (20 wt.% on carbon, 128 mg, 0.18 mmol, 1.20 equiv.) in AcOH/EtOH (2/1, 7.6 mL, 0.02 M) was sparged with a balloon of H2. The mixture was then stirred at room temperature under balloon pressure of H2 for 3 h. The reaction mixture was then filtered through a plug of celite, and the cake washed with MeOH (3 x 10 mL). The filtrate was concentrated to a residue then dissolved in DCM (20 mL). 1 M NaOH was added until a pH of ca. 10 was achieved. The layers were then separated, and the aqueous layer was extracted with DCM (5 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to a residue that was purified by flash column chromatography (silica gel, 2-5% MeOH in DCM) to give the product as a pale yellow residue (19.0 mg, 42%). 1

X-Ray Crystallography Data
CCDC 2133112 (Compound 3) and 2149746 (Compound 4) contain the supplementary crystallographic data for this study. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

Compound 3
X-ray quality crystals isolated by liquid-liquid diffusion at room temperature by dissolving the sample in MeCN and layering with Et2O. X-ray quality crystals isolated by liquid-liquid diffusion at room temperature by dissolving the sample in MeCN and layering with Et2O.

BMIDA Volume Calculation
Maximum Tolman cone angle measured mathematically to be 152.04º from SCXRD of compound 3 (assuming perfect free rotation, constraining C-B to 2.28 Å and rvdw(H) = 1.1 Å. Cf. calculated Θmax(Ph) = 129º in gas phase iodobenzene I-C(Ph) = 2.113 Å). 16 We attempted to model exact cone angle and solid angle using the methods described by Aggarwal and coworkers 17 using the scripts developed by Allen and coworkers 18 using the program Mathematica; 19 however, the software was unable to calculate a real value for either cone angle or solid angle.