A new approach to the pyrrolo[3,4-b ]indole ring system

We report an approach to the pyrrolo[3,4-b ]indole ring system that involves a new synthesis of pyrrolo[3,4-b ]indol-1(2 H )ones, which are known precursors to pyrrolo[3,4-b ]indoles. 3-Trifluoroacetylindole is prepared from indole and converted into indole carboxamides upon reaction with lithiated amines. Subsequent C-2 bromination followed by a tri-n -butyltin hydride induced 1,5-radical translocation and 5-endo - trig cyclization affords 3,4-dihydropyrrolo[3,4-b ]indol-1(2 H )-one which upon reduction with DIBAL by the method of Kreher gives pyrrolo[3,4-b ]indole

Our approach to the conversion of amide 8 to lactam 4 was predicated on a radical cyclization methodology that we reported in a similar system some years ago (Scheme 3). 21Thus, lithiation at C-2 of amide 8 followed by quenching with BrCl 2 CCCl 2 Br 22 gave the expected 2-bromoindole 11 in 86% yield.Treatment of 11 with tri-n-butyltin hydride and AlBN in toluene afforded the cyclized indoline 15 (51% yield) along with the debrominated indole 8 (22% yield).This reaction involves bromine abstraction to give the 2indolyl radical 12, which abstracts a methyl hydrogen (1,5-H) to give the α-amidoyl radical 13.This radical cyclizes (5-endo-trig) to the indole C-2 position giving the product 15 after hydrogen atom abstraction by 14.The relative lability of 15, although fully characterized, precluded forming crystals suitable for X-ray analysis.Indeed, prolonged exposure of 15 to air led to a blue-colored solid.Dehydrogenation of 15 to the known 4 was accomplished in 90% yield using Pd/C in refluxing xylene. 23Interestingly, other oxidation methods to install the indole double bond in indoline 15 resulted in no oxidation and only starting material was recovered (e.g.DDQ, ARKAT USA, Inc chloranil, NBS, PdCl 2 , air/DMSO).Reduction of 4 with DIBAL according to the procedure of Kreher 11 gave pyrrolo [3,4-b] An important extension of our methodology is that LiAlH 4 reduction of pyrrolo [3,4-b]indolones like 4 should yield the corresponding 1,2,3,4-tetrahydropyrrolo [3,4-b]indole, as shown by Welch. 7Thus, we have reported previously that the latter can be oxidized to the pyrrolo [3,4-b]indole ring system, albeit with a different indole N-protecting group (Scheme 4).It should be noted that other syntheses of pyrrolo [3,4-b]indolones and pyrrolo [3,4-b]indolines have been reported in recent years, [24][25][26][27]  and thaw method with argon.All references to "water" or "H 2 O" correspond to reverse osmosis deionized (RODI) water."Brine" is a saturated aqueous sodium chloride solution.All volume descriptions for extractions and washes are approximate."In vacuo" refers to solvent removal first by rotary evaporation followed by a lower pressure environment (≤ 0.2 Torr).Reaction temperatures ranging between -75 °C and -40 °C were achieved using a CO 2 /isopropanol bath.Reaction temperatures ranging between 0 °C and 10 °C were achieved using a ice/sodium chloride bath.Anhydrous reactions were performed with glassware dried for 24 h at a temperature of 120 °C or greater then assembled hot and cooled under an atmosphere of nitrogen.Alternatively, glassware was assembled, flame dried, cooled under an atmosphere of nitrogen, and the drying/cooling process was repeated.

N-(tert-Butyl)-N,1-dimethyl-1H-indole-3-carboxamide (8), Method A.
To a stirred suspension of NaOH (78.9 mg, 1.97 mmol, 1.3 eq.) in EtOH (50 mL) was added the amide 7 (349.1 mg, 1.52 mmol, 1 eq.) neat.The solution was stirred for 2 h at rt to allow for complete dissolution.The EtOH was removed under reduced pressure, and the residue was dissolved in acetone (25 mL).The suspension was stirred for 5 min, treated with MeI (0.1 mL, 1.52 mmol, 1 eq.) and stirred overnight at rt (ca.8 h).The solution was filtered under gravity, and the filtrate was then concentrated in vacuo to give a yellow oil.The oil was the triturated repeatedly with Et 2 O to yield 8 as a light yellow solid (359 mg, 97%).The solid was homologous by TLC and 1 H-NMR.All spectral data was identical to those of 8 prepared by Method B (vide infra).
The solution was stirred at -78 o C for 1 h.To the anion was added a solution of 3-trifluoroacetylindole (6) (6.67 g, 31.3 mmol, 1 eq.) in THF (50 mL) at 0 °C.The reaction mixture was allowed to gradually warm to rt over 12 h.This was poured onto ice H 2 O (100 mL) and stirred for 2 h before the aqueous solution was extracted with

N-(tert-Butyl)-N,1-dimethyl-1H-indole-3-carboxamide (8), Method B.
To a stirred suspension of KH (117 mg, 2.93 mmol, 1.2 eq.) in THF (10 mL) was added 18-crown-6 (775 mg, 2.93 mmol, 1.2 eq.) neat.The suspension was stirred at 0 °C under nitrogen for 1 h, at which time was added amide 10 (561.3 mg, 2.44 mmol, 1 eq.) in THF (34 mL) via an addition funnel.The solution was stirred at 0 °C for 1 h, treated with MeI (0.2 mL, 2.93 mmol, 1.2 eq.), and stirred overnight.The solution was poured onto ice H 2 O (100 mL) and stirred thoroughly.The white solid that formed was collected by vacuum filtration and dried under vacuum to give the amide 8 as a white solid (516 mg, 88%).The filtrate was extracted with CH 2 Cl 2 (3 x 65 mL) and the organic extracts were washed with brine (2 x 50 mL), dried (Na 2 SO 4 ), and concentrated in vacuo to give a yellow oil.Trituration of the oil with Et 2 O gave the desired amide 8 as a white solid (12.5 mg).Total yield of 8 was 88% (529 mg).Both solids were homologous by TLC and 1 H-NMR;
but which do not involve a radical cyclization/dehydrogenation methodology.These are shown in Scheme 5. Tetrahydrofuran (THF) was freshly distilled from sodium/benzophenone under N 2 .All amines and dichloromethane (CH 2 Cl 2 ) were distilled in the presence of calcium hydride.All alkyllithium reagents were standardized prior to use by titration against diphenylacetic acid in dilute THF.Azobisisobutyronitrile (AIBN) was recrystallized from ethanol.N-Bromosuccinimide was recrystallized prior to use from water and dried in vacuo in the presence of phosphorus pentoxide.Potassium hydride (KH) was purchased from Aldrich as a 35% dispersion in mineral oil.Sodium hydride (NaH) was purchased from Acros as a 60% dispersion in mineral oil.The hydrides were washed with hexanes under N 2 to remove the mineral oil and then dried under vacuum.1,2-Dibromo-1,1,2,2-tetrachloroethane (BrCl 2 CCCl 13 light.Alternative visualization was accomplished by dipping the plate into a solution of ceric ammonium sulfate in 10% aqueous H 2 SO 4 then drying.Flash chromatography was carried out using Silicycle ultra pure silica gel 60A (Angstrom). 1 H (300 MHz),13C (75 MHz), and 19 F (282.2 MHz) NMR spectra were recorded on a Varian XL-300 Fourier transform spectrometer unless otherwise indicated (by frequency) in which they were recorded on a Varian Unity plus spectrometer: 1 H (500 MHz) and13C (125 MHz).The chemical shifts are reported in δ (ppm) using the δ 7.27 signal of CHCl 3 ( 1 H-NMR) and the δ 77.23 signal of CDCl 3 ( 13 C-NMR), the δ 4.87 signal of CD 3 OH ( 1 H-NMR) and the δ 49.15 signal of CD 3 OD ( 13 C-NMR), the δ 2.51 signal of (CH 3 ) 2 SO ( 1 H-NMR) and the δ 39.50 signal of (CD 3 ) 2 SO ( 13 C-NMR), or the δ 2.05 signal of CO(CD 3 )CD 2 H ( 1 H-NMR) and δ 29.92 signal of CO(CD 3 ) 2 ( 13 C-NMR) and the 0.00 signal of CFCl 3 (Freon 11) ( 19 F NMR) as internal standards.The apparent multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad), the number of protons, and the coupling constants (in Hz) are reported where appropriate.Infrared spectra (IR) were recorded with a Perkin Elmer Series 1600 FTIR spectrophotometer and are referenced to the 1601 cm -1 band of polystyrene.IR spectra were obtained using either neat compounds (film) or solid potassium bromide pellets (KBr) and are reported in reciprocal centimeters.Ultraviolet (UV) spectra were recorded on a Hewlett-Packard 8451A Diode Array UV spectrophotometer and are reported in nanometers.Low-resolution mass spectra and high-resolution mass spectrometry (HRMS) were also performed at the University of Illinois (Urbana-Champaign) mass spectrometry laboratory.Elemental analyses were performed by Atlantic Microlab Inc. (Norcross, GA). 2 Br) was dried by dissolving the white solid in ether, drying over sodium sulfate, filtering under gravity, and removing the solvent in vacuo, prior to use.Unless otherwise indicated, all other reagents and solvents were purchased from commercial sources and were used without further purification.Inert atmospheres of nitrogen or argon were predried by flow through a column of Drierite 4 mesh with indicator.All reactions were done under a positive flow of nitrogen unless otherwise stated.Degassing was accomplished with a Firestone valve using the freeze, pump, © ARKAT USA, Inc 19, 82.1 mmol, 2.4 eq.) in Et 2 O (85 mL) at 0 °C was added a solution of indole (4.0 g, 34.2 mmol, 1 eq.) in Et 2 O (24 mL) over 1 h via an addition funnel.The solution was stirred at 0 o C for 8 h.The Et 2 O solution was washed with saturated NaHCO 3 (3 x 100 mL) and H 2 O (2 x 75 mL).The organic layers were combined, dried (Na 2 SO 4 ), and concentrated in vacuo to give a white solid which was recrystallized from Et 2 O to give 6 (6.02 g, 83%) as white crystals: mp 209-210 °C (lit.19mp208 °C); 1 H-NMR (CDCl 3 )  11.6 (s, 1H), 8.36 (m, 1H), 8.29 (m, 1H), 7.58 (m, 1H), 7.30 (m, 2H); 13 C-NMR (CO(CD 3 ) 2 )  205.9, 136.7, 126.5, 124.7, 123.7, 121.9, 119.5, 115.6, 112.9, 110.1; 19 F-NMR (CFCl 3 )  -73.4.