Synthesis of bis-4 H -furo[3,4-b ]indoles

We describe the synthesis of two novel bis-4 H -furo[3,4-b ]indoles from indole. Several alternative pathways to these potential DNA bis-intercalator precursors are discussed, and the synthesis of a novel semi-rigid tether is reported


Results and Discussion
In connection with our interest in the synthesis and antitumor activity of potential bis-DNA intercalators, 2,9,10 we utilized bis-furoindole 4 for the synthesis of 1,10-bis(6-methyl-5H-benzo[b]carbazol-11-yl)decane (Figure 2). 2 Although successful, our early synthesis of 4 was less efficient than we desired.We now describe syntheses of bis-furo [3,4-b]indoles 5 and 6 using our improved methodology 8 (Scheme 1).Our newer method avoids an extra reduction step featured earlier 1,2 and relies on an initial indole acylation protocol.

Scheme 1
Commercially available decanedioic acid (7) and tetradecanedioic acid (8) were converted into the respective diacid chlorides 9 and 10 in high yields (Scheme 1).Friedel-Crafts acylation 11 of 1-(phenylsulfonyl)indole (11)  12 with 9 and 10 afforded the respective 3-acylindoles 12 and 13 in good yields.In a one-pot operation, ketones 12 and 13 were transformed into the desired bis-furo [3,4-b]indoles 5 and 6 by a sequence of carbonyl protection as the bis-enol ethers 14 and 15, C-2 lithiation and quenching with acetaldehyde to generate intermediates 16 and 17, followed by trifluoroacetic acid-induced twin cyclodehydration to give the desired furoindoles 5 and 6.Although the final yields of these new bisfuroindoles 5 and 6 are low, the method is relatively short and should be amenable to the preparation of analogues and the subsequent synthesis of Diels-Alder cycloadducts. 2e explored an alternative approach to these bis-furo [3,4-b]indoles by removing the carbonyl groups at an early stage as shown in Scheme 2. Thus, bis-acylation of 1-(phenylsulfonyl)indole (11) with dodecanedioic acid chloride (18), prepared from dodecanedioic acid and thionyl chloride, gave diketone 19.Reduction 11 of 19 with NaBH 4 /TFA gave 20 in 85% yield.Unfortunately, attempts to effect bis-lithiation of 20 with sec-BuLi and quenching with acetaldehyde failed to afford a clean mixture of diastereomeric diols 21, and this alternative route was not further pursued.

Scheme 5
An attractive target for our future work on this project is bis-ellipticine 40 (Figure 3).The diphenyl ether tether imparts significant anticancer activity when tethered to two 9-aminoacridines. 9Accordingly, tethers such as 31-33 can be envisaged to forge 39 and, subsequently, bis-ellipticine 40.

Conclusions
We have synthesized the novel bis-4H-furo[3,4-b]indoles 5 and 6, which now join the first member, 4, of this family.These bis-dienes are suitable for double Diels-Alder cycloaddition reactions leading to potential DNA bis-intercalators. 2Furthermore, we prepared the bifunctional tether 31, which can be envisioned as leading to the semi-rigid bis-4H-furo [3,4-b]indole 39 and thence to bis-ellipticine 40.

Experimental Section
General.Thin layer chromatography was performed on precoated (0.2 mm) silica gel 60 F 254 plastic sheets with spots visualized using a 254 nm UV lamp.Flash chromatography was performed with 230-400 mesh Silicycle gel 60.Melting points were taken on a Laboratory Devices Mel Temp or a Buchi 510 melting point apparatus in open capillaries and are uncorrected. 1H and 13 C NMR spectra were recorded on Varian XL-300 and XL-500 Fourier transform spectrometers as noted.The chemical shifts noted from these spectra are reported in parts per million (ppm, δ) using the signal of chloroform-d 1 (δ 7.27) or acetone-d 6 (δ 1.94) or Me 4 Si as an internal standard.In a few cases a Varian EM 360A NMR Spectrometer measuringat 60 MHz was used.Infrared spectra were recorded with a Perkin Elmer 1600 FTIR or on a Perkin-Elmer 599 spectrophotometer and were obtained either neat or using solid potassium bromide pellets.Both low-resolution and highresolution mass spectra (MS and HRMS) were performed at the Mass Spectrometry Laboratory, School of Chemical Sciences, University of Illinois at Urbana Champaign, or were measured at 35 eV and 70 eV on a Finnigan EI-CI 4023 gas chromatograph-mass spectrometer.Elemental analyses were performed by Atlantic Microlab, Inc. (Norcross, GA).Tetrahydrofuran (THF) was distilled from sodium/benzophenone and the alkyl lithium reagents were standardized by titration against diphenylacetic acid.1,10-Decanedioyl dichloride (9).To a stirred solution of 1,10-decanedioic acid (7) (2.0 g, 10 mmol, 1 eq.) in anhydrous CH 2 Cl 2 (165 mL) under nitrogen was added oxalyl chloride (16.5 mL, 190 mmol, 10 eq.) rapidly via syringe.The reaction was stirred for 24 h, after which the solvent and unreacted oxalyl chloride were distilled off under reduced pressure.The resulting yellow liquid was concentrated via azeotrope with benzene (3 x 50 mL) in vacuo, following which it was redissolved in CH 2 Cl 2 and filtered to remove unreacted 7. The solvent was removed in vacuo and the product dried under a vacuum to yield (9) (2.21 g, 92%) as a yellow liquid; 1 H NMR (CDCl 3 ): δ 2.89 (t, 4H), 1.78-1.68(m, 4H), 1.31-1.25 (b, 8H).This was used directly in the next step with 11. 1,14-Tetradecanedioyl dichloride (10).To a stirred solution of 1,14-tetradecanedioic acid (8) (2.6 g, 10 mmol, 1 eq.) in anhydrous CH 2 Cl 2 (165 mL) under nitrogen was added oxalyl chloride (16.5 mL, 190 mmol, 10 eq.) rapidly via syringe.The reaction was stirred for 24 h, after which the solvent and unreacted oxalyl chloride were removed by distillation under reduced pressure.The resulting yellow liquid was concentrated via azeotrope with benzene (3 x 50 mL) in vacuo, following which it was redissolved in CH 2 Cl 2 and filtered to remove unreacted 8.The solvent was removed in vacuo and the product was dried under a vacuum to yield (10) (2.68 g, 91%) as a yellow liquid, which was used directly in the next step with 11. 1,10-Bis(1-(phenylsulfonyl)-1H-indol-3-yl)decane-1,10-dione) (12).To a stirred solution of AlCl 3 (2.24g, 16.8 mmol, 4 eq.) in CH 2 Cl 2 (90 mL) at 0 °C was added after 15 min a solution of 1,10-decanedioyl dichloride (9) (1.01 g, 4.2 mmol, 1 eq.) in CH 2 Cl 2 (3 mL) dropwise via an addition funnel.The solution was stirred 30 min, after which a solution of 1-(phenylsulfonyl)indole (11) (2.15 g, 8.41 mmol, 2 eq.) in CH 2 Cl 2 (20 mL) was added over 30 min via addition funnel.During this time the solution turned from light yellow to dark orange.The solution was allowed to come to rt and stirred for 2.5 h, during which the solution appeared dark red.The reaction was quenched with ice (150 g) in a 400 mL beaker and covered with a watch glass until the ice melted.The aqueous layer was then extracted with CH 2 Cl 2 (4 x 75 mL) and the combined organic extracts were washed with brine (2 x 50 mL), aqueous sodium carbonate (50 mL), and brine (2 x 50 mL).The organic layer was then dried (MgSO 4 ), filtered, and concentrated in vacuo to yield (12) as a white solid (2.54 g, 89%).The solid was washed with 4:1 hexane:EtOAc and recrystallized in CH 2 Cl 2 /hexane to yield white solid product (12)
After the solution was stirred for 15 min a solution of 1-(phenylsulfonyl)indole (11) (2.17 g, 8.43 mmol, 1 eq.) in CH 2 Cl 2 (17.5 mL) was added over 20 min via an addition funnel.During this time the solution turned from light yellow to dark orange-yellow.The solution was allowed to come to rt and stirred for 2.5 h, during which the solution appeared dark orange-red.The reaction was quenched with ice in a 300 mL beaker and allowed to stand overnight covered with a watch glass, during which the solution turned yellow-green.The solution was extracted with CH 2 Cl 2 (6 x 30 mL) and the combined organic extracts were washed with brine (50 mL), aqueous sodium carbonate (50 mL), and brine (50 mL).The organic layer was then dried (MgSO 4 ), filtered, and concentrated in vacuo to yield (35) as light peach crystals (2.76 g, 87%).The product was recrystallized from Et 2 O to give 35 with mp 121-123 °C; 1 H NMR (CDCl 3 ): δ 8.25 (s, 1H), 7.94-7.85(m, 2H), 7.63-7.56(m, 1H), 7.50-7.26(m, 6H), 4.21 (s, 2H). 13

3-Phenylpropanoyl chloride (37).
To a stirred solution of 3-phenylpropanoic acid (3.0 g, 20 mmol, 1 eq.) in anhydrous CH 2 Cl 2 (165 mL) under nitrogen was added oxalyl chloride (16.5 mL 190 mmol, 10 eq.) rapidly via syringe.The reaction mixture was stirred for 24 h, after which the solvent and unreacted oxalyl chloride were Removed by distillation under reduced pressure.The resulting yellow liquid was concentrated via azeotrope with benzene (3 x 50 mL) in vacuo and dried under a vacuum to yield 37 (3.4 g, ~100%) as a yellow liquid, which was used directly in the next step.