Syntheses of three naturally occurring polybrominated 3,3′-bi-1H-indoles

Abstract

The naturally occurring polybrominated indoles 2,2′,5,5′-tetrabromo-3,3′-bi-1H-indole, 2,2′,6,6′-tetrabromo-3,3′-bi-1H-indole, and 2,2′,5,5′,6,6′-hexabromo-3,3′-bi-1H-indole were synthesized using a palladium catalyzed, carbon monoxide mediated, double reductive N-heterocyclization of 2,3-bis(2-nitro-4(or 5)-bromophenyl)-1,4-butadienes as the key step.

Graphical Abstract

Introduction

A small number of 3,3′-bi-1H-indoles have been isolated from marine algae and from a terrestrial fungus. The first alkaloid of this kind to be isolated and characterized was 2,2′,5,5′-tetrabromo-3,3′-bi-1H-indole (1) isolated from the cyanobacterium Rivularia firma in 1982 (Figure 1).¹ The isomeric alkaloid, 2,2′,6,6′-tetrabromo-3,3′-bi-1H-indole (2) was later isolated from the same species.² More recently 2,2′,5,5′,6,6′-hexabromo-3,3′-bi-1H-indole (3) was isolated from the red alga Laurencia similis.³ Biindole 3 was shown to be a protein tyrosine phospholipase 1B inhibitor.⁴

Figure 1.

Naturally occurring polyhalogenated 3,3′-bi-1H-indoles.

In addition to compounds 1–3, the sulfur containing alkaloids 4,⁵ 5–6,⁶ 7,⁷ all produced by the red alga Laurencia brongniartii, and the polyfunctionalized biindole 8 from the green alga Chaetomorpha basiretorsa Setchell⁸ have been isolated. The only example of a 3,3′-bi-1H-indole from a terrestrial source is the parent compound isolated from the fungus Gliocladium catenulatum.⁹ To the best of our knowledge neither of the polyhalogenated biindoles 1–8 have been prepared synthetically to date.

We have recently disclosed a methodology for the synthesis of 3,3′-biindoles wherein a palladium catalyzed, carbon monoxide mediated, double reductive cyclization of 2,3-bis(2-nitrophenyl)-1,3-butadienes was employed in a key indolization step (Scheme 1).¹⁰ For example, reductive cyclization of 2,3-bis(2-nitrophenyl)-1,3-butadiene (9) gave the parent 3,3′-bi-1H-indole (10) in excellent isolated yield. Herein are described synthetic routes to biindoles 1–3 using a reductive cyclization of 2,3-bis(2-nitro-5/6-bromophenyl)-1,3-butadienes as the key step followed subsequent introduction of the remaining bromine atoms.

Scheme 1.

Palladium catalyzed double reductive cyclization to 3,3′-biindoles.

Results and Discussion

5-Bromo-2-nitro-1-iodobenzene (11) was used as the starting point for the synthesis of alkaloids 1 and 3. Sonogashira cross-coupling of 11 with trimethylsilylethyne gave 12 (Scheme 2). The silyl group was removed using potassium carbonate in a methanol-diethyl ether mixture to afford 13. Treatment of 13 with tributyltin hydride in the presence of bis(triphenylphosphine)palladium dichloride furnish vinyl tin derivative 14 with excellent α-selectivity (Scheme 2). No trace of the β-isomer was observed by ¹H NMR of the crude reaction mixture.¹¹ It should be noted that each of the first three steps afforded the desired compound in an excess of 91% yield and a 77% overall yield. Tin compound 14 smoothly underwent homocoupling to give diene 15 using an excess of copper chloride in N,N-dimethylformamide (DMF).¹⁰ Diene 15 was dissolved in DMF and treated with carbon monoxide (pCO = 6 atm, 120 °C) in the presence of a palladium catalyst system consisting of bis(dibenzylideneacetone)palladium (10-mol%) - 1,3-bis(diphenyl)propane (12-mol%) - 1,10-phenanthroline (20-mol%) to give 5,5′-dibromo-3,3′-bi-1H-indole 16.

Scheme 2.

Synthesis of 2,2′,5,5′-tetrabromo- and 2,2′,5,5′,6,6′-hexabromo-3,3′-bi-1H-indole.

Biindole (16) has previously been prepared by a palladium catalyzed oxidative dimerization of 5-bromoindole,¹² reductive cyclization of 17,¹³ and a two-step procedure employing a nucleophilic addition of 5-bromoindole (18) to 5-bromoisatine (19) followed by borane reduction of the intermediate (Scheme 5).¹⁴ The ¹H NMR and ¹³C NMR data recorded for 16 were in complete accordance with the reported values.

Scheme 5.

Polybromination of 23.

The two and four additional bromines in alkaloids 1 and 3 were envisioned to be introduced via bromination of 16 using N-bromosuccinimide (NBS) or bromine. Reactions of 16 with bromine under a variety of conditions did not afford any identifiable product nor was any starting material recovered. 3-Substituted indoles have been selectively brominated in the 2-position using NBS. For example, bromination of 3-methylindole using NBS in carbon tetrachloride (CCl₄) to give 2-bromo-3-methylindole in 97% yield has been reported.¹⁵ Based on this precedence, biindole 16 was treated with 2.0 equivalents of NBS in CCl₄ affording the naturally occurring tetrabrominated alkaloid 1 in 59% yield after chromatographic purification. Reactions of 16 with 4–6 equivalents of NBS in CCl₄ were not clean and afforded a number of inseparable products with low overall mass balance. However, replacing CCl₄ with a 1:1 mixture of tetrahydrofuran and dichloromethane as the solvent system gave 3 in 46% isolated yield upon treatment with six equivalents of NBS. All analytical data for 1¹ and 3³ were in complete agreement with the data reported for the isolated natural products.

A synthetic sequence similar to the one depicted in Scheme 2 was used to prepare the remaining 2,2′,6,6′-tetrabrominated alkaloid 2. 1-(4-Bromo-2-nitrophenyl)ethyne (20) served as the starting point for the synthesis of 2 (Scheme 4). Both the regioselective palladium catalyzed hydrostannylation of 20 furnishing vinyl tin 21 and the subsequent copper mediated homocoupling affording diene 22 proceeded uneventfully. Reductive cyclization of 22 furnished 6,6′-dibromo-3,3′-biindole (23) in 64% isolated yield. Compound 23 has previously been prepared via a palladium catalyzed oxidative dimerization of 6-bromoindole.¹⁶

Scheme 4.

Synthesis of 2,2′,6,6′-dibromo-3,3′-bi-1H-indole.

Similar to the synthesis of 1, biindole 23 was treated with 2.0 equivalents of NBS in CCl₄ affording the tetrabrominated biindole alkaloid 2 in 59% yield after chromatographic purification. All analytical data were in complete agreement with the data reported for isolated 2.¹

Compound 23 was also percieved to be a suitable precursor to the hexabromo substituted natural product 3 via the introduction of the four additional bromines in the 2,2′, 5,5′-positions, respectively. In the event, treatment of 23 with five equivalents of NBS in a THF-dichloromethane solvent system gave a separable mixture of the expected product 3 together with significant amount of 2,2′,5,6,6′-pentabromo-bi-1H-indole 24 (Scheme 5). All attempt to increase the yield of 3 at the expense of 24 were unsuccessful. For example, increasing the amount of NBS to eight equivalents gave roughly the same product ratio but in a much diminished yield (Scheme 5). In addition, an attempt to introduce the remaining bromine to the isolated pentabromo-biindole 24 using 3 equivalents of NBS was unsuccessful. The starting material was recovered in high yield (94%) after chromatography.

Precedence for direct regioselective 2,6-dibromination and 2,5,6-tribromination of 3-substituted indoles can be found in the literature. For example, 2,6-dibromination of 3-cyanomethylindole using NBS-SiO₂ in dichloromethane gave 2,6-dibromo-3-cyanomethylindole (81%), 2,5-dibromo-3-cyanomethylindole (3%), and 2,4-dibromo-3-cyanomethylindole (5%).¹⁷ 3-Methylindole afforded selectively 2,6-dibromo-3-methylindole using NBS-SiO₂ in dichloromethane¹⁸ and 3-phenylindole using NBS in acetic acid furnished a 6:1 ratio of 2,6-dibromo-3-phenylindole and 2,5-dibromo-3-phenylindole.¹⁹ In contrast, a 3:4 ratio of 2,6:2,5-dibromination was observed from brominations of methyltryptophan employing NBS in AcOH/HCOOH.²⁰ Tribromination of 3-methylindole with bromine in acetic anhydride gave 2,5,6-tribromo-3-methyl-N-acetylindole.²¹ Based on these previously reported brominations, polybrominations of the parent 3,3′-biindole 10 to give either 2 or 3, depending on the stoichiometry of the reagents, were also pursued. Thus, 3,3′-biindole 10 was treated with 4.0, 5.1, and 8.0 equivalents of NBS in THF/dichloromethane (Scheme 6). Bromination of 10 proved to be substantially more difficult and only low yields of product(s) were obtained. Using 4.0 equivalents of NBS gave a mixture of 2 and 24 both in 8% isolated yield. Increasing the amount of NBS to 5.1 equivalents eliminated the formation of biindole 2 but gave instead pentabrominated and hexabrominated compounds 24 and 3, respectively. Finally, treatment of 10 with 8.0 equivalents of NBS gave 3 in 16% yield. No other products were isolated from the three different bromination reactions of 10.

Scheme 6.

Bromination of 3,3′-bi-1H-indole (10).

In summary, short synthetic routes to three naturally occurring polybrominated 3,3′-bi-1H-indoles have been developed. All analytical data of the synthetically derived compounds were in all aspects identical to the naturally occurring biindoles.

Scheme 3.

Research highlights.

• Syntheses of three polybrominated biindole alkaloids have been completed.

• A palladium catalyzed reductive cyclization was used as key ring-closing step.

• N-Bromosuccinimide was used brominate the biindoles.