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. Author manuscript; available in PMC: 2008 Sep 29.
Published in final edited form as: J Org Chem. 2007 Jun 20;72(15):5832–5834. doi: 10.1021/jo070734v

Practical Synthesis of 7-Prenylindole

Xin Xiong 1, Michael C Pirrung 1,*
PMCID: PMC2556248  NIHMSID: NIHMS62496  PMID: 17580906

Abstract

7-Prenylindole is a useful building block for natural product and natural product analog synthesis. While there have been several past syntheses of 7-prenylindole, none of them is very practical for its preparation on scale. Using an aza-Claisen rearrangement as the key step, 7-prenylindole has been prepared in four steps from indoline in 62% overall yield.

7-Prenylindole is a component of many natural products, such as the annonidines,1 astechrome (as its iron complex),2 and the asterriquinones3 (Chart 1). It is also a (simple) natural product, mostly from plants, in its own right.4 We have used 7-prenylindole in several syntheses of asterriquinone targets, in particular demethylasterriquinone B15 (a lead compound for oral insulin mimics), as have others.6 7-Prenylindole has also served as a starting material for syntheses of the annonidines7 and astechrome.8 There are several literature preparations of 7-prenylindole,9 including one of our own.10 Because we identified the 7-prenylindole region of demethylasterriquinone B1 as a major part of its pharmacophore,5c we must prepare large numbers of compounds that include 7-prenylindole. This compound is therefore needed in ample supply, but in our experience all of its known preparations have drawbacks. Some do not scale up well, while others require expensive reagents or catalysts. We describe here a synthesis of 7-prenylindole that is readily performed with simple chemistry on a scale to prepare gram quantities.

Chart 1.

Chart 1

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7-Prenylindole-containing natural products

The synthesis (Scheme 1) begins with indoline, which is N-dimethylpropargylated using classical methods11 to give the known compound 1.12 The semi-hydrogenation of compound 1 proceeds rapidly, so quickly in fact that prompt monitoring of the reaction, conducted merely with a balloon containing hydrogen, is required. Within 20–30 min, the known dimethylallyl amine 2 is produced. The acid-promoted aza-Claisen rearrangement of N-allylanilines13 is a known transformation.9a,12 Heating 2 with trifluoroacetic acid in a microwave reactor introduces the prenyl group ortho to the nitrogen. Final oxidation of the indoline to the indole is conducted with manganese dioxide.14 Interestingly, when conducted in chloroform, this reaction gives appreciable quantities of compound 5. A putative mechanism to explain its formation is provided (Scheme 2), involving protonation (via HCl in the chloroform) of 7-prenylindole by analogy to the observations of Van Vranken with tryptophan.15 Addition of 7-prenylindoline to the imminium ionresults in compound 4, which would presumably be more susceptible to MnO2 oxidation in the indolinering that is activated with two nitrogens. Unfortunately, this compound’s structure is not related to any of the of dimeric 7-prenylindole natural products. As this reaction is a dimerization, it should be suppressed by conducting it at lower concentration, but given that significant quantities were obtained even at 0.1 M, further dilution was deemed impractical. Conducting the reaction in dichloromethane eliminates dimer formation.

Scheme 1.

Scheme 1

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The preparation of 7-prenylindole

Scheme 2.

Scheme 2

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The formation of a 7-prenylindole/7-prenylindoline dimer

Each compound in Scheme 1 has been reported, as were each of the conversions shown.16 Yet, none was described in sufficient detail to use this earlier work to prepare the target (in our hands). Overall, our synthesis proceeds in 62% yield. The fact that it gives the product in crystalline form when 7-prenylindole has such a low melting point attests to the purity of the material delivered by this synthetic route. It can be used to prepare gram batches of 7-prenylindole in one run requiring approx. 3 days of laboratory time to execute. As such, this synthesis should greatly increase access to 7-prenylindole.

EXPERIMENTAL

1-(2-methylbut-3-yn-2-yl)indoline (1)

To a 50 mL round-bottomed flask containing indoline (1.12mL, 10.0 mmol), 2-chloro-2-methylbut-3-yne (1.37 mL, 12.0 mmol), and CuCl (99 mg, 1.0 mmol) inanhydrous THF (20 mL) under an argon atmosphere was added Et3N (1.67 mL, 12.0 mmol) dropwise at 0°C. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixturewas filtered through a plug of silica gel and concentrated under reduced pressure. The crude material waspurified by column chromatography (CH2Cl2:hexane 1:4) to give the title compound (1.68 g, 91%) as a pale yellow oil. Rf = 0.34 (ethyl acetate:hexane 1:10); IR (neat) 3286, 2985, 2844, 1605, 1483, 1254, 744cm−1; 1 H NMR (300 MHz, CDCl3) δ 7.30 (1H, d, J = 7.9 Hz), 7.18 7.13 (1H, m), 6.80 (1H, m), 3.45 (2H, t, J = 8.1 Hz), 2.98 (2H, t, J = 8.1 Hz), 2.46 (1H, s), 1.69 (6H, s); 13C NMR (75 MHz, CDCl3) δ 150.2, 131.8, 127.0, 124.6, 118.6, 111.9, 87.7, 71.1, 51.2, 49.7, 28.4, 27.4; HRMS Calcd. for C13H15NH+(M +H)+ 186.1278, found 186.1278; Anal. Calcd. for C13H15N: C, 84.28; H, 8.16; N, 7.56. Found: C, 84.21; H,8.20; N, 7.32.

1-(2-methylbut-3-en-2-yl)indoline (2)

To a solution of alkyne 1 (3.18 g, 17.0 mmol) in MeOH (50mL) was added Lindlar catalyst (308 mg). The reaction mixture was then degassed and stirred under an atmosphere of H2 (balloon with needle) until starting material disappears, within 30 min, as indicated by TLC (longer exposure of the reactant to the reaction conditions leads to significant over-reduction, even complete conversion to the corresponding alkane). The reaction mixture was filtered through a short plug of silica gel and concentrated under reduced pressure. The crude material was purified by column chromatography (ethyl acetate:hexane 1:30) to yield the title compound (2.73 g, 86%) as a colorless oil. Rf = 0.51 (ethyl acetate:hexane 1:10); IR (neat) 2977, 2843, 1606, 1483, 1471, 1458, 1254, 1195, 913, 743cm−1; 1 H NMR (300 MHz, CDCl3) δ 7.07 (1H, d, J = 7.1 Hz), 6.96 (1H, dt, J = 8.0, 0.6 Hz), 6.80 (1H, d, J= 8.0 Hz), 6.64 (1H, m), 6.15 (1H, dd, J = 17.6, 10.7 Hz), 5.24 (1H, dd, J = 17.6, 0.9 Hz), 5.15 (1H, dd, J =10.7, 1.0 Hz), 3.44 (2H, t, J = 8.3 Hz), 2.92 (2H, t, J = 8.3 Hz), 1.36 (6H, s); 13C NMR (75 MHz, CDCl3) δ 151.0, 147.3, 131.6, 126.8, 124.5, 117.5, 112.4, 111.4, 57.6, 49.3, 28.4, 24.4; HRMS Calcd. for C13H17NH+ (M + H)+ 188.1435, found 188.1434; Anal. Calcd. for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.36; H, 9.20; N, 7.44.

7-(3-methylbut-2enyl)indoline (3)

To a solution of 2 (1.87 g, 10.0 mmol) in toluene (3 mL) was added TFA (0.1 mL, 1.3 mmol). The reaction mixture and a magnetic stir bar were sealed in the reaction vessel of a Discover® monomode microwave apparatus (CEM) and irradiated for 10 min at 150 °C. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (ethylacetate:hexane 1:8) to give the title compound (1.69 g, 90%) as a pale yellow oil. Rf = 0.20 (ethylacetate:hexane 1:10); IR (neat) 3375, 2969, 2913, 2850, 1601, 1455, 1306, 1254, 1059, 748 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.02 (1H, dd, J = 7.2, 0.6 Hz), 6.88 (1H, d, J = 7.5 Hz), 6.70 (1H, t, J = 7.4 Hz), 5.27 (1H, m), 3.70 (NH, br s), 3.58 (2H, t, J = 8.4 Hz), 3.20 (2H, d, J = 7.1 Hz), 3.06 (2H, t, J = 8.4 Hz),1.78–1.75 (6H, m); 13C NMR (75 MHz, CDCl3) δ 150.2, 133.4, 129.3, 127.3, 122.9, 122.6, 122.1, 119.1, 47.5, 30.8, 30.3, 26.0, 18.1; HRMS Calcd. for C13H17NH+(M + H)+ 188.1435, found 188.1436; Anal. Calcd. for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C, 83.34; H, 9.27; N, 7.42.

7-(3-methylbut-2-enyl)-1H-indole

A mixture of 3 (0.42 g, 2.2 mmol) and activated manganese(IV) oxide (0.57 g, 6.6 mmol) in dichloromethane (20 mL) was heated at reflux. After 1.5 h, additional activated manganese(IV) oxide (0.57 g, 6.6 mmol) was added to the reaction mixture. The mixture was kept refluxing for another 1.5 h, allowed to cool, and filtered through a short plug of silica gel. Concentration of the filtrate under reduced pressure was followed by column chromatography (ethyl acetate:hexane 1:30) to yield the title compound (0.36 g, 88%) as an off-white solid, mp 43–44 °C (lit.,1 mp 43–44 °C). Rf = 0.21(ethyl acetate:hexane 1:10); 1H NMR (300 MHz, CDCl3) δ 8.15 (NH, br s), 7.54 (1H, d, J = 7.56 Hz), 7.21 (1H, t, J = 2.8 Hz), 7.11−7.02 (2H, m), 6.58 (1H, dd, J = 3.2, 2.1 Hz), 5.45 (1H, m), 3.61 (2H, d, J = 7.0 Hz), 1.85 (3H, s), 1.82 (3H, d, J = 1.2 Hz); 13C NMR (75 MHz, CDCl3) δ 135.4, 133.6, 128.1, 124.2, 124.1, 122.5, 121.8, 120.3, 119.0, 103.2, 31.1, 26.0, 18.2; HRMS Calcd. for C13H15NH+ (M +H)+ 186.1278, found 186.1282. Anal. Calcd. for C13H15N: C, 84.28; H, 8.16; N, 7.56. Found: C, 84.28; H,8.28; N, 7.43.

7,7′-bis(3-methylbut-2-enyl)-2,3-dihydro-1′H-1,2′-biindole (5)

A mixture of 3 (0.56 g, 3.0 mmol) and activated manganese(IV) oxide (0.78 g, 9.0 mmol) in chloroform (30 mL) was heated at reflux. After 1.5 h, additional activated manganese(IV) oxide (0.78 g, 9.0 mmol) was added to the reaction mixture. The mixture was kept refluxing for another 1.5 h, allowed to cool, and filtered through a short plug of silica gel. Concentration of the filtrate under reduced pressure was followed by column chromatography (ethyl acetate:hexane 1:30) to yield the title compound (0.19 g, 35%) as a greenish-yellow oil. Rf = 0.19 (ethyl acetate:hexane 1:10). IR (neat) 3419, 2967, 2912, 2853, 1589, 1471, 1448, 1434, 1316, 1100,1067, 848, 758, 723 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.07 (NH, br s), 7.20−7.16 (2H, m), 7.08 (1H, d, J = 7. 1Hz), 6.94 (1H, d, J = 7.6 Hz), 6.87−6.80 (2H, m), 6.43 (1H, m), 5.41 (1H, m), 5.14 (1H, m), 3.93 (2H, t, J = 8.4 Hz), 3.54 (2H, d, J = 6.9 Hz), 3.11 (2H, t, J = 8.4 Hz), 2.83 (2H, d, J = 7.1Hz), 1.82 (3H, s), 1.78 (3H, s), 1.64 (3H, s), 1.38 (3H, s); 13C NMR (75 MHz, CDCl3) δ 148.5, 143.1, 133.6, 133.0, 132.6, 132.4, 128.5, 128.3, 126.8, 124.7, 124.5, 123.0, 122.6, 122.4, 120.6, 119.1,113.0, 103.1, 59.5, 31.2, 30.7, 29.8, 26.02, 26.00, 18.3, 17.9; HRMS Calcd. for C26H30N2H+ (M + H)+371.2483, found 371.2499.

Supplementary Material

si20070413_043. Supporting Information available.

1H NMR and 13C NMR spectra of all compounds (5 pages). This material is available free of charge via the Internet at http://pubs.acs.org.

Acknowledgments

Financial support from the NIH (DK-60532) is gratefully acknowledged. We thank CEM Corp. for providing the microwave reactor. The assistance of C. Crotts in administrative support of this work is greatly appreciated.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

si20070413_043. Supporting Information available.

1H NMR and 13C NMR spectra of all compounds (5 pages). This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS62496-supplement-si20070413_043.pdf (437.8KB, pdf)

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