Indole anion cycloadditions with methyl coumalate

The reaction of the anion of indoles with methyl coumalate followed by selective opening of the lactone led to the preparation of tricyclic intermediates for indole alkaloid synthesis.


Introduction
The construction of indoles remains an active area in synthetic and medicinal chemistry.The incredible diversity among indole-containing structures inspires new synthetic strategies that often require new methodology.Recent synthetic approaches to polycyclic indoles include the innovative strategies of Stoltz 1 and Sarpong. 2 The Gribble research group and others laid the groundwork for many of these achievements.His innovative studies on nucleophilic and radical additions to indoles and his use of furo [3,4-b]indoles in synthesis have had an impact on the field. 3,4,5,6Additionally, his reviews on indole chemistry have been widely referenced. 7e recently reported the preparation of substituted carbazoles from pyrones via the reaction of 3chloroindoles and methyl coumalate 1 at 200 °C as shown in Scheme 1. 8 This reaction involves an inverse electron demand Diels-Alder reaction followed by elimination of hydrogen chloride and carbon dioxide.A recent computational chemistry study of this reaction showed that the elimination of HCl preceded the elimination of carbon dioxide. 9Scheme 1. Diels-Alder reaction of 3-chloroindole and methyl coumalate.
In order to retain the lactone, we needed to accomplish this connection at much lower temperatures.We investigated the reaction of the anion of indole with methyl coumalate at subambient temperature.Annulations initiated by indole anions are not common.Bäckvall and coworkers reported an interesting cyclization of 2-sulfonyl dienes with the anion of indole at 0 °C. 10They obtained a tetrahydrocarbazole in good yield which they termed a sequential Michael addition reaction (Scheme 2).In a related approach, Marko showed that the anion of indole reacted with certain vinyl acrylates to generate useful yields of tetrahydrocarbazoles. 11 Scheme 2. Diels-Alder reaction of the indole anion and substituted dienes.

Results and Discussion
The reaction of coumalate 1 with the magnesium salt of indole (generated in situ at 0 °C with isopropylmagnesium chloride) in THF afforded tetracyclic lactone adduct as a mixture of isomers, which underwent a retro-Diels-Alder process at room temperature.Other attempts reacting indolemagnesium chloride with methyl coumalate in THF resulted in a mixture of cycloaddition adducts along with a low yield of 3a.Fortunately, changing the Grignard reagent to methylmagnesium bromide or methylmagnesium iodide gave a higher yield of 3a.Our best result was using a 1:1 mixture of toluene/diethyl ether as solvent and methylmagnesium iodide as the base, affording lactone ring opened product dihydrocarbazole acid 3a in 75% yield, in one pot (Scheme 3).The structure was supported by new 1 H NMR resonances at 7.83 ppm (Ha, singlet) and 7.61 ppm (Hb, doublet, J = 2.8 Hz).

Scheme 3. Synthesis of dihydrocarbazole 3a.
To our surprise, the reaction of methyl coumalate 1 with 3-methylindole 2b under the same conditions afforded the tetracyclic lactone 4 in 67% yield as a single diastereomer after recrystallization, which could also undergo a spontaneous retro-Diel-Alder process at room temperature.In an attempt to obtain the lactone ring-opened product 3b, we treated the cyclic lactone 4 with hydrochloric acid in THF/water mixture, but the ring opened product was not observed.Then 4 was treated with trifluoroacetic acid in THF, but no product was observed at -20 °C.Eventually, we found that 4 could be converted into dihydrocarbazole acid 3b by reaction with dilute trifluoromethanesulfonic acid at -20 °C in 29% yield (Scheme 4).The endo-structure of 4 was assigned by NOE experiments: an 1 H-NOE effect was observed between the methyl of the ester and the vinyl hydrogen, as well as between the quaternary methyl group and the vinyl hydrogen.Scheme 4. Synthesis of 3b.
Finally, reaction of 3-allyl indole 2c (produced from the palladium-catalyzed allylation of indole by the method of Larionov 12 ) with methyl coumalate gave lactone adducts as a 2:3 mixture of diastereomers (exo and endo) in 43% yield, which could be stored at ambient temperature for a shot time.Acid-catalyzed ring opening gave 3c in 31% yield (Scheme 5).Numerous natural products have been reported containing structures with a fused hydrocarbazole ring system, such as strychnine and tabersonine (Scheme 6). 13,14The allyl group in 3c could be potentially transformed to other functional groups.

Conclusions
We have successfully developed a method for construction of dihydrocarbazoles in a two-step transformation from commercially available materials.Construction of a quaternary center at the 3-position of the indole ring could also be achieved in moderate yield.This methodology could be applied to the synthesis of complex indoles.

Experimental Section
General.All starting materials were purchased from Sigma-Aldrich and AK Scientific Institution.Solvents were purchased from Sigma-Aldrich and Fisher Scientific, and used without further purification.All reactions were monitored by thin layer chromatography (TLC).All yields refer to separated yields after column chromatography.TLC was carried out on silica plates using UV light as a visualizing agent and phosphomolybdic acid (PMA) or potassium permanganate solution with heat.All columns were performed with silica gel 60Å, particle size 40-63 μm. 1 H and 13 C NMR spectra were acquired in deuterated solvents on a Varian MR-400 or Bruker Avance III 600 MHz spectrometer.
Scheme 6. Natural products with fused hydrocarbazole structure.