Synthesis of tetrahydro-β-carbolines from 2-indolylmethyl azides and propargylic alcohols

A facile and efficient route to tetrahydro-β-carbolines from 2-indolylmethyl azides and propargylic alcohols via acid-catalyzed dehydrative annulation reactions is described. This reaction proceeds through a cascade sequence of Friedel–Crafts-type alkylation followed by intramolecular “Click” reaction, involving the formation of multiple chemical bonds in a single operation with excellent atom-economy and broad functional group tolerance.


Introduction
Tetrahydro-b-carboline (THBC) derivatives are very important alkaloids with various biological activities and pharmaceutical applications and with extensive occurrence in natural products. 1 Consequently, intense efforts have been devoted to the development of efficient methods for their synthesis and signicant progress has been achieved. However, most current methods such as the classical Pictet-Spengler reaction are limited in product scope as mostly only products with substitution at the 1-position of the THBC ring are accessible. 2 Therefore, the development of methods with wide product diversity is still highly desirable.
Recently, our group have developed cascade processes using Nsulfonyl aziridines as a nitrogen source and simple electron-rich benzylic alcohols as a versatile three-carbon synthon for the synthesis of tetrahydro-b-carbolines and tetrahydroisoquinolines. 3 We then reasoned that the use of 2-indolylmethyl azides as a nitrogen source and the use of readily available propargylic alcohols as a three-carbon synthon may enable access to compounds with novel structures not easily accessible by other methods. One major challenge associated with this strategy is the competitive Friedel-Cras-type alkylations of 1 between the two resonance forms I and II of the carbocation intermediate generated from 2 in the presence of an acid catalyst (Scheme 1). 4 We disclose here that the selectivity of this process hinges on both the use of different acid catalysts and the substituents on propargylic alcohols, providing a new atom-economic way to tetracyclic tetrahydro-b-carboline derivatives with a fused triazole structure and indole azepines. 5

Results and discussion
The reaction of 2-(azidomethyl)-1H-indole 1a and propargylic alcohol 2a was selected as a model reaction for optimization of reaction conditions (Table 1). Using 1,2-dichloroethane (1,2-DCE) as solvent, four different rare-earth metal triates were screened, and two products 3aa and 4aa were generally obtained ( Table 1, entries 2-5). Yb(OTf) 3 was found to be the most efficient catalyst for this reaction, providing the highest overall yield of tetrahydro-b-carboline 3 and azepine 4 (Table 1, entry 5). No reaction occurred in the absence of the catalyst or when the reaction was performed at room temperature (Table 1, entries 1 and 6). Changing the solvent to toluene, DMF, 1,4-dioxane, or THF gave inferior results (Table 1, entries 7-10). Further screen of catalyst loading amount revealed that 10 mol% was optimal for the reaction, while lower (5 mol%) or higher (20 mol%) tetrahydro-b-carbolines 3 were isolated in moderate yields (Scheme 3). The reduced steric hindrance in the carbocation intermediate I (Scheme 1) might be partly responsible for this product selectivity. Propargylic alcohols 2 bearing electrondonating substituents on aryl groups (R 2 ) provided higher yields than those with electron-withdrawing ones (Scheme 3, 3ah-3ao). Moreover, when 9-uorenyl-substituted propargylic alcohols 2p-2s were subjected to the reaction conditions, spirocyclic products 3ap-3as could be formed in the yields of 51-56% as the only products. We also probed the reaction scope with regard to the synthesis of indole azepines via the TfOH-catalyzed formal [4 + 3]-annulation route. In general, only propargylic alcohols 2 bearing an electron-donating substituent on one of the aryl groups (R 1 , R 2 , R 3 ) worked in this system to provide the corresponding indole azepines in moderate yields (Scheme 4). While the use of 1a or 1b also gave comparable results, the corresponding tetrahydro-b-carboline products 3 were detected in only trace amount in these cases.
Based on the above experimental results, a plausible mechanism for the present cascade reactions was proposed (Scheme 5). First, in the presence of an acid catalyst, propargylic alcohol 2a would be converted to the propargylic carbocation I, which is in equilibrium with the allenic form II. Subsequent Friedel-Cras-type reaction with 1a would form the propargylic intermediate IV (from I) or allenic intermediate III (from II). Then intermediate IV would be transformed to the nal product tetrahydro-b-carboline 3aa by an intramolecular click reaction, while the allenic intermediate III would be transformed to the azepine product 4aa via an acid-catalyzed allene hydroamination with the concurrent release of a molecule of N 2 . Both the nature of the acid catalyst and the electronic and steric effects of the substituents on the propargylic alcohols have inuence on the product selectivity of the reaction.

Conclusions
In summary, two cascade reactions of 2-indolylmethyl azides and propargylic alcohols were developed by using simple Lewis acid and Brønsted acid catalysts. The good atom-and stepeconomy, readily available starting materials, easy operation, and mild reaction conditions render this method a useful alternative way to tetrahydro-b-carbolines and indole azepines. Efforts towards the utilization of the propargylic alcohols to the synthesis of other useful cyclic compounds are underway in our laboratories.

General comments
Infrared spectra were obtained on a FTIR spectrometer. 1 H NMR spectra were recorded on 300 MHz or 400 MHz spectrometer in DMSO-d 6 or CDCl 3 solution and the chemical shis were reported relative to internal standard TMS (0 ppm). The following abbreviations are used to describe peak patterns where appro- Coupling constants are reported in hertz (Hz). 13 C NMR were recorded on 75 MHz or 100 MHz and referenced to the internal solvent signals (central peak is 40.00 ppm in DMSO-d 6 or 77.00 ppm in CDCl 3 ). HRMS data were obtained using ESI ionization. Melting points were measured with micro melting point apparatus.
General procedure for the synthesis of 3 A solution of indole 1 (0.5 mmol), propargylic alcohols 2 (0.5 mmol) and Yb(OTf) 3 (0.05 mmol) in 1,2-DCE (5 mL, for 1a) at 84 C or THF (5 mL, for 1b) at 66 C was stirred under open air for 18 h. Aer being cooled down to room temperature, the mixture was diluted with ethyl acetate (50 mL), washed with saturated NaCl solution (10 mL) and dried over anhydrous Na 2 SO 4 . The solvent was evaporated and the crude product was puried by silica gel column chromatography with petroleum ether/ethyl acetate (1 : General procedure for the synthesis of 4 A solution of 2-(azidomethyl)-1H-indole 1 (0.5 mmol), the propargylic alcohols 2 (0.5 mmol) and TfOH (0.05 mmol) in 1,2-DCE (5 mL) was stirred under air at 84 C for 18 h. Aer being cooled down to room temperature, the mixture was diluted with ethyl acetate (50 mL), washed with saturated NaCl solution (10 mL) and dried over anhydrous Na 2 SO 4 . The solvent was evaporated and the crude product was puried by silica gel column chromatography with petroleum ether/ethyl acetate (6 : 1, v/v).