Oligomerization of Indole Derivatives with Incorporation of Thiols

Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.g. 1,2-ethanedithiol, in the presence of trifluoroacetic acid to yield adducts such as 3-[2-(2-amino-5-carboxyphenyl)-1-(2-mercaptoethylthio)ethyl]-1H-indole-5-carboxylic acid. Parallel formation of dimers, such as 2,3-dihydro-1H,1'H-2,3'-biindole-5,5'-dicarboxylic acid and trimers, such as 3,3'-[2-(2-amino-5-carboxy-phenyl)ethane-1,1-diyl]bis(1H-indole-5-carboxylic acid) of the indole derivatives was also observed. Reaction of a mixture of indole and indole-5-carboxylic acid with 2-phenylethanethiol proceeded in a regioselective way, affording 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H-indole-5-carboxylic acid. An additional product of this reaction was 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-2,3-dihydro-1H,1'H-2,3'-biindole-5'-carboxylic acid, which upon standing in DMSO-d6 solution gave 3-[2-(2-aminophenyl)-1-(phenethylthio)ethyl]-1H,1'H-2,3'-biindole-5'-carboxylic acid. Structures of all compounds were elucidated by NMR, and a mechanism for their formation was suggested.


Introduction
Multistage solid phase organic synthesis, which excludes isolation of intermediates steps, is an attractive method for the preparation of diverse chemical substances [1]. However, a high yield of desired product at each synthetic stage is particularly important for these methods [2], as various side reactions, lowering the chemical yield of the individual synthetic steps, are the main limitation of the method [3]. In order to make the method more efficient, a deeper understanding of these unwanted processes is desirable. Scheme 1. Incorporation of thiols. Proposed mechanism and related substances.
In our previous investigation of indole-5-carboxylic acid derivatives attached to carboxylated Wang polymer [4], LC/MS analysis after the cleavage step using trifluoroacetic acid and 1,2-ethanedithiol mixture unexpectedly showed the presence of compounds whose molecular mass corresponded to dimerization of the expected products with addition of 1,2-ethanedithiol.

Results and Discussion
To investigate the aforementioned unknown side reaction, in the present study we tried to prepare a similar compound from indole-5-carboxylic acid itself. Indole-5-carboxylic acid (1a, Scheme 1) was treated with trifluoroacetic acid and 1,2-ethanedithiol mixture. Indeed, the expected dimerization and addition reactions furnished the desired product. In addition, according to LC/MS, along with the dimer and trimer of indole-5-carboxylic acid, a product, whose molecular mass corresponded to the sum of mass of four molecules of indole-5-carboxylic acid and one molecule 1,2-ethanedithiol was detected.
1,2-Ethanedithiol is known to be a strong nucleophilic reagent, widely used as the most effective scavenger of carbonium ions [23]. Incorporation of dithiol could be explained in terms of the mechanism proposed by Smith [11] and Sundberg [24] for oligomerization of indole (Scheme 1). We suggest that ethanedithiol reacts with the indole-5-carboxylic acid dimer 4a (Scheme 1) forming an ethanedithiol adduct 5a. Competitive attachment of the third molecule of indole-5-carboxylic acid leads to parallel formation of trimer 3a (Figure 1). It is logical to assume that in a way similar to formation of 5a, the SH group in 5a reacts further with the protonated dimer 4a yielding a symmetric structure 6a (Scheme 1).

Scheme 2. Incorporation of 2-phenylethanethiol.
It was not possible to obtain an adduct from unsubstituted indole and 1,2-ethanedithiol under typical reaction conditions. Incorporation of this indole was only possible when it was used in a mixture with indole-5-carboxylic acid. In addition, it was noted that the reaction proceeded in a regioselective way yielding 9 (Scheme 3). This reactivity pattern of unsubstituted indole could be explained on the basis of mechanism shown in Scheme 1. Michael additions of thiols are known to be facilitated by the electrodeficiency of the participating alkenes [26]. Electron acceptors attached to the benzene ring of indole should decrease the electron density on the carbon atom being attacked by thiols in structures like 4a (Scheme 1), thereby promoting the reaction.

Scheme 3. Introduction of unsubstituted indole.
An additional indole oligomerization product 10, corresponding to the combination of two molecules of indole, one molecule of indole-5-carboxylic acid and one molecule of 2-phenylethanethiol was isolated from the reaction mixture (Scheme 3). Upon standing in DMSO-d 6 solution for one week, the indoline structure in 10 was oxidized quantitatively to yield indole 11.
Yields for the thiol incorporation products reached 30% (Table 1). They were higher if carbonyl (compounds 5a, 7a-c, 9) or nitrile (7d) groups were attached to the starting indole molecule. Much less reactive were halogenated indoles (products 7e and 7f). Particular low were the yields for tetramer 6a and trimer 10.

Conclusions
In summary, we have discovered a previously unknown indole oligomerization with incorporation of thiols, which has potential synthetic utility. The reaction proceeds with parallel formation of indole 3,3´-trimers; both processes require indole derivatives that are free of substitution at both the 2-and 3positions. The inclusion of electronegative substituents in benzene ring of indole is another crucial factor that makes incorporation of thiols possible. Adducts similar to those reported herein might be of interest as, e.g., potential enzyme inhibitors.

General
Reagents were obtained from Aldrich or Fluka. Evaporations of solvents were carried out on a vacuum rotary evaporator at 30 o C and 20 mbar. TLC was performed using Merck Silica gel 60 F 254 glass plates; flash chromatography was performed using Merck Silica gel (70-230 mesh, pore size 60Å). LC/MS was performed on a Perkin Elmer PE SCIEX API 150EX instrument with a Turboionspray Ion Source and equipped with a Dr. Maisch Reprosil-Pur C18-AQ, 5 μ, 150 × 3 mm HPLC column, using a water and acetonitrile gradient with 5 mM ammonium acetate additive. Semipreparative HPLC was carried out on a LKB system consisting of a 2150 HPLC Pump, 2152 LC Controller and 2151 Variable Wavelength Monitor and Vydac RP C 18 column (10 × 250 mm, 90 Å, 201HS1010), the eluent being an appropriate concentration of MeCN in water + 0.1% TFA, flow rate 5 mL/min, detection at 280 nm. Freeze-drying was performed at 0.1 milibar on a Lyovac GT2 Freeze-Dryer (Finn-Aqua) equipped with a Busch 010-112 vacuum pump and a liquid nitrogen trap. Exact molecular masses were determined on a Micromass Q-Tof2 mass spectrometer equipped with an electrospray ion source. 1 H-NMR spectra were recorded on a Jeol JNM-EX270 or Jeol JNM-EX400, Bruker DMX-600 spectrometer equipped with a cryoprobe or a Bruker DMX-500 spectrometer.
Chemical shifts are reported in ppm relative to residual solvent signal [δ ( 1 H) 2.50 ppm, δ ( 13 C) 39.5 ppm]. Two-dimensional spectra recorded included COLOC, HETRES, selective long range INEPT, COSY, ROESY, sensitivity-enhanced 13 C-HSQC and 13 C-1 H HMBC. ROESY mixing time was 0.1 s. Pulsed-field gradients were used for all 13 C correlation spectra. 13 C-HMBC spectra were recorded with coupling evolution delay for the generation of multiple-bond correlations set to 62.5 ms. ROESY, 13 C-HSQC and 13 C-1 H HMBC spectra were run with 4096*1024 points data matrix, giving τ 2max = 250 ms for 1 H nucleus in acquisition dimension and τ 1max = 200 ms for 1 H or τ 1max = 50 ms for 13 C for indirect dimension; prior to Fourier transform the data matrix was zero-filled twice and multiplication by shifted sine-bell window function applied. For 1 H-13 C HMBC the magnitude spectra were calculated.