Ethyl 5-Hydroxy-2-methyl-1-(pyridin-2-ylmethyl)benzo[ g ]indole-3-carboxylate

: Indole ring is widely represented in natural compounds, as well as in a great variety of drugs. In this paper, the synthesis of a 5-hydroxybenzoindole derivative carrying a pyridyl substituent on position 1 is reported. The method involved no chromatography for purification and used solvents and catalysts of very low toxicity.


Introduction
Indole ring is a common heterocycle found in thousands [1] of natural products, e.g., tryptophan and indole-3-carbinol, as well as synthetic drugs like tadalafil and sumatriptan.The oxidation of tryptophan via hydroxylase [2] leads to serotonin, melatonin, and other important metabolites carrying the 5-hydroxyindole moiety, as well as several active pharmaceutical ingredients such as indomethacin [3], umifenovir [4], anlotinib [5], and atevirdine [6].The possibility of synthesizing multifunctional compounds based on 5-hydroxyindole scaffold is therefore highly desirable and has been implemented by applying a variety of procedures, e.g., Fischer synthesis [7], Stille coupling [8], and amino-Claisen rearrangement [9].In this regard, Nenitzescu synthesis [10] is particularly attractive since the starting materials, enamines, and quinones are relatively cheap and of limited toxicity compared to phenylhydrazines or other precursors commonly employed in other pathways.Several advancements have been proposed to develop Nenitzescu synthesis, viz. the use of nitromethane as a solvent [11], as well as the application of Lewis acid catalysts [12,13] or enantioselective catalysts [14].Herein, for the first time, we report on the synthesis of a 5-hydroxybenzoindole with a pyridyl substituent based on the slight modification of a procedure that we recently developed [15].

Results
The procedure consisted in two steps: first, 2-picolylamine was added to ethyl acetoacetate in equimolar amounts without the addition of any solvent or catalyst; second, the resulting enaminoester (1 in Scheme 1) was treated with naphthoquinone in cyclopentyl methyl ether (CPME) with the aid of zinc chloride in catalytic amounts.The first step gave an isolated yield of 50%, while the second involved isolating the product (2 in Scheme 1) in a 21% yield.The overall yield was therefore 11%.

Discussion
The condensation of primary amines with beta-ketoesters is quite a straightforward reaction.Thus, we omi ed the use of a catalyst (e.g., acetic acid [16]) to avoid any carryover that could interfere with the second step.On the other hand, the reported synthesis [17] for compound 1 involved the use of 10 mol% of iodine, a heavy and rare [18] element with toxicity issues [19,20].At variance with our experience with Neni escu synthesis, this particular enamine gave small amounts of product when the reaction was left for 40 minutes, as previously reported [15], probably because of the heterogenous nature of the mixture and the ability of 1 to chelate zinc, therefore depressing its Lewis acidity.The reaction mixture turned to a dark orange color that did not fade with time; this is a sign of the formation of highly conjugated intermediates derived from additions to quinone (3 in Figure 1) that do not react further, as already pointed out in the literature [11,12].It should be pointed out that the procedure, despite the low yield which is often encountered in Neni escu synthesis, works entirely at room temperature.Moreover, purification is simple because the product precipitates completely and selectively from the reaction mixture, and the use of solvents is quite scarce and limited (only environmentally friendly ones, like ethanol and ethyl acetate [21], are typically used for work-up and CPME) [22].

Discussion
The condensation of primary amines with beta-ketoesters is quite a straightforward reaction.Thus, we omitted the use of a catalyst (e.g., acetic acid [16]) to avoid any carry-over that could interfere with the second step.On the other hand, the reported synthesis [17] for compound 1 involved the use of 10 mol% of iodine, a heavy and rare [18] element with toxicity issues [19,20].At variance with our experience with Nenitzescu synthesis, this particular enamine gave small amounts of product when the reaction was left for 40 min, as previously reported [15], probably because of the heterogenous nature of the mixture and the ability of 1 to chelate zinc, therefore depressing its Lewis acidity.The reaction mixture turned to a dark orange color that did not fade with time; this is a sign of the formation of highly conjugated intermediates derived from additions to quinone (3 in Figure 1) that do not react further, as already pointed out in the literature [11,12].

Discussion
The condensation of primary amines with beta-ketoesters is quite a straightforward reaction.Thus, we omi ed the use of a catalyst (e.g., acetic acid [16]) to avoid any carryover that could interfere with the second step.On the other hand, the reported synthesis [17] for compound 1 involved the use of 10 mol% of iodine, a heavy and rare [18] element with toxicity issues [19,20].At variance with our experience with Neni escu synthesis, this particular enamine gave small amounts of product when the reaction was left for 40 minutes, as previously reported [15], probably because of the heterogenous nature of the mixture and the ability of 1 to chelate zinc, therefore depressing its Lewis acidity.The reaction mixture turned to a dark orange color that did not fade with time; this is a sign of the formation of highly conjugated intermediates derived from additions to quinone (3 in Figure 1) that do not react further, as already pointed out in the literature [11,12].It should be pointed out that the procedure, despite the low yield which is often encountered in Neni escu synthesis, works entirely at room temperature.Moreover, purification is simple because the product precipitates completely and selectively from the reaction mixture, and the use of solvents is quite scarce and limited (only environmentally friendly ones, like ethanol and ethyl acetate [21], are typically used for work-up and CPME) [22].It should be pointed out that the procedure, despite the low yield which is often encountered in Nenitzescu synthesis, works entirely at room temperature.Moreover, purification is simple because the product precipitates completely and selectively from the reaction mixture, and the use of solvents is quite scarce and limited (only environmentally friendly ones, like ethanol and ethyl acetate [21], are typically used for work-up and CPME) [22].
All materials were used as received. 1H-NMR (400 MHz) and 13 C-NMR (101 MHz) spectra were recorded in CDCl 3 with a Bruker Ascend 400 spectrometer (Bruker, Ettlingen, Germany) in CDCl 3 or DMSO d 6 solutions, and residual solvents peaks were used for calibration at 7.26 ppm and 2.50 ppm, respectively.Mass spectra were acquired using a Thermo Finnigan Q Exactive spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) with an API-HESI source and a Fourier transform orbital trap (Orbitrap).Samples were introduced as acetonitrile solutions at a 0.1 mg/L concentration.

Conclusions
Ethyl 5-hydroxy-2-methyl-1-(pyridin-2-ylmethyl)benzo[g]indole-3-carboxylate was synthesized for the first time.The compound is highly functionalized and of potential interest in the field of medicinal chemistry.Despite the low yield, the method described entails no chromatography for purification and uses solvents and catalysts of very low toxicity.

Conclusions
Ethyl 5-hydroxy-2-methyl-1-(pyridin-2-ylmethyl)benzo[g]indole-3-carboxylate was synthesized for the first time.The compound is highly functionalized and of potential interest in the field of medicinal chemistry.Despite the low yield, the method described entails no chromatography for purification and uses solvents and catalysts of very low toxicity.

Figure 1 .
Figure 1.Structure of one of the possible intermediates.

Figure 1 .
Figure 1.Structure of one of the possible intermediates.

Figure 1 .
Figure 1.Structure of one of the possible intermediates.

Figure 2 .
Figure 2. Atom labelling for compound 2; numbers are used for reference in 13C NMR spectrum.