Three-Component Reaction of 3-Arylidene-3H-Indolium Salts, Isocyanides, and Alcohols

A novel isocyanide-based multicomponent synthesis of alkyl aryl(indol-3-yl)acetimidates has been established. Starting from aryl(indol-3-yl)methylium tetrafluoroborates, aromatic isocyanides and alcohols, the imidates were obtained in moderate to very good yields. Consecutive four-component synthesis of the above mentioned imidates from N-alkylindoles, aromatic aldehydes, aromatic isocyanides and alcohols was also proposed. In addition, it was shown that in the presence of water, aryl(indol-3-yl)methylium tetrafluoroborates reacted with isocyanides to furnish aryl(indol-3-yl)acetamides.

To the best of our knowledge, reactions of alkylideneindolenines or the corresponding salts with isocyanides have not been published yet. Herein, we report the three-component reaction of 3arylidenindolium salts with isocyanides and alcohols to form alkyl aryl(indol-3-yl)acetimidates.

RESULTS AND DISCUSSION
Starting salts 1a-f were obtained by alkylation of the corresponding indoles followed by reaction of N-benzylindoles 2a-c with aromatic aldehydes 3a-c under conditions similar to a previously published procedure (Figure 2) (Follet et al., 2015).
Tetrafluoroborates 1a-f containing a benzyl group in the indole 1-position remained unchanged after being stored at room temperature for several weeks and turned out to be more stable than their methyl analogs, whose lability was observed previously (Follet et al., 2015). In solution salts 1a-f exist as a mixture of E-and Z-isomers (for copies of NMR spectra of obtained compounds, see Supplementary Material), what was also noted for 2-unsubstituted derivatives earlier (Follet et al., 2015).
Next, the interaction of salt 1a with p-methoxyphenyl isocyanide (4a) in methanol (5a) was performed at room temperature. After treating the reaction mixture with sodium bicarbonate solution, the imidate 6a was isolated in moderate yield as a result of the expected three component interaction (Figure 3; Table 1, entry 1). This was stable upon chromatography on silica gel and further storage for several weeks. Unfortunately, our attempt to facilitate the reaction by heating was unsuccessful, due to significant tar formation ( Table 1, entry 2). The addition of potassium carbonate as a base increased the yield ( Table 1, entries 4, 7, 8), but led to the formation of ether 7, resulting from the two-component reaction with methanol. Sodium or cesium carbonate had nearly the same effect, while Et 3 N was less effective (Table 1, entries 3, 5, 6).  The formation of methoxy derivative 7 was not observed when the reaction was carried out in acetonitrile with 4 equiv of methanol and 1.5 equiv. of K 2 CO 3 , ( Table 1, entry 10). However, the highest yield of the target product 6a was achieved by using a mixture of equal amounts of methanol and acetonitrile as solvent ( Table 1, entry 12).
In these optimized conditions, the reaction was showing significant progress by TLC during the first 3 h. After 6 h, the yield did not change substantially ( Table 1, entries 11 and 12). It is worth noting that increasing the amount of isocyanide resulted in a drop of the yield ( Table 1, entry 9 vs. 7), whereas, performing the reaction without the addition of isocyanide in the presence of a base led to the formation of two-component reaction product 7. Without the addition of base, this product was only formed in trace amounts ( Table 1, entries 13, 14). With the optimized conditions in hand, the interaction of salts 1a-f with isocyanides 4a-d and methanol was investigated (Figure 4; Table 2). Moreover, salts 1g-j containing a methyl group at the indole nitrogen atom, which were obtained by a previously described procedure (Follet et al., 2015), were also involved. Reactions of aromatic isocyanides 4a-c led to the corresponding imidates 6 in moderate to good yields. The best results were observed for salts derived from anisaldehyde ( Table 2, entries 2, 5). Such results can be explained by stabilization of the 3-arylidene-3H-indolium salts 1b,h with the donor substituent (MeO) and, consequently, by reducing the rate of the starting compound degradation under the reaction conditions, in comparison with more electrophilic salts 1a,c,g,i. At the same time, the stronger electron-donating dimethylamino group notably reduced the electrophilicity of the substrate, which led to lowering the yield of the reaction product with isonitrile 4a (Table 2, entry 7) (for electrophilicity parameters of salts 1j-g, see Follet et al., 2015). Similarly, the presence of an electron-donating methoxy group at the indole 5-position slightly increased the yield of the corresponding imidate 6j ( Table 2, entry 1 vs. entry 10). The presence of a bromine atom in the same position decreased the yield ( Table 2, entry 8, 9).
Among aromatic isocyanides, the best results were also achieved for isocyanide 4a containing an electron-donating methoxy group. Furthermore, the alcohol component of this MCR could be varied and the reaction was carried out in a mixture of acetonitrile with alcohols 5b,c ( Table 2, entries 11-13).
It should be mentioned that, in case of the nonconjugated benzyl isocyanide 4d, it was not possible to isolate the corresponding imidate 6s. Within 12 h, the reaction did not show significant progress according to TLC. After work-up and purification by chromatography on silica gel, amide 8a was isolated in a low yield along with compound 7 ( Table 2, entry 19). Apparently, the amide 8a was formed by hydrolysis of the corresponding imidate 6s.
Next, the possibility of imidate synthesis from the indole and the aldehyde by a sequential one-pot four-component process, without isolation of the corresponding 3-arylidene-3H-indolium salt, was investigated ( Figure 5; Table 3). After acid-catalyzed condensation of the aldehyde with 1-alkylindole, an excess of K 2 CO 3 and a solution of isocyanide in the appropriate alcohol were added to the reaction mixture. To our great satisfaction, target imidate 6 was obtained in moderate to good yields.
Then we decided to extend our three-component imidate synthesis with the aim to obtain amides 8 (Figure 6; Table 4).
As it turned out, addition of 10 volume % of water to the reaction mixture delivered the desired amides. Moreover, under these conditions, the reaction with benzyl isocyanide 4d also proceeded very quickly. A white precipitate of the corresponding amide 8a appeared almost immediately after isocyanide 4d addition. The interaction with aromatic isocyanides 4a,c was slightly slower but also efficient ( Table 4, entries 7 and 8). Thus, 8 examples of amides 8 were obtained in a moderate to good yields employing this procedure (Table 4).
Previously, low yields were observed in formation of imidates with the conjugate addition of alkyl isocyanides to methyl acrylate and acrylonitrile in methanol (Saegusa et al., 1971). Amides were reported to be formed in reaction of dicyanoethylenes with isocyanides . Based on these facts and on the reported reactivity of 3arylidene-3H-indolium salts (Follet et al., 2015(Follet et al., , 2016, as well as on our own experiments, we suggest the following pathway for the multicomponent transformation of 3-arylidene-3Hindolium salts (Figure 7). The conjugate nucleophilic addition of isocyanide to the vinylogous iminium ion 1 leads to nitrilium salt A, which is further attacked by the nucleophile. This could be an alcoholate ion (or the corresponding alcohol). As a result, the imidate 4 is formed. Therefore, the role of the base in this process is to generate a small concentration of alcoholate ion as a strong nucleophile and to bind the released HBF 4 .
The unsuccessful attempt of the three-component reaction with non-conjugated isocyanide 4d can be explained by the  Me 6s 0 a a The corresponding amide 8a (see Table 4) was isolated in 17 % yield along with compound 7 in 25 % yield. Frontiers in Chemistry | www.frontiersin.org reversibility of the process and the lower stability of the corresponding imidate. In the case that water is present, the hydroxide ion acts as nucleophile leading to the imidic acid B, which is in equilibrium with the corresponding amide 8. This last step makes the entire sequence of reactions almost irreversible.

CONCLUSIONS
We have elaborated a three-component reaction of a 3arylidene-3H-indolium salt, an aromatic isocyanide and an alcohol, leading to a series of alkyl aryl(indol-3-yl)acetimidates with yields up to 87%. We have also established a consecutive four-component synthesis of the above mentioned imidates from a N-alkylindole, an aromatic aldehyde, an aromatic isocyanide and an alcohol. By using aqueous acetonitrilemethanol media we have expanded our method for the synthesis of aryl(indol-3-yl)acetamides. These reactions present a new practical synthetic approach to a series of compounds possessing a privileged indole scaffold and then also extend isocyanide-based MCRs by using vinylogous iminium ions.

General
Starting reagents were purchased from commercial sources and were used without any additional purification or were prepared according to literature procedures. 1     on a SMP-10 apparatus and were uncorrected. Solvents were distilled and dried according to standard procedures.

Synthesis of Imidates 6
Three-Component Synthesis of Imidates 6; General Procedure (GP1) An isocyanide 4 (0.65 mmol) was dissolved in a mixture of abs. alcohol (1 mL) and MeCN (1 mL). A salt 1 (0.5 mmol) and K 2 CO 3 (0.1 g, 0.75 mmol) were then added. The reaction mixture was stirred at r.t. for 12 h and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with NaHCO 3 (2 × 25 mL), brine (20 mL), and dried over anhydrous Na 2 SO 4 . The EtOAc was evaporated in vacuo. The residue was chromatographed on a column with silica gel with EtOAchexane.

General Procedure
A salt 1 (0.5 mmol) and K 2 CO 3 (100 mg, 0.75 mmol) were added to a solution of 0.65 mmol of isonitrile in a mixture of MeOH (1 mL), MeCN (1 mL) and H 2 O (0.2 mL). The reaction mixture was stirred at room temperature for 12 h. It was then diluted with 40 ml of EtOAc, washed with H 2 O (2 × 25 mL), brine (20 mL) and dried over anhydrous Na 2 SO 4 . The EtOAc was evaporated in vacuo. The residue was chromatographed on a column of silica gel with EtOAc-hexane.