Three-Component Reactions of 3-Arylidene-3H-Indolium Salts, Isocyanides and Amines

A multicomponent reaction of isocyanides with aryl(indol-3-yl)methylium salts and amines has been found. A series of aryl(indol-3-yl)acetimidamides was obtained in up to 96% yields. In the case of ethyl isocyanoacetate, the reaction is followed by cyclization to form 3,5-dihydro-4H-imidazol-4-one derivatives.

Recently we have developed a method for the synthesis of alkyl aryl(indol-3-yl)acetimidates and aryl(indol-3-yl)acetamides based on a three-component reaction of isocyanides with such a specific class of electrophilic reagents as 3-arylidene-3H-indolium salts and oxygencontaining nucleophiles, water and alcohols (Scheme 1a) [22]. 3-Arylidene-3H-indolium salts can be considered as stabilized diarylmethylium ions or as simple vinylogous iminium ions, the latter being in better agreement with the data of X-ray structural analyses of these compounds [23,24]. The use of 3-arylidene-3H-indolium salts as partners in the reaction with isocyanides provides access to compounds possessing indole scaffold, privileged from the medicinal chemistry point of view [25].
Herein, we report a three-component reaction of 3-aryliden-3H-indolium salts 1 with isocyanides and amines to form aryl(indol-3-yl)acetimidamides 2 (Scheme 1b). In the case of isocyanoacetic ester the reaction can be accompanied by subsequent cyclization with the formation of imidazolone derivatives 3. good yield after 3 h at room temperature, and 12 h was required to complete the reaction. An attempt to accelerate the reaction by increasing the temperature was unsuccessful due to a tar formation and an increase in the amount of the by-product 9. Scheme 3. Reaction of salt 1a with isonitrile 7a and amine 8a. According to the optimized procedure, a series of imidamides 2 was synthesized (Scheme 4). Compounds 2 containing an alkyl group together with an aryl group at the amidine nitrogen atoms are presented as the most stable tautomer according to NMR data [26], and compound 2j-as a tautomeric mixture (for copies of NMR spectra, see Supplementary Materials). Interestingly, amidine 2a was synthesized using two different combinations of isonitrile and amine, and the best yield was obtained by using benzyl isocyanide (7a) and p-anisidine (8a). Compound 2j was also obtained by two methods, by using either p-methoxyphenylisocyanide (7b) and p-chloroaniline (8c) or p-chlorophenylisocyanide (7c) and amine 8a. In this case both reagent combinations gave comparable results. The reaction with aliphatic cyclohexylamine, as well as with benzylamine (8b) proceeded with lower yield of target amidine 2i due to side processes.  According to the optimized procedure, a series of imidamides 2 was synthesized (Scheme 4). Compounds 2 containing an alkyl group together with an aryl group at the amidine nitrogen atoms are presented as the most stable tautomer according to NMR data [26], and compound 2j-as a tautomeric mixture (for copies of NMR spectra, see Supplementary Materials). Interestingly, amidine 2a was synthesized using two different combinations of isonitrile and amine, and the best yield was obtained by using benzyl isocyanide (7a) and p-anisidine (8a). Compound 2j was also obtained by two methods, by using either p-methoxyphenylisocyanide (7b) and p-chloroaniline (8c) or p-chlorophenylisocyanide (7c) and amine 8a. In this case both reagent combinations gave comparable results. The reaction with aliphatic cyclohexylamine, as well as with benzylamine (8b) proceeded with lower yield of target amidine 2i due to side processes.
When ethyl isocyanoacetate 7d was employed in this reaction with p-anisidine (8a), a new product, imidazolone 3a, was obtained in good yield (82%) instead of the corresponding imidamide (Scheme 5). Therefore, we continued to investigate the reaction of 3-arylidene-3H-indolium salts 1a-g with isocyanoacetic ester 7d and amines 9 in MeCN at room temperature (method A). Thus, we have obtained a series of imidazolones 3a-o using various aromatic amines (Scheme 5). The exceptions were sterically hindered orthosubstituted anilines and weakly nucleophilic ester of para-aminobenzoic acid, in these cases, cyclization did not occur, and amidines 10a-c containing ester group were isolated. We also failed to isolate the desired cyclization products with aliphatic amines. In the case of benzylamine, isopropylamine and cyclohexylamine a complex mixture of products that did not contain imidazolones 3p-s was formed, while sterically hindered tert-butylamine gave acyclic imidamide 10d. To our surprise, the reaction with O-benzylhydroxylamine led to the formation of only acyclic imidamides 10e,f, represented by a mixture of tautomers in a 1:1 ratio. It was possible to obtain imidazolones 3p-o using aliphatic amines (with the exception of tert-butylamine) with a low yield, when the reaction was carried out in a closed vessel under microwave irradiation at 130 • C (method B). The latter method, however, showed lower efficiency in comparison with the initial, method A, for the synthesis of imidazolones 3a,f from aromatic amines, and at the same time, it did not allow to obtain the corresponding cyclization products involving sterically hindered amines and O-benzylhydroxylamine. 6 When ethyl isocyanoacetate 7d was employed in this reaction with p-anisidine (8a), a new product, imidazolone 3a, was obtained in good yield (82%) instead of the corresponding imidamide (Scheme 5). Therefore, we continued to investigate the reaction of 3-arylidene-3H-indolium salts 1a-g with isocyanoacetic ester 7d and amines 9 in MeCN at room temperature (method A). Thus, we have obtained a series of imidazolones 3a-o using various aromatic amines (Scheme 5). The exceptions were sterically hindered ortho-substituted anilines and weakly nucleophilic ester of para-aminobenzoic acid, in these cases, cyclization did not occur, and amidines 10a-c containing ester group were isolated. We also failed to isolate the desired cyclization products with aliphatic amines. In the case of benzylamine, isopropylamine and cyclohexylamine a complex mixture of products that did not contain imidazolones 3p-s was formed, while sterically hindered tert-butylamine gave acyclic imidamide 10d. To our surprise, the reaction with O-benzylhydroxylamine led to the formation of only lower efficiency in comparison with the initial, method A, for the synthesis of imidazolones 3a,f from aromatic amines, and at the same time, it did not allow to obtain the corresponding cyclization products involving sterically hindered amines and O-benzylhydroxylamine.
EtOH + 3j, R = OMe, 83% 3k, R = OH, 72% 3l, R = Cl, 68%  The structure of compound 3d was unambiguously confirmed by X-ray structural analysis ( Figure 1) [27]. The structure of compound 3d was unambiguously confirmed by X-ray structural analysis ( Figure 1) [27]. Next, it is necessary to discuss the proposed mechanism of discovered transformations based on our observations and previous studies (Scheme 6) [22,23]. Isonitrile initially attacks 3-arylidene-3H-indolium salt, which acts as an electrophilic reagent, vinylogous iminium 3H-indolium ion. The formed nitrilium salt A then reacts with amine leading to amidinium tetrafluoroborate B, which upon treatment with NaHCO3 gives a mixture of tautomeric imidamides 2 and 2'. In the absence of steric or electronic restrictions imidamides 10 containing ester group undergo spontaneous cyclization leading to imidazolones 3. Scheme 6. Proposed mechanism for the reactions of 3-arylidene-3H-indolium salts 1 with isocyanides 7 and amines 8. Next, it is necessary to discuss the proposed mechanism of discovered transformations based on our observations and previous studies (Scheme 6) [22,23]. Isonitrile initially attacks 3-arylidene-3H-indolium salt, which acts as an electrophilic reagent, vinylogous iminium 3H-indolium ion. The formed nitrilium salt A then reacts with amine leading to amidinium tetrafluoroborate B, which upon treatment with NaHCO 3 gives a mixture of tautomeric imidamides 2 and 2'. In the absence of steric or electronic restrictions imidamides 10 containing ester group undergo spontaneous cyclization leading to imidazolones 3.

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The structure of compound 3d was unambiguously confirmed by X-ray structural analysis ( Figure 1) [27]. Next, it is necessary to discuss the proposed mechanism of discovered transformations based on our observations and previous studies (Scheme 6) [22,23]. Isonitrile initially attacks 3-arylidene-3H-indolium salt, which acts as an electrophilic reagent, vinylogous iminium 3H-indolium ion. The formed nitrilium salt A then reacts with amine leading to amidinium tetrafluoroborate B, which upon treatment with NaHCO3 gives a mixture of tautomeric imidamides 2 and 2'. In the absence of steric or electronic restrictions imidamides 10 containing ester group undergo spontaneous cyclization leading to imidazolones 3. Scheme 6. Proposed mechanism for the reactions of 3-arylidene-3H-indolium salts 1 with isocyanides 7 and amines 8.

General Information
Starting reagents were purchased from commercial sources and were used without any additional purification or were prepared according to literature procedures. 1 H and 13 C NMR spectra were acquired on a Jeol JNM-ECA 600 spectrometer (Jeol Ltd, Tokyo, Japan) (with operating frequencies of 600 and 150 MHz, respectively) at room temperature and referenced to the residual signals of the solvent. The solvent used for NMR was CDCl 3 . Chemical shifts are reported in parts per million (δ/ppm). Coupling constants are reported in Hertz (J/Hz). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; dd, doublet of doublets and br s, broad singlet. Infrared spectra were measured on an Infralum FT-801 FT/IR instrument. The wavelengths are reported in reciprocal centimeters (ν max /cm −1 ). Mass spectra were recorded with LCMS-8040 Triple quadrupole liquid chromatograph mass-spectrometer from Shimadzu (ESI) (Shimadzu, Tokyo, Japan). HRMS spectra were recorded on a Bruker MicrOTOF-Q II. Elemental analysis was performed on Euro Vector EA-3000 elemental analyzer. The reaction progress was monitored by TLC and the spots were visualized under UV light (254 or 365 nm). Column chromatography was performed using silica gel (230-400 mesh). Melting points were determined on SMP-10 apparatus and were uncorrected. Solvents were distilled and dried according to standard procedures.

Synthesis of Imidazolone 3 and Synthesis Imidamides 10a-f
Representative Procedure under Thermal Conditions (Method A). Ethyl isocyanoacetate 7d (0.65 mmol) and aromatic amine 8 (0.75 mmol) were dissolved in abs. MeCN (5 mL), and salt 1 (0.5 mmol) was 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 EtOAc-hexane.
Representative Procedure under Microwave Conditions (Method B). Ethyl isocyanoacetate 7d (0.65 mmol) and aromatic amine 8 (0.60 mmol) were dissolved in abs. MeCN (5 mL), salt 1 (0.5 mmol) and NaHCO 3 (1.5 equiv.) were then added. The reaction mixture in closed vial was placed into microwave reactor and irradiated at 130 • C for 30 min. Upon reaction completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), 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 with silica gel with EtOAc-hexane.