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A novel and green synthesis of indolone-N-amino acid derivatives via the Passerini three-component reactions in water
Chinese Chemical Letters 27 (2016) 345–348
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Chinese Chemical Letters journal homepage: www.elsevier.com/locate/cclet
Original article
A novel and green synthesis of indolone-N-amino acid derivatives via the Passerini three-component reactions in water Rong-Kun Li, Quan-Li Yang, Yi Liu, Dong-Wei Li, Nian-Yu Huang *, Ming-Guo Liu Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 September 2015 Received in revised form 26 October 2015 Accepted 2 November 2015 Available online 14 November 2015
A green Passerini three-component reaction of 2-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid with alkyl or aryl isocyanides and aldehydes was reported under aqueous conditions at 35 8C for 1 h, and 21 indolone-N-amino acid derivatives were prepared in high yields of 42%–99%. Their structures were characterized by IR, ESI–MS, NMR and elemental analysis, and the possible mechanisms have been also proposed. The highly efficient and eco-friendly method provides a facile access to a library of indoloneN-amino acid derivatives for future research on bioactivity screening. ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Keywords: Passerini three-component reaction Indolone-N-amino acid Green synthesis Heterocycles Isocyanide
1. Introduction As an important class of nitrogen-containing heterocycles, pyrroles have been found to possess interesting biological [1], synthetic [2] and optoelectronic properties [3]. Indolones represent a very significant class of fused pyrroles, represented in various natural products [4] and medicinal scaffolds [5] with diverse biological properties including antiplasmodial [6], antimalarial [7], human EP3 receptor antagonistic [8], antiviral [9] and antiproliferative [10] activities. Owing to the favorable intestinal absorption and resistance to glycosidic metabolism [11], the indolone-N-amino acid analogs have been developed as selective CRTh2 (DP2) receptor antagonist AZD1981 [12] and anticancer agents [13]. As a consequence, several synthetic methods were reported for the construction of the N-aminoacid-indolone derivatives, such as the Paal–Knorr synthesis [14] and [3+2] annulation of arynes [15]. The efficient and selective construction of complicated heterocycles is an ongoing challenge in synthetic chemistry. Accordingly, synthetic approaches such as multicomponent reactions (MCRs) that rapidly and efficiently generate complex multifunctional binding sites have attracted interest because of
* Corresponding author. E-mail address: [email protected] (N.-Y. Huang).
fewer steps and lower cost are involved [16]. Isocyanides (or isonitriles) have unique reactivity and can react with both nucleophiles and electrophiles at the same atom to form reactive a-adducts. Therefore, the isocyanide-based multicomponent reactions (I-MCRs) [17] have been proven as powerful approaches for the high-throughput synthesis of diverse libraries of potentially bioactive and densely functionalized molecules with high atom economy and convergency in one-pot procedures. Since the reaction of isocyanides, aldehydes and carboxylic acids to generate a-acyloxy carboxamides was discovered by Passerini in 1921, the Passerini three-component reaction (P-3CR) [18] has become a powerful tool in combinatorial chemistry and heterocyclic chemistry [19] for drug discovery as well as natural product synthesis [20]. Nowadays, the green organic reactions are attracting considerable attention in industry and academia due to the environmental and economic benefits. As a safe, readily available, cheap and environmentally benign solvent, water has been used in the development of green organic reactions with the advantages of simplified experimental procedures and unique solvating properties [21]. Therefore, the aqueous MCRs have been successfully utilized to construct g-iminolactone [22], 3-oxo-3-phenylpropanamid catalyzed by silica nanoparticles [23], benzimidazoles and benzothiazoles [24], thioformamide [25], a-(acyloxy)-a-(quinolin4-yl)acetamides [26] and propanamide derivatives [27]. For the rapid design and construction of a pharmacophore-based library of
http://dx.doi.org/10.1016/j.cclet.2015.11.008 1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
R.-K. Li et al. / Chinese Chemical Letters 27 (2016) 345–348
346
Table 1 Optimizing the conditions for the Passerini reaction.a
Scheme 1. Synthetic routes for the indolone-N-amino acid (4). Reagents and conditions: (a) chloroacetone, KOH, H2O, 20 8C, 6 h; (b) glycine ethyl ester hydrochloride, NaOAc, H2O, 50 8C, 4 h; and (c) KOH, CH3OH, H2O, 40 8C, 3 h; 1.0 mol/L HCl, 0 8C, 5 min.
indolone-N-amino acid derivatives, the concept of diversityoriented methodology of isocyanide-based aqueous Passerini reaction has been adopted in this work. 2. Experimental
Entry
Solvent
Temp (8C)
Time (h)
Yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Toluene THF Acetone DMF CH3OH CH3CN CH2Cl2 CHCl3 H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O
35 35 35 35 35 35 35 35 35 5 15 25 45 60 80 100 35 35 35 35 35 35
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 0.25 0.5 1 1.5 3 6
Trace Trace Trace Trace Trace 31 75 78 81 8 47 73 79 66 58 25 25 77 92 91 76 52
Considering the significant bioactivity of indolone-N-amino acid derivatives, the 2-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid (4) was prepared from commercially available 1,3dicarbonyl compound according to the Barraja’s method [28] (Scheme 1). Firstly, the reaction of 1,3-cyclohexanodione (1) with chloroacetone in a potassium hydroxide aqueous solution was stirred at 20 8C for 6 h to afford the 1,3-acetonylcyclohexandione (2), which could be used without further purification to cyclize to the methyl 2-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1yl)acetate (3) through the Paal–Knorr ring closure reaction [29] using glycine methylester hydrochloride as an amine source. Then, the carboxylic acid component (4) of the Passerini reaction is obtained by hydrolyzing 3. Initially, the P-3CR of carboxylic acid with various aldehydes and isocyanides was conducted at 35 8C for 2 h in different solvents according to the literature methods [30]. The reaction of 2-(4-oxo4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid (4, 0.1 mmol), n-butyl aldehyde (0.15 mmol) and 4-chlorophenyl isocyanide (0.1 mmol) was chosen as a model reaction (Scheme 2). As shown in Table 1, the organic solvents had an obvious influence on the yield of 1-(4chlorophenylamino)-1-oxopentan-2-yl 2-(2-methyl-4-oxo-4,5,6,7tetrahydro-1H-indol-1-yl)acetate (5c), and toluene, tetrahydrofuran (THF), acetone, N,N0 -dimethylformamide (DMF) and methanol were found to be ineffective (entries 1–5). The use of acetonitrile (CH3CN) resulted in a low yield of 31%. However, the P-3CR proceeded smoothly in dichloromethane (CH2Cl2) and chloroform (CHCl3) with higher yields of 75%–78% (entries 6–8). Although these results were satisfying, we attempted the aqueous P-3CR with the aim of establishing greener processes. Fortunately, we achieved an 81% yield of 5c when the model reaction was carried out in water (entry 9). In order to acquire the best conditions for the P-3CR, the influence of temperature and time on the model reaction were also investigated. The results indicated that temperatures below 35 8C gave decreased yields (Table 1, entry 10–12), and temperature beyond 35 8C also resulted in poorer yields because of the quick oxidation or hydrolysis of isocyanide (entry 13–16). Therefore, the most appropriate temperature proved to be around 35 8C. Next, we examined the suitable reaction time. It was found that the highest
All of the indolone-N-amino acid derivatives (5) were confirmed by their spectral data. The C5 5O absorption peaks at 1690–1760 cm1 could be clearly observed in the IR spectra. In the ESI–MS spectrum, the pseudo-molecular ion peak of (M+H)+ or (M+Na)+ were usually observed as the base peak ion for the targeted compounds. In the 1H NMR spectroscopy, the C(3)–H in the indole ring appeared as a single peak at 6.49–6.22 ppm, and the methylene proton signal of indol-N-CH2 was usually observed as an AB quartet with a coupling constant (J) of 17.6 Hz. The proton for O–CH exhibited a triplet or doublet splitting pattern at 5.09– 5.28 ppm when the substituent was allyl group for 5b–5g and
Scheme 2. The model Passerini reaction.
Scheme 3. Synthetic routes for the indolone-N-amino acid derivatives (5).
a Reactions were carried out using the carboxylic acid (4, 0.10 mmol), n-butyl aldehyde (0.10 mmol) and 4-chlorophenyl isocyanide (0.10 mmol) in corresponding solvent for appropriate time. b Isolated yields.
yield was achieved under the conditions of 1 h at 35 8C (entry 19). Prolonged reaction time seemed to produce dark by-products and resulted in lower isolated yields (entries 21, 22). Finally, the optimized conditions for the P-3CR were summarized as the follows: the carboxylic acid 4, an aldehyde and an isocyanide were stirred in water at 35 8C for 1 h. To explore the scope of P-3CR with respect to various substrates, the carboxylic acid (4) was examined to react with alkyl or aryl isocyanides and aldehydes in the one-pot procedure, and 21 indolone-N-amino acid derivatives (5) were efficiently prepared with satisfactory yields of 42%-99% (Scheme 3, Table 2). It is noteworthy that this reaction could proceed smoothly when paraformaldehyde was used. The ethyl 2-isocyanoacetate exhibited similar reactivity to the 4-chlorophenyl isocyanide under the aqueous conditions. 3. Results and discussion
R.-K. Li et al. / Chinese Chemical Letters 27 (2016) 345–348 Table 2 Synthesis of the indolone-N-amino acid derivatives (5). Compd.
R1
R2
Yield (%)a
5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p 5q 5r 5s 5t 5u
HEtn-Pri-Pri-Bun-Hexyl Cyclohexyl 3-Cl-Ph2-Cl-Ph2-Br-Ph4-Br-PhPyridin-2-yl Etn-Pri-Pri-BuNeopentyl Cyclohexyl 2-Cl-PhPyridin-2-yl Naphthalen-1-yl
4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph–CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt
56 46 92 99 99 68 60 56 67 42 42 47 79 61 70 65 44 65 61 96 48
a
Isolated yields.
5m–5r, which gave lower-field shift of 6.10–6.34 ppm when substituted by an aryl group in 5h–5l and 5s–5u. Compared with 9.14–7.61 ppm of the N–H for the 4-chlorophenylamino group in 5a–5l, and the N–H of 2-ethoxy-2-oxoethylamino group in 5m–5u were assigned to 6.50–6.15 ppm as a broad singlet. The carbon signals in 13C NMR of the targeted compounds were also in accord with the characteristic peaks in the molecular structures. Furthermore, the relative configuration of compound 5b was also characterized by 2D NMR spectroscopy. The quartets at 4.68 ppm for indol-N-CH2 signals displayed correlation with the carbon signal at 45.3 ppm in the heteronuclear single-quantum correlation (HSQC) NMR spectrum, which also showed the key correlations with the peaks at 144.2 ppm and 166.4 ppm (C5 5O in acetate group) in heteronuclear multiple-bond correlation spectroscopy (HMBC). All of these correlations indicated that a methylene group linked the indole moiety to the acetate group, whose two magnetically inequivalent protons might be caused by the large steric hindrance from the substituents.
Scheme 4. Proposed mechanism for the formation of indolone-N-amino acid derivatives (5).
347
A possible mechanism for the formation of the indoloneN-amino acid derivatives (5) has been proposed according to related literature [31] (Scheme 4). Initially, the aldehyde was protonated by the carboxylic acid (4), which was attacked by the isocyanide to give the nitrilium ion (A). Then the intermediate (B) was formed by the nucleophilic addition of the carboxylate. Finally, an intramolecular acyl transfer and amide tautomerization completed the P-3CR process. The reaction described here might be an ‘‘in water’’ suspension [32] because all the substrates were almost water-insoluble organic compounds. The highly efficient synthesis of indolone-N-amino acids might be attributed to the polar characteristic of the solvent on the aqueous-organic interface, and the intermediates could be stabilized by the strong hydrogen bonds with water molecules. 4. Conclusion In summary, a series of the indolone-N-amino acid derivatives have been synthesized through an aqueous Passerini threecomponent reaction with satisfactory yields. Compared to the classical methods, the advantages of the present procedure are milder conditions, shorter reaction time and higher operational simplicity. Further investigations on extending the scope for the multi-component reactions of indolone-N-amino acid and evaluating their biological activity are in progress. Acknowledgments The authors thank the financial support by the Natural Science Foundation of China (No. 21272136), Scientific Foundation from graduate school (2015PY089) and Youth Talent Development Foundation of China Three Gorges University.
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Contents lists available at ScienceDirect
Chinese Chemical Letters journal homepage: www.elsevier.com/locate/cclet
Original article
A novel and green synthesis of indolone-N-amino acid derivatives via the Passerini three-component reactions in water Rong-Kun Li, Quan-Li Yang, Yi Liu, Dong-Wei Li, Nian-Yu Huang *, Ming-Guo Liu Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 September 2015 Received in revised form 26 October 2015 Accepted 2 November 2015 Available online 14 November 2015
A green Passerini three-component reaction of 2-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid with alkyl or aryl isocyanides and aldehydes was reported under aqueous conditions at 35 8C for 1 h, and 21 indolone-N-amino acid derivatives were prepared in high yields of 42%–99%. Their structures were characterized by IR, ESI–MS, NMR and elemental analysis, and the possible mechanisms have been also proposed. The highly efficient and eco-friendly method provides a facile access to a library of indoloneN-amino acid derivatives for future research on bioactivity screening. ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Keywords: Passerini three-component reaction Indolone-N-amino acid Green synthesis Heterocycles Isocyanide
1. Introduction As an important class of nitrogen-containing heterocycles, pyrroles have been found to possess interesting biological [1], synthetic [2] and optoelectronic properties [3]. Indolones represent a very significant class of fused pyrroles, represented in various natural products [4] and medicinal scaffolds [5] with diverse biological properties including antiplasmodial [6], antimalarial [7], human EP3 receptor antagonistic [8], antiviral [9] and antiproliferative [10] activities. Owing to the favorable intestinal absorption and resistance to glycosidic metabolism [11], the indolone-N-amino acid analogs have been developed as selective CRTh2 (DP2) receptor antagonist AZD1981 [12] and anticancer agents [13]. As a consequence, several synthetic methods were reported for the construction of the N-aminoacid-indolone derivatives, such as the Paal–Knorr synthesis [14] and [3+2] annulation of arynes [15]. The efficient and selective construction of complicated heterocycles is an ongoing challenge in synthetic chemistry. Accordingly, synthetic approaches such as multicomponent reactions (MCRs) that rapidly and efficiently generate complex multifunctional binding sites have attracted interest because of
* Corresponding author. E-mail address: [email protected] (N.-Y. Huang).
fewer steps and lower cost are involved [16]. Isocyanides (or isonitriles) have unique reactivity and can react with both nucleophiles and electrophiles at the same atom to form reactive a-adducts. Therefore, the isocyanide-based multicomponent reactions (I-MCRs) [17] have been proven as powerful approaches for the high-throughput synthesis of diverse libraries of potentially bioactive and densely functionalized molecules with high atom economy and convergency in one-pot procedures. Since the reaction of isocyanides, aldehydes and carboxylic acids to generate a-acyloxy carboxamides was discovered by Passerini in 1921, the Passerini three-component reaction (P-3CR) [18] has become a powerful tool in combinatorial chemistry and heterocyclic chemistry [19] for drug discovery as well as natural product synthesis [20]. Nowadays, the green organic reactions are attracting considerable attention in industry and academia due to the environmental and economic benefits. As a safe, readily available, cheap and environmentally benign solvent, water has been used in the development of green organic reactions with the advantages of simplified experimental procedures and unique solvating properties [21]. Therefore, the aqueous MCRs have been successfully utilized to construct g-iminolactone [22], 3-oxo-3-phenylpropanamid catalyzed by silica nanoparticles [23], benzimidazoles and benzothiazoles [24], thioformamide [25], a-(acyloxy)-a-(quinolin4-yl)acetamides [26] and propanamide derivatives [27]. For the rapid design and construction of a pharmacophore-based library of
http://dx.doi.org/10.1016/j.cclet.2015.11.008 1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
R.-K. Li et al. / Chinese Chemical Letters 27 (2016) 345–348
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Table 1 Optimizing the conditions for the Passerini reaction.a
Scheme 1. Synthetic routes for the indolone-N-amino acid (4). Reagents and conditions: (a) chloroacetone, KOH, H2O, 20 8C, 6 h; (b) glycine ethyl ester hydrochloride, NaOAc, H2O, 50 8C, 4 h; and (c) KOH, CH3OH, H2O, 40 8C, 3 h; 1.0 mol/L HCl, 0 8C, 5 min.
indolone-N-amino acid derivatives, the concept of diversityoriented methodology of isocyanide-based aqueous Passerini reaction has been adopted in this work. 2. Experimental
Entry
Solvent
Temp (8C)
Time (h)
Yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Toluene THF Acetone DMF CH3OH CH3CN CH2Cl2 CHCl3 H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O
35 35 35 35 35 35 35 35 35 5 15 25 45 60 80 100 35 35 35 35 35 35
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 0.25 0.5 1 1.5 3 6
Trace Trace Trace Trace Trace 31 75 78 81 8 47 73 79 66 58 25 25 77 92 91 76 52
Considering the significant bioactivity of indolone-N-amino acid derivatives, the 2-(4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid (4) was prepared from commercially available 1,3dicarbonyl compound according to the Barraja’s method [28] (Scheme 1). Firstly, the reaction of 1,3-cyclohexanodione (1) with chloroacetone in a potassium hydroxide aqueous solution was stirred at 20 8C for 6 h to afford the 1,3-acetonylcyclohexandione (2), which could be used without further purification to cyclize to the methyl 2-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1yl)acetate (3) through the Paal–Knorr ring closure reaction [29] using glycine methylester hydrochloride as an amine source. Then, the carboxylic acid component (4) of the Passerini reaction is obtained by hydrolyzing 3. Initially, the P-3CR of carboxylic acid with various aldehydes and isocyanides was conducted at 35 8C for 2 h in different solvents according to the literature methods [30]. The reaction of 2-(4-oxo4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid (4, 0.1 mmol), n-butyl aldehyde (0.15 mmol) and 4-chlorophenyl isocyanide (0.1 mmol) was chosen as a model reaction (Scheme 2). As shown in Table 1, the organic solvents had an obvious influence on the yield of 1-(4chlorophenylamino)-1-oxopentan-2-yl 2-(2-methyl-4-oxo-4,5,6,7tetrahydro-1H-indol-1-yl)acetate (5c), and toluene, tetrahydrofuran (THF), acetone, N,N0 -dimethylformamide (DMF) and methanol were found to be ineffective (entries 1–5). The use of acetonitrile (CH3CN) resulted in a low yield of 31%. However, the P-3CR proceeded smoothly in dichloromethane (CH2Cl2) and chloroform (CHCl3) with higher yields of 75%–78% (entries 6–8). Although these results were satisfying, we attempted the aqueous P-3CR with the aim of establishing greener processes. Fortunately, we achieved an 81% yield of 5c when the model reaction was carried out in water (entry 9). In order to acquire the best conditions for the P-3CR, the influence of temperature and time on the model reaction were also investigated. The results indicated that temperatures below 35 8C gave decreased yields (Table 1, entry 10–12), and temperature beyond 35 8C also resulted in poorer yields because of the quick oxidation or hydrolysis of isocyanide (entry 13–16). Therefore, the most appropriate temperature proved to be around 35 8C. Next, we examined the suitable reaction time. It was found that the highest
All of the indolone-N-amino acid derivatives (5) were confirmed by their spectral data. The C5 5O absorption peaks at 1690–1760 cm1 could be clearly observed in the IR spectra. In the ESI–MS spectrum, the pseudo-molecular ion peak of (M+H)+ or (M+Na)+ were usually observed as the base peak ion for the targeted compounds. In the 1H NMR spectroscopy, the C(3)–H in the indole ring appeared as a single peak at 6.49–6.22 ppm, and the methylene proton signal of indol-N-CH2 was usually observed as an AB quartet with a coupling constant (J) of 17.6 Hz. The proton for O–CH exhibited a triplet or doublet splitting pattern at 5.09– 5.28 ppm when the substituent was allyl group for 5b–5g and
Scheme 2. The model Passerini reaction.
Scheme 3. Synthetic routes for the indolone-N-amino acid derivatives (5).
a Reactions were carried out using the carboxylic acid (4, 0.10 mmol), n-butyl aldehyde (0.10 mmol) and 4-chlorophenyl isocyanide (0.10 mmol) in corresponding solvent for appropriate time. b Isolated yields.
yield was achieved under the conditions of 1 h at 35 8C (entry 19). Prolonged reaction time seemed to produce dark by-products and resulted in lower isolated yields (entries 21, 22). Finally, the optimized conditions for the P-3CR were summarized as the follows: the carboxylic acid 4, an aldehyde and an isocyanide were stirred in water at 35 8C for 1 h. To explore the scope of P-3CR with respect to various substrates, the carboxylic acid (4) was examined to react with alkyl or aryl isocyanides and aldehydes in the one-pot procedure, and 21 indolone-N-amino acid derivatives (5) were efficiently prepared with satisfactory yields of 42%-99% (Scheme 3, Table 2). It is noteworthy that this reaction could proceed smoothly when paraformaldehyde was used. The ethyl 2-isocyanoacetate exhibited similar reactivity to the 4-chlorophenyl isocyanide under the aqueous conditions. 3. Results and discussion
R.-K. Li et al. / Chinese Chemical Letters 27 (2016) 345–348 Table 2 Synthesis of the indolone-N-amino acid derivatives (5). Compd.
R1
R2
Yield (%)a
5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 5m 5n 5o 5p 5q 5r 5s 5t 5u
HEtn-Pri-Pri-Bun-Hexyl Cyclohexyl 3-Cl-Ph2-Cl-Ph2-Br-Ph4-Br-PhPyridin-2-yl Etn-Pri-Pri-BuNeopentyl Cyclohexyl 2-Cl-PhPyridin-2-yl Naphthalen-1-yl
4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph4-Cl-Ph–CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt –CH2COOEt
56 46 92 99 99 68 60 56 67 42 42 47 79 61 70 65 44 65 61 96 48
a
Isolated yields.
5m–5r, which gave lower-field shift of 6.10–6.34 ppm when substituted by an aryl group in 5h–5l and 5s–5u. Compared with 9.14–7.61 ppm of the N–H for the 4-chlorophenylamino group in 5a–5l, and the N–H of 2-ethoxy-2-oxoethylamino group in 5m–5u were assigned to 6.50–6.15 ppm as a broad singlet. The carbon signals in 13C NMR of the targeted compounds were also in accord with the characteristic peaks in the molecular structures. Furthermore, the relative configuration of compound 5b was also characterized by 2D NMR spectroscopy. The quartets at 4.68 ppm for indol-N-CH2 signals displayed correlation with the carbon signal at 45.3 ppm in the heteronuclear single-quantum correlation (HSQC) NMR spectrum, which also showed the key correlations with the peaks at 144.2 ppm and 166.4 ppm (C5 5O in acetate group) in heteronuclear multiple-bond correlation spectroscopy (HMBC). All of these correlations indicated that a methylene group linked the indole moiety to the acetate group, whose two magnetically inequivalent protons might be caused by the large steric hindrance from the substituents.
Scheme 4. Proposed mechanism for the formation of indolone-N-amino acid derivatives (5).
347
A possible mechanism for the formation of the indoloneN-amino acid derivatives (5) has been proposed according to related literature [31] (Scheme 4). Initially, the aldehyde was protonated by the carboxylic acid (4), which was attacked by the isocyanide to give the nitrilium ion (A). Then the intermediate (B) was formed by the nucleophilic addition of the carboxylate. Finally, an intramolecular acyl transfer and amide tautomerization completed the P-3CR process. The reaction described here might be an ‘‘in water’’ suspension [32] because all the substrates were almost water-insoluble organic compounds. The highly efficient synthesis of indolone-N-amino acids might be attributed to the polar characteristic of the solvent on the aqueous-organic interface, and the intermediates could be stabilized by the strong hydrogen bonds with water molecules. 4. Conclusion In summary, a series of the indolone-N-amino acid derivatives have been synthesized through an aqueous Passerini threecomponent reaction with satisfactory yields. Compared to the classical methods, the advantages of the present procedure are milder conditions, shorter reaction time and higher operational simplicity. Further investigations on extending the scope for the multi-component reactions of indolone-N-amino acid and evaluating their biological activity are in progress. Acknowledgments The authors thank the financial support by the Natural Science Foundation of China (No. 21272136), Scientific Foundation from graduate school (2015PY089) and Youth Talent Development Foundation of China Three Gorges University.
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