Chinese Chemical Letters  2016, Vol.27 Issue (03): 345-348   PDF    
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
Abstract: 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℃ 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 indolone-N-amino acid derivatives for future research on bioactivity screening.
Key words: 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 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-(quinolin- 4-yl)acetamides [26] and propanamide derivatives [27]. For the rapid design and construction of a pharmacophore-based library of indolone-N-amino acid derivatives,the concept of diversityoriented methodology of isocyanide-based aqueous Passerini reaction has been adopted in this work.

2. Experimental

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 1,3- dicarbonyl 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 ℃ 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-1- yl)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.

Download:
Scheme 1.Synthetic routes for the indolone-N-amino acid (4). Reagents and conditions: (a) chloroacetone,KOH,H2O,20 ℃,6 h; (b) glycine ethyl ester hydrochloride,NaOAc,H2O,50 ℃,4 h; and (c) KOH,CH3OH,H2O,40 ℃,3 h; 1.0 mol/L HCl,0 ℃,5 min.

Initially,the P-3CR of carboxylic acidwith various aldehydes and isocyanides was conducted at 35 ℃ for 2 h in different solvents according to the literature methods [30]. The reaction of 2-(4-oxo- 4,5,6,7-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 amodel reaction (Scheme 2). As shownin Table 1,the organic solvents had an obvious influence on the yield of 1-(4- chlorophenylamino)-1-oxopentan-2-yl 2-(2-methyl-4-oxo-4,5,6,7- tetrahydro-1H-indol-1-yl)acetate (5c),and toluene,tetrahydrofuran (THF),acetone,N,N'-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).

Download:
Scheme 2.The model Passerini reaction.

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 ℃ gave decreased yields (Table 1,entry 10-12),and temperature beyond 35 ℃ 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 ℃. Next,we examined the suitable reaction time. It was found that the highest yield was achieved under the conditions of 1 h at 35 ℃ (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 ℃ for 1 h.

Table 1
Optimizing the conditions for the Passerini reaction.a

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.

Download:
Scheme 3.Synthetic routes for the indolone-N-amino acid derivatives (5).

Table 2
Synthesis of the indolone-N-amino acid derivatives (5).
3. Results and discussion

All of the indolone-N-amino acid derivatives (5) were confirmed by their spectral data. The C=O absorption peaks at 1690-1760 cm-1 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 themethylene proton signal of indol-N-CH2 was usually observed as an AB quartetwith 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 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. Comparedwith 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 NMRof the targeted compoundswere 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 (C=O 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 protonsmight be caused by the large steric hindrance from the substituents.

A possible mechanism for the formation of the indolone- N-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.

Download:
Scheme 4.Proposed mechanism for the formation of indolone-N-amino acid derivatives (5).
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.

Appendix A. Supplementary data

Supplementary material related to this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2015.11008.

References
[1] (a) L.H. Meng, X.M. Li, Y.B.G. Liu, Polyoxygenated dihydropyrano[2,3-c]pyrrole-4,5-dione derivatives from the marine mangrove-derived endophytic fungus Penicillium brocae MA-231 and their antimicrobial activity, Chin. Chem. Lett. 26(2015) 610-612;(b) T.L. Su, T.C. Lee, R. Kakadiya, The development of bis (hydroxymethyl) pyrrole analogs as bifunctional DNA cross-linking agents and their chemotherapeutic potential, Eur. J. Med. Chem. 69(2013) 609-621.
[2] V. Estévez, M. Villacampa, J.C. Menéndez, Recent advances in the synthesis of pyrroles by multicomponent reactions, Chem. Soc. Rev. 43(2014) 4633-4657.
[3] D. Holten, D.F. Bocian, J.S. Lindsey, Probing electronic communication in covalently linked multiporphyrin arrays. A guide to the rational design of molecular photonic devices, Acc. Chem. Res. 35(2002) 57-69.
[4] (a) J. Chen, J.J. Chen, X.J. Yao, K. Gao, Kopsihainanines A and B, two unusual alkaloids from Kopsia hainanensis, Org. Biomol. Chem. 9(2011) 5334-5366;(b) O. Wagnières, Z. Xu, Q. Wang, J. Zhu, Unified strategy to monoterpene indole alkaloids:total syntheses of (±)-Goniomitine, (±)-1,2-Dehydroaspidospermidine, (±)-Aspidospermidine. (±)-Vincadifformine, and (±)-Kopsihainanine A, J. Am. Chem. Soc. 136(2014) 15102-15108;(c) C.J. Gartshore, D.W. Lupton, Enantioselective palladium-catalyzed decarboxylative allylation of carbazolones and indolones:formal synthesis of (+)-Kopsihainanine A, Angew. Chem. (Ⅰ)nt. Ed. 52(2013) 4113-4116.
[5] (a) C.C. Chiang, Y.H. Lin, S.F. Lin, et al., Discovery of pyrrole-indoline-2-ones as Aurora kinase inhibitors with a different inhibition profile, J. Med. Chem. 53(2010) 5929-5941;(b) C.W. Zapf, J.D. Bloom, J.L. McBean, et al., Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity, Bioorg. Med. Chem. Lett. 21(2011) 2278-2282.
[6] (a) E. Najahi, A. Valentin, P.L. Fabre, K. Reybier, F. Nepveu, 2-Aryl-3H-indol-3-ones:synthesis, electrochemical behaviour and antiplasmodial activities, Eur. J. Med. Chem. 78(2014) 269-274;(b) E. Najahi, N.V. Rakotoarivelo, A. Valentin, F. Nepveu, Amino derivatives of indolone-N-oxide:preparation and antiplasmodial properties, Eur. J. Med. Chem. 76(2014) 369-375.
[7] F. Nepveu, E. Najahi, A. Valentin, Antimalarial activities of indolones and derivatives, Curr. Top. Med. Chem. 14(2014) 1643-1652.
[8] M. O'Connell, W. Zeller, J. Burgeson, et al., Peri-substituted hexahydro-indolones as novel, potent and selective human EP3 receptor antagonists, Bioorg. Med. Chem. Lett. 19(2009) 778-782.
[9] X. Li, R. Vince, Conformationally restrained carbazolone-containing α,γ-diketo acids as inhibitors of H(Ⅰ)V integrase, Bioorg. Med. Chem. 14(2006) 2942-2955.
[10] (a) P. Barraja, L. Caracausi, P. Diana, et al., Synthesis and antiproliferative activity of the ring system[1,2] oxazolo[4,5-g]indole, Bioorg.Med. Chem. 7(2012) 1901-1904;(b) R. Martínez, A. Clarα-Sosa, M.T.R. Apan, Synthesis and cytotoxic evaluation of new (4,5,6,7-tetrahydro-indol-1-yl)-3-R-propionic acids and propionic acid ethyl esters generated bymolecularmimicry, Bioorg.Med. Chem. 15(2007) 3912-3918.
[11] Y. Kim, Y.J. You, N.H. Nam, B.Z. Ahn, Prodrugs of 4'-demethyl-4-deoxypodophyllotoxin:synthesis and evaluation of the antitumor activity, Bioorg. Med. Chem. Lett. 12(2002) 3435-3438.
[12] M. Sulur, P. Sharma, R. Ramakrishnan, et al., Development of scalable manufacturing routes to AZD1981. Application of the Semmler-Wolff aromatisation for synthesis of the indole-4-amide core, Org. Process Res. Dev. 16(2012) 1746-1753.
[13] A. Sato, L. McNulty, K. Cox, et al., A novel class of in vivo active anticancer agents:achiral seco-amino-and seco-hydroxy cyclopropylbenzo[e]indolone (seco-CB(Ⅰ)) analogues of the duocarmycins and CC-1065, J. Med. Chem. 48(2005) 3903-3918.
[14] S. Werner, P.S. (Ⅰ)yer, M.D. Fodor, et al., Solution-phase synthesis of a tricyclic pyrrole-2-carboxamide discovery library applying a Stetter-Paal-Knorr reaction sequence, J. Comb. Chem. 8(2006) 368-380.
[15] D.C. Rogness, R.C. Larock, Rapid synthesis of the indole-indolone scaffold via[3+2] annulation of arynes by methyl indole-2-carboxylates, Tetrahedron Lett. 50(2009) 4003-4008.
[16] (a) C. Graaff, E.R. Ruijter, V.A. Orru, Recent developments in asymmetric multicomponent reactions, Chem. Soc. Rev. 41(2012) 3969-4009;(b) B.H. Rotstein, S. Zaretsky, V. Rai, A.K. Yudin, Small heterocycles in multicomponent reactions, Chem. Rev. 114(2014) 8323-8359;(c) J.J. Sahn, B.A. Granger, S.F. Martin, Evolution of a strategy for preparing bioactive small molecules by sequential multicomponent assembly processes, cyclizations, and diversification, Org. Biomol. Chem. 12(2014) 7659-7672.
[17] (a) A. Dömling, Recent developments in isocyanide based multicomponent reactions in applied chemistry, Chem. Rev. 106(2006) 17-89;(b) G. Koopmanschap, E. Ruijter, R.V.A. Orru, (Ⅰ)socyanide-based multicomponent reactions towards cyclic constrained peptidomimetics, Beilstein J. Org. Chem. 10(2014) 544-598;(c) A. Ramazani, A. Rezaei, Novel one-pot, four-component condensation reaction:an efficient approach for the synthesis of 2,5-disubstituted 1,3,4-oxadiazole derivatives by a Ugi-4CR/aza-Wittig sequence, Org. Lett. 12(2010) 2852-2855.
[18] (a) J.A. Jee, S. Song, J.G. Rudick, Enhanced reactivity of dendrons in the Passerini three-component reaction, Chem. Commun. 51(2015) 5456-5459;(b) F.D. Moliner, L. Banfi, R. Riva, A. Basso, Beyond Ugi and Passerini reactions:multicomponent approaches based on isocyanides and alkynes as an efficient tool for diversity oriented synthesis, Comb. Chem. High Throughput Screen. 14(2011) 782-810;(c) A.R. Kazemizadeh, A. Ramazani, Synthetic applications of Passerini reaction, Curr. Org. Chem. 16(2012) 418-450.
[19] (a) L. Wang, Z.L. Ren, M. Chen, M.W. Ding, One-pot synthesis of 24,5-trisubstituted oxazoles via a tandem Passerini three-component coupling/Staudinger/Aza-Wittig/(Ⅰ)somerization reaction, Synlett 25(2014) 721-723;(b) J. Wu, J.C. Liu, L. Wang, M.W. Ding, Facile synthesis of 5-carboxamideoxazolines via a Passerini 3CC-Staudinger-aza-Wittig sequence, Synlett 19(2011) 2880-2882.
[20] (a) A. Domling, W. Wang, K. Wang, Chemistry and biology of multicomponent reactions, Chem. Rev. 112(2012) 3083-3135;(b) B.H. Rotstein, S. Zaretsky, V. Rai, A.K. Yudin, Small heterocycles in multicomponent reactions, Chem. Rev. 114(2014) 8323-8359.
[21] (a) U.M. Lindstrom, Stereoselective organic reactions in water, Chem. Rev. 102(2002) 2751-2772;(b) Y. Peng, G. Song, R. Dou, Surface cleaning under combined microwave and ultrasound irradiation:flash synthesis of 4H-pyrano[2,3-c]pyrazoles in aqueous media, Green Chem. 8(2006) 573-575.
[22] A. Ramazani, A. Rezaei, A.T. Mahyari, M. Rouhani, M. Khoobi, Three-component reaction of an isocyanide and a dialkyl acetylene dicarboxylate with a phenacyl halide in the Presence of water:an efficient method for the one-pot synthesis of γ-iminolactone derivatives, Helv. Chim. Acta 93(2010) 2033-2036.
[23] A. Ramazani1, K. Dastanra, F.Z. Nasrabadi, et al., Silica nanoparticles as a high efficient catalyst for the one-pot synthesis of 3-oxo-3-phenylpropanamid derivatives from isocyanides, phenylacetaldehyde and secondary amines, Turk. J. Chem. 36(2012) 467-476.
[24] H. Eshghi, M. Rahimizadeh, A. Shiri, P. Sedaghat, One-pot synthesis of benzimidazoles and benzothiazoles in the presence of Fe(HSO4)3 as a new and efficient oxidant, Bull. Korean Chem. Soc. 33(2012) 515-518.
[25] A. Ramazani, S.W. Joo, F.Z. Nasrabadi, Environmentally green synthesis of thioformamide derivatives, Turk. J. Chem. 37(2013) 405-412.
[26] J. Taran, A. Ramazani, S.W. Joo, K.Ś lepokura, T. Lis, Synthesis of novel a-(acyloxy)-a-(quinolin-4-yl)acetamides by a three-component reaction between an isocyanide, quinoline-4-carbaldehyde, and arenecarboxylic acids, Helv. Chim. Acta 97(2014) 1088-1096.
[27] (a) A. Jafari, A. Ramazani, M. Rouhani, Efficient one-pot synthesis of substituted propanamide derivatives by a three-component reaction of 2-oxopropyl benzoate. 1,1,3,3-Tetramethylbutyl isocyanide and aromatic carboxylic acids in water, Bulg. Chem. Commun. 47(2015) 156-160;(b) A. Ramazani, M. Rouhani, S.W. Joo, Catalyst-free sonosynthesis of highly substituted propanamide derivatives in water, Ultrason. Sonochem. 28(2016) 393-399.
[28] P. Barraja, P. Diana, A. Lauria, et al., Pyrrolo[2,3-h]quinolinones:synthesis and photochemotherapic activity, Bioorg. Med. Chem. Lett. 13(2003) 2809-2811.
[29] A.R. Bharadwaj, K.A. Scheidt, Catalytic multicomponent synthesis of highly substituted pyrroles utilizing a one-pot Sila-Stetter/Paal-Knorr strategy, Org. Lett. 6(2004) 2465-2468.
[30] (a) H. Yu, T. Gai, W.L. Sun, M.S. Zhang, Radical reduction of Passerini 3CR adducts by Sm(Ⅰ)2/HMPA, Chin. Chem. Lett. 22(2011) 379-381;(b) S.C. Solleder, M.A.R. Meier, Sequence control in polymer chemistry through the Passerini three-component reaction, Angew. Chem. (Ⅰ)nt. Ed. 53(2014) 711-714;(c) A.A. Esmaeili, S.A. Ghalandarabad, S. Jannati, A novel and efficient synthesis of 3,3-disubstituted indol-2-ones via Passerini three-component reactions in the presence of 4Å molecular sieves, Tetrahedron Lett. 54(2013) 406-408.
[31] (a) H.G.O. Alvim, E.N. Silva Júnior, B.A.D. Neto, What do we know about multicomponent reactions?. Mechanisms and trends for the Biginelli, Hantzsch, Mannich, Passerini and Ugi MCRs, RSC Adv. 4(2014) 54282-54299;(b) S. Maeda, S. Komagawa, M. Uchiyama, K. Morokuma, Finding reaction pathways for multicomponent reactions:the Passerini reaction is a four-component reaction, Angew. Chem. 123(2011) 670-675;(c) R. Ramozzi, K. Morokuma, Revisiting the Passerini reaction mechanism:existence of the nitrilium, organocatalysis of its formation, and solvent effect, J. Org. Chem. 80(2015) 5652-5657.
[32] (a) A. Chanda, V.V. Fokin, Organic synthesis "on water", Chem. Rev. 109(2009) 725-748;(b) N. Shapiro, A. Vigalok, Highly efficient organic reactions "on water", "in water", and both, Angew. Chem. (Ⅰ)nt. Ed. 47(2008) 2891-2894.