Divergent reactivity of α-azidochalcones with metal β-diketonates: tunable synthesis of substituted pyrroles and indoles

Abstract

A divergent reactivity of α-azidochalcones with metal β-diketonates for the synthesis of substituted pyrroles and indoles is described. Metal β-diketonates have been applied as bifunctional reactive partners. With a copper complex, the synthesis of substituted pyrroles in micellar media via 2H-azirine intermediates has been achieved under mild conditions, while with Fe(acac)₂ as a catalyst, the reaction proceeds smoothly to yield indoles regioselectively.

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Introduction

The advancement of synthetic methods for synthesizing the privileged heterocyclic frameworks has acquired substantial consideration by synthetic chemists.¹ Aza heterocycles are indispensable frameworks in many natural products with an extensive array of bioactivity. Particularly pyrrole and its benzo-fused analogue indole are widespread structural entities in biologically active natural and unnatural components, as well as in other functional materials (Fig. 1).² The contradictory synthetic strategy seems to be common and expedient in the construction of aza heterocycles, demanding an understanding of the reactivity of intermediates chemoselectively.³ Many protocols involve direct C–N bond formation by the loss of H₂, N₂, or H₂O to construct complex nitrogen heterocycles.⁴

Fig. 1 Examples of biologically active pyrrole and indole moieties.

In recent times, vinyl azides are being focused largely for their inimitable properties which permit them to act as a nucleophile, electrophile, or radical acceptor for the synthesis of diverse heterocycles.⁵ It is common that vinyl azides undergo photolysis or thermolysis to yield highly strained three-membered 2H-azirines, which can act as building blocks in organic synthesis.⁶ α-Azidochalcones in particular retain distinctive chemical reactivity and aid as resourceful synthons for the synthesis of numerous aza heterocycles.⁷ The synthesis of indoles and carbazoles can be achieved by the intramolecular C–H amination by photolysis or thermal decomposition of azides. Still, these methods suffer from harsh conditions with an inadequate scope.⁸ Metal β-diketonates are gaining substantial attention as they can be used as catalysts in organic synthetic transformations and have enormous material applications.⁹

Results and discussion

Earlier we have reported the indium trichloride catalyzed synthesis of substituted pyrrole in water.^7b In continuation of our exploitation of α-azidochalcones as precursors for aza heterocycles, the regioselective syntheses of pyrroles have been reinvestigated under milder reaction conditions compared to the reported methods.¹⁰ Apart from that, the regioselective synthesis of indoles¹⁰ has also been accomplished (Scheme 1). α-Azidochalcones can be synthesized from the corresponding chalcones in two steps following the literature method.^7b,e,11

Scheme 1 Synthesis of aza heterocycles 2 and 3.

As a green reaction medium, water has several advantages as it is copiously accessible in nature, virtually safe and environment friendly among all the existing solvents.¹² However, the solubility of most of the organic reactants in water is an issue that affects the execution of reactions in aqueous media. The introduction of aqueous surfactants by the materialization of micelles enriches the reactivity of water mediated reactions.¹³

During the course of our investigation for the construction of aza heterocycles from α-azidochalcones, we have intended to synthesise indoles from α-azidochalcones through the intramolecular C–H amination strategy in water using copper(II) acetylacetonate as a catalyst. Accordingly, we have initiated our experiment with α-azidochalcone 1 (R¹ = 4-Cl, R² = 2,4-di-OCH₃) and Cu(acac)₂ (0.1 equiv.) at 100 °C in a micellar medium employing cetyl trimethyl ammonium chloride (CTAC) (0.015 equiv.) as a surfactant for 12 h, but there was no product formation. The reaction was continued by increasing the catalytic loading upto 0.4 equiv. at 100 °C and decreasing the reaction time to 10 minutes. After completion of the reaction, a solid was obtained, when the reaction mixture was treated with a saturated solution of ammonium chloride and subsequently recrystallized from ethanol.¹⁴ Upon characterization by using NMR and mass spectral data, the product formed was found to be the substituted pyrrole 2a and not the expected indole 3a. The acetylacetonate component from Cu(acac)₂ has been incorporated with an acceptable yield of 2a (Table 1, entries 2 and 3). A relatively good yield of pyrrole 2a (94%) was obtained by increasing the amount of Cu(acac)₂ to 0.5 equiv. under the same reaction conditions (Table 1, entry 4).

Table 1 Screening the catalyst for the formation of 2a and 3a

S. no.	Catalyst (equiv.)	Conditions	Yield^a %
			2a	3a
a Isolated yield. b Reaction under a nitrogen atmosphere. c Surfactant: 0.015 equiv.
1^b	Cu(acac)2 (0.1)	H2O, CTAC,^c 100 °C, 12 h	—	—
2	Cu(acac)2 (0.2)	H2O, CTAC,^c 100 °C, 10 min	31	—
3	Cu(acac)2 (0.4)	H2O, CTAC,^c 100 °C, 10 min	66	—
4	Cu(acac)2 (0.5)	H2O, CTAC,^c 100 °C, 10 min	94	—
5	Ni(acac)2 (0.5)	H2O, CTAC,^c 100 °C, 1 h	66	—
6	Fe(acac)2 (0.5)	H2O, CTAC,^c 100 °C, 1 h	73	—
7^b	Cu(acac)2 (0.5)	CH3CN, 80 °C, 8 h	52	—
8	Cu(acac)2 (0.5)	DMF, 100 °C, 3 h	43	—
9	Cu(acac)2 (0.5)	Dioxane, 80 °C, 3 h	36	—
10	Cu(acac)2 (0.5)	n-BuOH, 80 °C, 8 h	68	—
11	Ni(acac)2 (0.5)	CH3CN, 80 °C, 8 h	43	—
12^b	Fe(acac)2 (0.5)	CH3CN, 80 °C, 8 h	64	23
13^b	Fe(acac)2 (0.2)	Toluene, 100 °C, 12 h	12	73
14^b	Fe(acac)2 (0.01)	DCE, 80 °C, 7 h	—	53
15^b	Fe(acac)2 (0.02)	DCE, 80 °C, 4 h	—	87
16^b	Fe(acac)3 (0.2)	DCE, 80 °C, 3 h	33	—
17^b	Pd(acac)2 (0.2)	DCE, 80 °C, 16 h	—	—
18^b	Ni(acac)2 (0.2)	DCE, 80 °C, 16 h	—	—

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The investigation was further carried out by changing a number of experimental variables such as solvents, catalysts and temperature, but there is no improvement in the yield of 2a (Table 1, entries 5–11). When the experiment was carried out with 0.5 equiv. of Fe(acac)₂ in acetonitrile at 80 °C for 8 h, the formation of pyrrole 2a (64%) was accompanied by a minor amount of substituted indole 3a (23%) (Table 1 entry 12). Attempts to improve the yield of 3a over 2a were made and when the reaction was carried out in toluene at 100 °C for 12 h with a reduced amount of Fe(acac)₂ (0.2 equiv.), the formation of 3a was appreciable (73%) with a poor yield of 2a (12%) (Table 1, entry 13). Exclusive formation of 3a was possible in dichloroethane at 80 °C in 4 h with a very small amount of Fe(acac)₂ (Table 1, entry 15). Nickel and palladium diketonates did not participate in the reaction, either as the catalyst or as the substrate (Table 1, entries 17 and 18).

With the optimal reactivity of α-azidochalcones with copper β-diketonates, the scope of the reaction was extended towards the synthesis of substituted pyrroles 2a–2o (Table 2). The reaction proficiency was not greatly affected by the electron donating or withdrawing substituents at different positions of the aryl rings of α-azidochalcones. Under the optimized conditions, the reaction is much compatible with α-azidocinnamate as well (Table 2).

Table 2 Synthesis of substituted pyrroles 2a–2o^a

a Reaction conditions: α-azidochalcone (0.10 mmol), metal-β-diketonate (0.5 mmol) and CTAC (0.015 equiv.) in water (5 mL) heated at 100 °C for 10 min under open air.

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We were then prompted to explore the generality of this pyrrole formation using mixed ligand complexes with different β-diketone ligands, which could be easily prepared in a straightforward manner.¹⁵ The reaction of α-azidochalcones and the mixed ligand complexes of β-diketonates under the optimized reaction conditions went on successfully yielding mixtures of substituted pyrroles in appreciable yields (Table 3).

Table 3 Synthesis of substituted pyrroles 2 from mixed ligand complexes of β-diketonates^a

a Reaction conditions: α-azidochalcone (0.10 mmol), mixed ligand complexes of metal-β-diketonate (0.5 mmol) and CTAC (15 mol%) in water (5 mL) heated at 100 °C for 10 min under open air.

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The mechanism for the formation of substituted pyrroles 2 is given in Scheme 2. Initially, thermolysis of α-azidochalcone results in denitrogenative decomposition to form a cyclic imine, a highly strained three membered 2H-azirine, 4. The solvolysis of metal β-diketonate followed by the addition of intermediate 4 results in the aziridine adduct 5, which then undergoes intramolecular nucleophilic addition on the carbonyl group with a nitrogen lone pair, yielding 2,5-dihydro-1H-pyrrole intermediate 6. Further isomerization yields the substituted pyrrole 2 ultimately.^10c

Scheme 2 Mechanism for the formation of pyrroles 2.

Regarding the mode of cyclization involving the unsymmetrical β-diketone-aziridine adduct 5, a lone pair of electrons on the nitrogen prefers the more electrophilic carbonyl carbon and leads to the respective substituted pyrrole regioselectively (Scheme 3). This is well supported by the single crystal X-ray structures of 2b and 2j (Fig. 2) with the expected regioisomers in each case.¹⁶

Scheme 3 Regiochemical preferences in cyclization for pyrrole 2.

Fig. 2 X-ray crystal structures of 2b and 2j. Thermal ellipsoids are shown at 50% probability level.

The scope and the chemistry of the Fe(acac)₂ promoted C–H amination strategy for the synthesis of substituted indoles from various α-azidochalcones have been studied with further interest. The reaction progressed fairly with substrates comprising various substituents on the aryl ring (–R²) and the synthesized library of compounds is summarized in Table 4. Fascinatingly, this optimized C–H amination works well with the heteroaromatic system (3n) as well. The reaction takes place even with α-azido cinnamaldehyde instead of α-azidochalcone resulting in indole-2-carbaldehyde (3o) in good yield. An attempt to accomplish the transformation with the diazido substrate under the optimized conditions is successful yielding 3p.

Table 4 Synthesis of substituted indoles 3a–3f^a

a Reaction conditions: α-azidochalcone (0.10 mmol) and Fe(acac)₂ (0.02 equiv.; 0.04 equiv. for 3p) in DCE (3 mL) heated at 80 °C for 4 h under a nitrogen atmosphere.

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Initially, thermolysis of α-azidochalcone would have produced strained 2H-azirine intermediate 4, which forms iron azirine complex 7 with Fe(II) and subsequent cleavage of the C–N bond would afford iron vinyl nitrene complex 8. A five centered 6-π electrocyclization¹⁷via intermediate 9 results in indole 3 (Scheme 4).¹⁸

Scheme 4 Mechanism for the formation of indole 3.

The cyclization occurs at the styryl ring rather than the aroyl ring, probably due to the deactivation of the aroyl ring towards a five centered 6-π electrocyclization step (Scheme 5). This hypothesis has been proved as evidenced by the single crystal X-ray analysis of 3c (Fig. 3)¹⁹ and also by the fact that the reaction goes well with α-azido cinnamaldehyde giving an indole derivative. Though a catalyst free conversion has been reported,^10g the milder reaction conditions of the present method of generating 3 are noteworthy.

Scheme 5 Regioselectivity in C–H amination for indole formation 3.

Fig. 3 X-ray crystal structure of 3c. Thermal ellipsoids are shown at 50% probability level.

When water is employed as the solvent the free ligand gets released in the equilibrium enabling the stoichiometric involvement of the complex in the reaction. But when DCE is employed the liberation of the free ligand for the pyrrole formation is restricted, where the Lewis acidic behaviour of iron dominates the course of the reaction. Thus the solvent polarity seems to be vital in dictating the course of the reaction. In the present protocol, the yields of both substituted pyrroles and indoles were poor at higher temperature. The poor atom economy associated with the formation of 2 is also a matter of concern.

Conclusions

In summary, the reactivity of α-azidochalcones with metal β-diketonates towards the synthesis of substituted pyrroles in micellar media via the 2H-azirine intermediate has been achieved. Regioselective Fe(II) catalyzed C–H amination of α-azidochalcones leading to substituted indoles has also been described. Thus the diverged reactivity of α-azidochalcones with metal β-diketonates as bifunctional reactive partners by variation of the reaction conditions has been demonstrated.

Acknowledgements

The authors thank DST, New Delhi for assistance under the IRHPA program for the NMR facility.

Notes and references

1. (a) H.-J. Knçlker and K. R. Reddy, Chem. Rev., 2002, 102, 4303; (b) M. D'Ischia, A. Napolitano and A. Pezzella, in Comprehensive Heterocyclic Chemistry III, ed. A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier, Oxford, 2008, vol. 3, p. 353; (c) H. Fan, J. Peng, M. T. Hamann and J.-F. Hu, Chem. Rev., 2008, 108, 264; (d) A. J. K. Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489; (e) A. W. Schmidt, K. R. Reddy and H.-J. Knçlker, Chem. Rev., 2012, 112, 3193.
2. (a) D. Black, in Science of Synthesis, ed. G. Maas, Thieme, Stuttgart, 2000, vol. 9, p. 441; (b) J. A. Joule, in Science of Synthesis, ed. E. J. Thomas, Thieme, Stuttgart, 2000, vol. 10, p. 361; (c) T. Gallagher, in Science of Synthesis, ed. E. J. Thomas, Thieme, Stuttgart, 2000, vol. 10, p. 693; (d) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045; (e) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875; (f) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644; (g) S. Cacchi and G. Fabrizi, Chem. Rev., 2011, 111, 215; (h) M. Platon, R. Amardeil, L. Djakovitch and J. C. Hierso, Chem. Soc. Rev., 2012, 41, 3929; (i) M. Inman and C. Moody, J. Chem. Sci., 2013, 4, 29.
3. (a) S. L. Schreiber, Science, 2000, 287, 1964; (b) F. G. Kuruvilla, A. F. Shamji, S. M. Sternson, P. J. Hergenrother and S. L. Schreiber, Nature, 2002, 416, 653; (c) D. D. Dixon, J. W. Lockner, Q. Zhou and P. S. Baran, J. Am. Chem. Soc., 2012, 134, 8432; (d) H.-X. Dai, A. F. Stepan, M. S. Plummer, Y.-H. Zhang and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 7222.
4. (a) M. Lhassani, O. Chavignon, J.-M. Chezal, J.-C. Teulade, J.-P. Chapat, R. Snoeck, G. Andrei, J. Balzarini, E. De Clercq and A. Gueiffier, Eur. J. Med. Chem., 1999, 34, 271; (b) K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth, D. E. Cavender, G. C. Olini, B. Fahmy and J. J. Siekierka, Bioorg. Med. Chem. Lett., 2003, 13, 347; (c) C. E. Gueiffier and A. Gueiffier, Mini-Rev. Med. Chem., 2007, 7, 888.
5. (a) W. T. Chen, M. Hu, J. W. Wu, H. B. Zou and Y. P. Yu, Org. Lett., 2010, 12, 3863; (b) Y. Wang, K. K. Toh, E. P. J. Ng and S. Chiba, J. Am. Chem. Soc., 2011, 133, 6411; (c) B. Hu, Z. Wang, N. Ai, J. Zheng, X. Liu, S. Shan and Z. Wang, Org. Lett., 2011, 13, 6362; (d) N. Jung and S. Brase, Angew. Chem., Int. Ed., 2012, 51, 12169; (e) B. K. Dinda, A. K. Jana and D. Mal, Chem. Commun., 2012, 48, 3999; (f) G. Zhang, H. Ni, W. Chen, J. Shao, H. Liu and Y. Yu, Org. Lett., 2013, 15, 5967; (g) Y. F. Wang, G. H. Lonca and S. Chiba, Angew. Chem., Int. Ed., 2014, 53, 1067; (h) S. Liu, W. Chen, J. Luo and Y. Yu, Chem. Commun., 2014, 50, 8539; (i) S. Liu, J. Shao, X. Guo, J. Luo, M. Zhao, G. Zhang and Y. Yu, Tetrahedron, 2014, 70, 1418; (j) B. Hu and S. G. Di Magno, Org. Biomol. Chem., 2015, 13, 3844.
6. (a) F. W. Fowler and A. Hassner, J. Am. Chem. Soc., 1968, 90, 2875; (b) A. Kakehi, S. Ito, T. Manabe, H. Amano and Y. Shimaoka, J. Org. Chem., 1976, 41, 2739; (c) F. Palacios, A. M. O. de Retana, E. M. de Marigorta and J. M. de los Santos, Eur. J. Org. Chem., 2001, 2401; (d) T. Ooi, M. Takahashi, K. Doda and K. Maruoka, J. Am. Chem. Soc., 2002, 124, 7640; (e) T. M. V. D. Pinhoe Melo, A. L. Cardoso, C. S. B. Gomes and A. M. d'A Rocha Gonsalves, Tetrahedron Lett., 2003, 44, 6313; (f) D. A. Candito and M. Lautens, Org. Lett., 2010, 12, 3312; (g) S. Jana, M. D. Clements, B. K. Sharp and N. Zheng, Org. Lett., 2010, 12, 3736; (h) A. F. Khlebnikov, M. V. Golovkina, M. S. Novikov and D. S. Yufit, Org. Lett., 2012, 14, 3768; (i) A. F. Khlebnikov and M. S. Novikov, Tetrahedron, 2013, 69, 3363; (j) A. Prechter, G. Henrion, P. Faudot dit Bel and F. Gagosz, Angew. Chem., Int. Ed., 2014, 53, 4959; (k) K. Rajaguru, A. Mariappan, R. Suresh, P. Manivannan and S. Muthusubramanian, Beilstein J. Org. Chem., 2015, 11, 2021.
7. (a) R. Suresh, S. Muthusubramanian, M. Boominathan and G. Manickam, Tetrahedron Lett., 2013, 54, 2315; (b) R. Suresh, S. Muthusubramanian, M. Nagaraj and G. Manickam, Tetrahedron Lett., 2013, 54, 1779; (c) R. Suresh, S. Muthusubramanian, N. Paul, N. Kalidhasan and V. Shanmugaiah, Med. Chem. Res., 2014, 23, 4367; (d) K. Rajaguru, R. Suresh, A. Mariappan, S. Muthusubramanian and N. Bhuvanesh, Org. Lett., 2014, 16, 744; (e) K. Rajaguru, A. Mariappan, S. Muthusubramanian and N. Bhuvanesh, ChemistrySelect, 2016, 1, 1636.
8. T. G. Driver, Org. Biomol. Chem., 2010, 8, 3831.
9. (a) A. González, F. Güell, J. Marquet and M. M. Mañas, Tetrahedron Lett., 1985, 26, 3735; (b) M. Kimura, A. Ezoe, S. Tanaka and Y. Tamaru, Angew. Chem., Int. Ed., 2001, 40, 3600; (c) M. Taillefer, N. Xia and A. Ouali, Angew. Chem., Int. Ed., 2007, 46, 934; (d) S. L.-F. Chan, K.-H. Low, C. Yang, S. H.-F. Cheung and C.-M. Che, Chem. – Eur. J., 2011, 17, 4709; (e) Q. Chen, L. Ilies, N. Yoshikai and E. Nakamura, Org. Lett., 2011, 13, 3232; (f) T. P. A. Goossens, F. A. C. Vrielynck, N. G. C. Hosten and K. J. A. V. Aken, Transesterification process using mixed salt acetylacetonates catalysis, US2013/0090492A1, 2013; (g) C. Pan, J. Han, H. Zhang and C. Zhu, J. Org. Chem., 2014, 79, 5374; (h) H. E. Ho, K. Oniwa, Y. Yamamoto and T. Jin, Org. Lett., 2016, 18, 2487.
10. (a) H. Hemetsberger and D. Knittel, Monatsh. Chem., 1972, 103, 194; (b) B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey and T. G. Driver, J. Am. Chem. Soc., 2007, 129, 7500; (c) S. Chiba, Y.-F. Wang, G. Lapointe and K. Narasaka, Org. Lett., 2008, 10, 313; (d) F. Lehmann, M. Holm and S. Laufer, Tetrahedron Lett., 2009, 50, 1708; (e) B. J. Stokes, B. Jovanović, H. Dong, K. J. Richert, R. D. Riell and T. G. Driver, J. Org. Chem., 2009, 74, 3225; (f) D. Hong, Z. Chen, X. Lin and Y. Wang, Org. Lett., 2010, 12, 4068; (g) J. Bonnamour and C. Bolm, Org. Lett., 2011, 13, 2012; (h) E. P. J. Ng, Y.-F. Wang, B.-W. Q. Hui, G. Lapointe and S. Chiba, Tetrahedron, 2011, 67, 7728; (i) H. G. Bonacorso, F. M. Libero, G. M. D. Forno, E. P. Pittaluga, L. M. F. Porte, M. A. P. Martins and N. Zanatta, Tetrahedron Lett., 2015, 56, 5190; (j) I. T. Alt and B. Plietker, Angew. Chem., Int. Ed., 2016, 55, 1519; (k) C. Pooran, C. Jason, C. Brian, T. Gilles, T. Sucheta and T. John, Small molecule inhibitors of pfkfb3 and glycolytic flux and their methods of use as anti-cancer therapeutics, WO2011103557, 2011.
11. V. Nair and T. G. George, Tetrahedron Lett., 2000, 41, 3199.
12. C. Li and L. Chen, Chem. Soc. Rev., 2006, 35, 68.
13. G. L. Sorella, G. Strukul and A. Scarso, Green Chem., 2015, 17, 644.
14. (a) S. Tu, C. Li, G. Li, L. Cao, Q. Shao, D. Zhou, B. Jiang, J. Zhou and M. Xia, J. Comb. Chem., 2007, 9, 1144; (b) S. Tu, S. Wu, S. Yan, W. Hao, X. Zhang, X. Cao, Z. Han, B. Jiang, F. Shi, M. Xia and J. Zhou, J. Comb. Chem., 2009, 11, 239; (c) N. Ma, B. Jiang, G. Zhang, S.-J. Tu, W. Weverb and G. Li, Green Chem., 2010, 12, 1357; (d) C. Cheng, B. Jiang, S.-J. Tu and G. Li, Green Chem., 2011, 13, 2107.
15. R. L. Prasad, A. Kushwaha and B. P. S. Gautam, J. Coord. Chem., 2009, 62, 2983.
16. CCDC number for 2b: 1482069; 2j: 1482068.
17. I. W. Davies, V. A. Guner and K. N. Houk, Org. Lett., 2004, 6, 743.
18. S. Jana, M. D. Clements, B. K. Sharp and N. Zheng, Org. Lett., 2010, 12, 3736.
19. CCDC number for 3c: 1482067.

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Footnote

† Electronic supplementary information (ESI) available: The copies of ¹H and ¹³C NMR spectra for all the synthesized compounds. CCDC 1482067–1482069. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00541a

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