Palladium catalyzed oxidative Suzuki coupling reaction of indolizine at the 3-position using oxygen gas as the only oxidant

Abstract

Stoichiometric metal oxidant applied in the functionalization of indolizine at the 3-position through C–H activation in a previous report was found to increase the cost of the synthesis and worsen the environmental pollution. In this paper, we developed a Pd(OAc)₂/O₂ catalytic system with or without ligands for an oxidative Suzuki coupling reaction of indolizine at the 3-position through C–H activation. As reported in the literature, some indolizines dimerized when catalyzed by palladium acetate under ligand-free conditions. However, we found that the dimerization of 2,3-unsubstituted indolizines was inhibited by the addition of ligands. Based on this finding, the arylation of these indolizines can be successfully achieved via a Pd(OAc)/O₂ system using picolinic acid as a ligand. 1,2-disubstituted indolizines that do not easily dimerize can react smoothly with arylboronic acids under ligand-free conditions. Furthermore, broad group tolerance was shown in both indolizine and arylboronic acid. Finally, this method has the advantages of mild conditions, a broad array of starting materials and the use of a green oxidant.

---

Introduction

Carbon–carbon bond formation reactions are among the most important processes in chemistry because they occur in key steps to build more complex molecules from simple precursors. Among these reactions, sp² C–sp² C bond formation can be used for the construction of biaryls, which are important structural motifs in many organic molecules. Therefore, the development of methods for new sp² C–sp² C bond formation remains an ongoing challenge for organic chemists. Inspired by the need for green and sustainable chemistry,¹ synthetic chemists are seeking more efficient ways to construct sp² C–sp² C bonds of biheteroaryl compounds. Compared to the traditional palladium catalyzed cross-coupling reaction, C–H activation reaction uses a C–H bond instead of a C–X bond, thus making synthetic routes shorter and more efficient.² For example, oxidative Suzuki coupling reaction can synthesize biheteroaryl compounds directly from C–H bond (Scheme 1).³

Scheme 1 The comparison of traditional Suzuki coupling and oxidative Suzuki coupling reaction.

Recently, indolizine derivatives attracted interests of many chemists because they were an omnipresent component of a wide range of naturally occurring and biologically active molecules.⁴ In addition, polycyclic indolizine derivatives were observed to have long-wavelength absorption and fluorescence in the visible light spectrum. Thus, the successful synthesis of this type of compounds will facilitate the development of novel class of dyes and biological markers.⁵

Therefore, functionalization of indolizine through palladium catalyzed C–H activation drew great interests of synthetic chemists.⁶ Recently, several groups have reported palladium catalyzed C–H activation reactions^7,8 or traditional Suzuki cross-coupling reactions⁹ of indolizine at the 3-position for the synthesis of 3-aryl-indolizines (Scheme 2). However, halogenated aromatic hydrocarbons^7,9 or stoichiometric metal oxidant⁸ was applied in these reactions, which increased the cost of synthesis and environmental pollution. Compared with halogenated aromatic hydrocarbons, organic boronic acids were green coupling partner, whose by-product was environmentally friendly boric acid.⁸ Furthermore, oxygen gas is well known for a green oxidant as it comes from air and its solo by-product is water.¹⁰ Naturally, it's envisioned that the use of oxygen gas as oxidant and arylboronic acid as coupling partner would greatly decrease the cost of synthesis and environmental pollution.

Scheme 2 The comparison of this paper with previous work.

As a follow-up of our reported methods,^6e,11 we herein report an oxidative Suzuki cross-coupling reaction of indolizines with arylboronic acids to synthesize 3-aryl-substituted indolizines. The reaction proceeded selectively at the 3-position through palladium catalyzed C–H activation under mild conditions. Notably oxygen gas was used as a solo and terminal oxidant to make the reaction greener.

Results and discussion

In the preliminary study, indolizine 1a (0.20 mmol, 1.0 equiv.) and phenylboronic acid 2a (2.0 equiv.) were chosen as our model system. Pd(OAc)₂ was used as catalyst and oxygen gas (1 atm) as terminal oxidant (Scheme 2). As results shown in Table 1, the yield of the proposed product 3aa only reached 24% under ligand-free conditions (Table 1, entry 1). However, when L3 (picolinic acid) was added (10%) as a ligand, the yield increased to 68%. Other ligands were found less efficient than picolinic acid (entry 2–8). Notably, when potassium bicarbonate (3.0 equiv.) was added as a base, the result was superior to either other bases (such as potassium carbonate) added or weak acids (such as acetic acid) added (entry 9–14). This result was consistent with our previous work^6e but different from other groups' results.⁸

Table 1 Optimization of reaction conditions

Entry	Ligand^a (%)	Base, equiv.	Pd(OAc)2 (%)	Solvent^b	Yield^d (%)
a L1 = 2,2′-bipyridine, L2 = 1,10-phenanthroline, L3 = picolinic acid, L4 = quinolin-8-ol, L5 = 4,7-diphenyl-1,10-phenanthroline, L6 = pyrazine-2-carboxylic acid, L7 = pyridine-2,6-dicarboxylic acid.b 2.0 mL solvent otherwise indicated, DMSO = dimethyl sulfoxide, DMF = dimethylformamide, DMA = dimethylacetamide, NMP = N-methylpyrrolidone.c 1.0 mL solvent.d Isolated yield.e NA = no addition.
1	NA^e	KHCO3, 3	10	DMSO	24
2	L1 (10)	KHCO3, 3	10	DMSO	26
3	L2 (10)	KHCO3, 3	10	DMSO	54
4	L3 (10)	KHCO3, 3	10	DMSO	68
5	L4 (10)	KHCO3, 3	10	DMSO	52
6	L5 (10)	KHCO3, 3	10	DMSO	44
7	L6 (10)	KHCO3, 3	10	DMSO	39
8	L7 (10)	KHCO3, 3	10	DMSO	17
9	L3 (10)	NA^e	10	DMSO	17
10	L3 (10)	K2CO3, 3	10	DMSO	37
11	L3 (10)	HOAc, 3	10	DMSO	0
12	L3 (10)	KOAc, 3	10	DMSO	27
13	L3 (10)	Pyridine, 3	10	DMSO	53
14	L3 (10)	NEt3, 3	10	DMSO	Trace
15	L3 (30)	KHCO3, 3	10	DMSO	63
16	L3 (20)	KHCO3, 3	10	DMSO	78
17	L3 (20)	KHCO3, 3	10	NMP	67
18	L3 (20)	KHCO3, 3	10	DMA	42
19	L3 (20)	KHCO3, 3	10	DMF	50
20	L3 (10)	KHCO3, 3	5	DMSO^c	86
21	L3 (10)	KHCO3, 3	5	DMSO	76

---

When the amount of L3 was increased to 20%, the yield of desired product 3aa also increased to 78% (entry 16). However, when the amount of L3 was increased to 30%, the yield of 3aa decreased to 67% (entry 15).

Dimethyl sulfoxide was the solvent of choice, for other media provided a lower yield (entry 16–19). The best yield was achieved under condition A, in which the catalytic loading was decreased to 5% with 10% picolinic acid added as a ligand and the concentration of 1a was increased to 0.20 M as well (entry 20: reaction condition A).

To explore the substrate scope of arylboronic acids, an array of arylboronic acids were reacted with indolizine 1a under condition A (Scheme 3). As shown in Scheme 3, either the electronic effects (electron donating or electron withdrawing) or the position (ortho, meta or para) of substitution groups had little effect on the yield of corresponding indolizine.

Scheme 3 The results of indolizines 1a reacting with different arylboronic acids under reaction condition A.

As regarding to the substrate scope of indolizine, an array of indolizines with phenylboronic acid 2a as coupling partner were studied under reaction condition A (Scheme 4). As shown in Scheme 4, several 2-unsubstituted indolizines generated corresponding 3-phenyl-indolizines smoothly. Notably, indolizines with fused phenyl ring (1h and 1i) reacted with phenylboronic acid under 120 °C to give corresponding product in moderate yields. However, the 1,2-disubstituted indolizines gave very low yield or do not have any desired product under reaction condition A.

Scheme 4 The results of indolizines reacting with phenylboronic acid under reaction condition A.

As reported previously, 1,2-disubstituted indolizines were much less reactive than those without any substitution group at 2 or 3-position under palladium catalysis.^6e,i Therefore, the way to improve the reactivity of 1,2-disubstituted indolizines under ligand free condition is being planned. As a result, indolizine 1j (0.20 mmol, 1.0 equiv.) and phenylboronic acid 2a (2.0 equiv.) were chosen as model system to re-optimize reaction conditions. The results were shown in Table 2.

Table 2 Re-optimization of reaction conditions of indolizine 1j

a 3.0 equiv. base used.b 1.0 mL solvent otherwise indicated.c 0.10 mmol DMSO was added.d 1.0 mL solvent, Isolated yield.
Entry	Base^a	Pd(OAc)2 (%)	Solvent^b	Yield^d (%)
1	KOAc	5	DMSO	40
2	KOAc	10	DMSO	59
3	KOAc	10	NMP	82
4	KOAc	10	DMF	70
5	KOAc	10	DMA	68
6	KOAc	10	NMP/DMSO = 9/1	90
7	KOAc	5	NMP/DMSO = 9/1	81
8	KOAc	5	NMP/DMSO = 19/1	91
9	KOAc	5	NMP^c	85

---

As shown in Table 2, when potassium acetate was used as a base and NMP as a solvent, the yield of 3ja was increased to 82% (Table 2, entry 3). The highest yield (91%) was achieved when mixed solvent of NMP and DMSO was used (NMP/DMSO = 19/1, Table 2, entry 8: reaction condition B).

The scope of arylboronic acid was then checked under re-optimized reaction condition B. The results were shown in Scheme 5. As shown in Scheme 5, arylboronic acids gave corresponding product in moderate to good yield. However, the arylboronic acids bearing a strong electron donating group or a group at ortho position did not gave corresponding indolizines.

Scheme 5 The results of indolizine 1g reacting with different arylboronic acids under reaction condition B.

To explore the substrate scope of 1,2-disubstitutted indolizine, several indolizines were reacted with phenylboronic acid 2a under reaction condition B (Scheme 6). Some indolizines previously reported not reactive⁸ were able to react smoothly with phenylboronic acids to give corresponding product. However, the indolizines bearing a phenyl group at 2-position gave desired product in poor yield under either reaction condition A or reaction condition B (Scheme 7).

Scheme 6 The results of indolizines reacting with phenylboronic acid under reaction condition B.

Scheme 7 The indolizines gave desired product in poor yield either under reaction condition A or reaction condition B.

Conclusion

An oxidative Suzuki coupling reaction of 3-unsubstituted indolizines with arylboronic acids to produce 3-aryl-indolizines was reported. The reaction took place at the 3-position through palladium catalyzed C–H activation, followed by a Suzuki type cross-coupling reaction under mild conditions. Notably, the reaction used oxygen gas as solo and terminal oxidant and not sensitive to moistures. In addition, the use of cheap ligand or ligand free condition was another notable point. Further study of replacement of expensive arylboronic acids by cheaper and greener partner such as arenes is being thoroughly investigated.

Experimental

General methods and materials

Unless otherwise noted, all commercial reagents and solvents were obtained from the commercial provider and used without further purification. ¹H NMR and ¹³C NMR spectra were recorded on Bruker 400 MHz spectrometers. Chemical shifts were reported relative to internal tetramethylsilane (δ 0.00 ppm) or CDCl₃ (δ 7.26 ppm) for ¹H NMR and CDCl₃ (δ 77.0 ppm) for ¹³C NMR. Flash column chromatography was performed on 300–400 mesh silica gels. Analytical thin layer chromatography was performed with pre-coated glass baked plates (250 μ) and visualized by fluorescence. HRMS were recorded on Bruker micrOTOF-Q spectrometer. IR spectra were recorded by Nicolet Avatar 360 spectrometer.

General procedure for arylation of indolizines (1a–1g)

Indolizine (0.20 mmol), arylboronic acid (0.40 mmol), palladium acetate (2.2 mg, 0.01 mmol), picolinic acid (2.5 mg, 0.02 mmol), KHCO₃ (60.0 mg, 0.60 mmol) and 1.0 mL DMSO were added to a reaction tube equipped with a balloon charged with O₂ gas. Then the mixture was stirred at 100 °C for 24 h. The reaction was monitored by TLC. When the reaction finished, the mixture was cooled down to room temperature, poured into water and extracted with CHCl₃ (10 mL × 3). The organic layers were combined and dried with Na₂SO₄ and filtered. Then the mixture was evaporated under vacuum and the crude mixture was purified by flash chromatography (silica gel, eluted by petroleum ether–ethyl acetate).

General procedure for arylation of indolizines (1h–1i)

Indolizine (0.20 mmol), arylboronic acid (0.40 mmol), palladium acetate (2.2 mg, 0.01 mmol), picolinic acid (2.5 mg, 0.02 mmol), KHCO₃ (60.0 mg, 0.60 mmol) and 1.0 mL DMSO were added to a reaction tube equipped with a balloon charged with O₂ gas. Then the mixture was stirred at 120 °C for 24 h. The reaction was monitored by TLC. When the reaction finished, the mixture was cooled down to room temperature, poured into water and extracted with CHCl₃ (10 mL × 3). The organic layers were combined and dried with Na₂SO₄ and filtered. Then the mixture was evaporated under vacuum and the crude mixture was purified by flash chromatography (silica gel, eluted by petroleum ether–ethyl acetate).

General procedure for arylation of indolizines (1j–1m)

Indolizine (0.20 mmol), arylboronic acid (0.40 mmol), palladium acetate (0.01 mmol), KOAc (0.60 mmol) and 0.95 mL NMP and 0.050 mL DMSO were added to a reaction tube equipped a balloon charged O₂ gas. Then the mixture was heated at 100 °C under stirred for 4 h. The reaction was monitored by TLC. After the reaction finished, the mixture was cooled down to room temperature, poured into water and extracted with CHCl₃ (10 mL × 3). The organic layers were combined and dried with Na₂SO₄ and filtered. Then the mixture was evaporated under vacuum and the crude mixture was purified by flash chromatography (silica gel, eluted by petroleum ether–ethyl acetate).

Acknowledgements

We are grateful to funding of NSFC (no.: 21202058), NSF of Jiangsu Province (no.: BK2011408), CPSF (no.: 2012M511645, 2013T60483), Education Department of Jiangsu Province (no. 13KJA150001), JSKLCLDM (no.: SKC11093), MOHRSS (no. 11zs0104), CSCSE (no. 13zs1102) and NBRPC (no.: 2011CB933503) for their financial support.

Notes and references

1. For reviews on green chemistry, see: (a) C.-J. Li and B. M. Trost, Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 13197–13202; (b) P. T. Anastas and J. C. Warner, in Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998.
2. For recent reviews of C–H activation reactions, see: (a) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369–375; (b) S. Rousseaux, B. Liegault and K. Fagnou, in Modern Tools for the Synthesis of Complex Bioactive Molecules, John Wiley & Sons, Inc., Hoboken, New Jersey, 2012, pp. 1–32; (c) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788–802; (d) S. I. Kozhushkov and L. Ackermann, Chem. Sci., 2013, 4, 886–896; (e) M. C. White, Synlett, 2012, 23, 2746–2748; (f) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Commun., 2010, 46, 677–685; (g) C. Pan, X. Jia and J. Cheng, Synthesis, 2012, 44, 677–685; (h) J.-Q. Yu and Z.-J. Shi, in C–H Activation, Topics in Current Chemistry, Springer, 2010, vol. 292; (i) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780–1824; (j) Y. Wu, J. Wang, F. Mao and F. Y. Kwong, Chem.–Asian J., 2014, 9, 26–47.
3. For recent progress in oxidative Suzuki coupling reaction, see: (a) K. M. Engle and J.-Q. Yu, J. Org. Chem., 2013, 78, 8927–8955; (b) Y. W. Kim, M. J. Niphakis and G. I. Georg, J. Org. Chem., 2012, 77, 9496–9503; (c) H. Li, W. Wei, Y. Xu, C. Zhang and X. Wan, Chem. Commun., 2011, 47, 1497–1499; (d) T. Nishikata, A. R. Abela, S. Huang and B. H. Lipshutz, J. Am. Chem. Soc., 2010, 132, 4978–4979; (e) M. Catellani, E. Motti and C. N. Della, Acc. Chem. Res., 2008, 41, 1512–1522.
4. (a) W. Flisch, in Comprehensive Heterocyclic Chemistry, ed. A. R. Katritzky and C. W. Rees, Pergamon, Oxford, 1984, vol. 4, pp. 476–495; (b) J. Ewing, G. K. Hughes, E. Ritchie and W. C. Taylor, Nature, 1952, 169, 618–619; (c) A. K. Ghosh, G. Bilcer and G. Schiltz, Synthesis, 2001, 2203–2229; (d) B. List and C. Castello, Synlett, 2001, 1687–1689; (e) P. Sonnet, P. Dallemagne, J. Guillon, C. Enguehard, S. Stiebing, J. Tanguy, R. Bureau, S. Rault, P. Auvray, S. Moslemi, P. Sourdaine and G. E. Seralini, Bioorg. Med. Chem., 2000, 8, 945–949; (f) O. B. Ostby, B. Dalhus, L.-L. Gundersen, F. Rise, A. Bast and G. R. M. M. Haenen, Eur. J. Org. Chem., 2000, 3763–3770; (g) B. E. Maryanoff, J. L. Vaught, R. P. Shank, D. F. McComsey, M. J. Costanzo and S. O. Nortey, J. Med. Chem., 1990, 33, 2793–2797; (h) V. H. Lillelund, H. H. Jensen, X. Liang and M. Bols, Chem. Rev., 2002, 102, 515–554; (i) J. Gubin, H. D. Vogelaer, H. Inion, C. Houben, J. Lucchetti, J. Mahaux, G. Rosseels, M. Peiren, M. Clinet, P. Polster and P. Chatelain, J. Med. Chem., 1993, 36, 1425–1433; (j) J. Bermudez, C. S. Fake, G. F. Joiner, K. A. Joiner, F. D. King, W. D. Miner and G. J. Sanger, J. Med. Chem., 1990, 33, 1924–1929.
5. (a) F. D. Saeva and H. R. Luss, J. Org. Chem., 1988, 53, 1804–1806; (b) G. L. Fletetcher, S. L. Bender and D. H. Wadsworth, US Pat., 4577024, 1986Chem. Abstr. 1984, 100, 122772; (c) H. Sonnenschein, G. Henrich, U. Resch-Genger and B. Schulz, Dyes Pigm., 2000, 46, 23–27; (d) A. Vlahovici, M. Andrei and I. Druta, J. Lumin., 2002, 96, 279–285; (e) A. Vlahovici, I. Druta, M. Andrei, M. Cotlet and R. Dinica, J. Lumin., 1999, 82, 155–162; (f) A. V. Rotaru, L. D. Druta, T. Deser and T. J. Mueller, Helv. Chim. Acta, 2005, 88, 1798–1812; (g) F. Delattre, P. Woisel, G. Surpateanu, F. Cazier and P. Blach, Tetrahedron, 2005, 61, 3939–3945.
6. (a) I. V. Seregin, V. Ryabova and V. Gevorgyan, J. Am. Chem. Soc., 2007, 129, 7742–7743; (b) Y. Yang, K. Cheng and Y. Zhang, Org. Lett., 2009, 11, 5606–5609; (c) Y. Yang, L. Chen, Z. Zhang and Y. Zhang, Org. Lett., 2011, 13, 1342–1345; (d) Y. Ma, J. You and F. Song, Chem.–Eur. J., 2013, 19, 1189–1193; (e) H. Hu, Y. Liu, H. Zhong, Y. Zhu, C. Wang and M. Ji, Chem.–Asian J., 2012, 7, 884–888; (f) N. Chernyak, D. Tilly, Z. Li and V. Gevorgyan, ARKIVOC, 2011, 76–91; (g) Y. Huang, F. Song, Z. Wang, P. Xi, N. Wu, Z. Wang, J. Lan and J. You, Chem. Commun., 2012, 48, 2864–2866; (h) P. Xi, F. Yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu and J. You, J. Am. Chem. Soc., 2010, 132, 1822–1824; (i) J. Xia, X.-Q. Wang and S.-L. You, J. Org. Chem., 2009, 74, 456–458.
7. (a) C.-H. Park, V. Ryabova, I. V. Seregin, A. W. Sromek and V. Gevorgyan, Org. Lett., 2004, 6, 1159–1162; (b) B. Liegault, D. Lapointe, L. Caron, A. Vlassova and K. Fagnou, J. Org. Chem., 2009, 74, 1826–1834; (c) D. Lapointe, T. Markiewicz, C. J. Whipp, A. Toderian and K. Fagnou, J. Org. Chem., 2011, 76, 749–759; (d) B. Liu, Z. Wang, N. Wu, M. Li, J. You and J. Lan, Chem.–Eur. J., 2012, 18, 1599–1603.
8. (a) B. Liu, X. Qin, K. Li, X. Li, Q. Guo, J. Lan and J. You, Chem.–Eur. J., 2010, 16, 11836–11839; (b) B. Zhao, Org. Biomol. Chem., 2012, 10, 7108–7119.
9. J.-B. Xia and S.-L. You, Org. Lett., 2009, 11, 1187–1190.
10. For recent reviews for the reactions of oxygen gas as oxidant, see: (a) T. Punniyamurthy, S. Velusamy and J. Iqbal, Chem. Rev., 2005, 105, 2329–2364; (b) Y. Ishii and S. Sakaguchi, Catal. Today, 2006, 117, 105–113; (c) F. Recupero and C. Punta, Chem. Rev., 2007, 107, 3800–3842; (d) J.-E. Bäckvall, in Modern Oxidation Methods, Wiley-VCH Verlag GmbH & Co. KgaA, Weinheim, 2005; (e) C. Parmeggiani and F. Cardona, Green Chem., 2012, 14, 547–564; (f) I. W. C. E. Arends, G.-J. ten Brink and R. A. Sheldon, J. Mol. Catal. A: Chem., 2006, 251, 246–254; (g) S. S. Stahl, Angew. Chem., Int. Ed., 2004, 43, 3400–3420.
11. (a) Y. Liu, H.-Y. Hu, Q.-J. Liu, H.-W. Hu and J.-H. Xu, Tetrahedron, 2007, 63, 2024–2033; (b) H. Hu, K. Shi, R. Hou, Z. Zhang, Y. Zhu and J. Zhou, Synthesis, 2010, 4007–4014; (c) Y. Liu, H.-Y. Hu, Y. Zhang, H.-W. Hu and J.-H. Xu, Org. Biomol. Chem., 2010, 8, 4921–4926; (d) H. Hu, J. Feng, Y. Zhu, N. Gu and Y. Kan, RSC Adv., 2012, 2, 8637–8644; (e) Y. Liu, H.-Y. Hu, X.-B. Su, J.-W. Sun, C.-S. Cao and Y.-H. Shi, Eur. J. Org. Chem., 2013, 2020–2026.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra03799e

---