3,6-Di(pyridin-2-yl)-1,2,4,5-tetrazine capped Pd(0) nanoparticles: a catalyst for copper-free Sonogashira coupling of aryl halides in aqueous medium

Abstract

3,6-Di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) capped Pd(0) nanoparticles (TzPdNPs) as a catalyst in the Sonogashira coupling of aryl halides in aqueous medium with diminished homocoupling is reported. The methodology provides a facile route to obtain polyfunctional alkynes under ligand- and copper-free conditions. The procedure is also efficient for aryl chlorides.

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Introduction

The synthesis of new donor–acceptor terminal alkynes or π-conjugated aromatic alkynes has always required demanding starting materials in organic synthesis including natural products.¹ Moreover, their recent application in OLEDs as nonlinear optical materials² and in molecular electronics³ has enhanced the importance of the synthetic route. Sonogashira cross-coupling⁴ proves to be a most reliable practical tool for this challenging objective in the construction of these alkynes.

Traditionally this cross-coupling of aryl halides and alkynes proceeded in the presence of palladium and copper but it suffered from several limitations like homogeneous catalytic conditions, a higher activity of the palladium-based catalyst⁵ and the formation of undesired Glaser–Hay homocoupling products.⁶ A lot of modifications are under process, using other metal co-catalysts,^1a,b,h,7 or copper free⁸ and co-catalyst free⁷ conditions to diminish self-coupling. Another current challenge associated with the Sonogashira coupling reaction is its inefficiency when “unreactive” aryl chlorides are used. The application of aryl chlorides is advantageous due to their low cost relative to aryl bromides or iodides and increased availability. To date, few methods have been reported involving aryl chlorides in Sonogashira cross-coupling.⁹ It is also important to remove the expensive ligand choices which are generally used to activate the alkyl halides especially for reactions with chlorides as a coupling partner. Consequently, the search for a new protocol, using a green solvent, which diminishes other side products and activates aryl chlorides without using ligands is quintessential. Recently, a ligand- and copper salt-free Sonogashira reaction in aqueous medium using heterogeneous 10% Pd/C as the catalyst has also been developed but the catalyst is only active with aryl iodides.¹⁰ Herein we report the synthesis of 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) capped Pd(0) nanoparticles (TzPdNPs) which are a potential catalyst in the cross-coupling of aryl halides including aryl chloride and aryl acetylenes with diminished homocoupling in aqueous medium using tetrabutyl ammonium bromide (TBAB) as the phase transfer catalyst (PTC).

Results and discussion

The synthesis of TzPdNPs was carried out according to the method reported earlier by us.¹¹ An aqueous solution of Na₂PdCl₄ was reacted with 3,6-di(pyridin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine (H₂pytz) in ethanol under sonication (details in ESI†). In this synthesis 3,6-di(pyridin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine (H₂pytz) acts as a reducing agent for Na₂PdCl₄. On the other hand, H₂pytz oxidizes to 3,6-di(pyridin-2-yl)-1,2,4,5-s-tetrazine (pytz) which finally caps the Pd(0) nanoparticles to produce TzPdNPs. The TzPdNPs were characterized using FT-IR, powder X-ray diffraction (PXRD) and transmission electron microscopy (TEM). The crystallinity and purity of the TzPdNPs were examined (Fig. 1a) by the powder X-ray diffraction (XRD) technique. The XRD pattern of the TzPdNPs shows the inter planar d-spacing of XRD peaks corresponding to the (111), (200), (220) and (311) planes of Pd(0) with fcc structure (JCPDS no. 01-1310), without any impurity phase. The XRD pattern of TzPdNPs is similar to that of pure PdNPs, indicating that the nanoparticles have not been affected by the capping with pytz. The fairly intense peaks observed are indicative of crystallinity, whereas, the peak broadening indicates the presence of smaller materials (particle size). The morphology and size distribution of the prepared nanoparticles were elucidated from the transmission electron micrographs. Fig. 1b exhibits a morphological image of the prepared palladium nanoparticles. The size of the particles varies from 1.5 to 3 nm and the average size observed was 2.2 ± 0.4 nm (Fig. S1†). The shape of the particles is almost spherical, showing no faceted surfaces. It can also be noted that, despite the small size, the particles are separated from one another and no significant aggregation is observed. The SAED pattern of the TzPdNPs (Fig. 1c) shows spots and the rings indexed to the (111) and (200) planes of palladium with an fcc structure. This is in agreement with the X-ray diffraction studies. The HRTEM image, depicted in Fig. 1d shows lattice fringes corresponding to the (111) plane of Pd metal. The FT-IR spectrum of the TzPdNPs exhibits all the characteristic bands observed for pytz (Fig. S2†).

Fig. 1 (a) Powder XRD pattern, (b) TEM image, (c) SAED pattern and (d) HRTEM image of TzPdNPs.

We began our investigation with the coupling of phenylacetylene and iodobenzene at room temperature in the presence of 2 mg of catalyst. Initial results revealed that the presence of 2 equiv. of K₂CO₃ in water afforded the desired coupled product at room temperature with a 94% yield in 2 h (Table 1, entry 1). This preliminary catalytic system was also capable of coupling both bromobenzene and chlorobenzene (Table 1, entries 4 and 5) in high yield. The formation of the desired product was observed with an 86% yield within 3 h for chlorobenzene, although the reaction proceeded at 100 °C. The coupling of bromobenzene was also furnished with an excellent yield of 90% after 3 h at 60 °C.

Table 1 Initial studies^a

Entry	X	Catalyst (mg)	Time (h)	Yield^b (%)
a Reaction conditions (unless otherwise specified): 1 (2 mmol), 2 (2 mmol), catalyst (2 mg), TBAB (20 mg), water (10 mL), K2CO3 (2 mmol), room temperature.b Yield of the isolated product.c Temperature: 60 °C, time: 3 h.d Temperature: 100 °C, time: 3 h.
1	I	2	2	94
2	I	1	2	72
3	I	3	2	95
4	Br^c	2	3	90
5	Cl^d	2	3	86

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With a preliminary idea of the limitations of the protocol, we chose the coupling of chlorobenzene and phenylacetylene to further optimize our catalytic system. Various common organic solvents like DMF, DMSO, THF, 1,4-dioxane and toluene were also screened, but they were not as effective as water (Table 2, entries 2–6) and also produced a substantial amount of the undesired homo-coupled product. Utilizing water as the solvent, we next examined the effect of the base in the model coupling of phenylacetylene and chlorobenzene.

Table 2 Optimization of the reaction parameters^a

Entry	Catalyst	Solvent	Base	Yield^b (%)
a Reaction conditions (unless otherwise specified): 1 (2 mmol), 2 (2 mmol), catalyst (2 mg), TBAB (20 mg), solvent (10 mL), base (2 mmol), temperature: 100 °C, time: 3 h.b Yield of the isolated product.c PVP stabilized Pd(0) nanoparticles.
1	TzPdNPs	H2O	K2CO3	92
2	TzPdNPs	DMF	K2CO3	10
3	TzPdNPs	DMSO	K2CO3	15
4	TzPdNPs	THF^c	K2CO3	5
5	TzPdNPs	Dioxane	K2CO3	7
6	TzPdNPs	Toluene	K2CO3	12
7	TzPdNPs	H2O	EtNH2	5
8	TzPdNPs	H2O	Et2NH	12
9	TzPdNPs	H2O	Et3N	20
10	TzPdNPs	H2O	Cs2CO3	82
11	PdCl2	H2O	K2CO3	Trace
12	Pd(PPh3)2Cl2	H2O	K2CO3	Trace
13	Pd(0) NPs^c	H2O	K2CO3	11

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Several organic bases ranging from primary to tertiary amines afforded poor yields (Table 2, entries 7–9) with a considerable quantity of homo-coupled products. On the other hand, inorganic bases like K₂CO₃ or Cs₂CO₃ resulted in good yields (Table 2, entries 1 and 10). We chose K₂CO₃ as it is a low cost material and also as the product yield is relatively higher. Then we screened different Pd-catalysts like PdCl₂, Pd(PPh₃)₂Cl₂ and PVP stabilized Pd(0) nanoparticles.¹² However, the reaction did not proceed at all in the presence of PdCl₂ and Pd(PPh₃)₂Cl₂ (Table 2, entries 11 and 12). The PVP stabilized Pd(0) (for PXRD, see Fig. S3†) nanoparticles furnished very poor yields (Table 2, entry 13).

With the optimized conditions in hand, at first a variety of aryl chlorides were coupled with aryl alkynes (Scheme 1).

Scheme 1 Sonogashira reactions of aryl chlorides and aryl acetylenes catalyzed by TzPdNPs. Reaction conditions: (1–5) aryl chloride (2 mmol), aryl acetylene (2 mmol), catalyst (2 mg), TBAB (20 mg), water (10 mL), temperature: 100 °C, time: 3 h; (6) aryl chloride (2 mmol), aryl acetylenes (4 mmol). The isolated yields are shown.

Phenyl acetylene was coupled with a series of neutral (Scheme 1, 1, 6), electron-rich (Scheme 1, 2, 3), electron-poor (Scheme 1, 4) and heterocyclic chlorides (Scheme 1, 5), in yields ranging from 62% to 95%. With respect to the aryl chlorides, both the electron-neutral and electron-poor aryl chlorides reacted with phenyl acetylene to afford the products in excellent yields. More remarkable was that even the extremely electron-rich aryl chloride 4-chloroanisole (Scheme 1, 2) coupled efficiently with alkynes in the presence of this catalyst. When 1,4-dicholorobenzene was reacted with phenyl acetylene, 1,4-bis(phenylethynyl)benzene (Scheme 1, 6) was obtained almost exclusively irrespective of the ratio of the reactants. Application of trimethylsilyl acetylene under the same conditions predominantly affords the corresponding diaryl acetylenes. These results indicate that the present catalyst system also exhibited high catalytic activity to catalyze the cross-coupling reaction of aryl chlorides with 1-aryl-2-(trimethylsilyl) acetylene via activation of the C–Si bond at high temperature.¹³

In further experiments to expand the scope of this method, several heterocyclic iodo compounds were coupled with trimethylsilyl acetylene to afford the corresponding 1-aryl-2-(trimethylsilyl) acetylenes (Scheme 2, 1–7) at ambient temperature in aqueous medium. The C–Si bonds in the 1-aryl-2-(trimethylsilyl) acetylenes can be easily hydrolyzed in the presence of KOH in aqueous medium at ambient temperature to produce pyridine, pyrazine, quinoline and quinoxaline based terminal alkynes (Scheme 3, 1–8) in one pot. Pyridine, pyrazine, quinoline, quinoxaline and their derivatives have been widely used as functional building blocks in the fabrication of the π-conjugated host materials for organic light-emitting diodes (OLEDs),¹⁴ saccharide recognition,¹⁵ nonlinear optical materials,¹⁶ solar cells¹⁷ and columnar mesophases¹⁸ due to their specific optical and electrochemical properties.

Scheme 2 Sonogashira reactions of heterocyclic iodides and trimethylsilyl acetylene catalyzed by TzPdNPs. Reaction conditions for Sonogashira coupling: heterocyclic iodide (2 mmol), trimethylsilyl acetylene (2 mmol), catalyst (2 mg), TBAB (20 mg), water (10 mL), room temperature, time: 2 h. The isolated yields are shown.

Scheme 3 One pot synthesis of pyridine, pyrazine, quinoline and quinoxaline based terminal alkynes in the presence of KF. Reaction conditions for Sonogashira coupling: heterocyclic iodide (2 mmol), trimethylsilyl acetylene (2 mmol), catalyst (2 mg), TBAB (20 mg), water (10 mL), room temperature, time: 2 h. Reaction conditions for hydrolysis: 1-aryl-2-(trimethylsilyl) acetylenes (2 mmol), KOH (1.0 mmol), water (10 mL), room temperature, time: 1 h. The isolated yields are shown.

A plausible mechanism for the reaction is illustrated in Scheme 4, based on the classical description of the Sonogashira reaction.¹⁹ The catalytic cycle goes through Pd⁰/Pd^II/Pd⁰ oxidative addition/transmetalation/reductive elimination processes. Initially oxidative addition of the organohalide R–X to the TzPdNPs gives rise to the intermediate I. During the formation of the intermediate I, capping tetrazine (Tz) molecules act as ligands for Pd(II). The subsequent steps are the attachment of the alkyne to the complex I, followed by deprotonation which results in the cis-configured complex (III). Then the acetylenic derivative is formed through reductive elimination, and the active, low oxidation state palladium catalyst is regenerated.

Scheme 4 Proposed mechanism for TzPdNP catalysed Sonogashira reaction.

Conclusion

In summary we have developed a 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (pytz) capped Pd(0) nanoparticle catalysed efficient procedure for the Sonogashira cross coupling reaction of aryl chlorides with aryl acetylenes in aqueous medium under copper free conditions. Another advantage of the protocol is that the reaction operates at mild conditions for aryl iodides. This protocol is also suitable for the synthesis of terminal alkynes from the reaction of aryl iodides with trimethylsilyl acetylene. In addition, an inert atmosphere is not required to carry out the reaction, offering a simple methodology for the Sonogashira reaction.

Acknowledgements

S. D. and S. S. are indebted to CSIR, India for their Senior Research Fellowship (SRF) [08/003(0072)/2010-EMR-I] and [08/003(0083)/2011-EMR-1], respectively. P. B. acknowledges CSIR-India for the Project (Sanction letter no. 01(2459)/11/EMR-II dated 16/05/2011). The authors also acknowledge the Sophisticated Analytical Instruments Facility (SAIF) at North Eastern Hill University (SAIF-NEHU) for ¹H NMR and TEM analysis.

References

1. (a) U. H. F. Bunz, Chem. Rev., 2000, 100, 1605; (b) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed., 2005, 44, 4442; (c) T. J. J. Müller and D. M. D’Souza, Pure Appl. Chem., 2008, 80, 609; (d) M. S. Shiedel, C. A. Briehn and P. J. Baüerle, Organomet. Chem., 2002, 653, 200; (e) C. Hortholary and C. Coudret, J. Org. Chem., 2003, 68, 2167; (f) C. Torborg and M. Beller, Adv. Synth. Catal., 2009, 351, 3027; (g) R. Chinchilla and C. Najera, Chem. Rev., 2007, 107, 874; (h) Z. Novák, A. Szabó, J. Répási and A. Kotschy, J. Org. Chem., 2003, 68, 3327.
2. (a) H. S. Nalwa and S. Miyata, Nonlinear Optics of Organic Molecules and Polymers, CRC Press, Boca Raton, FL, 1997; (b) C.-H. Lee and T. Yamamoto, Tetrahedron Lett., 2001, 42, 3993; (c) N. Matsumi, K. Naka and Y. Chujo, J. Am. Chem. Soc., 1998, 120, 5112; (d) G. Wegner and K. Müllen, Electronic Materials, The Oligomer Approach, Wiley-VCH, Weinheim, 1998; (e) R. E. Martin and F. Diederich, Angew. Chem., Int. Ed., 1999, 38, 1350; (f) M. Inouye, K. Takahashi and H. Nakazumi, J. Am. Chem. Soc., 1999, 121, 341–345.
3. (a) J. Suffert and R. Ziessel, Tetrahedron Lett., 1991, 32, 757; (b) S. H. Chanteau and J. M. Tour, Tetrahedron Lett., 2001, 42, 3057.
4. (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett., 1975, 16, 4467; (b) K. Takahashi, Y. Kuroyama, K. Sonogashira and N. Hagihara, Synthesis, 1980, 627; (c) J. A. Marsden and M. M. Haley, in Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijre and F. Diederich, Wiley-VCH, Weinheim, Germany, 2nd edn, 2004, pp. 317–394; (d) K. Sonogashira, in Handbook of Organopalladium Chemistry for Organic Synthesis, ed. E.-I. Negishi, John Wiley & Sons, Inc., Hoboken, N. J., 2002, vol. 1, pp. 493–529.
5. J. Liu, X. Peng, W. Sun, Y. Zhao and C. Xia, Org. Lett., 2008, 18, 3933.
6. (a) A. S. Hay, J. Org. Chem., 1962, 27, 3320; (b) C. Glaser, Ann. Chem. Pharm., 1870, 154, 137; (c) C. Glaser, Ber. Dtsch. Chem. Ges., 1869, 2, 422.
7. (a) A. Molnar, Chem. Rev., 2011, 111, 2251; (b) H. Doucet and J.-C. Hierso, Angew. Chem., Int. Ed., 2007, 46, 834; (c) R. L. Duncan and J. Macquarrie, Org. Biomol. Chem., 2009, 7, 1627; (d) A. Komaromi and Z. Novak, Chem. Commun., 2008, 4968; (e) K. Sonogashira, J. Organomet. Chem., 2002, 653, 46; (f) A. L. K. Shi Shun and R. R. Tykwinski, Angew. Chem., Int. Ed., 2006, 45, 1034; (g) V. Farina, Adv. Synth. Catal., 2004, 346, 1553.
8. (a) C. Torborg, J. Huang, T. Schulz, B. Schäffner, A. Zapf, A. Spannenberg, A. Börner and M. Beller, Chem.–Eur. J., 2009, 15, 1329; (b) L. Yang, P. Guan, P. He, Q. Chen, C. Cao, Y. Peng, Z. Shi, G. Pang and Y. Shi, Dalton Trans., 2012, 41, 5020; (c) V. P. W. Böhm and W. A. Herrmann, Eur. J. Org. Chem., 2000, 3679; (d) X. Pu, H. Li and T. J. J. Colacot, Org. Chem., 2013, 78, 568; (e) C. Yi and R. Hua, J. Org. Chem., 2006, 71, 2535; (f) M. K. Samantaray, M. M. Shaikh and P. Ghosh, J. Organomet. Chem., 2009, 694, 3477; (g) B. H. Lipshutz, D. W. Chung and B. Rich, Org. Lett., 2008, 10, 3793; (h) A. Soheili, J. Albaneze-Walker, J. A. Murry, P. G. Dormer and D. L. Hughes, Org. Lett., 2003, 5, 4191; (i) Y. Ma, C. Song, W. Jiang, Q. Wu, Y. Wang, X. Liu and M. B. Andrus, Org. Lett., 2003, 5, 3317; (j) L. Yang, Y. Li, Q. Chen, Y. Du, C. Cao, Y. Shi and G. Pang, Tetrahedron, 2013, 69, 5178; (k) A. Gogoi, A. Dewana and U. Bora, RSC Adv., 2015, 5, 16; (l) S. Urgaonkar and J. G. Verkade, J. Org. Chem., 2004, 69, 5428.
9. (a) M.-J. Jin and D.-H. Lee, Angew. Chem., Int. Ed., 2010, 6, 1137; (b) H. Huang, H. Liu, H. Jiang and K. Chen, J. Org. Chem., 2008, 15, 6037; (c) D. Gelman and S. L. Buchwald, Angew. Chem., Int. Ed., 2003, 42, 5993; (d) M. R. Eberhard, Z. H. Wang and C. M. Jensen, Chem. Commun., 2002, 8, 818; (e) A. Köllhofer, T. Pullmann and H. Plenio, Angew. Chem., Int. Ed., 2003, 42, 1056; (f) H. Remmele, A. Köllhofer and H. Plenio, Organometallics, 2003, 22, 4098; (g) C. A. Fleckenstein and H. Plenio, Organometallics, 2007, 26, 2758; (h) C. Y. Yi and R. M. Hua, J. Org. Chem., 2006, 71, 2535; (i) Y. Liang, Y.-X. Xie and J.-H. Li, J. Org. Chem., 2006, 71, 379; (j) S. Protti, M. Fagnoni and A. Albini, Angew. Chem., Int. Ed., 2005, 44, 5675; (k) K. Heuzé, D. Méry, D. Gauss, J.-C. Blais and D. Astruc, Chem.–Eur. J., 2004, 10, 3936; (l) B. M. Choudary, S. Madhi, N. S. Chowdari, M. L. Kantam and B. Sreedhar, J. Am. Chem. Soc., 2002, 124, 14127; (m) W.-B. Yi, C. Cai and X. Wang, Eur. J. Org. Chem., 2007, 3445.
10. S. Mori, T. Yanase, S. Aoyagi, Y. Monguchi, T. Maegawa and H. Sajiki, Chem.–Eur. J., 2008, 14, 6994.
11. S. Samanta, S. Das and P. Biswas, Sens. Actuators, B, 2014, 202, 23.
12. Y. Li, E. Boone and M. A. El-Sayed, Langmuir, 2002, 18, 4921.
13. (a) U. S. Sorense and E. Pombo-Villar, Tetrahedron, 2005, 61, 2697; (b) C. Yi and R. Hua, J. Org. Chem., 2006, 71, 2535.
14. (a) H. Sasabe and J. Kido, Chem. Mater., 2011, 23, 621; (b) S.-J. Su, H. Sasabe, T. Takeda and J. Kido, Chem. Mater., 2008, 20, 1691; (c) P. K. Koech, E. Polikarpov, J. E. Rainbolt, L. Cosimbescu, J. S. Swensen, A. L. V. Ruden and A. B. Padmaperuma, Org. Lett., 2010, 12, 5534; (d) S. V. Rocha and N. S. Finney, Org. Lett., 2010, 12, 2598; (e) C. Huang, C.-G. Zhen, S. P. Su, K. P. Loh and Z.-K. Chen, Org. Lett., 2005, 7, 391; (f) T. Lifka, A. Oehlhof and H. Meier, J. Heterocycl. Chem., 2008, 45, 935.
15. H. Abe, H. Machiguchi, S. Matsumoto and M. Inouye, J. Org. Chem., 2008, 73, 4650.
16. (a) Y.-X. Yan, X.-T. Tao, Y.-H. Sun, C.-K. Wang, G.-B. Xu, J.-X. Yang, Y. Ren, X. Zhao, Y.-Z. Wu, X.-Q. Yua and M.-H. Jiang, J. Mater. Chem., 2004, 14, 2995; (b) H. Wang, Z. Li, P. Shao, Y. Liang, H. Wang, J. Qin and Q. Gong, New J. Chem., 2005, 29, 792; (c) A. Abbotto, L. Beverina, R. Bozio, A. Facchetti, C. Ferrante, G. A. Pagani, G. Pedron and R. Signorini, Chem. Commun., 2003, 2144; (d) P. Poornesh, P. Hegde, M. Manjunatha, G. Umesh and A. Adhikari, Polym. Eng. Sci., 2009, 49, 875.
17. (a) Y. Ooyama, T. Nagano, S. Inoue, I. Imae, K. Komaguchi, J. Ohshita and Y. Harima, Chem.–Eur. J., 2011, 17, 14837; (b) Y. Ooyama, S. Inoue, T. Nagano, K. Kushimoto, J. Ohshita, I. Imae, K. Komaguchi and Y. Harima, Angew. Chem., Int. Ed., 2011, 50, 7429; (c) Y. Ooyama, S. Inoue, R. Asada, G. Ito, K. Kushimoto, K. Komaguchi, I. Imae and Y. Harima, Eur. J. Org. Chem., 2010, 92.
18. (a) A.-J. Attias, C. Cavalli, B. Donnio, D. Guillon, P. Hapiot and J. Malthete, Chem. Mater., 2002, 14, 375; (b) A.-J. Attias, C. Cavalli, B. Donnio, D. Guillon, P. Hapiot and J. Malthete, Mol. Cryst. Liq. Cryst., 2004, 415, 169.
19. M. García-Melchor, M. C. Pacheco, C. Nájera, A. Lledós and G. Ujaque, ACS Catal., 2012, 2, 135 and references therein.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, ¹H NMR data and spectra. See DOI: 10.1039/c5ra13252e

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