Unexpected and powerful effect of chlorobenzene in direct palladium-catalyzed cascade Sonogashira–hydroarylation reaction

Abstract

A ubiquitous accelerating effect of chlorobenzene (PhCl) was observed unexpectedly in the Pd-catalyzed cascade Sonogashira–hydroarylation reaction. This new type of carbon–carbon bond forming cross-coupling reaction was efficiently catalysed by Pd₂(dba)₃ in the presence of a catalytic amount of PhCl, which provides a facile and direct approach to the synthesis of trisubstituted olefins.

---

Palladium-catalyzed cross-coupling reactions are one of the most important transformations in organic synthesis.¹ With the development of Pd catalysis, various carbon–carbon bond forming reactions have been developed successfully except the classic Suzuki reaction, Sonogashira reaction, and others. For example, the palladium-catalyzed hydroarylation of diarylacetylenes with aryl halides,² Heck diarylation of arylvinylenes,³ and double Suzuki–Miyaura couplings of 1,1′-dihalo-2-aryl-ethenes⁴ have been applied to synthesize trisubstituted olefins. Recently, a sequential Sonogashira coupling and hydroarylation reaction provided a concise two-step synthesis of triarylethylenes from simple starting materials, aryl iodides and terminal alkynes.⁵ Notably, triarylethene subunits are valuable building blocks in organic synthesis for various functional compounds.⁶ As chemotherapeutic agents, tamoxifen and clomiphene have been applied for the treatment of breast cancer and infertility, respectively.⁷ Because of their unique extended π-conjugated system, triarylethene compounds are also of great interest as molecular photomaterials, such as 4,4′-bis(2,2-diphenylvinyl)-1,1′-biphenyl (DPVBi), 4′,4′′-(2-phenyl-ethene-1,1-diyl)dibiphenyl-4-amine (TriPEDA), aggregation induced emission (AIE) materials, and conjugated dendrimers.⁸

Inspired by the previous works in the catalytic synthesis of trisubstituted olefins, herein, we report an unexpected finding that the reactivity of the Pd catalyst was significantly accelerated by the chlorobenzene and tuned by varying the Pd loading. The phosphine-free Pd catalyst system featured a catalytic amount of chlorobenzene as the additive for the direct preparation of triarylethenes from aryl iodides and aryl acetylenes. It should be noted that, although phosphine ligands play crucial roles in classical Pd-catalyzed organic transformations, phosphine-free and direct palladium-catalyzed cross-coupling reactions are still highly desirable in practical organic synthesis.

In the preliminary experiment, chlorobenzene significantly changed the products distribution of the one-pot reaction of iodobenzene and a three-fold excess of phenylacetylene. To determine whether PhCl was responsible for the selective formation of triphenylethylene 4, three parallel experiments were conducted in ethanol with K₂CO₃ as the base (Scheme 1). In experiment 1a, the Pd(OAc)₂/PPh₃ system catalyzed the cross-coupling of iodobenzene with phenylacetylene to afford the cross-coupling product 3 in 79% yield and the sequential hydroarylation product 4 in only 8% yield. Interestingly, the reaction course significantly changed when the phosphine ligand was not used. Experiment 1b afforded 3 in 10% yield, whereas the yield of 4 increased to 28%. The results indicate that PPh₃ accelerated the Pd-catalyzed Sonogashira coupling, but inhibited the Pd-catalyzed hydroarylation.⁹ To our delight, in the presence of 10 mol% PhCl, experiment 1c afforded 4 in 45% isolated yield. These experiments clearly demonstrated that PhCl can accelerate not only the Sonogashira coupling reaction but also the hydroarylation reaction.

Scheme 1 The preliminary results for the Pd(OAc)₂-catalyzed cascade Sonogashira–hydroarylation reactions of PhCCH and PhI. Reaction conditions of experiments 1a/1b/1c: phenylacetylene, 0.5 mmol; iodobenzene, 1.5 mmol; K₂CO₃, 2 equiv.; additive, 10 mol%; 5 mL ethanol at 70 °C for 10 h.

To optimize the reaction conditions, iodobenzene and phenylacetylene were selected as the substrates. The tandem reactions were conducted in the presence of PhX (X = F, Cl, and Br) under suitable reaction conditions (Table 1). After screening several catalyst systems, the PhCl/Pd₂(dba)₃ system was found to exhibit the best catalytic activity. In the presence of Pd₂(dba)₃ (5 mol%) and PhCl (10 mol%), the tandem reaction of 1 with 2 occurred at 70 °C, and the product was obtained in 80% yield (Table 1, entry 4). The reaction has the same outcome as the N-heterocyclic carbene (NHC)/Pd-catalyzed Sonogashira–hydroarylation sequential reactions. However, the reaction is mild and clean in the absence of HOOCCF₃.⁵ The course of the reaction was monitored by gas chromatography-mass spectrometry (Fig. 1 and ESI†), indicating the importance of PhCl in this reaction. PhF and PhBr also accelerated the formation of 4 but with inferior activity (65% and 62% yields, respectively; Table 1, entries 5 and 6). In the blank experiment (without PhCl), 4 was isolated in only 58% yield along with 2% unconverted diphenylacetylene 3 (Table 1, entry 7). To our surprise, the reactivity of the PhCl/Pd system is dependent on the catalyst loading, in which the use of 0.01 mol% Pd₂(dba)₃ promoted an efficient Sonogashira coupling of iodobenzene with phenylacetylene selectively, and no hydroarylation of diphenylacetylene was observed (Table 1, entry 8). Higher catalyst loading significantly accelerated the hydroarylation process. When >1 mol% catalyst was used, the hydroarylation process dominated, and 60% product was obtained using 3 mol% Pd (Table 1, entries 10 and 11). However, a further increase in the catalyst decreased the yield of 4 (Table 1, entries 12 and 13). Notably, when the amount of PhCl was decreased to 1 mol% or 5 mol%, the yield of the desired product 4 was not good (50–55%, Table 1, entries 14 and 15). It further suggested that 10 mol% of PhCl was necessary to give a significant effect on the catalytic activity of Pd₂(dba)₃.

Table 1 PhCl accelerated Pd-catalyzed cascade Sonogashira–hydroarylation reaction of PhCCH and PhI^a

Entry	Catalyst (mol%)	Additive	3 [% yield]^b	4 [% yield]^b
a Reaction conditions: phenylacetylene, 0.5 mmol; iodobenzene, 1.5 mmol; K2CO3, 2 equiv.; additive, 10 mol%; 5 mL ethanol at 70 °C for 2 h.b Isolated yield.c 12 h.d PhCl, 1 mol%.e PhCl, 5 mol%.
1	PdCl2 (5%)	PhCl	5	52
2	Pd(PPh3)2Cl2 (5%)	PhCl	1	56
3	Pd(PPh3)4 (5%)	PhCl	95	0
4	Pd2(dba)3 (5%)	PhCl	0	80
5	Pd2(dba)3 (5%)	PhF	3	65
6	Pd2(dba)3 (5%)	PhBr	7	62
7	Pd2(dba)3 (5%)	—	2	58
8	Pd2(dba)3 (0.01%)	PhCl	78^c	0
9	Pd2(dba)3 (0.1%)	PhCl	75	13
10	Pd2(dba)3 (1%)	PhCl	22	54
11	Pd2(dba)3 (3%)	PhCl	0	60
12	Pd2(dba)3 (8%)	PhCl	5	57
13	Pd2(dba)3 (10%)	PhCl	8	43
14	Pd2(dba)3 (5%)	PhCl^d	Trace	55%
15	Pd2(dba)3 (5%)	PhCl^e	Trace	50%

---

Fig. 1 The kinetic effect of PhCl on the Pd-catalyzed cascade Sonogashira–hydroarylation reaction of PhCCH and PhI.

The substrate scope and limitations of these new methods were then investigated with various aryl iodides and alkynes. For symmetrical trisubstituted olefins, product 4b with para-methoxy substituents was obtained in 72% yield, whereas the products with methyl groups at the para- (4c) and meta- (4d) positions were obtained in moderate yield. A para-Br (4e) substituent was well tolerated, offering the potential for further orthogonal functionalization.¹⁰ Unsymmetrical triarylethenes were prepared by varying the aryliodide or arylacetylene. Alkynes with strong electron-donating substituents afforded acceptable yields. The methyl groups at para- (4h and 4l) and meta- (4i, 4j, and 4k) positions resulted in lower reactivity. The ratios of the triarylethene regioisomers were determined by comparing the integration of the corresponding methyl protons.¹¹ In these reactions, gem- and trans- isomers were formed equally, indicating that the steric bulkiness of these substituents are too close for any significant regioselectivity. To further illustrate the regioselectivity of this method, the reaction of 1-hexyne with iodobenzene was investigated. To our delight, the two regioisomers could be separated by column chromatography (Fig. S9†). trans-Isomer 4m was isolated in 38% yield, whereas only a trace amount of the gem-isomer 4m (12%) was isolated, indicating that the hydroarylation of the internal alkyne intermediate preferentially occurred with a less sterically congested trans-configuration (Table 2).

Table 2 Substrate scope for the synthesis of trisubstituted olefins^a,b

a Reaction conditions: alkyne 0.5 mmol; aryl iodide 1.5 mmol; Pd₂(dba)₃ (Pd 5 mol%); K₂CO₃, 2 equiv.; chlorobenzene, 10 mol%; 5 mL EtOH at 70 °C, 12 h.b Isolated yield.c 2-Bis(4-bromophenyl)ethyne, 0.08 mmol.d Determined by ¹H NMR spectroscopy.

---

The combined PhCl/Pd catalyst systems were successfully applied for the construction of extended π-conjugated systems (Scheme 2). Starting from 1,3-diiodobenzene (5), mono- (8) and di- (7) acetylide benzenes were obtained in 22% and 58% yield using 0.1 mol% Pd and 10 mol% PhCl, respectively. The hydroarylation of 7 catalysed by 5 mol% Pd and 10 mol% PhCl afforded two triaryl conjugated structures, the trans- (9) and gem- (10) isomers, in 62% and <5% yields, respectively. 3-Alkyne biphenyl (11) was prepared in 95% yield by a Suzuki–Miyaura cross-coupling using 1 mol% Pd and 10 mol% PhCl. Next, the hydroarylation reaction of 11 afforded trans-aryl ethene (12) and the gem-isomer (13) in 57% and 13% yields, respectively. The low yield of 13 can be attributed to the steric factor during the insertion of the substituted internal alkyne intermediate into the Pd–Ar bond.

Scheme 2 The construction of extensive π-conjugated systems on the basis of a PhCl-accelerated Pd-catalyzed Sonogashira–hydroarylation reactions.

To identify the origin of the vinyl proton in the product, a deuterium labelling experiment was conducted in CD₃OH. In the ¹H NMR spectrum of the isolated triphenylethylene (Fig. S10†), the vinyl proton was exchanged with deuterium from CD₃OH, indicating that the proton may originate from the methyl group of the alcoholic solvent. Therefore, the β-H elimination of coordinated ethoxide was proposed to rationalize the formation of the Pd species, finally affording the triphenylethylene product 4 through reductive elimination. On the basis of our experimental results as well as previous reports, the effect of PhCl on the palladium-catalyzed cascade Sonogashira–hydroarylation reaction was quite interesting. Although the true role of PhCl was not clear, we suggested that the PhCl could possibly act as an electron-deficient π ligand to promote the reductive elimination step in this cascade Sonogashira–hydroarylation reaction. In other words, the role of PhCl in this palladium-catalyzed cascade Sonogashira–hydroarylation reaction might be similar to that of dibenzylideneacetone (bda). Further studies on the PhCl-assisted palladium-catalyzed cascade Sonogashira–hydroarylation reaction will be carried out and reported in the near future.

Conclusions

In summary, we have reported an unexpected PhCl-accelerated Pd-catalyzed Sonogashira–hydroarylation reaction for the direct synthesis of trisubstituted olefins. A catalytic amount of PhCl additive was found to be an efficient additive to promote the Pd-catalyzed Sonogashira–hydroarylation reaction. Thus, the combined PhCl/Pd system could be successfully applied for the synthesis of symmetrical and unsymmetrical trisubstituted olefins in moderate-to-good yield. In addition, two extensive π-conjugated systems were constructed from 1,3-diiodobenzene via the Pd-catalyzed Sonogashira coupling, sequential Suzuki–Miyaura coupling, and hydroarylation reactions with the aid of a catalytic amount of PhCl. Although the true mechanistic procedure of the PhCl-accelerated Pd-catalyzed Sonogashira–hydroarylation is not clear at present, this work provided a facile and practical approach for the synthesis of multisubstituted and conjugated olefins.

General procedure for the Pd/PhCl-catalyzed direct preparation of trisubstituted olefins

Under the protection of N₂, 5 mL EtOH was cannula-transferred into a Schlenk tube containing Pd₂(dba)₃ (0.0114 g, 0.0125 mmol) and K₂CO₃ (0.138 g, 1 mmol). Alkyne (0.5 mmol), aryl iodine (1.5 mmol), chlorobenzene (5 μL, 0.05 mmol) were added by a syringe. The reaction mixture was stirred at 70 °C for 12 h. After the reaction cooled down to room temperature, the solvent was removed under vacuum and the crude products were filtered off and purified by column chromatography on silica gel using dichloromethane/petroleum ether as the eluent. All products were identified by comparing their spectral data with those of authentic samples.

Acknowledgements

This work was supported by the 111 Project (B14041), the Innovative Research Team in University of China (IRT1070), the National Natural Science Foundation of China (21171112, 21271124, 21371112), the Fundamental Doctoral Fund of Ministry of Education of China (20120202120005), the Shaanxi Innovative Team of Key Science and Technology (2013KCT-17), the Natural Science Basic Research Plan in Shaanxi Province of China (2012JM2006).

Notes and references

1. C. M. So and F. Y. Kwong, Chem. Soc. Rev., 2011, 40, 4963–4972; A. R. Kapdi and D. Prajapati, RSC Adv., 2014, 4, 41245–41259; S. Mondala and G. Panda, RSC Adv., 2014, 4, 28317–28358; F. Sun, L. Lv, M. Huang, Z. Zhou and X. Fang, Org. Lett., 2014, 16, 5024–5027; S. Ge, S. I. Arlow, M. G. Mormino and J. F. Hartwig, J. Am. Chem. Soc., 2014, 136, 14401–14404; H. Li, Z. Zhang, X. Shangguan, S. Huang, J. Chen, Y. Zhang and J. Wang, Angew. Chem., Int. Ed., 2014, 53, 11921–11925; S. Otsuka, D. Fujino, K. Murakami, H. Yorimitsu and A. Osuka, Chem.–Eur. J., 2014, 20, 13146–13149.
2. T. Kitamura, Eur. J. Org. Chem., 2009, 2009, 1111–1125; S. Cacchi, Pure Appl. Chem., 1990, 62, 713–722; S. Cacchi, G. Fabrizi and A. Goggiamani, J. Mol. Catal. A: Chem., 2004, 214, 57–64.
3. D. Xu, C. Lu and W. Chen, Tetrahedron, 2012, 68, 1466–1474; C. L. Sun, Y. F. Gu, B. Wang and Z. J. Shi, Chem.–Eur. J., 2011, 17, 10844–10847.
4. Y. Zhu, P. Sun, H. Yang, L. Lu, H. Yan, M. Creus and J. Mao, Eur. J. Org. Chem., 2012, 2012, 4831–4837; S. Gu, H. Xu, N. Zhang and W. Chen, Chem.–Asian J., 2010, 5, 1677–1686.
5. L. Yang, Y. Li, Q. Chen, Y. Du, C. Cao, Y. Shi and G. Pang, Tetrahedron, 2013, 69, 5178–5184.
6. Z. Chi, X. Zhang, B. Xu, X. Zhou, C. Ma, Y. Zhang, S. Liu and J. Xu, Chem. Soc. Rev., 2012, 41, 3878–3896; C. Thomas and J. A. Gustafsson, Nat. Rev. Cancer, 2011, 11, 597–608; H. Chen, S. Li, Y. Yao, L. Zhou, J. Zhao, Y. Gu, K. Wang and X. Li, Bioorg. Med. Chem. Lett., 2013, 23, 4785–4789; D. Jana and B. K. Ghorai, Tetrahedron Lett., 2012, 53, 6838–6842; Y. Qiu, P. Wei, D. Q. Zhang, J. Qiao, L. Duan, Y. K. Li, Y. D. Gao and L. D. Wang, Adv. Mater., 2006, 18, 1607–1611.
7. D. A. Lee, J. L. Bedont, T. Pak, H. Wang, J. Song, A. Miranda-Angulo, V. Takiar, V. Charubhumi, F. Balordi, H. Takebayashi, S. Aja, E. Ford, G. Fishell and S. Blackshaw, Nat. Neurosci., 2012, 15, 700–702; A. Hurtado, K. A. Holmes, C. S. Ross-Innes, D. Schmidt and J. S. Carroll, Nat. Genet., 2011, 43, 27–33; G. T. Wurz, L. H. Soe and M. W. Degregorio, Maturitas, 2013, 74, 220–225; R. Gust, W. Beck, G. Jaouen and H. Schönenberger, Coord. Chem. Rev., 2009, 253, 2760–2779.
8. K. Itami, K. Tonogaki, T. Nokami, Y. Ohashi and J. Yoshida, Angew. Chem., Int. Ed., 2006, 45, 2404–2409; Y. Liu, Y. Zhang, Q. Lan, S. Liu, Z. Qin, L. Chen, C. Zhao, Z. Chi, J. Xu and J. Economy, Chem. Mater., 2012, 24, 1212–1222; R. Gomez, D. Veldman, B. M. W. Langeveld, J. L. Segura and R. A. J. Janssen, J. Mater. Chem., 2007, 17, 4274; C. Hosokawa, H. Higashi, H. Nakamura and T. Kusumoto, Appl. Phys. Lett., 1995, 67, 3853–3855.
9. G. F. Marten Ahlquist, S. Cacchi and P.-O. Norrby, J. Am. Chem. Soc., 2006, 128, 12785–12793.
10. H. Li, Z. Chi, B. Xu, X. Zhang, Z. Yang, X. Li, S. Liu, Y. Zhang and J. Xu, J. Mater. Chem., 2010, 20, 6103–6110; Z. Yang, Z. Chi, T. Yu, X. Zhang, M. Chen, B. Xu, S. Liu, Y. Zhang and J. Xu, J. Mater. Chem., 2009, 19, 5541–5546.
11. M. J. Wu, L. M. Wei, C. F. Lin, S. P. Leou and L. L. Wei, Tetrahedron, 2001, 57, 7839–7844.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13979h

---