Heterogeneous palladium-catalysed Catellani reaction in biomass-derived γ-valerolactone

Abstract

Herein, we report the unprecedented use of a heterogeneous palladium catalyst for the step-economical Catellani reaction. The substrate scope with encapsulated Pd(OAc)₂ (Pd EnCat™ 30) or Pd/Al₂O₃ proved to be broad, while the renewable biomass-derived γ-valerolactone (GVL) was identified as an effective reaction medium. Mechanistic studies highlighted the possible heterogeneous nature of the Pd/Al₂O₃ catalyst, while showing that the reaction performed in the presence of Pd EnCat™ 30 is most likely catalysed by leached homogeneous palladium species. The heterogeneous Pd/Al₂O₃ catalyst can be easily recovered at the end of the reaction and efficiently reused in consecutive reaction runs.

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Introduction

In recent years, the direct C–H functionalization of arenes has emerged as a particularly attractive alternative to classical cross-coupling approaches, allowing for late-stage diversifications without the need of prefunctionalization steps.¹ Typically, directing groups are required for achieving site-selectivity in intermolecular transformations, mostly occurring at the ortho-position. The Catellani reaction represents an alternative strategy in which the palladium-catalysed C–H ortho-functionalization of aryl iodides is mediated by norbornene, which allows for subsequent ipso-substitution. In the original report by Catellani and coworkers the dialkylation of the aryl iodide in the two ortho-positions was followed by an ipso-vinylation through a Mizoroki–Heck-type process.² Several modifications to this reaction have subsequently been devised, allowing for different functionalizations to occur both on the ortho- as well as on the ipso-position. The most synthetically useful approaches towards the ipso-functionalization, apart from the Mizoroki–Heck-type alkenylation, include arylations through a Suzuki–Miyaura-type reaction, the alkynylation through a Sonogashira-type process and the hydrogenolysis of the aryl-palladium intermediate.³

Thus far, the vast majority of C–H functionalization reactions have relied on homogeneous transition metal catalysis. Only recently the attention has shifted to the use of versatile heterogeneous catalysts for C–H activation chemistry.⁴ However, to the best of our knowledge, examples of heterogeneous metal-catalysed Catellani reactions have as of yet proven elusive. It is particularly noteworthy that the use of heterogeneous catalysts offers great advantages as compared to homogeneous catalysts, especially in terms of recoverability of the catalysts, ease of purification and minimization of metal contamination.

Thus far, the Catellani reaction has largely been conducted in polar aprotic solvents, such as DMF, DMA or acetonitrile. These solvents, particularly DMF and DMA, present major issues related to their toxicity, and their substitution is highly desirable, especially for large-scale applications.⁵ Acetonitrile is typically considered the “greenest” option among polar aprotic solvents.⁶ However, this actually represents a rather poor alternative due to its volatility and toxicity.⁷

γ-Valerolactone (GVL), is a renewable biomass-derived chemical featuring high polarity, high boiling point, and good stability towards bases and acids. Only few applications employing GVL as reaction media have been disclosed.⁸ Recently, we have reported for the first time that GVL can be used as an environmentally-benign alternative to common toxic polar aprotic solvents.^8i–k In some cases we have also observed that the use of GVL in combination with a heterogeneous catalyst lead to lower product contamination by the metal, compared to the same reaction performed in common polar aprotic solvents.^8i–k This is particularly relevant since metal contamination represent a major issue in the synthesis of pharmaceutical compounds.^9,10

In this article we report the first example of a Catellani reaction catalysed by a heterogeneous palladium species. The reaction is performed in a sustainable reaction media (GVL) and the optimal catalyst can be easily recovered and reused for consecutive reaction runs. Experimental mechanistic investigations were also conducted in order to clarify the nature of the catalytically active species.

Results and discussion

At the outset of our studies, we tested representative heterogeneous palladium catalysts in the Catellani reaction with methyl 2-iodobenzoate (1a) and methyl acrylate (2a), using K₂CO₃ as the base and GVL as the medium (Table 1).¹¹ Commercially available encapsulated Pd(OAc)₂,¹² either with or without PPh₃ (Pd EnCat™ 30 and Pd EnCat™ TPP30, respectively) performed with high efficacy, affording the expected product 3a in more than 90% yield (Table 1, entries 1 and 2). The simple Pd/C catalyst gave comparable results, with an isolated yield of 94% (Table 1, entry 3). The addition of 2.5 equivalents of PPh₃, either soluble or immobilized on a polystyrene support, led to a slight decrease in catalytic activity, with the product being obtained in 82–87% yield (Table 1, entries 4 and 5). Also commercially available Pd/Al₂O₃ gave excellent results, providing the expected product in 95% yield (Table 1, entry 6). DMF, NMP, and MeCN were also tested as representative aprotic reaction media (Table 1, entries 7–9). While in the case of DMF satisfactory results were obtained, the use of NMP and MeCN led to poor conversion of the substrate 1a.

Table 1 Heterogeneous catalysts and reaction media optimization^a

Entry	Palladium catalyst	Reaction medium	Yield^b (%)
a Reaction conditions: 1a (0.330 mmol), 2a (0.195 mmol), norbornene (0.127 mmol), K2CO3 (0.340 mmol), [Pd] (5 mol%), reaction medium (3.75 mL). b Isolated yields. c PPh3 (15 mol%).
1	Pd EnCat™ 30	GVL	93
2	Pd EnCat™ TPP30	GVL	92
3	Pd/C	GVL	94
4	Pd/C, TPP^c	GVL	82
5	Pd/C, PS-TPP^c	GVL	87
6	Pd/Al2O3	GVL	95
7	Pd/Al2O3	DMF	82
8	Pd/Al2O3	NMP	58
9	Pd/Al2O3	MeCN	20

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The effect of different bases – both organic and inorganic – on the reaction was also investigated, with K₂CO₃ giving the best results (see ESI†).

Next, we explored the scope of the reaction between methyl 2-iodobenzoate (1a) and several olefins 2. We chose to conduct all reactions with Pd EnCat™ 30 as well as Pd/Al₂O₃, in order to investigate possible differences in reactivity between these two rather diverse heterogeneous catalysts. Generally, both catalysts performed well, providing the expected products in moderate to very good yields. In several cases Pd EnCat™ 30 gave slightly better results in terms of yields than Pd/Al₂O₃. α,β-Unsaturated esters and ketones (2a–c) were efficiently converted to the product by either of the two catalytic systems in yields ranging from 60% to 95% (Tables 2 and 3, entries 1–3). Acrylonitrile (2d) furnished good results in the reaction catalysed by Pd EnCat™ 30 (Table 2, entry 4), while much lower yield was obtained using Pd/Al₂O₃, which also needed longer reaction times (Table 3, entry 4).

Table 2 Scope of the Catellani reaction using Pd EnCat™ 30 as catalyst^a

Entry	2	R^1	R^2	Time	Yield^b (%)
a Reaction conditions: 1a (0.330 mmol), 2a (0.195 mmol), norbornene (0.127 mmol), K2CO3 (0.340 mmol), [Pd] (5 mol%,), GVL (3.75 mL). b Isolated yields. c Product deriving from the ether hydrolysis and subsequent keto/enol tautomerization. d 1.6 : 1 mixture of the acetylated product and the phenol from ester hydrolysis, see ESI for details.
1	2a	CO2Me	H	24 h	93 (3a)
2	2b	CO2nBu	H	24 h	73 (3b)
3	2c	COMe	H	24 h	77 (3c)
4	2d	CN	H	24 h	68 (3d)
5	2e	OnBu	H	—	—
6	2f	OEt	H	24 h	48^c (3f)
7	2g	Ph	H	24 h	63 (3g)
8	2h	p-AcO-C6H4	H	24 h	79^d (3h + 3′h)
9	2i	p-Cl-C6H4	H	24 h	68 (3i)
10	2j	CO2Me	Me	2 d	50 (3j : 4j 1 : 1.9)
11	2k	CHO	Me	24 h	68 (3k : 4k 1 : 1.6)

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Table 3 Scope of the Catellani reaction using Pd/Al₂O₃ as catalyst^a

Entry	2	R^1	R^2	Time	Yield^b (%)
a Reaction conditions: 1a (0.330 mmol), 2a (0.195 mmol), norbornene (0.127 mmol), K2CO3 (0.340 mmol), [Pd] (5 mol%,), GVL (3.75 mL). b Isolated yields. c As a 1 : 4 mixture of the expected product and the phenol deriving from the ester hydrolysis.
1	2a	CO2Me	H	24 h	95 (3a)
2	2b	CO2nBu	H	3 d	60 (3b)
3	2c	COMe	H	24 h	68 (3c)
4	2d	CN	H	3 d	32 (3d)
5	2e	OnBu	H	2 d	40 (3e)
6	2f	OEt	H	—	—
7	2g	Ph	H	24 h	74 (3g)
8	2h	p-AcO-C6H4	H	24 h	54^c (3h + 3′h)
9	2i	p-Cl-C6H4	H	24 h	86 (3i)
10	2j	CO2Me	Me	7 d	41 (3j : 4j 1 : 3.2)
11	2k	CHO	Me	3 d	57 (3k : 4k 1 : 1.5)

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Vinyl alkyl ethers (2e–f) proved to be more challenging, and the efficacy was strongly dependent on the nature of the catalyst (Tables 2 and 3, entries 5 and 6).

Moreover, the reaction conducted on vinyl ethyl ether (2f) with Pd EnCat™ 30 delivered the formyl-substituted product through a Domino Catellani reaction along with hydrolysis and keto/enol tautomerization. Styrene (2g) and para-substituted styrenes (2h–i) reacted efficiently with both catalysts (Tables 2 and 3, entries 7–9).

Interestingly, in both the reactions performed with the two catalysts, the chlorine functionality was well tolerated (Tables 2 and 3, entry 9), which should prove instrumental for further late-stage diversifications.

1,1-Disubstituted olefins were also subjected to the optimized reaction conditions with either Pd EnCat™ 30 or Pd/Al₂O₃ as the catalysts (Tables 2 and 3, entries 10 and 11). Their reactivity was in line with that observed for the monosubstituted olefins, with yields ranging from 41% to 68%. However, due to the presence of the methyl group on the substrate, the β-elimination step of the final Mizoroki–Heck-type reaction could occur in two positions, thus generating two isomeric products (3 and 4). As to the substitution pattern on the aryl iodides 1, the optimized palladium catalyst also enabled the synthesis of products 3l–3o (Scheme 1).

Scheme 1 Further examples of Pd/Al₂O₃ catalysed Catellani reactions.

The coupling of the Catellani reaction with a terminal hydrogenolysis step provides step-economical access to meta-difunctionalized aromatic species.^3,13 We tested the applicability of this strategy under the optimized reaction conditions with Pd/Al₂O₃ as the catalyst and benzyl alcohol as hydride donor (Scheme 2). The reaction proceeded efficiently, affording the expected coupling product 5 in high yield.

Scheme 2 Catellani reaction with terminal hydrogenolysis.

A major issue associated with transition metal catalysis, and in particular with palladium chemistry, is the nature of the catalytic active species. Indeed, it frequently was noted that operationally heterogeneous reactions actually occur through the catalysis of soluble leached metal species or, vice versa, that operationally homogeneous reactions were catalysed by in situ formed insoluble metal particles.¹⁴ This problem is also of key relevance for C–H functionalization reactions.⁴ It is worth considering that the actual nature of the catalyst is not only important for mechanistic reasons, but also has practical implications, since it finally controls the possibility to reuse the recovered catalyst and the metal contamination of the products. Unfortunately, assessing the nature of the catalytic active species (homogeneous vs. heterogeneous) is not a simple task. Several experiments have been proposed but none of them is able to give conclusive evidence about the mechanism. Instead, it is necessary to rely on multiple experiments in order to possibly obtain sufficient support to one of the mechanistic scenarios.¹⁴

For these reasons, we decided to investigate the nature of the catalytically active species through various approaches, for both the reactions catalysed by Pd EnCat™ 30 and by Pd/Al₂O₃. First, we performed a hot-filtration test by removing the solid catalyst one hour after the beginning of the representative reaction between 1a and 2a, and allowing the filtrate to stir for 3 days at 105 °C. Interestingly, the two catalysts led to quite different results. Thus, while Pd/Al₂O₃ gave a very low conversion (7%), Pd EnCat™ 30 furnished 3a in 37% conversion. Second, for the same reaction we performed a mercury-poisoning test for both catalysts. Again, the two catalysts behaved differently. In fact, while the addition of Hg(0) completely hampered the catalytic activity of Pd/Al₂O₃ with only 4% conversion after 20 hours, the reaction with Pd EnCat™ 30 gave 46% conversion under otherwise identical reaction conditions (see ESI†). These results suggest that leached palladium species might play a key role in the reaction catalysed by Pd EnCat™ 30, but not in the reaction with Pd/Al₂O₃.¹⁵

Third, we measured the amount of palladium leached into the crude product by inductively coupled plasma optical emission spectrometry (ICP-OES), for both catalysts, before and after aqueous work-up (Table 4). The amount of palladium leached from Pd/Al₂O₃ was very low, even before aqueous work-up (∼2 ppm). However, the extent of metal leaching from Pd EnCat™ 30 is relatively high (52.4 and 10.5 ppm before and after aqueous work-up, respectively), and in line with previous findings¹⁵ and with our hot-filtration and Hg-poisoning tests.

Table 4 Palladium leaching measured by ICP-OES analysis at the end of the reaction between 1a and 2a in GVL

Catalyst	Palladium leaching (ppm)
Pd EnCat™ 30	no work-up	52.4
	aq. work-up	10.5
Pd/Al2O3	no work-up	2.2
	aq. work-up	0.5

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Overall, these results suggest that the two tested catalysts exert their catalytic activity in different ways. While Pd EnCat™ 30 is proposed to catalyse the reaction by releasing homogeneous soluble palladium species, the C–H activation catalysed by Pd/Al₂O₃ is either genuinely heterogeneous or may proceed through a “release and catch” mechanism.¹⁶

From sustainability and chemical efficiency point of views, it is mostly important that the amount of palladium leached into the product is very low and that the solid catalyst can be efficiently reused. Therefore we tested the recyclability of Pd/Al₂O₃ in the reaction between 1a and 2a in GVL, by recovering the catalyst by simple filtration. The catalyst fully retained its activity for at least three reaction runs, constantly giving full conversion to the products. Thus, the reaction of substrates 1a and 2a was repeated for four consecutive runs giving the desired product 3a constantly in 93–95% yield (Fig. 1).

Fig. 1 Reuse of Pd/Al₂O₃ in the reaction of 1a and 2a.

Conclusions

In conclusion, we have developed the first Catellani reaction catalysed by a solid palladium catalyst. The reaction proceeded efficiently on a variety of alkenes in the renewable biomass-derived medium GVL. The process could also be merged with a terminal hydrogenolysis, which gave step-economical access to valuable meta-difunctionalized¹⁷ arenes. The nature of the catalytically active species was investigated and provided support for the versatile Pd/Al₂O₃ catalyst to operate in a heterogeneous fashion. Importantly, the catalyst could be efficiently recovered and reused, featuring a very low metal leaching. Studies on the use of other economically attractive organic electrophiles are currently ongoing in our laboratories and will be reported in due course.

Experimental

Typical procedure for the Catellani reaction

To a 4 mL vial containing the palladium catalyst (0.00825 mmol, 5 mol%), the base (0.340 mmol), and 2-norbornene (12 mg, 0.127 mmol) was added a GVL solution (3.75 mL) of the aryl iodide 1 (0.33 mmol) and the terminal olefin 2 (0.195 mmol). The resulting mixture was stirred at 105 °C.

The solids were then separated from the solution by vacuum filtration and rinsed with cyclopentyl methyl ether. The organic layer was washed with water and dried over anhydrous Na₂SO₄. The products were isolated by flash column chromatography using a 4 : 1 mixture of petroleum ether and ethyl acetate as the eluent.

Procedure for catalyst recovery and recycling

After stirring at 105 °C for 24 h, the reaction mixture was centrifuged and the solvent was decanted. The catalyst was washed, first with water (0.2 mL) and GVL (3.0 mL), then with GVL (3.8 mL). New substrates (1a and 2a), reagents and solvent were added and left for 24 h at 105 °C for the next run. In four consecutive reaction runs Pd/Al₂O₃ consistently led to full conversion to the expected product in 24 h.

Acknowledgements

Generous support by the European Research Council under the European Community's Seventh Framework Program (FP7 2007-2013)/ERC Grant agreement no. 307535 is acknowledged. We gratefully acknowledge the Università degli Studi di Perugia and the “Fondazione Cassa di Risparmio di Terni e Narni” for financial support. S. S. gratefully acknowledges the MIUR for financial support through the fellowship PGR123GHQY, funded within “Programma Giovani Ricercatori, Rita Levi Montalcini”. This work was also supported by the REU program of the National Science Foundation under award number DMR-1262908. D. R. was supported by EC 7th Framework Program project REGPOT-CT-2013-316149 Innovabalt.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, characterization data, and copies of NMR spectra of known (3a and 5) and new compounds (3b–3o, 3′h, 4j, 4k). See DOI: 10.1039/c6gc01393g

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