C–H arylations of 1,2,3-triazoles by reusable heterogeneous palladium catalysts in biomass-derived γ-valerolactone

Abstract

C–H arylations were accomplished with a user-friendly heterogeneous palladium catalyst in the biomass-derived γ-valerolactone (GVL) as an environmentally-benign reaction medium. The user-friendly protocol was characterized by ample substrate scope and high functional group tolerance in the C–H arylation of 1,2,3-triazoles, and the palladium catalyst could be recycled and reused in the C–H activation process.

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Fully functionalized 1,2,3-triazoles¹ constitute key structural motifs in various applied areas, such as medicinal chemistry, bioorganic chemistry, and material sciences, among others.² The copper(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition³ (CuAAC)^4,5 has emerged as the most valuable tool for the preparation of 1,2,3-triazoles with high levels of regio control.^6,7 However, the CuAAC approach is largely⁸ limited to terminal alkynes and, hence, fails short in providing general access to fully trisubstituted triazoles. In recent years, catalyzed C–H activations have been identified as a transformative platform for the atom-⁹ and step-economical¹⁰ preparation of heterocyclic compounds.¹¹ Particularly, the nexus of CuAAC and C–H functionalization technology proved instrumental for the efficient assembly of fully decorated 1,2,3-triazoles with excellent levels of positional selectivity.¹² Hence, copper-^13,14 and palladium-based^15–22 catalysts were shown to enable the site-selective C–H arylation of 1,2,3-triazoles.²³ Despite these undisputable advances, C–H arylations on 1,2,3-triazoles were thus far solely accomplished with homogeneous catalysts, rendering a recycling and reuse of the metal catalysts challenging, while, at the same time, leading to considerable amounts of undesired metal impurities in the target products. Moreover, the catalyzed C–H functionalizations of 1,2,3-triazoles were predominantly performed in dipolar aprotic solvents, such as dimethylformamide (DMF), N-methylpyrroldin-2-one (NMP) and N,N-dimethylacetamide (DMA). Unfortunately, these solvents face considerable environmental and safety issues, which is of particular relevance for the practitioner in academia and industries.²⁴ Within our program directed towards sustainable C–H activation technology,^25,26 we have developed the first triazole C–H arylation by the aid of a recyclable heterogeneous^27–31 catalyst (Fig. 1). Thus, a versatile palladium catalyst was effectively reused in the C–H activation of synthetically meaningful 1,2,3-triazoles. Importantly, we herein also describe the use of bio-based γ-valerolactone (GVL)^32,33 – available from renewable lignocellulosic biomass^34,35 – as an environmentally-sound medium in direct C–H arylation.

Fig. 1 Sustainable heterogeneous C–H arylation in GVL.

At the outset of our studies, we optimized reaction conditions for the envisioned palladium-catalyzed C–H arylation of triazole 1a with aryl bromide 2a in the biomass-derived GVL as the solvent (Table 1). The C–H arylation occurred smoothly by means of palladium on charcoal catalysis in the presence of the carboxylic acid MesCO₂H as the cocatalyst³⁶ and with K₂CO₃ as the base, thereby delivering the desired product 3aa (entries 1–3). The C–H functionalization proceeded with excellent positional selectivity, and only trace amounts of the diarylated product 4aa were detected (entry 3). Among a representative set of bases (entries 3–9), K₂CO₃ and KTFA furnished optimal results (entries 7 and 9), with a slightly improved efficacy at a higher reaction temperature (entries 3 and 7).

Table 1 Optimization of palladium-catalyzed C–H arylations in GVL^a

Entry	Base	3aa (%)	4aa (%)
a Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol), Pd/C (5.0 mol%), MesCO2H (30 mol%), base (3 equiv.), GVL (1.0 mL), 150 °C, 16 h. b ^1H NMR conversion with CH2Br2 as internal standard, yields of isolated products are given in parentheses. c 130 °C.
1	NEt3^c	—	—
2	Cs2CO3^c	—	—
3	K2CO3^c	70	8
4	NH4OAc	—	—
5	Na2CO3	45	5
6	KHCO3	78	14
7	K 2 CO 3	82 (55)	16 (4)
8	KOAc	66 (42)	16 (4)
9	KTFA	86 (63)	14 (8)

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With the optimized reaction conditions in hand, we initially probed the catalyst's versatility in the C–H arylation of N-alkyl-substituted 1,2,3-triazoles 1a–1d in GVL (Scheme 1). Thus, both mono- and 1,4-di-substituted 1,2,3-triazoles 1a,b were efficiently converted. The triazole 1b displaying two alkyl-substituents delivered the corresponding products 3bb–3bh selectively as the sole products. Here, the robust nature of the heterogeneous palladium catalyst was reflected by fully tolerating valuable electrophilic functional groups, such as chloro, ester or enolizable ketone substituents. Likewise, the hindered 2-naphthyl electrophile 2h was transformed with high catalytic efficacy, as were alkyl-substituted 1,2,3-triazoles 1c,d.

Scheme 1 C–H arylation of N-alkyl triazoles 1 in GVL.

Subsequently, we evaluated the power of the Pd/C catalyst in the C–H functionalization of 1,2,3-triazole 1e–1k bearing N-aryl motifs (Scheme 2). Hence, differently decorated arenes were well tolerated by the user-friendly catalyst, enabling the synthesis of regio-selectively arylated products 3 with excellent positional control. Substrates 1f–1j with electron-withdrawing or electron-donating N-aryl groups furnished the desired tri-substituted 1,2,3-triazoles 3ef–3jf, again featuring good functional group tolerance. Thereby, our strategy provided atom-economical access to the selectively tri-arylated 1,2,3-triazole 3kf as well.

Scheme 2 C–H arylation of N-arylated triazoles 1 in GVL.

The heterogeneous catalyst was not restricted to intermolecular C–H arylations in GVL. Indeed, the intramolecular C–H functionalization with substrate 4a proved viable with comparable levels of efficacy, thereby delivering the triazolo[1,5-a]isoindole 5a (Scheme 3).

Scheme 3 Intramolecular C–H arylation in GVL.

In consideration of the remarkable efficacy of the versatile palladium C–H activation catalyst, we became attracted to probing its recyclability and reusability. To this end, we developed an effective protocol for the recycle of the heterogeneous palladium catalyst (Table 2), thereby allowing for the robust reuse of the catalyst. It is noteworthy that only a minor amount of palladium was detected by detailed ICP-MS analysis of the crude product.³⁷ This observation indicated only minor leaching,³⁸ that is within the specifications for active pharmaceutical ingredients produced by palladium-catalyzed processes.³⁹ Our findings were further in line with a hot-filtration test and mercury poisoning studies,³⁷ which provided strong support for a heterogeneous mode of action. Likewise, the three-phase test suggested that no active homogeneous palladium species were formed.³⁷

Table 2 Recovery and reuse of palladium catalyst^a

Run	1st	2nd	3rd
a Reaction conditions: 1l (0.30 mmol), 2f (0.45 mmol), Pd/C (5.0 mol%), MesCO2H (30 mol%), K2CO3 (0.60 mmol), GVL (2.0 mL), 120 °C, 24 h. b By ICP-MS analysis.^37
3lf (%)	90	90	90
Pd-leaching^b (ppm)	5.5	4.1	3.6

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In summary, we have developed the first C–H arylation of 1,2,3-triazoles by a heterogeneous catalyst in environmentally-sound γ-valerolactone (GVL)⁴⁰ as the reaction medium. Thus, a broadly applicable palladium catalyst allowed for inter- as well as intramolecular C–H functionalizations with ample scope. The biomass-derived solvent further set the stage for the efficient reuse of the heterogeneous palladium catalyst in positional selective C–H activations. The use of the biomass-based GVL as environmentally-benign solvent in C–H functionalization technology should prove instrumental for the future development of sustainable processes.⁴¹

Generous support by the European Research Council under the European Community's Seventh Framework Program (FP7 2007–2013)/ERC Grant agreement no. 307535, the Alexander von Humboldt foundation (fellowship to X. T.), and the CSC (fellowship to F. Y.) is gratefully acknowledged. Further, we thank the Università degli Studi di Perugia, the EC 7th Framework Program project REGPOT-CT-2013-316149 Innovabalt, and the “Fondazione Cassa di Risparmio di Terni e Narni” for financial support.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, and ¹H and ¹³C NMR spectra for products. See DOI: 10.1039/c6cc03468c

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