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

Article abstract of DOI:10.1039/c6cc03468c

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 hig

Full text of DOI:10.1039/c6cc03468c

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DOI: 10.1039/C6CC03468C
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C–H Arylations of 1,2,3‐Triazoles by Reusable Heterogeneous Palladium Catalysts in
Biomass‐Derived γ‐Valerolactone
Xu Tian,a Fanzhi Yang,a Dace Rasina,b Michaela Bauer,a Svenja Warratz,a Francesco Ferlin,b Luigi
Vaccaro,*b Lutz Ackermann*a
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
methylpyrroldin-2-one (NMP) and
N,N-dimethylacetamide
CH arylations were accomplished with
a user-friendly
(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 heterogeneous27-31
catalyst (Figure 1). Thus, a versatile palladium catalyst was
effectively reused in the C–H activation of synthetically
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.
meaningful 1,2,3-triazoles. Importantly, we herein also describe
Introduction
33
the use of bio-based
from renewable lignocellulosic biomass
environmentally-sound medium in direct C–H arylation.
γ
-valerolactone (GVL)32,
– available
34, 35
–
as an
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-based15-22 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
Sustainable C–H Activation
heterogeneous Pd/C
recyclable & reusable
ample scope & robust
N
N
R
R
intra- and intermolecular
functional group tolerant
biomass-derived solvent (GVL)
N
N
N
N
Pd
Ar
R'
H
R'
Figure 1. Sustainable heterogeneous C–H arylation in GVL.
Results and Discussion
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 cocatalyst336 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
solvents,
such
as
dimethylformamide
(DMF),
N-
(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).
a. Institut für Organische und Biomolekulare Chemie, Georg‐August‐Universität,
Tammannstraße 2, 37077 Goettingen, Germany. E‐mail:
Lutz.Ackermann@chemie.uni‐goettingen.de.
b. Laboratory of Green Synthetic Organic Chemistry, Dipartimento di Chimica
Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto, 8
06123 Perugia, E‐mail: luigi.vaccaro@unipg.it.
† Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data, and 1H and 13C NMR spectra for products. See
DOI: 10.1039/b000000x
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Table 1. Optimization of palladium‐catalyzed C–H arylations in GVL.a
Subsequently, we evaluated the power of the Pd/C catalyst in the
C–H functionalization of 1,2,3-triazole 1e–1k bearingVNiew-aArryticllemOontliinfes
DOI: 10.1039/C6CC03468C
(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.
Entry
Base
3aa (%)b
---
4aa (%)b
c
1
2
3
4
5
6
7
8
9
---
NEt3
c
---
---
Cs2CO3
c
70
8
K2CO3
---
---
NH4OAc
Na2CO3
KHCO3
K2CO3
KOAc
45
5
78
14
82 (55)
66 (42)
86 (63)
16 (4)
16 (4)
14(8)
KTFA
[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.
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 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.
Scheme 1. C–H arylation of N-alkyl triazoles 1 in GVL.
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[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
Conclusions
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
12.
13.
14.
15.
16.
17.
18.
Acknowledgements
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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