Ruthenium(II) oxidase catalysis for C-H alkenylations in biomass-derived γ-valerolactone

Article abstract of DOI:10.1039/c7gc03353b

Ruthenium(ii) biscarboxylate oxidase catalysis is a powerful tool for the assembly of functionalized arenes with oxygen as a green oxidant, but this strategy was thus far limited to its use in traditional organic solvents. Herein, we report on a green procedure for the ruthenium(ii) biscarboxylate-catalysed C-H functionalisation in biomass-derived γ-valerolactone as the reaction medium. The oxidase catalysis was characterized by ample substrate scope and proceeded efficiently with oxygen as the sole oxidant. The overall green nature of this C-H-activation methodology is reflected by H₂O being the only by-product.

Full text of DOI:10.1039/c7gc03353b

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DOI: 10.1039/C7GC03353B
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Ruthenium(II) oxidase catalysis for C–H alkenylations in biomass-
derived γ-valerolactone
Alexander Bechtoldt,a Marcel E. Baumert,a Luigi Vaccaro, b and Lutz Ackermanna,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Ruthenium(II) biscarboxylate oxidase catalysis is a powerful tool this approach was thus far limited to traditional, toxic organic
for the assembly of functionalized arenes with oxygen as a green solvents, compromising the overall green nature of our strategy.
oxidant, but this strategy was thus far limited to its use in Moreover, undesired transesterifications and solvent oxidation
traditional organic solvents. Herein, we report on a green occurred unfortunately as side reactions when using n-BuOH.
procedure for the ruthenium(II) biscarboxylate-catalysed C–H During the past decade, major efforts have been made to identify
functionalisation in biomass-derived γ-valerolactone as the novel approaches to convert biomass into raw materials and energy
reaction medium. The oxidase catalysis was characterized by sources.9 In order to obtain a broad range of chemicals in a cost-
ample substrate scope and proceeded efficiently with oxygen as effective manner, several platform molecules have emerged, with
the sole oxidant. The overall green nature of this C–H-activation γ-valerolactone (GVL) being a particularly attractive sustainable
methodology is reflected by H2O being the only by-product.
solvent.10 In spite of the broad range of transformations that render
γ-valerolactone a versatile precursor for bulk and fine chemicals,10d,
j, 11
The transition metal-catalysed activation of otherwise inert C–H
bonds has emerged as a powerful tool in molecular synthesis.1 In
contrast to conventional methods, the C–H functionalization
approach avoids the installation and interconversion of functional
groups, thereby improving the overall step- and atom-economy for
a more sustainable access to organic molecules. In this context,
it has unique properties that allow its use as a aprotic polar
solvent,10f-h which was very recently exploited for palladium-
catalysed direct functionalizations.12 In stark contrast, we herein
disclose the first ruthenium(II) oxidase C–H activation with
molecular oxygen as the sole oxidant in green biomass-derived
γ-valerolactone (Scheme 1). In this context, it is noteworthy that
the organic reactants could largely be obtained from natural
feedstocks, with the only by-product of the oxidase catalysis being
environmentally-benign water. Furthermore, GVL is characterized
by a higher flash point of 81 °C as compared to 35 °C for n-BuOH,
leading to improved safety features.
ruthenium(II) biscarboxylate catalysis was identified as
a
particularly broadly applicable tool,2 enabling inter alia C–H
arylations,3 C–H alkylations4 or remote C–H functionalizations.5
Notably,
oxidative
reaction
control
further
enabled
dehydrogenative twofold C–H functionalizations with alkenes or
alkynes, but they usually required the use of stoichiometric
amounts of silver(I) or copper(II) salts as the terminal oxidant.6
However, within our program on sustainable C–H activation,7 we
very recently devised ruthenium(II) biscarboxylates for oxidase
catalysis using oxygen as the sole oxidant in n-BuOH.8 An additional
green asset of this approach was represented by the formation of
water as the only by-product.8 Despite the indisputable progress,
a.A. Bechtoldt, M. E. Baumert, Prof. Dr. L. Ackermann
Institute for Organic and Biomolecular Chemistry
Georg-August-Universität Göttingen
Tammannstr. 2, 37077 Göttingen, Germany.
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
b.Prof. Dr. Luigi Vaccaro
Dipartimento di Chimica, Biologia e Biotecnologie
Università di Perugia
Scheme 1: Ruthenium(II) oxidase catalysis in biomass-derived GVL.
Via Elce di Sotto 8, 06123 Perugia, Italy.
We commenced our studies by probing various reaction conditions
for the envisioned oxidative twofold C–H functionalisation of 2-
c. DZHK (German Centre for Cardiovascular Research)
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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J. Name., 2013, 00, 1-3 | 1
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methylbenzoic acid (1a) with n-butyl acrylate (2a) (Table 1 and
Table S-1 in the Electronic Supporting Information, ESI). A catalytic
system consisting of [RuCl2(p-cymene)]2 and KOAc in GVL (0.3M)
(entry 1) under an ambient atmosphere of oxygen directly resulted
in the effective formation of the desired product 3aa. The dilution
of pure GVL to a 2:1 GVL/H2O mixture resulted in a somewhat
decreased yield (entry 2). Reducing the amount of KOAc led to a
lower catalytic efficacy (entry 3). The addition of equimolar
amounts of HOAc gave a slightly better performance (entry 4), that
could be further improved by increasing the substrate
concentration. Control experiments confirmed the essential nature
of the acetate additive and the ruthenium catalyst (Table S-1), while
other typical ruthenium sources did not display any catalytic activity
(entries 5-7).
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DOI: 10.1039/C7GC03353B
Table 1: Optimisation of the ruthenium(II) oxidase C–H alkenylation of benzoic acid 1aa.
Entry
1
[Ru]
1a [M]
0.3
0.3
0.3
0.3
1.0
1.0
1.0
Yield [%]b
75
49
65
81
traces
88
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(cod)]n
2c
3d
4e
5
6
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
7 e
90
a
Reaction conditions: 1a (1.00 mmol), 2a (1.50 mmol), [Ru] (10 mol %), KOAc (1.00
mmol), GVL (M), O2 (1 atm), 80 °C, 18 h. b Isolated yield. c GVL (2.0 mL), H2O (1.0 mL).
d
KOAc (0.5 mmol). e HOAc (1.0 mmol) added.
With the optimized reaction conditions in hand, we probed its
versatility with differently decorated benzoic acids 1. Thus, various
functional groups, such as aryl, alkyl, ether, amino, bromo, iodo and
ketone substituents, were well tolerated in the C–H activation, even
in the ortho-position. These findings highlight the outstanding
selectivity of the ruthenium(II) oxidase catalysis, while indicating its
potential for further late-stage diversifications. The robustness of
the oxidase C–H alkenylation was illustrated by the gram-scale
preparation of phtalide 3aa in an excellent isolated yield of 97%.
The use of aprotic GVL as the reaction medium extended the scope
of the C–H alkenylation to substrates bearing reactive tosylates and
mesylates (3fa and 3ga), again setting the stage for post-synthetic
modifications towards bioactive compounds in medicinal chemistry
and pharmaceutical industries. The positional selectivity of
intramolecular competition experiments with meta-substituted
arenes 1m, 1o and 1p were dominated by steric interactions.
Moreover, the naturally-occurring vanillic acid featuring the
reactive hydroxyl group was chemo-selectively transformed to the
phthalides 3la.
Scheme 2: Ruthenium(II) oxidase catalysis with benzoic acids 1.
2 | J. Name., 2012, 00, 1-3
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Subsequently, we probed the robustness of the twofold C–H Since the aerobic C–H activation is exploiting oxygen as sole oxidant
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DOI: 10.1039/C7GC03353B
functionalization in GVL with a representative set of alkenes 2 we explored the kinetic profile of the ruthenium(II) oxidase catalysis
(Scheme 2). Thus, the generality of the green oxidase catalysis was by its oxygen consumption, highlighting more than 80% conversion
reflected by successfully providing access to various phthalides 3, in less than 2 hours.
featuring among others a remote alkene in product 3ak.
100
80
60
40
20
0
0
200
400
time [min]
Figure 1: Oxygen consumption study.
Because the use of molecular oxygen in the presence of flammable
organic solvents can represent a potential safety hazard, we were
pleased to find that the use of operationally-simple aqueous H2O2
could be similarly employed as the terminal oxidant (Scheme 4).
Scheme 3: Ruthenium(II)-catalysed oxidative annulation of alkenes 2.
Scheme 4: Formation of 3aa with hydrogen peroxide as oxidant.
As to the reaction mechanism, a kinetic isotope effect (KIE) was not
observed, when comparing the initial rates of transformations with
substrates 1a and [D1]-1a (kh/kD = 1.0, see ESI), highlighting fast C–H
activation in aprotic GVL. Based on our findings, we propose the
plausible catalytic cycle depicted in Scheme 5. The in-situ generated
ruthenium(II) biscarboxylate complex 4 undergoes facile base-
assisted internal electrophilic-type substitution (BIES)13 type C–H
ruthenation of benzoic acid 1 to form the metallacycle 5. The
coordination of the alkene 2, along with its insertion and a
subsequent isomerisation, delivers complex 7. Finally, the desired
product 3 is obtained by β-hydride elimination and intramolecular
oxa-Michael addition, while the catalytically active species 4 is
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Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem.
regenerated by a two electron oxidation step. Notably, the only
stoichiometric by-product of the aerobic C–H alkenylation is H2O.
Int. Ed., 2009, 48, 5094-5115; g) L. Ackermann,VRie.wVAicrteicnleteOnalninde
DOI: 10.1039/C7GC03353B
A. R. Kapdi, Angew. Chem. Int. Ed., 2009, 48, 9792-9826.
a) S. De Sarkar, W. Liu, S. I. Kozhushkov and L. Ackermann,
Adv. Synth. Catal., 2014, 356, 1461-1479; b) P. B. Arockiam,
C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879-
5918; c) L. Ackermann and R. Vicente, Top. Curr. Chem., 2010,
292, 211-229.
a) P. Nareddy, F. Jordan and M. Szostak, ACS Catal., 2017,
DOI: 10.1021/acscatal.7b01645, 5721-5745; b) A. Schischko,
H. Ren, N. Kaplaneris and L. Ackermann, Angew. Chem. Int.
Ed., 2017, 56, 1576-1580; c) M. Moselage, J. Li, F. Kramm and
L. Ackermann, Angew. Chem. Int. Ed., 2017, 56, 5341-5344; d)
M. Simonetti, G. J. P. Perry, X. C. Cambeiro, F. Juliá-
Hernández, J. N. Arokianathar and I. Larrosa, J. Am. Chem.
Soc., 2016, 138, 3596-3606; e) J. Hubrich and L. Ackermann,
Eur. J. Org. Chem., 2016, 3700-3704; f) R. Mei, C. Zhu and L.
Ackermann, Chem. Commun., 2016, 52, 13171-13174; g) P. B.
Arockiam, C. Fischmeister, C. Bruneau and P. H. Dixneuf,
Angew. Chem. Int. Ed., 2010, 49, 6629-6632; h) L. Ackermann
and M. Mulzer, Org. Lett., 2008, 10, 5043-5045; i) L.
Ackermann, R. Vicente and A. Althammer, Org. Lett., 2008,
10, 2299-2302.
2.
3.
4.
5.
a) N. Y. P. Kumar, T. Rogge, S. R. Yetra, A. Bechtoldt, E. Clot
and
L.
Ackermann,
Chem.
Eur.
J.,
DOI:
10.1002/chem.201703680; b) C.-S. Wang, P. H. Dixneuf and
J.-F. Soulé, ChemCatChem, 2017, 9, 3117-3120; c) L.
Ackermann, P. Novák, R. Vicente and N. Hofmann, Angew.
Chem. Int. Ed., 2009, 48, 6045-6048.
Scheme 5: Proposed mechanistic cycle for the ruthenium oxidase.
a) S. Warratz, D. J. Burns, C. Zhu, K. Korvorapun, T. Rogge, J.
Scholz, C. Jooss, D. Gelman and L. Ackermann, Angew. Chem.
Int.Ed., 2017, 56, 1557-1560; b) J. A. Leitch and C. G. Frost,
Chem. Soc. Rev., 2017, DOI: 10.1039/C7CS00496F; c) J. Li, K.
Korvorapun, S. De Sarkar, T. Rogge, D. J. Burns, S. Warratz
and L. Ackermann, Nat. Commun., 2017, 8, 15430; d) J. Li, S.
De Sarkar and L. Ackermann, Top. Organomet. Chem., 2016,
55, 217-257; e) J. Li, S. Warratz, D. Zell, S. De Sarkar, E. E.
Ishikawa and L. Ackermann, J. Am. Chem. Soc., 2015, 137,
13894-13901; f) A. J. Paterson, S. St John-Campbell, M. F.
Mahon, N. J. Press and C. G. Frost, Chem. Commun., 2015, 51,
12807-12810; g) N. Hofmann and L. Ackermann, J. Am. Chem.
Soc., 2013, 135, 5877-5884; h) O. Saidi, J. Marafie, A. E. W.
Ledger, P. M. Liu, M. F. Mahon, G. Kociok-Köhn, M. K.
Whittlesey and C. G. Frost, J. Am. Chem. Soc., 2011, 133,
19298-19301; i) L. Ackermann, N. Hofmann and R. Vicente,
Org. Lett., 2011, 13, 1875-1877.
Conclusion
In summary, we have reported on the first merger of oxidative
ruthenium(II)-catalysed C–H functionalisation with a biomass-
derived solvents. Thus, γ-valerolactone as green reaction
medium set the stage for aerobic twofold C–H
functionalizations between benzoic acids and alkenes. The
oxidase
ruthenium(II)
biscarboxylate
catalysis
was
characterized by excellent levels of positional and chemo-
selectivity, fully tolerating reactive bromo, iodo or hydroxyl
groups. The oxidative double C–H functionalizations employed
molecular oxygen as the sole oxidant, generating
environmentally-benign H2O as the only stoichiometric by-
product.
6.
a) J. A. Leitch, H. P. Cook, Y. Bhonoah and C. G. Frost, J. Org.
Chem., 2016, 81, 10081-10087; b) L. Ackermann, J. Pospech,
K. Graczyk and K. Rauch, Org. Lett., 2012, 14, 930-933; c) L.
Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem. Int.
Ed., 2011, 50, 6379-6382; d) L. Ackermann and J. Pospech,
Org. Lett., 2011, 13, 4153-4155.
Acknowledgements
Generous Support by the H-CCAT program (Horizon2020 project
ID 720996) and the DFG (Gottfried-Wilhelm-Leibniz prize) is
gratefully acknowledged. The Universities of Perugia and
Göttingen are also thankfully acknowledged for financial
support.
7.
8.
L. Ackermann, Acc. Chem. Res., 2014, 47, 281-295.
a) A. Bechtoldt, C. Tirler, K. Raghuvanshi, S. Warratz, C.
Kornhaaß and L. Ackermann, Angew. Chem. Int. Ed., 2016, 55,
264-267; b) S. Warratz, C. Kornhaaß, A. Cajaraville, B.
Niepötter, D. Stalke and L. Ackermann, Angew. Chem. Int. Ed.,
2015, 54, 5513-5517.
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