Mild Decarboxylative C?H Alkylation: Computational Insights for Solvent-Robust Ruthenium(II) Domino Manifold

Article abstract of DOI:10.1002/chem.201703680

Computational studies on decarboxylative C?H alkenylations provided key insights into the solvent-robust nature of C?H activation/decarboxylation domino reactions. These properties were exploited for ruthenium(II)-catalyzed C?H alkylations by a decarboxylative process with ample scope under copper-free and silver-free reaction conditions.

Full text of DOI:10.1002/chem.201703680

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Title: Mild Decarboxylative C-H Alkylation: Computational Insights for
Solvent-Robust Ruthenium(II) Domino Manifold
Authors: Phani Kumar, Torben Rogge, Santhivardhana Reddy Yetra,
Alexander Bechtholdt, Eric Clot, and Lutz Ackermann
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To be cited as: Chem. Eur. J. 10.1002/chem.201703680
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Mild Decarboxylative C–H Alkylation: Computational Insights for
Solvent-Robust Ruthenium(II) Domino Manifold
N. Y. Phani Kumar,[a]† Torben Rogge,[a]† Santhivardhana Reddy Yetra,[a]† Alexander Bechtoldt,[a] Eric
Clot,[b] and Lutz Ackermann*[a]
Abstract: Computational studies on decarboxylative C–H
alkenylations provided key insights into the solvent-robust nature of
C–H activation/decarboxylation domino reactions, which was
exploited for ruthenium(II)-catalyzed C–H alkylations by
decarboxylative ruthenium(II) catalysis with ample scope under
copper- and silver-free reaction conditions.
Transition metal-catalyzed C–H functionalizations have emerged
as a powerful tool for molecular syntheses, with transformative
applications to medicinal chemistry, materials science and
agrochemicals.[1] Carboxylic acids are particularly useful
substrates, since they are readily accessible, inexpensive and
can undergo a wealth of chemical transformations.[2] Thus,
carboxylic acids have proven instrumental for the development
of inter alia cross-couplings,[3] and C–H activation.[4, 2a] The last
decade has witnessed major progress through the use of
Scheme 1. Ruthenium(II)-catalyzed decarboxylative C–H alkylation.
carboxylic acid as traceless directing groups in C–H
functionalization.[5] Despite major advances, the practical utility
We initiated our studies by exploring the mechanism of our
of these methods is compromised by two-step operations, the
10]
decarboxylative C–H alkenylation[6,
by means of DFT
use of more than one metal in (sub)stoichiometric amounts and
high reaction temperatures. Very recently, single step
transformations using monometallic systems have been
concurrently discovered by Ackermann,[6] Zhao,[7] and Gooßen[8]
using ruthenium(II)-catalysis, thereby achieving domino C–H
alkenylation/decarboxylations.[9] A recent computational study on
the mechanism of these ruthenium(II)-catalyzed decarboxylative
C–H alkenylations of benzoic acids with alkynes proposed that
the chemoselectivity of the reaction is fully controlled by the
polarity of the reaction medium.[10] Within our own computational
studies, we unraveled a solvent-robust decarboxylative C–H
activation manifold, which enabled a unified strategy for domino
calculations. Our computational studies for decarboxylative C–H
alkenylations with alkyne at the PBE0-D3(BJ)/def2-
M
QZVP*+SMD//PBE0/def2-SVP[13] level of theory revealed that
the reaction proceeds via C–H ruthenation,[14] followed by
migratory insertion, and decarboxylation for the final two-fold
proto-demetallation (Figure 1). Moreover, we uncovered that the
key activation barriers were not significantly altered by the
nature of the reaction medium (see also Table S1 in the
Supporting Information).
C–H
alkylation/decarboxylation
to
access
succinimide
derivatives which feature anticonvulsant[11] and anticancer
activity.[12] Salient features of our approach include (i)
computational and experimental mechanistic insights into
decarboxylative C–H activation, (ii) carboxylic acids as traceless
directing groups for positional selective C–H alkylation and (iii) a
user-friendly single-component ruthenium catalyst for one step
access to meta-substituted arenes.
[a]
[b]
Dr. N. Y. P. Kumar, T. Rogge, Dr. S. R. Yetra, A. Bechtoldt,
Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen, Germany
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
[†] N.Y.P.K., T.R. and S.R.Y. contributed equally
Dr. E. Clot
Institut Charles Gerhardt Montpellier
UMR 5253 CNRS-UM-ENSCM, Université de Montpellier, cc 1501
Place Eugène Bataillon, 34095 Montpellier, Cedex 5, France
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Figure 1. Relative Gibbs free energy diagram of the reaction path with alkyne M in different solvents; values are shown for 1,2-DCE.
With the solvent-robust chemo-selectivity of the domino C–H
alkenylation/decarboxylation suggested, we computationally
explored the envisioned decarboxylative transformation with
maleimides 2 (Figure 2).[15] A potential annulation pathway was
unfavorable, while the influence of the reaction medium on all
activation energies was again found largely to be negligible (see
also Table S2 in the SI).[13] Moreover, an analysis by Grimme’s
D3 dispersion correction[16] revealed that dispersion interactions
significantly stabilize key intermediates and transition states,
with differences of up to 27 kcal mol-1 for intermediate J’ (Figure
S2 in the SI). Based on our computational insights, we thereafter
became attracted to probe the desired decarboxylative C–H
alkylation by experiment. After considerable optimization (Table
S5 in the SI),[13] we were pleased to identify the well-defined
ruthenium(II)
bis(carboxylate)
complex
[Ru(O2CMes)2(p-
cymene)] (4a)[17] as a single-component catalyst for the desired
domino decarboxylative C–H alkylation of benzoic acids 1,
thereby furnishing meta-decorated arenes 3. As indicated by our
computational analysis (vide supra), various solvents proved
amenable, ranging from aprotic toluene and 1,2-dichloroethane
(DCE) to polar protic 2,2,2-trifluoroethanol (TFE) and even H2O.
The outstanding chemo-selectivity of the versatile ruthenium(II)
catalyst was reflected by fully tolerating valuable functional
groups, such as iodo, bromo, hydroxyl, cyano, ester and nitro
substituents (Scheme 2a). The high catalytic efficacy also
enabled efficient catalysis even at a considerably lower reaction
temperature of only 50 °C, and the step-economical synthesis of
the anticonvulsant drug Phensuximide (3he) and its analogues
3ha/3hg.[18]
Figure 2. Relative Gibbs free energy diagram of the reaction with maleimides
2 in different solvents with respect to A; values are shown for 1,2-DCE.
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The remarkable reactivity of our ruthenium(II) catalyst was
further illustrated by an extremely short reaction time of only 30
minutes. Notably, free (NH)-maleimide 2h was also well
tolerated. When using the meta-substituted benzoic acid 1k, the
para-alkylated product 3ke was obtained. Considering the
importance of heterocyclic motifs in medicinal chemistry and
natural products,[19] we were pleased to identify heteroarenes as
viable substrates under otherwise identical reaction conditions
(Scheme 2c).
Furthermore, the user-friendly ruthenium(II) biscarboxylate
complex 4a was not limited to C–H functionalization of arenes 1.
Indeed, the versatile single-component catalyst 4a likewise
enabled alkenylic C–H activation on challenging acylic acids and
cyclohexene carboxylic acid 5 (Scheme 3).[20]
Scheme 3. Decarboxylative C–H alkylation of alkenyl carboxylic acids 5.
Given the remarkably high efficiency of the domino
C−H alkylation/decarboxylation, we performed experiments to
gain further experimental insights into its modus operandi. To
probe the decarboxylative nature of the domino C−H
alkylation/decarboxylation regime, we first examined the CO2
evolution during the course of the reaction, revealing
conversion of more than 50% in only 4 hours. (Figure 3).[13]
a
Figure 3. CO2 evolution during ruthenium(II)-catalyzed C–H alkylation.
Given the importance of the cycloruthenated complexes as
proposed intermediates in the ruthenium(II)-catalyzed domino
C−H alkylation/decarboxylation reaction, we subsequently
Scheme 2. Decarboxylative C–H alkylation with alkenes 2. [a] In H2O. [b] In
TFE at 50 °C. [c] t = 30 min.
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performed successful reactions with the well-defined complex 7,
illustrating the organometallic mode of the C–H activation
(Scheme 4a). A negligible kinetic isotope effect (KIE) of
kH/kD ≈ 1.05 was observed by in situ monitoring of the reaction
by IR spectroscopy, which suggested that the C–H ruthenation
is not the turnover-limiting step. This observation is in good
agreement with a calculated KIE value of 1.08 (Scheme 4b).[13]
In line with our KIE and computational studies, reactions
performed with isotopically labeled compounds provided strong
support for a facile C–H ruthenation event (Scheme 4c).
arenes, heteroarenes and alkenes. Key to success was
represented by carboxylate assistance, which allowed chemo-
and site-selective domino C−H alkylation/decarboxylation with
ample scope at reaction temperatures as low as 50 °C under
copper- and silver-free reaction conditions. In contrast to
previous catalytic systems, the robust single-component catalyst
was operative under exceedingly mild reaction conditions in a
large variety of solvents, ranging from apolar toluene and DCE
to polar solvents, even including H2O.
Acknowledgements
Generous support by the COST program (CA15106 CHAOS),
and the DFG (SPP1807 and Gottfried-Wilhelm-Leibniz prize) is
gratefully acknowledged.
Keywords: Density functional calculations • C–H activation •
decarboxylation • ruthenium • reaction mechanism
[1]
a) J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q. Yu,
Chem. Rev. 2017, 117, 8754-8786; b) L. Vaccaro, F.
Ferlin, S. Santoro, L. Luciani, L. Ackermann, Green Chem.
2017, 19, 1601-1612; c) O. Daugulis, J. Roane, L. D. Tran,
Acc. Chem. Res. 2015, 48, 1053-1064; d) B. Li, P. H.
Dixneuf, Chem. Soc. Rev. 2013, 42, 5744-5767; e) J.
Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369-375;
f) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev.
2012, 112, 5879-5918; g) L. Ackermann, Chem. Rev.
2011, 111, 1315-1345; h) X. Chen, K. M. Engle, D.-H.
Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094-
5115; i) L. Ackermann, R. Vicente, A. R. Kapdi, Angew.
Chem. Int. Ed. 2009, 48, 9792-9826; j) F. Kakiuchi, N.
Chatani, Adv. Synth. Catal. 2003, 345, 1077-1101, and
cited references.
[2]
[3]
a) Y. Wei, P. Hu, M. Zhang, W. Su, Chem. Rev. 2017, 117,
8864-8907; b) M. Pichette Drapeau, L. J. Gooßen, Chem.
Eur. J. 2016, 22, 18654-18677; c) I. Larrosa, J. Cornella,
Synthesis 2012, 44, 653-676; d) N. Rodríguez, L. J.
Gooßen, Chem. Soc. Rev. 2011, 40, 5030-5048.
a) S. Bhadra, W. I. Dzik, L. J. Goossen, J. Am. Chem. Soc.
2012, 134, 9938-9941; b) L. J. Goossen, N. Rodrꢀguez, C.
Linder, J. Am. Chem. Soc. 2008, 130, 15248-15249; c) L.
J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662-
664; d) A. G. Myers, D. Tanaka, M. R. Mannion, J. Am.
Chem. Soc. 2002, 124, 11250-11251.
[4]
Representative examples: R. Mei, S. K. Zhang, L.
Ackermann, Org. Lett. 2017, 19, 3171-3174; b) A. Mandal,
S. Dana, H. Sahoo, G. S. Grandhi, M. Baidya, Org. Lett.
2017, 19, 2430-2433; c) G.-C. Li, P. Wang, M. E. Farmer,
J.-Q. Yu, Angew. Chem. Int. Ed. 2017, 56, 6874-6877; d)
M. Simonetti, D. M. Cannas, A. Panigrahi, S. Kujawa, M.
Kryjewski, P. Xie, I. Larrosa, Chem. Eur. J. 2017, 23, 549-
553; e) R. Mei, C. Zhu, L. Ackermann, Chem. Commun.
2016, 52, 13171-13174; f) A. Biafora, T. Krause, D.
Hackenberger, F. Belitz, L. J. Gooßen, Angew. Chem. Int.
Ed. 2016, 55, 14752-14755; g) L. Huang, D. J. Weix, Org.
Lett. 2016, 18, 5432-5435; h) A. Bechtoldt, C. Tirler, K.
Raghuvanshi, S. Warratz, C. Kornhaaß, L. Ackermann,
Angew. Chem. Int. Ed. 2016, 55, 264-267; i) S. Warratz, C.
Kornhaaß, A. Cajaraville, B. Niepötter, D. Stalke, L.
Ackermann, Angew. Chem. Int. Ed. 2015, 54, 5513-5517;
j) N. Dastbaravardeh, T. Toba, M. E. Farmer, J.-Q. Yu, J.
Am. Chem. Soc. 2015, 137, 9877-9884; k) Y. Zhang, H.
Zhao, M. Zhang, W. Su, Angew. Chem. Int. Ed. 2015, 54,
3817-3821; l) C. Zhu, Y. Zhang, J. Kan, H. Zhao, W. Su,
Scheme 4. Summary of key mechanistic findings.
In summary, we report on computational studies on ruthenium-
catalyzed domino C−H activation/decarboxylations that highlight
the solvent-robust nature of decarboxylative C−H alkenylations.
These studies set the stage for the development of versatile
ruthenium(II)-catalyzed decarboxylative C−H alkylations that
provide step-economical access to meta- and para-alkylated
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Org. Lett. 2015, 17, 3418-3421; m) C. Arroniz, A.
[18]
[19]
H. J. Teschendorf, R. Kretzschmar, in Antiepileptic Drugs
(Eds.: H.-H. Frey, D. Janz), Springer Berlin Heidelberg,
Berlin, Heidelberg, 1985, pp. 557-574.
a) A. P. Taylor, R. P. Robinson, Y. M. Fobian, D. C.
Blakemore, L. H. Jones, O. Fadeyi, Org. Biomol. Chem.
2016, 14, 6611-6637; b) E. Vitaku, D. T. Smith, J. T.
Njardarson, J. Med. Chem. 2014, 57, 10257-10274; c) A.
Gomtsyan, Chem. Heterocycl. Compd. 2012, 48, 7-10.
Thus far, aliphatic carboxylic acids led to less satisfactory
results.
Ironmonger, G. Rassias, I. Larrosa, Org. Lett. 2013, 15,
910-913; n) L. Ackermann, J. Pospech, K. Graczyk, K.
Rauch, Org. Lett. 2012, 14, 930-933; o) P. Hu, M. Zhang,
X. Jie, W. Su, Angew. Chem. Int. Ed. 2012, 51, 227-231;
p) L. Ackermann, J. Pospech, Org. Lett. 2011, 13, 4153-
4155; q) T. Ueyama, S. Mochida, T. Fukutani, K. Hirano, T.
Satoh, M. Miura, Org. Lett. 2011, 13, 706-708; r) M.
Yamashita, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2009,
11, 2337-2340; s) A. Maehara, H. Tsurugi, T. Satoh, M.
Miura, Org. Lett. 2008, 10, 1159-1162, and cited
references.
[20]
[5]
a) M. Font, J. M. Quibell, G. J. P. Perry, I. Larrosa, Chem.
Commun. 2017, 53, 5584-5597; b) J. Cornella, M. Righi, I.
Larrosa, Angew. Chem. Int. Ed. 2011, 50, 9429-9432; c) S.
Mochida, K. Hirano, T. Satoh, M. Miura, J. Org. Chem.
2011, 76, 3024-3033; d) S. Mochida, K. Hirano, T. Satoh,
M. Miura, Org. Lett. 2010, 12, 5776-5779; e) J. Luo, S.
Preciado, I. Larrosa, J. Am. Chem. Soc. 2014, 136, 4109-
4112.
[6]
[7]
[8]
N. Y. P. Kumar, A. Bechtoldt, K. Raghuvanshi, L.
Ackermann, Angew. Chem. Int. Ed. 2016, 55, 6929-6932.
J. Zhang, R. Shrestha, J. F. Hartwig, P. Zhao, Nat. Chem.
2016, 8, 1144-1151.
a) A. Biafora, B. A. Khan, J. Bahri, J. M. Hewer, L. J.
Gooßen, Org. Lett. 2017, 19, 1232-1235; b) L. Huang, A.
Biafora, G. Zhang, V. Bragoni, L. J. Gooßen, Angew.
Chem. Int. Ed. 2016, 55, 6933-6937.
[9]
[10]
M. Simonetti, I. Larrosa, Nat. Chem. 2016, 8, 1086-1088.
J.-L. Yu, S.-Q. Zhang, X. Hong, J. Am. Chem. Soc. 2017,
139, 7224-7243.
[11]
a) J. Obniska, M. Kopytko, A. Zagórska, I. Chlebek, K.
Kamiński, Arch. Pharm. 2010, 343, 333-341; b) P. N.
Patsalos, Epilepsia 2005, 46, 140-148; c) P. G. Kostyuk, E.
A. Molokanova, N. F. Pronchuk, A. N. Savchenko, A. N.
Verkhratsky, Neuroscience 1992, 51, 755-758; d) D. A.
Coulter, J. R. Huguenard, D. A. Prince, Neurosci. Lett.
1989, 98, 74-78.
[12]
a) S. H. Han, S. Kim, U. De, N. K. Mishra, J. Park, S.
Sharma, J. H. Kwak, S. Han, H. S. Kim, I. S. Kim, J. Org.
Chem. 2016, 81, 12416-12425; b) A. M. Crider, T. M.
Kolczynski, K. M. Yates, J. Med. Chem. 1980, 23, 324-326.
For detailed information, see the Supporting Information.
For representative examples of computational studies on
ruthenium-catalyzed C−H activation, see: a) J. A. Leitch, C.
L. McMullin, M. F. Mahon, Y. Bhonoah, C. G. Frost, ACS
Catal. 2017, 7, 2616-2623; b) C. Shan, X. Luo, X. Qi, S.
Liu, Y. Li, Y. Lan, Organometallics 2016, 35, 1440-1445;
c) J. A. Leitch, P. B. Wilson, C. L. McMullin, M. F. Mahon,
Y. Bhonoah, I. H. Williams, C. G. Frost, ACS Catal. 2016,
6, 5520-5529; d) A. Gray, A. Tsybizova, J. Roithova,
Chem. Sci. 2015, 6, 5544-5553; e) A. G. Algarra, W. B.
Cross, D. L. Davies, Q. Khamker, S. A. Macgregor, C. L.
McMullin, K. Singh, J. Org. Chem. 2014, 79, 1954-1970; f)
I. Özdemir, S. Demir, B. Çetinkaya, C. Gourlaouen, F.
Maseras, C. Bruneau, P. H. Dixneuf, J. Am. Chem. Soc.
2008, 130, 1156-1157; g) Y. Boutadla, D. L. Davies, S. A.
Macgregor, A. I. Poblador-Bahamonde, Dalton Trans.
2009, 5887-5893.
[13]
[14]
[15]
a) Z. Zhang, S. Han, M. Tang, L. Ackermann, J. Li, Org.
Lett. 2017, 19, 3315-3318; b) K. R. Bettadapur, V. Lanke,
K. R. Prabhu, Chem. Commun. 2017, 53, 6251-6254; c) P.
Keshri, K. R. Bettadapur, V. Lanke, K. R. Prabhu, J. Org.
Chem. 2016, 81, 6056-6065; d) K. R. Bettadapur, V.
Lanke, K. R. Prabhu, Org. Lett. 2015, 17, 4658-4661.
a) S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem.
2011, 32, 1456-1465; b) S. Grimme, J. Antony, S. Ehrlich,
H. Krieg, J. Chem. Phys. 2010, 132, 154104-154119.
L. Ackermann, P. Novák, R. Vicente, N. Hofmann, Angew.
Chem. Int. Ed. 2009, 48, 6045-6048
[16]
[17]
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N. Y. Phani Kumar, Torben Rogge,
Santhivardhana Reddy Yetra, Alexander
Bechtoldt, Eric Clot, and Lutz
Ackermann*
Page No. – Page No.
Text for Table of Contents
Mild Decarboxylative C–H Alkylation:
Computational Insights for Solvent-
Robust Ruthenium(II) Domino
Manifold
Ex silico: Decarboxylative C–H alkylations were realized through key mechanistic insights, enabling
ruthenium(II)-catalyzed domino C–H activation/decarboxylation under exceedingly mild condition.
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