Ruthenium(II)-Catalyzed Decarboxylative C-H Activation: Versatile Routes to meta-Alkenylated Arenes

Article abstract of DOI:10.1002/anie.201600490

Ruthenium(II) bis(carboxylate)s proved highly effective for two decarboxylative C-H alkenylation strategies. The decarboxylation proceeded efficiently at rather low temperatures. The unique versatility of the decarboxylative ruthenium(II) catalysis is reflected in the oxidative olefinations with alkenes as well as the redox-neutral hydroarylations of alkynes. Two birds with one Ru: Ruthenium(II) catalysis enabled decarboxylative C-H olefinations by carboxylate assistance at low temperature. It is applicable to both alkenes for oxidative olefinations, as well as alkynes for redox-neutral hydroarylations. Neither silver nor copper salts are required and meta-substituted products can be accessed with this method.

Full text of DOI:10.1002/anie.201600490

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201600490
German Edition: DOI: 10.1002/ange.201600490
CÀH Activation
À
Ruthenium(II)-Catalyzed Decarboxylative C H Activation: Versatile
Routes to meta-Alkenylated Arenes
+
+
N. Y. Phani Kumar , Alexander Bechtoldt , Keshav Raghuvanshi, and Lutz Ackermann*
Abstract: Ruthenium(II) bis(carboxylate)s proved highly
effective for two decarboxylative CÀH alkenylation strategies.
The decarboxylation proceeded efficiently at rather low
temperatures. The unique versatility of the decarboxylative
ruthenium(II) catalysis is reflected in the oxidative olefinations
with alkenes as well as the redox-neutral hydroarylations of
alkynes.
[
1]
T
he alkenylation of otherwise inert CÀH bonds has
emerged as an increasingly powerful platform for the late-
stage manipulation of arenes. In the recent years, particular
[2]
advances were achieved with versatile ruthenium(II) com-
[3]
plexes. In this context, we have identified ruthenium(II)
Figure 1. Ruthenium(II)-catalyzed decarboxylative CÀH olefination.
bis(carboxylate)s as catalysts for cross-dehydrogenative CÀH
functionalizations of benzoic acids with alkenes and alkynes,
thereby providing step-economical access to phthalides and
isocoumarins through CÀH/CÀH and CÀH/OÀH cleavage,
[17]
set the stage for novel redox-neutral hydroarylations
of
alkynes, using the exact same ruthenium(II) bis(carboxylate)
[
4]
respectively. The oxidative CÀH functionalization processes
catalyst [Ru(O CMes) (p-cymene)].
2
2
could be rendered aerobic by performing these transforma-
We initiated our studies by probing reaction conditions for
[
5]
tions under an ambient atmosphere of air (Figure 1a).
the ruthenium(II)-catalyzed CÀH functionalization of the
While performing further detailed investigations on these
oxidative couplings between benzoic acids and alkenes, we
probed representative oxidants under inert atmospheres. As
a result of these studies, we identified reaction conditions for
unprecedented decarboxylative CÀH olefination by
benzoic acid 1a with the alkene 2a (Table 1, and see Table S1
[18]
in the Supporting Information). The decarboxylative CÀH
alkenylation occurred under an inert atmosphere of either
[a]
ruthenium(II) catalysis, on which we report herein. It is
Table 1: Ruthenium(II)-catalyzed decarboxylative CÀH alkenylation.
[
6]
noteworthy that elegant decarboxylative CÀH couplings
have previously been accomplished with palladium or rho-
dium catalysts and stoichiometric amounts of either silver(I)
[7]
or copper(II) salts, with key contributions towards useful
[
8]
[9]
meta-substituted arenes by the groups of Gooßen, Miura,
[
10]
[11]
Larossa, and Su. In contrast, our catalytic system features
[12]
[13]
largely underappreciated ruthenium complexes. Notably,
the optimized ruthenium(II) bis(carboxylate) catalysts
proved operative at rather low reaction temperatures and
did not require any copper(II) or silver(I) salts, thereby
giving efficient access to meta-substituted
[a]
Entry
Additive
Solvent
Yield [%]
[14]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
–
PhMe
PhMe
PhMe
PhMe
PhMe
28
32
30
31
39
15
22
27
55
48
–
60
–
[15]
Na S O
7
2
2
[
16]
norbornadiene
tBuC(O)Me
MnO2
V2O5
V2O5
arenes (Fig-
ure 1b). Moreover, the key insights into the oxidative
decarboxylative alkenylation by ruthenium(II) catalysis also
H O
2
DCE
V2O5
n-hexane
MeCN
DMF
DMSO
m-xylene
PhMe
[
+]
[+]
[
*] N. Y. P. Kumar, A. Bechtoldt, K. Raghuvanshi,
Prof. Dr. L. Ackermann
V
V
V
V
V
V
2
2
2
2
2
2
O
O
O
O
O
O
5
5
5
5
5
5
[
[
[
[
b]
b]
b]
c]
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
PhMe
60
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
[
a] Reaction conditions: 1a (3.0 mmol), 2a (1.0 mmol), 4 (10.0 mol%),
+
[
] These authors contributed equally to this work.
additive (1.0 equiv), PhMe (3.0 mL), 18 h, under either Ar or N . Yield of
2
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600490.
isolated product. [b] 1508C. [c] Without [Ru]. DCE=1,2-dichloroethane.
DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide.
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ambient argon or nitrogen, and notably, even in the absence
of an additional oxidant (entry 1). Yet, the decarboxylative
oxidative CÀH functionalization proved to be more effective
when using additives. While sodium persulfate, norborna-
diene, pinacolone, or MnO2 failed to show any beneficial
effect (entries 2–5), optimal results were obtained using V O ,
2
5
with the best solvent being toluene (entry 6–14). Moreover,
the crucial importance of the ruthenium(II) catalyst was
unambiguously verified (entries 13 and 14).
With the optimized reaction conditions in hand, we
probed the versatility of the ruthenium(II)-catalyzed decar-
boxylative CÀH alkenylation of benzoic acids (1) with alkenes
2
(Scheme 1). The ruthenium(II) bis(carboxylate) complex 4
Scheme 2. Decarboxylative hydroarylation.[a] 4 (5.0 mol%). [b] In DCE.
selectively furnishing the meta-alkenylated arenes 3. Again,
the versatile complex 4 proved chemoselective, as was
illustrated by the synthesis of the products 3 featuring
fluoro, chloro, bromo, and nitro groups among others. It is
noteworthy that the simple benzoic acid 1n, being devoid of
a stabilizing ortho-substituent, could be employed as well,
albeit with somewhat diminished efficacy. Furthermore, the
unsymmetrical alkynes 5k,l were successfully employed to
furnish the corresponding meta-substituted products 3ak,al
with excellent regioselectivity, generally placing the aryl
group distal to the benzoic acidꢀs aromatic moiety. Impor-
tantly, the domino hydroarylation/decarboxylation protocol
was not limited to substrates bearing stabilizing ortho groups.
Indeed, the para-substituted benzoic acids 1p–r proved
amenable to the CÀH olefination process as well, hence,
Scheme 1. Scope of the decarboxylative domino CÀH alkenylation with
benzoic acids (1) and alkenes (2). THF=tetrahydrofuran-2-yl,
MOE=2-methoxyethyl.
enabled the decarboxylative CÀH alkenylation of various
acids (1) with ample substrate scope. The robustness of the
catalyst 4 was reflected by full toleration of a variety of
valuable electrophilic functional groups, including ester,
chloro, and bromo substituents, as well as the sensitive
cholesteryl moiety in alkene 2 f.
In consideration of our previous successful use of alkynes
5
in ruthenium(II)-catalyzed oxidative annulations by benzoic
allowing the synthesis of the meta-substituted products 3pg–
rg (Scheme 2b). In more general terms, the two decarbox-
ylative CÀH alkenylation approaches are complementary not
[
4b, 5b]
acids,
we further explored the acetylene derivatives 5
[18]
under an inert atmosphere (Scheme 2, and see Table S2).
Interestingly, here we observed a novel isohypsic, that is,
redox-neutral, decarboxylative hydroarylation, thus chemo-
only in terms of the reaction conditions, but also the viable
substitution patterns.
6
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To probe the decarboxylative nature of the ruthenium(II)-
(FP7 2007–2013)/ERC Grant agreement no. 307535, and the
catalyzed oxidative CÀH alkenylation regime we studied the
DAAD (fellowships to N.Y.P. K. and K.R.) is gratefully
acknowledged.
CO evolution during the course of the domino olefination
2
[18]
(
Figure 2, and see Table S3). Our studies clearly illustrate
Keywords: alkenes · arenes · CÀH activation ·
reaction mechanisms · ruthenium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6929–6932
Angew. Chem. 2016, 128, 7043–7046
[
1] Representative reviews on CÀH activation: a) J. G. Kim, K.
Shin, S. Chang, Top. Organomet. Chem. 2016, 55, 29 – 51; b) B.
Ye, N. Cramer, Acc. Chem. Res. 2015, 48, 1308 – 1318; c) O.
Daugulis, J. Roane, L. D. Tran, Acc. Chem. Res. 2015, 48, 1053 –
1
064; d) Y. Segawa, T. Maekawa, K. Itami, Angew. Chem. Int.
Ed. 2015, 54, 66 – 81; Angew. Chem. 2015, 127, 68 – 83; e) N.
Kuhl, N. Schroeder, F. Glorius, Adv. Synth. Catal. 2014, 356,
1
443 – 1460; f) S. A. Girard, T. Knauber, C.-J. Li, Angew. Chem.
Int. Ed. 2014, 53, 74 – 100; Angew. Chem. 2014, 126, 76 – 103; g) J.
Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5, 369 – 375;
h) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45,
9
1
36 – 946; i) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212 –
1222; j) L. Ackermann, R. Vicente, A. Kapdi, Angew. Chem.
Int. Ed. 2009, 48, 9792 – 9826; Angew. Chem. 2009, 121, 9976 –
0011; k) R. G. Bergman, Nature 2007, 446, 391 – 393, and
1
references therein.
[
[
[
2] For recent reviews that feature CÀH olefinations, see: a) L.
Zhou, W. Lu, Chem. Eur. J. 2014, 20, 634 – 642; b) S. I.
Kozhushkov, L. Ackermann, Chem. Sci. 2013, 4, 886 – 896;
c) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012,
Figure 2. CO evolution during ruthenium(II)-catalyzed CÀH alkenyla-
2
1
1
12, 5879 – 5918; d) J. Le Bras, J. Muzart, Chem. Rev. 2011, 111,
170 – 1214; e) T. Satoh, M. Miura, Synthesis 2010, 3395 – 3409.
tion.
3] For recent reviews on ruthenium(II)-catalyzed CÀH bond
functionalizations, see: a) C. Bruneau, Top. Organomet. Chem.
2015, 48, 195 – 236; b) L. Ackermann, Org. Process Res. Dev.
2015, 19, 260 – 269; c) B. Li, P. H. Dixneuf, Chem. Soc. Rev. 2013,
that CO is formed during the course of the CÀH function-
2
alization process. These observations further highlighted the
considerable efficacy of the ruthenium(II) catalysis, with
more than 60% conversion in 4 hours at a comparably low
reaction temperature of only 1008C. In addition, mechanistic
studies provided strong support for a kinetically relevant CÀH
4
2
2, 5744 – 5767; d) L. Ackermann, R. Vicente, Top. Curr. Chem.
009, 292, 211 – 229, and references therein.
4] a) L. Ackermann, J. Pospech, Org. Lett. 2011, 13, 4153 – 4155;
b) L. Ackermann, J. Pospech, K. Graczyk, K. Rauch, Org. Lett.
2
012, 14, 930 – 933; c) M. Deponti, S. I. Kozhushkov, D. S. Yufit,
ruthenation event with a kinetic isotope effect (KIE) of k /k
H
D
L. Ackermann, Org. Biomol. Chem. 2013, 11, 142 – 148; see also:
d) R. K. Chinnagollaa, M. Jeganmohan, Chem. Commun. 2012,
48, 2030 – 2032; e) H. Zhao, T. Zhang, T. Yan, M. Cai, J. Org.
Chem. 2015, 80, 8849 – 8855.
[18]
ꢀ
2.6.
In summary, we have reported on unprecedented ruthe-
nium-catalyzed decarboxylative oxidative CÀH functionali-
[
[
5] a) A. Bechtoldt, C. Tirler, K. Raghuvanshi, S. Warratz, C.
Kornhaaß, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55, 264 –
zations which furnish meta-substituted arenes. Key to the
[19]
success was carboxylate assistance which allowed domino
decarboxylation/alkenylations in the absence of either
2
67; Angew. Chem. 2016, 128, 272 – 267; b) S. Warratz, C.
Kornhaaß, A. Cajaraville, B. Niepçtter, D. Stalke, L. Acker-
mann, Angew. Chem. Int. Ed. 2015, 54, 5513 – 5517; Angew.
Chem. 2015, 127, 5604 – 5608.
[20]
copper(II) or silver(I) salts at rather low reaction temper-
atures. The ruthenium(II) bis(carboxylate) catalysis is highly
chemo-, positional-, and regio-selective, and proceeds with
ample substrate scope, including substrates without an
activating ortho substituent. The unique versatility of the
ruthenium(II) bis(carboxylate) complex [Ru(O CMes) (p-
6] For reviews, see: a) J. Xuan, Z.-G. Zhang, W.-J. Xiao, Angew.
Chem. Int. Ed. 2015, 54, 15632 – 15641; Angew. Chem. 2015, 127,
1
5854 – 15864; b) W. I. Dzik, P. P. Lange, L. J. Gooßen, Chem.
Sci. 2012, 3, 2671 – 2678; c) J. Cornella, I. Larrosa, Synthesis 2012,
6
4
2
2
53 – 676; d) N. Rodríguez, L. J. Gooßen, Chem. Soc. Rev. 2011,
0, 5030 – 5048; e) J. D. Weaver, A. Recio, A. J. Grenning, J. A.
cymene)] is reflected in the two complementary protocols
for decarboxylative CÀH olefination which proved viable
Tunge, Chem. Rev. 2011, 111, 1846 – 1913; f) L. J. Gooßen, N.
Rodriguez, K. Gooßen, Angew. Chem. Int. Ed. 2008, 47, 3100 –
with both alkenes and alkynes.
3
120; Angew. Chem. 2008, 120, 3144 – 3164; g) L. J. Gooßen, K.
Gooßen, N. Rodriguez, M. Blanchot, C. Linder, B. Zimmer-
mann, Pure Appl. Chem. 2008, 80, 1725 – 1733.
7] For representative examples, see: a) D. Lee, S. Chang, Chem.
Eur. J. 2015, 21, 5364 – 5368; b) X. Qin, D. Sun, Q. You, Y.
Cheng, J. Lan, J. You, Org. Lett. 2015, 17, 1762 – 1765; c) K.
Yang, X. Chen, Y. Wang, W. Li, A. A. Kadi, H.-K. Fun, H. Sun,
Acknowledgments
[
Generous support by the European Research Council under
the European Communityꢀs Seventh Framework Program
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Communications
Chemie
Y. Zhang, G. Li, H. Lu, J. Org. Chem. 2015, 80, 11065 – 11072;
d) L. Chen, L. Ju, K. A. Bustin, J. M. Hoover, Chem. Commun.
[12] a) H. Tan, H. Li, J. Wang, L. Wang, Chem. Eur. J. 2015, 21, 1904 –
1907; b) X.-Y. Shi, X.-F. Dong, J. Fan, K.-Y. Liu, J.-F. Wei, C.-J.
Li, Sci. China Chem. 2015, 58, 1286 – 1291.
2
015, 51, 15059 – 15062; e) L. Luo, D. Wu, W. Li, S. Zhang, Y. Ma,
S. Yan, J. You, Org. Lett. 2014, 16, 6080 – 6083; f) K. RousØe, C.
Schneider, S. Couve-Bonnaire, X. Pannecoucke, V. Levacher, C.
Hoarau, Chem. Eur. J. 2014, 20, 15000 – 15004; g) K. Yang, C.
Zhang, P. Wang, Y. Zhang, H. Ge, Chem. Eur. J. 2014, 20, 7241 –
[13] For related transformations, see: a) L. Claes, J. Verduyckt, I.
Stassen, B. Lagrain, D. E. D. Vos, Chem. Commun. 2015, 51,
6528 – 6531; b) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan,
A. Lei, Angew. Chem. Int. Ed. 2014, 53, 502 – 506; Angew. Chem.
2
014, 126, 512 – 516; c) E. C. Burger, J. A. Tunge, Org. Lett. 2004,
7
2
244; h) P. Hu, M. Zhang, X. Jie, W. Su, Angew. Chem. Int. Ed.
012, 51, 227 – 231; Angew. Chem. 2012, 124, 231 – 235; i) C.
6, 2603 – 2605, and references therein.
[
14] a) M. Schinkel, I. Marek, L. Ackermann, Angew. Chem. Int. Ed.
013, 52, 3977 – 3980; Angew. Chem. 2013, 125, 4069 – 4072; b) L.
Wang, S. Rakshit, F. Glorius, J. Am. Chem. Soc. 2010, 132,
2
1
5
2
4006 – 14008; j) J. Cornella, P. Lu, I. Larrosa, Org. Lett. 2009, 11,
506 – 5509; k) C. Wang, I. Piel, F. Glorius, J. Am. Chem. Soc.
009, 131, 4194 – 4195; decarboxylative Mizoroki-Heck-type
Ackermann, P. Novak, R. Vicente, N. Hofmann, Angew. Chem.
Int. Ed. 2009, 48, 6045 – 6048; Angew. Chem. 2009, 121, 6161 –
6
164.
reactions: l) D. Tanaka, S. P. Romeril, A. G. Myers, J. Am.
Chem. Soc. 2005, 127, 10323 – 10333, and references therein.
8] a) S. Bhadra, W. I. Dzik, L. J. Gooßen, Angew. Chem. Int. Ed.
[
[
[
15] For an elegant study, see: L. J. Gooßen, N. Rodriguez, C. Linder,
P. P. Lange, A. Fromm, ChemCatChem 2010, 2, 430 – 442.
16] J. Li, S. D. Sarkar, L. Ackermann, Top. Organomet. Chem. 2016,
[
[
2
013, 52, 2959 – 2962; Angew. Chem. 2013, 125, 3031 – 3035; for
pioneering work: b) L. J. Gooßen, G. Deng, L. M. Levy, Science
006, 313, 662 – 664.
9] a) S. Mochida, K. Hirano, T. Satoh, M. Miura, J. Org. Chem.
011, 76, 3024 – 3033; b) S. Mochida, K. Hirano, T. Satoh, M.
5
5, 217 – 257.
17] Recent reviews on catalytic hydroarylation reactions, see: a) K.
2
Gao, N. Yoshikai, Acc. Chem. Res. Acc. Chem. Soc. 2014, 47,
1
208 – 1219; b) Y. Nakao, Chem. Rec. 2011, 11, 242 – 251; c) A.
2
Foley, J. P. Lee, Z. Ke, T. B. Gunnoe, T. R. Cundari, Acc. Chem.
Res. 2009, 42, 585 – 597; d) M. Bandini, E. Emer, S. Tommasi, A.
Umani-Ronchi, Eur. J. Org. Chem. 2006, 3527 – 3544; e) C. Liu,
C. F. Bender, X. Han, R. A. Widenhoefer, Chem. Commun.
Miura, Org. Lett. 2010, 12, 5776 – 5779; c) M. Yamashita, K.
Hirano, T. Satoh, M. Miura, Org. Lett. 2009, 11, 2337 – 2340;
d) A. Maehara, H. Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008,
1
0, 1159 – 1162.
10] a) J. Luo, S. Preciado, I. Larrosa, J. Am. Chem. Soc. 2014, 136,
109 – 4112; b) R. Grainger, J. Cornella, D. C. Blakemore, I.
2
2
007, 3607 – 3618; f) F. Kakiuchi, N. Chatani, Adv. Synth. Catal.
003, 345, 1077 – 1101, and references therein.
[
[
4
[
[
18] For detailed information, see the Supporting Information.
19] L. F. Tietze, G. Brasche, K. M. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006.
Larrosa, J. M. Campanera, Chem. Eur. J. 2014, 20, 16680 – 16687;
c) C. Arroniz, A. Ironmonger, G. Rassias, I. Larrosa, Org. Lett.
2
013, 15, 910 – 913; d) J. Cornella, M. Righi, I. Larrosa, Angew.
Chem. Int. Ed. 2011, 50, 9429 – 9432; Angew. Chem. 2011, 123,
601 – 9604.
11] Y. Zhang, H. Zhao, M. Zhang, W. Su, Angew. Chem. Int. Ed.
015, 54, 3817 – 3821; Angew. Chem. 2015, 127, 3888 – 3892.
[
20] J. Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev.
2
011, 40, 4740 – 4761.
9
Received: January 16, 2016
Published online: March 21, 2016
2
6
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