Ruthenium Oxidase Catalysis for Site-Selective C-H Alkenylations with Ambient O2 as the Sole Oxidant

Article abstract of DOI:10.1002/anie.201507801

Ruthenium(II) oxidase catalysis by direct dioxygen-coupled turnover enabled step-economical oxidative C-H alkenylation reactions at ambient pressure. Versatile ruthenium(II) biscarboxylate catalysts displayed ample substrate scope and proved applicable to

Full text of DOI:10.1002/anie.201507801

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201507801
German Edition: DOI: 10.1002/ange.201507801
À
C H Activation
Ruthenium Oxidase Catalysis for Site-Selective C–H Alkenylations
with Ambient O2 as the Sole Oxidant
Alexander Bechtoldt, Carina Tirler, Keshav Raghuvanshi, Svenja Warratz, Christoph Kornhaaß,
and Lutz Ackermann*
In memory of Jonas Bang
Abstract: Ruthenium(II) oxidase catalysis by direct dioxygen-
a removable directing group.[8] In contrast, we have very
recently identified the beneficial effect of carboxylates[9] for
aerobic alkyne annulations.[10] Within our program on sus-
À
coupled turnover enabled step-economical oxidative C H
alkenylation reactions at ambient pressure. Versatile
ruthenium(II) biscarboxylate catalysts displayed ample sub-
strate scope and proved applicable to weakly coordinating and
tainable C H functionalizations,[11] we herein report the first
À
ruthenium(II)-catalyzed positional selective alkenylations
with O2 as the sole oxidant. Notable features of the versatile
ruthenium oxidase catalysis by direct dioxygen-coupled
turnover include: a) an unparalleled broad substrate scope
À
removable directing groups. The twofold C H functionaliza-
tion strategy was characterized by exceedingly mild reaction
conditions as well as excellent positional selectivity.
À
in aerobic alkenylations, b) sustainable aerobic C H activa-
[1]
À
O
xidative alkenylation by twofold C H activation argu-
tions that produce H2O as the only by-product, c) exceedingly
mild reaction conditions, and d) oxidative olefinations with
weakly coordinating[12] or removable[13] directing groups
(DG; Figure 1). As to the reaction mechanism, we provide
ably represents the most efficient and step-economical
strategy for the assembly of selectively substituted olefins.[2]
Based on pioneering studies by Fujiwara and Moritani,[3]
tremendous progress has been made in metal-catalyzed
cross-dehydrogenative olefinations, most notably in the area
of palladium catalysis.[2,4] In contrast, versatile ruthenium(II)
complexes[5] have only recently emerged as powerful catalysts
for oxidative C H functionalizations. Despite these indis-
putable advances, ruthenium(II)-catalyzed oxidative alkeny-
lations using chelation assistance have been thus far limited to
the use of antibacterial copper(II) or expensive silver(I) salts
as the oxidants.[6] Thereby, undesired metal waste is gener-
[6]
À
À
ated, which contradicts the sustainable nature of C H
activation technology. A notable elegant exception was
developed by Milstein and co-workers, which indicated the
potential of ruthenium catalysis.[7] Unfortunately, the catalyst
was severely limited to rather harsh reaction conditions, such
as high pressure reactions with CO at 8 atm and a reaction
temperature of 1808C. Moreover, mixtures of regioisomeric
products which were difficult to separate were largely
obtained when using substituted arenes.[7] As a consequence,
there is a strong demand for ruthenium-catalyzed aerobic
À
Figure 1. Ruthenium oxidase catalysis for C H alkenylations.
strong support for a ruthenium oxidase catalysis manifold. It
is also noteworthy that aerobic C H alkenylations with more
costly rhodium(III) complexes required strongly coordinating
N-directing groups and thus far have not been accomplished
with removable auxiliaries.[14]
À
We commenced our studies by exploring various reaction
À
À
C H functionalizations with positional selectivity under mild
reaction conditions. In this context, Rueping and co-workers
conditions for the aerobic C H alkenylation of tosylbenz-
amide 1a with alkene 2a[15] under an atmosphere of ambient
oxygen (Table 1; Table S1 in the Supporting Information). We
were pleased to observe that the unprecedented ruthenium-
À
elegantly merged photoredox catalysis and C H activation
catalysts for simple and general aerobic alkenylations with
À
(II)-catalyzed domino C H alkenylation proved viable in the
À
absence of copper(II) or silver(I) oxidants. The aerobic C H
[*] A. Bechtoldt, C. Tirler, K. Raghuvanshi, S. Warratz, C. Kornhaaß,
Prof. Dr. L. Ackermann
functionalization proceeded most efficiently in the absence of
a solvent (cf. entry 5 with entries 1–4). Among different
acetate additives, KOAc was identified as being optimal (cf.
entry 5 with entry 6). Furthermore, we verified that the
ruthenium catalyst and the metal carboxylate were essential
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
À
for the C H activation process (entries 7 and 8).
Thereafter, we probed the versatility of the ruthenium(II)
carboxylate catalyst in the aerobic assembly of isoindolinones
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507801.
264
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 264 –267

Angewandte
Communications
Chemie
Table 1: Aerobic ruthenium(II)-catalyzed alkenylation with amide 1a.[a]
Entry
Solvent
MOAc
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
MeOH
DMF
DMF
DMF
–
–
–
–
CsOAc
CsOAc
CsOAc
KOAc
CsOAc
KOAc
CsOAc
–
80
80
30
20
26
100
100
100
100
100
100
35
68[b]
86[b]
[c]
–
–
[a] Reactions conditions: 1a (0.50 mmol), 2a (1.5 mmol), [{RuCl2(p-
cymene)}2] (5.0 mol%), MOAc (1.0 equiv), solvent (2.0 mL), 1008C,
18 h, O2 (1 atm), yield of isolated product. [b] 2a (2.5 mmol).[c] In the
absence of [{RuCl2(p-cymene)}2]. DMF=dimethylformamide;
p-cymene=4-isopropyltoluene; Ts=tosyl.
À
Scheme 2. Oxidase catalysis for C H alkenylation with a removable
DG. py=pyridyl; Mes=mesityl.
used to successfully catalyze reactions with excellent chemo-
and positional selectivity.
Even challenging, weakly coordinating benzoic acids 6
proved to be suitable substrates.[18] Here, KOAc and CsOAc
emerged as the ideal additives, which even allowed for
À
aerobic C H functionalization to occur under ambient air or
at a reaction temperature of 258C (Table 2; Table S3).
Thereby, differently functionalized benzoic acids 6 proved
amenable for the step-economical synthesis of phthalides 7[19]
(Scheme 3)—key structural motifs in numerous bioactive
natural products.[20] The outstanding chemoselectivity of the
ruthenium(II) catalyst was reflected by the successful prep-
aration of phthalides 7aa–7gb displaying reactive bromo and
[a]
À
Table 2: Oxidase catalysis for C H alkenylation of acid 6a.
Scheme 1. Aerobic ruthenium(II)-catalyzed assembly of isoindolinones
3. [a] KOAc instead of CsOAc.
3 (Scheme 1). The oxidative cascade reaction occurred
smoothly with ortho-substituted N-tosylamides 1a–1 f bearing
synthetically useful functional groups, such as nitro or halo
substituents. However, the ruthenium oxidase catalysis was
Entry
Solvent
MOAc
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
EtOH
tAmOH
nBuOH
nBuOH
nBuOH
MeOH
MeOH
CsOAc
KOAc
NaOAc
–
KOAc
KOAc
CsOAc
KOAc
KOAc
KOAc
KOAc
60
60
60
60
60
60
60
80
80
37
25
82
88
74
–
78
67
90
90
À
not restricted to ortho-substituted amides 1. Indeed, the C H
functionalization with meta- or para-substituted arenes 1g–1k
proceeded with excellent positional selectivity as well, with
the latter transformations occurring at the less sterically
À
hindered C H bonds.
9
10
11
77[b]
82[c]
53[c]
The versatile ruthenium(II) oxidase catalysis was not
limited to the preparation of benzannulated heterocycles 3.
À
Indeed, the aerobic C H functionalization also enabled
[a] Reactions conditions: 1a (2.00 mmol), 2b (1.0–1.1 mmol), [{RuCl2(p-
cymene)}2] (5.0 mol%), MOAc (1.0 equiv), solvent (3.0 mL), 608C, 18 h,
O2 (1 atm), yield of isolated product. [b] Under air (1 atm). [c] 2.5 days.
tAmOH=2-methyl-2-butanol.
aerobic alkenylations of phenol derivatives 4[16] having
a removable directing group (Scheme 2; Table S2). Thus,
single-component ruthenium(II) biscarboxylates[17] could be
Angew. Chem. Int. Ed. 2016, 55, 264 –267
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
265

Angewandte
Communications
Chemie
À
redox-neutral, C H metalation with ruthenium(II) biscar-
boxylate 8, thereby furnishing cyclometalated intermediate 9
(Scheme 4). Thereafter, migratory alkene insertion delivers
metallacyle 11, which upon b-hydride elimination furnishes
the ruthenium(II) hydrido complex 12. Reductive elimination
Scheme 3. Aerobic ruthenium(II)-catalyzed synthesis of phthalides 7.
iodo substituents among others, which should prove instru-
mental for further postsynthetic diversifications.
To probe the aerobic nature of the ruthenium(II)-
À
catalyzed C H activation process, we investigated the
oxygen uptake during the course of the domino annulation
(Figure 2). Our studies clearly showed that O2 served as the
À
Scheme 4. Proposed catalytic cycle for ruthenium oxidase C H alkeny-
lation. L=ligand.
subsequently leads to the ruthenium(0) intermediate 13,
which is oxidized by molecular oxygen at ambient pressure.
The desired benzannulated product 3 is finally formed
through an intramolecular aza-Michael reaction.
In summary, we have reported on ruthenium(II)-cata-
lyzed oxidative alkenylation reactions with ambient oxygen as
the sole oxidant under exceedingly mild[21] reaction condi-
tions. The ruthenium oxidase catalysis occurred with ample
substrate scope, and thus allowed for the olefination of arenes
with weakly coordinating or removable directing groups
À
À
through twofold C H functionalizations. The aerobic C H
functionalization was characterized by user-friendly reaction
conditions, even enabling oxidative olefinations even at
ambient pressure at 258C. Finally, the green and sustainable
nature of our oxidase catalysis approach was reflected by the
production of water as the sole by-product.
À
Figure 2. Oxygen consumption during ruthenium(II)-catalyzed C H
activation.
À
sole terminal oxidant in the C H functionalization process
with a direct dioxygen-coupled turnover. These findings also
highlighted the efficacy of the oxidase catalysis, with 90%
conversion of substrate 6a in less than 4 hours. Additionally,
mechanistic studies provided strong support for a rate-
Acknowledgements
Generous support by the European Research Council under
the European Communityꢀs Seventh Framework Program
FP7 2007–2013 (ERC Grant agreement no. 307535), the
DAAD (fellowship to K.R.), and the CaSuS PhD program is
gratefully acknowledged.
À
determining C H ruthenation event with a kinetic isotope
effect (KIE) of kH/kD ꢀ 3.0.[18]
Based on our mechanistic studies, we propose the aerobic
À
C H alkenylation to be initiated by an isohypsic, that is,
266
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 264 –267

Angewandte
Communications
Chemie
À
[9] a) S. D. Sarkar, W. Liu, S. I. Kozhushkov, L. Ackermann, Adv.
Keywords: alkenes · C H activation · oxidation · ruthenium ·
synthetic methods
Synth. Catal. 2014, 356, 1461 – 1479; b) B. Li, T. Roisnel, C.
Darcel, P. H. Dixneuf, Dalton Trans. 2012, 41, 10934 – 10937;
c) E. F. Flegeau, C. Bruneau, P. H. Dixneuf, A. Jutand, J. Am.
Chem. Soc. 2011, 133, 10161 – 10170; d) L. Ackermann, Chem.
Rev. 2011, 111, 1315 – 1345; e) P. B. Arockiam, C. Fischmeister,
C. Bruneau, P. H. Dixneuf, Angew. Chem. Int. Ed. 2010, 49,
6629 – 6632; Angew. Chem. 2010, 122, 6779 – 6782; f) Y. Bouta-
dla, D. L. Davies, S. A. Macgregor, A. I. Poblador-Bahamonde,
Dalton Trans. 2009, 5820 – 5831; g) L. Ackermann, R. Vicente,
A. Althammer, Org. Lett. 2008, 10, 2299 – 2302.
How to cite: Angew. Chem. Int. Ed. 2016, 55, 264–267
Angew. Chem. 2016, 128, 272–275
À
[1] For representative recent reviews on C H activation, see: a) B.
Ye, N. Cramer, Acc. Chem. Res. 2015, 48, 1308 – 1318; b) J. Li, S.
De Sarkar, L. Ackermann, Top. Organomet. Chem. 2015, DOI:
10.1007/3418_2015_130; c) K. Shin, H. Kim, S. Chang, Acc.
Chem. Res. 2015, 48, 1040 – 1052; d) O. Daugulis, J. Roane, L. D.
Tran, Acc. Chem. Res. 2015, 48, 1053 – 1064; e) Y. Segawa, T.
Maekawa, K. Itami, Angew. Chem. Int. Ed. 2015, 54, 66 – 81;
Angew. Chem. 2015, 127, 68 – 83; f) N. Kuhl, N. Schroeder, F.
Glorius, Adv. Synth. Catal. 2014, 356, 1443 – 1460; g) T. Mesga-
naw, J. A. Ellman, Org. Process Res. Dev. 2014, 18, 1097 – 1104;
h) S. Tani, T. N. Uehara, J. Yamaguchi, K. Itami, Chem. Sci. 2014,
5, 123 – 135; i) S. A. Girard, T. Knauber, C.-J. Li, Angew. Chem.
Int. Ed. 2014, 53, 74 – 100; Angew. Chem. 2014, 126, 76 – 103; j) L.
Ackermann, J. Org. Chem. 2014, 79, 8948 – 8954; k) E. Naka-
mura, T. Hatakeyama, S. Ito, K. Ishizuka, L. Ilies, M. Nakamura,
Org. React. 2014, 83, 1 – 209; l) K. Gao, N. Yoshikai, Acc. Chem.
Res. 2014, 47, 1208 – 1219; m) G. Rouquet, N. Chatani, Angew.
Chem. Int. Ed. 2013, 52, 11726 – 11743; Angew. Chem. 2013, 125,
11942 – 11959; n) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013,
5, 369 – 375; o) D. J. Schipper, K. Fagnou, Chem. Mater. 2011, 23,
1594 – 1600; p) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
1215 – 1292; q) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16,
11212 – 11222; r) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q.
Yu, Chem. Soc. Rev. 2009, 38, 3242 – 3272; s) L. Ackermann, R.
Vicente, A. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792 – 9826;
Angew. Chem. 2009, 121, 9976 – 10011; t) X. Chen, K. M. Engle,
D.-H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094 –
5115; Angew. Chem. 2009, 121, 5196 – 5217; u) R. G. Bergman,
Nature 2007, 446, 391 – 393, and references therein.
[10] S. Warratz, C. Kornhaaß, A. Cajaraville, B. Niepçtter, D. Stalke,
L. Ackermann, Angew. Chem. Int. Ed. 2015, 54, 5513 – 5517;
Angew. Chem. 2015, 127, 5604 – 5608.
[11] a) L. Ackermann, Acc. Chem. Res. 2014, 47, 281 – 295; b) L.
Ackermann, Pure Appl. Chem. 2010, 82, 1403 – 1413.
[12] K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012,
45, 788 – 802.
[13] a) F. Zhang, D. R. Spring, Chem. Soc. Rev. 2014, 43, 6906 – 6919;
b) G. Rousseau, B. Breit, Angew. Chem. Int. Ed. 2011, 50, 2450 –
2494; Angew. Chem. 2011, 123, 2498 – 2543.
[14] a) G. Zhang, L. Yang, Y. Wang, Y. Xie, H. Huang, J. Am. Chem.
Soc. 2013, 135, 8850 – 8853. See also: b) L. Yang, G. Zhang, H.
Huang, Adv. Synth. Catal. 2014, 356, 1509 – 1515; c) G. Zhang, H.
Yu, G. Qin, H. Huang, Chem. Commun. 2014, 50, 4331 – 4334.
[15] For rhodium-catalyzed reactions, see: a) C. Zhu, J. R. Falck, Org.
Lett. 2011, 13, 1214 – 1217; b) C. Zhu, J. R. Falck, Chem.
Commun. 2012, 48, 1674 – 1676.
[16] a) H. Kinuta, M. Tobisu, N. Chatani, J. Am. Chem. Soc. 2015,
137, 1593 – 1600; b) B. Liu, H.-Z. Jiang, B.-F. Shi, J. Org. Chem.
2014, 79, 1521 – 1526; c) W. Ma, L. Ackermann, Chem. Eur. J.
2013, 19, 13925 – 13928.
[17] a) L. Ackermann, P. Novµk, R. Vicente, N. Hofmann, Angew.
Chem. Int. Ed. 2009, 48, 6045 – 6048; Angew. Chem. 2009, 121,
6161 – 6164; b) L. Ackermann, J. Pospech, H. K. Potukuchi, Org.
Lett. 2012, 14, 2146 – 2149.
À
[2] For recent reviews that feature C H olefinations, see: a) L.
[18] For detailed information, see the Supporting Information.
[19] Copper(II) salts have been used as (co)-oxidants in phthalide
syntheses. For examples with ruthenium catalysts, see: a) H.
Zhao, T. Zhang, T. Yan, M. Cai, J. Org. Chem. 2015, 80, 8849 –
8855; b) L. Ackermann, J. Pospech, Org. Lett. 2011, 13, 4153 –
4155; Rhodium: c) K. Ueura, T. Satoh, M. Miura, Org. Lett.
2007, 9, 1407 – 1409; Palladium: d) M. Miura, T. Tsuda, T. Satoh,
S. Pivsa-Art, M. Nomura, J. Org. Chem. 1998, 63, 5211 – 5215.
[20] For selected reviews, see: a) M. C. Willis, Angew. Chem. Int. Ed.
2010, 49, 6026 – 6027; Angew. Chem. 2010, 122, 6162 – 6164;
b) J. J. Beck, S.-C. Chou, J. Nat. Prod. 2007, 70, 891 – 900, and
references therein. For representative reports, see: c) K. Tian-
panich, S. Prachya, S. Wiyakrutta, C. Mahidol, S. Ruchirawat, P.
Kittakoop, J. Nat. Prod. 2011, 74, 79 – 81; d) K. Yoshikawa, N.
Kokudo, T. Hashimoto, K. Yamamoto, T. Inose, T. Kimura, Biol.
Pharm. Bull. 2010, 33, 1355 – 1359; e) Z. Ye, G. Lv, W. Wang, M.
Zhang, J. Cheng, Angew. Chem. Int. Ed. 2010, 49, 3671 – 3674;
Angew. Chem. 2010, 122, 3753 – 3756; f) M. Singh, N. P. Argade,
J. Org. Chem. 2010, 75, 3121 – 3124, and references therein.
[21] J. Wencel-Delord, T. Droege, F. Liu, F. Glorius, Chem. Soc. Rev.
2011, 40, 4740 – 4761.
Zhou, W. Lu, Chem. Eur. J. 2014, 20, 634 – 642; b) P. B.
Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112,
5879 – 5918; c) J. Le Bras, J. Muzart, Chem. Rev. 2011, 111, 1170 –
1214; d) T. Satoh, M. Miura, Synthesis 2010, 3395 – 3409.
[3] a) I. Moritani, Y. Fujiwara, Tetrahedron Lett. 1967, 8, 1119 –
1122; b) C. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res.
2001, 34, 633 – 639.
[4] S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400 – 3420; Angew.
Chem. 2004, 116, 3480 – 3501.
À
[5] For recent reviews on ruthenium(II)-catalyzed C H bond
functionalizations, see: a) L. Ackermann, Org. Process Res.
Dev. 2015, 19, 260 – 269; b) C. Bruneau, Top. Organomet. Chem.
2015, 48, 195 – 236; c) V. S. Thirunavukkarasu, S. I. Kozhushkov,
L. Ackermann, Chem. Commun. 2014, 50, 29 – 39; d) B. Li, P. H.
Dixneuf, Chem. Soc. Rev. 2013, 42, 5744 – 5767; e) L. Acker-
mann, R. Vicente, Top. Curr. Chem. 2009, 292, 211 – 229, and
references therein.
[6] S. I. Kozhushkov, L. Ackermann, Chem. Sci. 2013, 4, 886 – 896.
[7] H. Weissman, X. Song, D. Milstein, J. Am. Chem. Soc. 2001, 123,
337 – 338.
[8] a) D. C. Fabry, J. Zoller, S. Raja, M. Rueping, Angew. Chem. Int.
Ed. 2014, 53, 10228 – 10231; Angew. Chem. 2014, 126, 10392 –
10396; b) D. C. Fabry, M. A. Ronge, J. Zoller, M. Rueping,
Angew. Chem. Int. Ed. 2015, 54, 2801 – 2805; Angew. Chem.
2015, 127, 2843 – 2847.
Received: August 20, 2015
Revised: September 27, 2015
Published online: October 22, 2015
Angew. Chem. Int. Ed. 2016, 55, 264 –267
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
267