Aldehyde-Assisted Ruthenium(II)-Catalyzed C-H Oxygenations

Article abstract of DOI:10.1002/anie.201405647

Versatile ruthenium(II) complexes allow for site-selective C-H oxygenations with weakly-coordinating aldehydes. The challenging C-H functionalizations proceed with high chemoselectivity by rate-determining C-H metalation. The new method features an ample substrate scope, which sets the stage for the step-economical preparation of various bioactive heterocycles.

Full text of DOI:10.1002/anie.201405647

Angewandte
Chemie
DOI: 10.1002/anie.201405647
ꢀ
C H Activation
Hot Paper
ꢀ
Aldehyde-Assisted Ruthenium(II)-Catalyzed C H Oxygenations**
Fanzhi Yang, Karsten Rauch, Katharina Kettelhoit, and Lutz Ackermann*
Abstract: Versatile ruthenium(II) complexes allow for site-
ꢀ
selective C H oxygenations with weakly-coordinating alde-
ꢀ
hydes. The challenging C H functionalizations proceed with
ꢀ
high chemoselectivity by rate-determining C H metalation.
The new method features an ample substrate scope, which sets
the stage for the step-economical preparation of various
bioactive heterocycles.
ꢀ
T
he catalytic functionalization of unactivated C H bonds is
an increasingly viable method for organic synthesis.[1] In
ꢀ
ꢀ
particular, C H activations that lead to the formation of C O
bonds have recently provided step-economical access to
ꢀ
Scheme 1. Chemoselectivity in the C H activation of benzaldehyde.
substituted phenols.[2] Chelation-assisted C H oxygenations
were accomplished with the assistance of pyridine, ketoxime,
ꢀ
[a]
ꢀ
Table 1: Optimization of the aldehyde-assisted C H oxygenation.
or amide groups, for example, mostly utilizing palladium,
rhodium, or ruthenium catalysts.[1,2] C H oxygenations with
ꢀ
weakly coordinating directing groups pose a major chal-
lenge.[3,4] Notable recent progress was achieved by the use of
[5–7]
ꢀ
ketones for site-selective C H oxygenations.
In stark
ꢀ
Entry
[TM]
Additive
T [8C]
Yield [%]
contrast, C H oxygenations with significantly more challeng-
ing aldehydes have unfortunately proven elusive thus far,
despite the unique utility of the formyl group in organic
1a
II
2a
1
2
3
4
5
6
7
8
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[RuCl2(PPh3)3]
KOAc
AgSbF6
KPF6
–
80
80
80
80
80
80
80
50
100
120
100
100
100
100
44
51
35
32
51
51
69
73
26
26
12
37
79
70
32
9
3
5
synthesis.[8,9] The lack of available C H activation methods is
ꢀ
15
39
43
5
0
0
<2
47
40
72
0
likely due to the inherent tendency of aldehydes to undergo
facile overoxidation under the strongly oxidizing reaction
conditions of metal-catalyzed C H functionalizations (Sche-
9
–
–
–
–
–
–
–
–
16
34
5
9
3
3
2
38
14
11
ꢀ
RuCl3
–
me 1a). As part of our program on sustainable organic
synthesis,[1b,10] we herein present the first aldehyde-directed
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
[{RuCl2(p-cymene)}2]
Pd(OAc)2
ꢀ
C H oxygenation, which proved viable with highly selective
9
ruthenium(II)[11,12] catalysts (Scheme 1b). Notably, the versa-
tile ruthenium(II) catalysts override the inherent substrate-
controlled formyl oxidation by chelation-controlled aromatic
10
11[b]
12[b]
13[b]
14[b]
[Ni(acac)2]
[{RhCp*Cl2}2]
–
–
0
0
ꢀ
C H activation.
At the outset of our studies, we probed the chemoselective
C H oxygenation of aldehyde 1a (Table 1 and Table S1 in the
Supporting Information). Preliminary experiments identified
hypervalent iodine(III) reagents as the oxidants of choice.
[a] Reaction conditions: 1a (0.5 mmol), [TM] (5.0 mol%), additive
ꢀ
(20 mol%), PhI(OTFA)2 (1.0 equiv), DCE (2.0 mL), 8 h. Yields of isolated
products are given. [b] PhI(OTFA)2 (1.5 equiv). acac=acetylacetonate,
Cp*=pentamethylcyclopentadienyl, DCE=1,2-dichloroethane,
OTFA=trifluoroacetate.
Among
a variety of ruthenium complexes, [{RuCl2(p-
cymene)}2] provided optimal results, notably in the absence
of cocatalytic additives (entries 1–6), whereas the desired
product 2a was not obtained without a ruthenium catalyst
(entry 7). Superior results were obtained at a reaction tem-
perature of 1008C (entries 8–10) with PhI(OTFA)2 as the
terminal oxidant (entry 11). Intriguingly, the desired alde-
[*] M. Sc. F. Yang, K. Rauch, M. Sc. K. Kettelhoit, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
ꢀ
hyde-assisted C H oxygenation was not accomplished with
ꢀ
typical palladium, nickel, or rhodium C H functionalization
catalysts (entries 12–14)—a strong testament to the unique
[**] Generous support by the European Research Council under the
European Community’s Seventh Framework Program (FP7 2007–
2013; ERC Grant 307535), the CaSuS program, and the Chinese
Scholarship Program (fellowship to F.Y.) is gratefully acknowledged.
potential of mild ruthenium(II) catalysis.[13,14]
With the optimized reaction conditions in hand, we
ꢀ
probed the scope of the aldehyde-assisted C H oxygenation
with diversely decorated substrates 1 (Scheme 2). Avariety of
para-substituted benzaldehydes 1b–k provided the desired
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405647.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Scheme 3. Competition experiments with different aldehydes 1.
ꢀ
Scheme 2. Scope of the aldehyde-assisted C H oxygenation.
[a] [{RuCl2(p-cymene)}2] (5.0 mol%).
products with high chemoselectivities. Substrates 1l and 1m
displaying meta substituents gave the corresponding com-
pounds 2l and 2m as the sole products with excellent site
selectivity through functionalization of the less congested
ꢀ
C H bond. The more sterically hindered ortho-substituted
arenes 1n–s were converted with comparable catalytic
efficacy, whereas useful electrophilic halide functional
groups (F, Cl, Br) were well tolerated by the highly chemo-
selective ruthenium(II) catalyst.[15]
In light of the unique features of the aldehyde-assisted
ruthenium catalysis, we performed mechanistic studies to
delineate the catalystꢀs mode of action. To this end, inter-
molecular competition experiments between differently sub-
stituted substrates 1 indicated that electron-rich arenes
inherently react preferentially (Scheme 3). This observation
can, for instance, be rationalized in terms of an electrophilic
[16]
ꢀ
base-assisted C H ruthenation.
Scheme 4. Comparison of the directing group power.
Further intermolecular competition experiments between
arenes with different directing groups clearly highlighted the
challenges that are associated with the use of very weakly
coordinating aldehydes (Scheme 4a). Namely, amides, Wein-
reb amides, and even ketones were identified as significantly
the aldehyde carbonyl group is pre-coordinated to the active
ruthenium catalyst.[17]
Finally, we exploited the unique utility of the formyl group
ꢀ
ꢀ
more potent directing groups in the chelation-assisted C H
for the late-stage derivatization of the obtained C H
oxygenation. The excellent chemoselectivity was further
reflected by intramolecular competition experiments (Sche-
me 4b).
activation products 2. Importantly, aside from salen-[18–20] or
flavan-derived polyphenols,[21] a variety of bioactive hetero-
cycles could be accessed in a step-economical fashion,
including coumarin 5, chromene 6, benzopyran-4-one 7, and
the substituted benzofurans 8 and 9 (Scheme 6).[22,23]
ꢀ
Ruthenium-catalyzed C H oxygenations with isotopically
labelled substrate [D4]-1p revealed in independent experi-
ments an intermolecular kinetic isotope effect (KIE) of kH/kD
ꢁ 3.1 (Scheme 5a), which is suggestive of a kinetically
ꢀ
In summary, we have reported the first C H oxygenation
by assistance of very weakly coordinating aldehydes. A user-
friendly ruthenium(II) complex efficiently catalyzed the site-
selective hydroxylation of various benzaldehydes with ample
scope. The direct oxygenation occurred by a kinetically
ꢀ
relevant C H metalation step. The intramolecular KIE with
substrate [D1]-1x was determined to be kH/kD ꢁ 4.3 (Sche-
me 5b). The considerably different inter- and intramolecular
KIEs strongly suggest formation of an intermediate in which
ꢀ
relevant C H metalation, and the products thus obtained
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
ꢀ
Keywords: aldehydes · C H activation · chemoselectivity ·
oxygenation · ruthenium
.
ꢀ
[1] For representative recent reviews on C H activation, see:
a) S. A. Girard, T. Knauber, C.-J. Li, Angew. Chem. Int. Ed.
2014, 53, 74 – 100; Angew. Chem. 2014, 126, 76 – 103; b) L.
Ackermann, Acc. Chem. Res. 2014, 47, 281 – 295; c) J. Wencel-
Delord, F. Glorius, Nat. Chem. 2013, 5, 369 – 375; d) K. M. Engle,
T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788 – 802;
e) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212 – 11222; f) L.
Ackermann, R. Vicente, A. Kapdi, Angew. Chem. Int. Ed. 2009,
48, 9792 – 9826; Angew. Chem. 2009, 121, 9976 – 10011; g) J. C.
Lewis, R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2008, 41,
1013 – 1025; h) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev.
2007, 107, 174 – 238; i) R. G. Bergman, Nature 2007, 446, 391 –
393, and references therein.
Scheme 5. Studies of the kinetic isotope effect.
[2] For recent reviews, see: a) V. S. Thirunavukkarasu, S. I. Koz-
hushkov, L. Ackermann, Chem. Commun. 2014, 50, 29 – 39; b) S.
Enthaler, A. Company, Chem. Soc. Rev. 2011, 40, 4912 –
4924; c) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010,
110, 1147 – 1169, and references therein.
[3] K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem.
Res. 2012, 45, 788 – 802.
ꢀ
[4] For
a
recent review on ruthenium-catalyzed C H
functionalizations with weakly coordinating directing
groups, see: S. D. Sarkar, W. Liu, S. I. Kozhushkov, L.
Ackermann, Adv. Synth. Catal. 2014, 356, 1461 – 1479,
and references therein.
[5] V. S. Thirunavukkarasu, L. Ackermann, Org. Lett. 2012,
14, 6206 – 6209.
[6] G. Shan, X. Yang, L. Ma, Y. Rao, Angew. Chem. Int. Ed.
2012, 51, 13070 – 13074; Angew. Chem. 2012, 124,
13247 – 13251.
[7] F. Mo, L. J. Trzepkowski, G. Dong, Angew. Chem. Int.
Ed. 2012, 51, 13075 – 13079; Angew. Chem. 2012, 124,
13252 – 13256.
[8] R. C. Larock, Comprehensive Organic Transformations,
2nd ed., Wiley-VCH, Weinheim, 1999.
[9] X.-F. Wu, X. Fang, L. Wu, R. Jackstell, H. Neumann, M.
Beller, Acc. Chem. Soc. 2014, 47, 1041 – 1053.
[10] L. Ackermann, Pure Appl. Chem. 2010, 82, 1403 – 1413.
Scheme 6. Modification of products 2. Reaction conditions: a) 1) Ph3PCH3Br,
KOtBu, THF, 238C, 2 h, followed by 2z, ꢀ788C!238C, 20 h; 2) acryloyl
chloride, NEt3, CH2Cl2, 238C, 16 h; 3) Grubbs’ 2nd generation catalyst, CH2Cl2,
458C, 24 h. b) 1) 2z, MeI, NaH, THF, DMF, 08C, 2 h, then 238C, 12 h;
ꢀ
[11] For recent reviews on ruthenium-catalyzed C H bond
=
2) Ph3P CHCO2Et, CH2Cl2, 408C, 3 h; 3) BBr3, CH2Cl2, 508C, 5 h. c) 1) 2z, 3-
functionalizations, see: a) S. I. Kozhushkov, L. Acker-
mann, Chem. Sci. 2013, 4, 886 – 896; b) B. Li, P. H.
Dixneuf, Chem. Soc. Rev. 2013, 42, 5744 – 5767; c) P. B.
Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012,
112, 5879 – 5918; d) L. Ackermann, R. Vicente, Top.
Curr. Chem. 2010, 292, 211 – 229, and references therein.
For bond dissociation energies, see: e) S. J. Blanksby,
G. B. Ellison, Acc. Chem. Res. 2003, 36, 255 – 263.
bromopropene, K2CO3, acetone, 608C, 2 h; 2) Ph3PCH3Br, NaH, THF, 08C!
238C, 2 h; 3) Grubbs’ 1st generation catalyst, CH2Cl2, 238C, 2 h. d) 1) 2z,
1-hexyne, nBuLi, THF, ꢀ788C, 1 h; 2) MnO2, CH2Cl2, 238C, 1 h; K2CO3, acetone,
708C, 1 h. e) 1) 2z, NH4OAc, AcOH, MeNO2, 1358C, 3 h; 2) NaBH4, 1,4-
dioxane, EtOH, 08C, 1 h; 3) Bu4NI, NEt3, PhI(OAc)2, MeCN, 358C, 30 min.
f) 1) PPh3, CBr4, CH2Cl2, 08C, 10 min, followed by NEt3, 2z, 08C, 30 min, then
238C, 1 h; 2) PhB(OH)2, Pd(OAc)2 (5.0 mol%), CuI (5.0 mol%), PPh3, K3PO4,
1,4-dioxane, 1008C, 24 h.
[12] For selected recent examples of ruthenium-catalyzed
ꢀ
C H functionalizations, see: a) V. P. Mehta, J.-A.
Garcia-Lopez, M. F. Greaney, Angew. Chem. Int. Ed.
2014, 53, 1529 – 1533; Angew. Chem. 2014, 126, 1555 –
were easily converted into various valuable heterocycles. The
high catalytic activity and unique chemoselectivity of the
1559; b) A. Tlili, J. Schranck, J. Pospech, H. Neumann, M. Beller,
Angew. Chem. Int. Ed. 2013, 52, 6293 – 6297; Angew. Chem. 2013,
125, 6413 – 6417; c) N. Hofmann, L. Ackermann, J. Am. Chem.
Soc. 2013, 135, 5877 – 5884; d) J. Nan, Z. Zuo, L. Luo, L. Bai, H.
Zheng, Y. Yuan, J. Liu, X. Luan, Y. Wang, J. Am. Chem. Soc.
2013, 135, 17306 – 17309; e) J. Zhang, A. Ugrinov, P. Zhao,
Angew. Chem. Int. Ed. 2013, 52, 6681 – 6684; Angew. Chem.
2013, 125, 6813 – 6816; f) K. Padala, M. Jeganmohan, Org. Lett.
2012, 14, 1134 – 1137; g) S. Reddy Chidipudi, I. Khan, H. W.
Lam, Angew. Chem. Int. Ed. 2012, 51, 12115 – 12119; Angew.
Chem. 2012, 124, 12281 – 12285; h) L. Ackermann, A. V. Lygin,
N. Hofmann, Angew. Chem. Int. Ed. 2011, 50, 6379 – 6382;
ꢀ
ruthenium(II) complexes in the challenging C H oxygen-
ation with weak aldehyde coordination illustrate the remark-
able power of versatile and mild ruthenium(II) catalysis for
ꢀ
the selective functionalization of unactivated C H bonds.
Received: May 26, 2014
Revised: July 25, 2014
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Angew. Chem. 2011, 123, 6503 – 6506; i) P. B. Arockiam, C.
Fischmeister, C. Bruneau, P. H. Dixneuf, Angew. Chem. Int. Ed.
2010, 49, 6629 – 6632; Angew. Chem. 2010, 122, 6779 – 6782; j) L.
Ackermann, A. Althammer, R. Born, Angew. Chem. Int. Ed.
2006, 45, 2619 – 2622; Angew. Chem. 2006, 118, 2681 – 2685; k) F.
Kakiuchi, T. Sato, K. Igi, N. Chatani, S. Murai, Chem. Lett. 2001,
386 – 387; for examples of direct oxygenations, see: l) X. Yang, G.
Shan, Y. Rao, Org. Lett. 2013, 15, 2334 – 2337; m) V. S. Thiruna-
vukkarasu, J. Hubrich, L. Ackermann, Org. Lett. 2012, 14, 4210 –
4213, and references therein.
[15] 4-Nitrobenzaldehyde has provided only unsatisfactory results
thus far. Heteroaromatic aldehydes, such as pyridyl or thio-
phenyl derivatives, were not converted by the ruthenium
catalyst, whereas an indole carbaldehyde reacted unselectively.
[16] L. Ackermann, Chem. Rev. 2011, 111, 1315 – 1345.
[17] W. D. Jones, F. J. Feher, Acc. Chem. Res. 1989, 22, 91 – 100.
[18] T. Katsuki, Coord. Chem. Rev. 1995, 140, 189 – 214.
[19] E. N. Jacobsen, Acc. Chem. Soc. 2000, 33, 421 – 431.
[20] M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Science
1997, 277, 936 – 938.
[13] Minor amounts of 3-chloro-4-methoxybenzaldehyde were also
[21] K. Ohmori, Chem. Rec. 2011, 11, 252 – 259.
ꢀ
isolated as side products in all of the C H oxygenations.
[14] Under otherwise identical reaction conditions, 1.25 mol% of the
[22] For detailed information, see the Supporting Information.
[23] S. G. Newman, V. Aureggi, C. S. Bryan, M. Lautens, Chem.
Commun. 2009, 5236 – 5238.
ruthenium catalyst delivered product 2a in 43% yield.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
ꢀ
C H Activation
F. Yang, K. Rauch, K. Kettelhoit,
L. Ackermann*
&&&& — &&&&
Aldehyde-Assisted Ruthenium(II)-
ꢀ
Catalyzed C H Oxygenations
ꢀ
The weakest link: Challenging aryl C H
catalysts under mild reaction conditions.
oxygenations with very weakly coordinat-
ing aldehydes proceed chemoselectively
in the presence of versatile ruthenium(II)
This transformation features an ample
substrate scope and excellent positional
selectivity.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!