Oxidative alkenylation of aromatic esters by ruthenium-catalyzed twofold C-H bond cleavages

Article abstract of DOI:10.1021/ol301759v

Cationic ruthenium(II) complexes enabled catalytic twofold C-H bond functionalizations with weakly coordinating aromatic esters in a highly chemo-, site- and diastereo-selective as well as site selective fashion. The oxidative Fujiwara-Moritani-type alkenylation provided step-economical access to diversely substituted styrenes and proved viable in an aerobic manner. Mechanistic studies were indicative of a reversible acetate-assisted cycloruthenation step.

Full text of DOI:10.1021/ol301759v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Oxidative Alkenylation of Aromatic Esters
by Ruthenium-Catalyzed Twofold CÀH
Bond Cleavages
Karolina Graczyk, Wenbo Ma, and Lutz Ackermann*
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received June 27, 2012
ABSTRACT
Cationic ruthenium(II) complexes enabled catalytic twofold CÀH bond functionalizations with weakly coordinating aromatic esters in a highly
chemo-, site- and diastereo-selective as well as site selective fashion. The oxidative FujiwaraÀMoritani-type alkenylation provided step-
economical access to diversely substituted styrenes and proved viable in an aerobic manner. Mechanistic studies were indicative of a reversible
acetate-assisted cycloruthenation step.
Styrene derivatives are useful intermediates in synthetic
organic chemistry, and one of their most atom- and step-
economical syntheses exploits catalyzed CÀH bond
functionalizations.1 While early studies revealedpalladium
complexes as effective catalysts,2 important recent pro-
gress was achieved by inter alia Miura and Satoh, Yu, Li,
and Glorius with the development of versatile protocols
for selective palladium- and rhodium-catalyzed cross-
dehydrogenative alkenylations.3 In contrast, rather inex-
pensive ruthenium complexes have only recently been
exploited as catalysts for oxidative CÀH bond alkenyla-
tions on arenes.4,5 While these chelation-assisted reactions
were site selectively accomplished utilizing benzamides or
benzoic acids, ruthenium-catalyzed6 oxidative7 alkenyla-
tions with readily available, yet only weakly coordinating
esters have thus far proven elusive (Scheme 1).
Scheme 1. Ruthenium-Catalyzed Double CÀH Bond Functio-
nalizations
(1) Illustrative reviews on CÀH bond functionalizations: (a) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–1292. (b) Wencel-
€
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
4740–4761. (c) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem.
2010, 8, 4503–4513. (d) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84.
(e) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–685. (f)
Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1119–1126. (g) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (h)
Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde,
A. I. Dalton Trans. 2009, 5820–5831. (i) Ackermann, L.; Vicente, R;
Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792–9826 and references
cited therein.
(2) (a) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 8, 1119–
1122. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
633–639. Early reports on rhodium-catalyzed oxidative alkenylations:
(c) Matsumoto, T.; Yoshida, H. Chem. Lett. 2000, 29, 1064–1065.
(d) Matsumoto, T.; Periana, R. A.; Taube, D. J.; Yoshida, H. J. Catal.
2002, 206, 272–280.
Within our research program on the use of CÀH bonds
as latent functional groups in organic synthesis,8 we thus
became attracted by cross-dehydrogenative alkenylations
of aromatic esters and, particularly, by devising challen-
ging intermolecular twofold CÀH bond functionalizations
r
10.1021/ol301759v
XXXX American Chemical Society

between two different esters in a chemoselective fashion.
Herein, we wish to disclose our9 findings on the develop-
ment of versatile ruthenium-catalyzed oxidative alkenyla-
tions of easily modifiable (hetero)aromatic esters, which
were even achieved in an aerobic manner. Furthermore, we
present the first detailed mechanistic studies, providing
strong support for a reversible CÀH bond ruthenation step.
We commenced our studies by probing a variety of
cocatalytic additives and solvents for the envisioned two-
fold CÀH bond functionalization between aromatic ester
salts, with AgSbF6 proving to be optimal (entries 5À8).10
Notably, the use of CuBr2 as the oxidant did not deliver the
desired product 3a (entry 9), thereby indicating carboxy-
late assistance to be of relevance.11 Among a variety of
solvents, DCE was found to allow the most efficient
catalysis (entries 8À14). It is furthermore noteworthy that
the catalyzed double CÀH bond functionalization could
also be performed in the absence of a solvent (entry 15),
while AcOH as the (co)solvent did not improve the yield
(entries 16À17).
1aand alkenylic ester 2a, employing Cu(OAc)2 H2O asthe
3
oxidant under an atmosphere of ambient air (Table 1).
While different metal carboxylates as well as KPF6 as the
additives gave only unsatisfactory yields (entries 1À4),
more promising results were accomplished using silver(I)
Table 1. Optimization of CÀH Bond Alkenylation of Ester 1aa
(3) Selected recent examples: (a) Baxter, R. D.; Sale, D.; Engle,
K. M.; Yu, J.-Q.; Blackmond, D. G. J. Am. Chem. Soc. 2012,
134, 4600–4606. (b) Patureau, F. W.; Nimphius, C.; Glorius, F.
Org. Lett. 2011, 13, 6346–6349. (c) Rakshit, S.; Grohmann, C.;
Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350–2353.
(d) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed.
2011, 50, 1064–1067. (e) Mochida, S.; Hirano, K.; Satoh, T.; Miura,
M. J. Org. Chem. 2011, 76, 3024–3033. (f) Li, X.; Gong, X.; Zhao,
M.; Song, G.; Deng, J.; Li, X. Org. Lett. 2011, 13, 5808–5811.
(g) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982–
9983. (h) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 5916–5921. (i) Ueura, K.; Satoh, T.; Miura, M. Org.
Lett. 2007, 1407–1409. (j) Dams, M.; De Vos, D. E.; Celen, S.;
Jacobs, P. A. Angew. Chem., Int. Ed. 2003, 42, 3512–3515. (k) Boele,
M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc.
2002, 124, 1586–1587. Recent reviews: (l) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. (m) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651–3678. (n) Satoh,
T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212–11222 and references
cited therein.
(4) Oxidative alkenylations: (a) Hashimoto, Y.; Ortloff, T.; Hirano,
K.; Satoh, T.; Bolm, C.; Miura, M. Chem. Lett. 2012, 41, 151–153. (b) Li,
B.; Ma, J.; Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett. 2012, 14,
736–739. (c) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Org.
Lett. 2012, 14, 728–731. (d) Hashimoto, Y.; Ueyama, T.; Fukutani, T.;
Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2011, 40, 1165–1166.
(e) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Green
Chem. 2011, 13, 3075–3078. (f) Ackermann, L.; Pospech, J. Org. Lett.
2011, 13, 4153–4155. (g) Ueyama, T.; Mochida, S.; Fukutani, T.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706–708.
(h) Kwon, K.-H.; Lee, D. W.; Yi, C. S. Organometallics 2010, 29,
5748–5750 and references cited therein. See also: (i) Weissman, H.;
Song, X.; Milstein, D. J. Am. Chem. Soc. 2001, 123, 337–338.
(5) For examples of related oxidative annulations of alkynes, see: (a)
Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011,
50, 6379–6382. (b) Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett.
2011, 13, 3278–3281. (c) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13,
6548–6551. (d) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K.
Org. Lett. 2012, 14, 930–933. (e) Ackermann, L.; Wang, L.; Lygin, A. V.
Chem. Sci. 2012, 3, 177–180. (f) Chinnagolla, R. K.; Jeganmohan, M.
Chem. Commun. 2012, 48, 2030–2032. (g) Ackermann, L.; Lygin, A. V.
Org. Lett. 2012, 14, 764–767. (h) Parthasarathy, K.; Senthilkumar, N.;
Jayakumar, J.; Cheng, C.-H. Org. Lett. 2012, 14, 3478–3481.
(i) Thirunavukkarasu, V. S.; Donati, M.; Ackermann, L. Org. Lett.
2012, 14, 3416–3419.
t
yield
(%)
entry
additive
solvent
(°C)
1
À
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
H2O
100
100
100
100
100
100
100
100
100
120
120
120
100
120
100
100
100
À
2
NaOAc
CsOAc
À
3
À
4
KPF6
À
5
AgOAc
AgBF4
À
6
30b
48
62
7
AgO3SCF3
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
8
c
9
À
10
11
12
13
14
15
16
17
À
DMF
À
o-xylene
À
1,4-dioxane
t-AmOH
27b
13
40
19
8b
À
DCE/AcOH (1.8/0.2)
AcOH
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Cu(OAc)2 H2O
(1.0 mmol), [RuCl2(p-cymene)]2 (5.0 mol %), solvent (2.0 mL); isolated
3
yields, under air. b GC conversion. c CuBr2 (1.0 mmol) as the oxidant.
With an optimized catalytic system in hand, we subse-
quently explored its scope in the oxidative alkenylation of
diversely decorated esters 1 (Scheme 2). Notably, the cationic
ruthenium(II) catalyst efficiently converted para- and
more sterically congested ortho-substituted esters 1, thereby
chemoselectively delivering the mono-ortho-alkenylated are-
nes 3aÀ3g and 3hÀ3m as the sole products, respectively.
Likewise, a more hindered ester group could be present
(6) An elegant rhodium-catalyzed olefination of arene esters was
reported by Chang and coworkers: Park, S. H.; Kim, J. Y.; Chang, S.
Org. Lett. 2011, 13, 2372–2375.
(7) For examples of ruthenium-catalyzed hydroarylations with aro-
matic esters, see: (a) Kakiuchi, F.; Ohtaki, H.; Sonoda, M.; Chatani, N.;
Murai, S. Chem. Lett. 2001, 918–919. (b) Neisius, N. M.; Plietker, B.
Angew. Chem., Int. Ed. 2009, 48, 5752–5755 and references cited therein.
(8) Recent reviews: (a) Ackermann, L. Pure Appl. Chem. 2010, 82,
1403–1413. (b) Ackermann, L. Isr. J. Chem. 2010, 50, 652–663.
(9) During the preparation of our manuscript a related independent
study was disclosed: Padala, K.; Pimparkar, S.; Madasamy, P.;
Jeganmohan, M. Chem. Commun. 2012, 48, 7140–7142.
(11) Recent examples of carboxylate-assisted ruthenium-catalyzed
CÀH bond activations: (a) Ackermann, L.; Pospech, J.; Potukuchi,
H. K. Org. Lett. 2012, 14, 2146–2149. (b) Ackermann, L.; Diers, E.;
Manvar, A. Org. Lett. 2012, 14, 1154–1157. (c) Ackermann, L.; Lygin,
A. Org. Lett. 2011, 13, 3332–3335. (d) Ouellet, S. G.; Roy, A.; Molinaro,
C.; Angelaud, R.; Marcoux, J.-F.; O’Shea, P. D.; Davies, I. W. J. Org.
Chem. 2011, 76, 1436–1439. (e) Ackermann, L.; Vicente, R.; Potukuchi,
H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–5035. (f) Ackermann, L.;
ꢀ
(10) The desired product 3a was not formed when using
[RuCl2(PPh3)3] as the catalyst.
Novak, P.; Vicente, R.; Hofmann, N. Angew. Chem., Int. Ed. 2009, 48,
6045–6048 and references cited therein.
B
Org. Lett., Vol. XX, No. XX, XXXX

within the twofold CÀH bond functionalization strategy
to furnish the desired product of cross-dehydrogenative
alkenylation (3n).12
Scheme 4. Intramolecular Competition Experiments
Scheme 2. Scope of Oxidative Alkenylation with Esters 1
Scheme 5. Intermolecular Competition Experiments
Importantly, the oxidative CÀH bond functionalization
was also viable in an aerobic fashion, using cocatalytic
amounts of Cu(OAc)2 H2O under an atmosphere of am-
3
bient air (Scheme 3). The aerobic oxidative alkenylation
site selectively occurred on arenes as well as heteroarenes 2
with high catalytic efficacy.
Scheme 6. Oxidative Alkenylation with Isotopically Labeled
Substrate or Cosolvent
Scheme 3. Aerobic Oxidative Alkenylation with Esters 1a
Given the remarkable catalytic activity of the cationic
ruthenium(II) complex, we initiated mechanistic studies to
a Isolated yields. b The corresponding hydroarylation product was
formed in 8% yield (by 1H NMR).
(12) The use of para-bromo- or para-amino-substituted benzoic acid
esters provided thus far only unsatisfactory low conversions.
Org. Lett., Vol. XX, No. XX, XXXX
C

Mechanistic studies with isotopically labeled substrate
[D]5-1t or in the presence of the cosolvent D2O highlighted
a H/D scrambling, thus indicating the CÀH bond ruthena-
tion step to be reversible in nature (Scheme 6).
Scheme 7. Proposed Catalytic Cycle
Based on these mechanistic studies we propose the
catalytic cycle to involve an initial reversible acetate-
assisted13 cycloruthenation to form complex 4 (Scheme 7).
Subsequent migratory insertion of alkene 2 and β-hydride
elimination furnish desired product 3, while reductive elim-
ination and reoxidation by Cu(OAc)2 regenerate the cata-
lytically active cationic species.
In summary, we have reported on site-selective ruthenium-
catalyzed oxidative alkenylations of arenes bearing weakly
coordinating esters. Importantly, cationic ruthenium(II)
complexes served as efficient catalysts for cross-dehydro-
genative CÀH bond functionalizations between aryl- and
alkenyl-substituted esters in a highly chemo-/diastereoselec-
tive as well as site selective fashion. The optimized catalyst
proved to be broadly applicable and also allowed for
aerobic oxidative alkenylations with cocatalytic amounts of
Cu(OAc)2 H2O, utilizing air as an inexpensive terminal
3
oxidant. Detailed mechanistic studies were suggestive of a
reversible cycloruthenation step through acetate assistance.
Further studies on ruthenium-catalyzed oxidative CÀH
bond functionalizations are currently ongoing in our labora-
tories and will be reported in due course.
unravel its mode of action. To this end, we performed
intramolecular competition experiments, which showed
that the selectivity of the conversion with arene 1r was
largely influenced by steric interactions. On the contrary,
meta-fluoro-substituted substrate 1s exclusively led to the
functionalization at the position C-2 (Scheme 4).
Moreover, intermolecular competition experiments be-
tween differently substituted arenes 1 revealed electron-
rich esters to be preferentially converted (Scheme 5).
Acknowledgment. Financial support by AstraZeneca
and the Chinese Scholarship Council (fellowship to W.M.)
is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
(13) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345.
D
Org. Lett., Vol. XX, No. XX, XXXX