Ruthenium-catalyzed C-H bond arylations of arenes bearing removable directing groups via six-membered ruthenacycles

Article abstract of DOI:10.1021/ol3000876

Ruthenium-catalyzed direct arylations of phenols bearing removable directing groups were accomplished through carboxylate assistance via six-membered ruthenacycles as key intermediates.

Full text of DOI:10.1021/ol3000876

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1154–1157
Ruthenium-Catalyzed CꢀH Bond
Arylations of Arenes Bearing Removable
Directing Groups via Six-Membered
Ruthenacycles
Lutz Ackermann,* Emelyne Diers, and Atul Manvar
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received January 13, 2012
ABSTRACT
Ruthenium-catalyzed direct arylations of phenols bearing removable directing groups were accomplished through carboxylate assistance via
six-membered ruthenacycles as key intermediates.
In recent years, transition-metal-catalyzed direct aryla-
tions have emerged as increasingly viable alternatives to
traditional cross-coupling reactions.1 Particularly, ruthe-
nium catalysts have proven to be valuable tools for sus-
tainable CꢀH bond arylations, with recent applications to
step economical syntheses of bioactive compounds in
academia and pharmaceutical industries.2,3 However, de-
spite this remarkable recent progress, ruthenium-catalyzed
CꢀH bond arylations of arenes with aryl halides continue
to lack generality, as illustrated by their severe limita-
tion to substrates that form five-membered ruthenacycles
(Scheme 1).2,3 As a direct consequence, ruthenium-
catalyzed4 direct arylations with aryl (pseudo)halides were
thus far unfortunately not viable with arenes5 displaying
removable directing groups. Recently, we introduced car-
boxylates as effective cocatalysts for most generally
(3) For illustrative examples, see: (a) Lakshman, M. K.; Deb, A. C.;
Chamala, R. R.; Pradhan, P.; Pratap, R. Angew. Chem., Int. Ed. 2011,
50, 11400–11404. (b) Seki, M.; Nagahama, M. J. Org. Chem. 2011, 76,
10198–10206. (c) Doherty, S.; Knight, J. G.; Addyman, C. R.; Smyth,
C. H.; Ward, N. A. B.; Harrington, R. W. Organometallics 2011, 30,
6010–6016. (d) Seki, M. ACS Catal. 2011, 1, 607–610. (e) Yu, B.; Yan,
X.; Wang, S.; Tang, N.; Xi, C. Organometallics 2010, 29, 3222–3226. (f)
Miura, H.; Wada, K.; Hosokawa, S.; Inoue, M. Chem.;Eur. J. 2010, 16,
4186–4189. (g) Ackermann, L.; Born, R.; Vicente, R. ChemSusChem.
€
2009, 546–549. (h) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen,
C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008,
130, 1156–1157. (i) Oi, S.; Sasamoto, H.; Funayama, R.; Inoue, Y.
Chem. Lett. 2008, 37, 994–995. (j) Ackermann, L.; Althammer, A.; Born,
R. Tetrahedron 2008, 64, 6115–6124. (k) Ackermann, L.; Althammer,
A.; Born, R. Synlett 2007, 2833–2836. (l) Ackermann, L.; Born, R.;
(1) Selected recent reviews on CꢀH bond functionalizations: (a)
Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–1292. (b)
Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503–
4513. (c) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84. (d) Sun, C.-L.;
Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677–685. (e) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624–655. (f)
Ackermann, L. Chem. Commun. 2010, 46, 4866–4877. (g) Fagnou, K.
Top. Curr. Chem. 2010, 292, 35–56. (h) Giri, R.; Shi, B.-F.; Engle, K. M.;
Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242–3272.
(i) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed.
2009, 48, 9792–9826. (j) Thansandote, P.; Lautens, M. Chem.;Eur. J.
2009, 15, 5874–5883. (k) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–
205 and references cited therein.
ꢀ
Alvarez-Bercedo, P. Angew. Chem., Int. Ed. 2007, 46, 6364–6367. (m)
Ackermann, L. Org. Lett. 2005, 7, 3123–3125. (n) Oi, S.; Aizawa, E.;
Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113–3119 and references
cited therein.
(4) For representative examples of palladium-catalyzed CꢀH bond
functionalizations of arenes bearing removable directing groups, see: (a)
Huang, C.-H.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc.
2011, 133, 12406–12409. (b) Chu, J.-H.; Lin, P.-S.; Wu, M.-J. Organo-
metallics 2010, 29, 4058–4065. (c) Chernyak, N.; Dudnik, A. S.; Huang,
C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270–8272. (d) Gu, S.;
Chen, C.; Chen, W. J. Org. Chem. 2009, 74, 7203–7206 and references
cited therein.
(2) A review: Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292,
211–229.
(5) For direct arylations of heteroarenes, see: Ackermann, L.; Lygin,
A. V. Org. Lett. 2011, 13, 3332–3335.
r
10.1021/ol3000876
Published on Web 02/07/2012
2012 American Chemical Society

applicable ruthenium(II)-catalyzed direct arylations in
various solvents.6,7 In continuation of our studies,8 we
devised first ruthenium-catalyzed direct arylations of arenes
via six-membered ruthenacycles that set the stage for a
removable directing group strategy, the development of
which we report herein.
secondary phosphine oxide10 5 or carboxylic acid 6,8a while
unsatisfactory results were obtained with either N-heterocyc-
lic carbene precursors or tertiary phosphines (entries 1ꢀ5).
The catalytic CꢀH bond arylation occurred in NMP as the
solvent, yet proceeded also efficiently in H2O as a sustainable
reaction medium (entries 6ꢀ8). Furthermore, carboxylate
assistance enabled high-yielding direct arylations in toluene,
with K2CO3 being the optimal base (entries 9ꢀ17).
Scheme 1. Removable Directing Group Strategy via Six-
Membered Ruthenacycles
Table 1. Optimization of Direct Arylation with Arene 1aa
entry
cocatalyst
base
solvent 3aa (%) 4aa (%)
1
ꢀ
K2CO3
K2CO3
K2CO3
NMP
NMP
NMP
NMP
NMP
H2O
ꢀ
ꢀ
6
2
HIPrCl
PPh3
4
3
17
54
14
ꢀ
ꢀ
44
73
ꢀ
ꢀ
31
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
24
4
(1-Ad)2P(O)H (5) K2CO3
MesCO2H (6)b
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
6
ꢀ
c
7
KPF6
H2O
ꢀ
8
MesCO2H (6)b
ꢀ
H2O
50
ꢀ
9
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
10
11
12
13
14
15
16
17
HIPrCl
PPh3
ꢀ
ꢀ
c
KPF6
ꢀ
MesCO2H (6)b
MesCO2H (6)b
MesCO2H (6)b
MesCO2H (6)b
MesCO2H (6)b
ꢀ
At the outset, we tested representative in situ gen-
erated ruthenium catalysts in the direct arylation of
2-phenoxypyridine9 (1a) (Table 1). Interestingly, the most
efficient catalysis was achieved with catalysts derived from
NaOAc
ꢀ
Na2CO3 PhMe
32
20
66
Ag2CO3
K2CO3
PhMe
PhMe
a Reaction conditions: 1a (1.50 mmol), 2a (0.50 mmol), [RuCl2(p-
cymene)]2 (2.5 mol %), cocatalyst (10 mol %), K2CO3 (1.00 mmol),
solvent (2.0 mL), 120 °C, 20 h; HIPr = N,N0-bis(2,6-di-isopropylphenyl)-
imidazolium, yields of isolated products. b 6 (30 mol %). c 40 mol %.
(6) (a) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008,
10, 2299–2302. (b) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10,
5043–5036. (c) Ackermann, L.; Novak, P. Org. Lett. 2009, 11, 4966–
ꢀ
4969. (d) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922–4925. (e)
ꢀ
Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.; Novak, P.;
€
Buttner, L. Org. Lett. 2010, 12, 2056–2059. (f) Ackermann, L.; Vicente,
To further explore the influence of the additive and the
base on catalytic efficacy, we probed the direct arylation of
ortho-fluoro-substituted arene 1b (Table 2). Thus, the most
effective catalysis was again achieved with MesCO2H (6)
as the cocatalyst and K2CO3 as the base, while KO2CMes
as the stoichiometric base was found to be ineffective.8a
Generally, the ruthenium(II) carboxylate catalysts dis-
played a remarkably high chemoselectivity, and products
stemming from catalytic CꢀF11 bond functionalizations
were hence not observed.
R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032–5035. (g)
ꢀ
Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K.
Synthesis 2010, 2245–2253. (h) Ackermann, L.; Hofmann, N.; Vicente,
R. Org. Lett. 2011, 13, 1875–1877. Oxidative transformations: (i)
Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed.
2011, 50, 6379–6382. (j) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13,
4153–4155. (k) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548–
6551.
(7) For subsequent reports, see: (a) Flegeau, E. F.; Bruneau, C.;
Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161–10170.
(b) Stefane, B.; Fabris, J.; Pozgan, F. Eur. J. Org. Chem. 2011, 3474–
3481. (c) 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. (d)
Li, W.; Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H.
Green Chem. 2011, 13, 2315–2319. (e) Arockiam, P. B.; Fischmeister, C.;
Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2010, 49, 6629–6632.
(f) Arockiam, P.; Poirier, V.; Fischmeister, C.; Bruneau, C.; Dixneuf,
P. H. Green Chem. 2009, 11, 1871–1875.
The scope of the optimized catalytic system was there-
after explored in the direct arylation of differently sub-
stituted 2-aryloxypyridines 1 (Scheme 2).
(8) For reviews, see: (a) Ackermann, L. Chem. Rev. 2011, 111, 1315–
1345. (b) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413. (c)
Ackermann, L.; Born, R.; Spatz, J. H.; Althammer, A.; Gschrei, C. J.
Pure Appl. Chem. 2006, 78, 209–214.
(10) Reviews: (a) Ackermann, L. Isr. J. Chem. 2010, 50, 652–663.
(b) Ackermann, L. Synlett 2007, 507–526.
(9) For a ruthenium-catalyzed cross-dehydrogenative silylation, see:
Kakiuchi, F.; Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani, N.;
Murai, S. Chem. Lett. 2002, 396–397.
(11) (a) Kawamoto, K.; Kochi, T.; Sato, M.; Mizushima, E.; Kakiuchi,
F. Tetrahedron Lett. 2011, 52, 5888–5890. (b) See also: Ackermann, L.;
Wechsler, C.; Kapdi, A. R.; Althammer, A. Synlett 2010, 294–298.
Org. Lett., Vol. 14, No. 4, 2012
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Table 2. Ruthenium-Catalyzed Direct Arylation of Arene 1ba
Scheme 3. Scope of Direct Arylations with Aryl Chlorides 7
entry
cocatalyst
base
3ba
1
2
3
4
5
6
7
8
ꢀ
ꢀ
K2CO3
KOAc
ꢀ
61%
91%
<5%
<5%
30%
98%
<5%
KOAc
K2CO3
KOAc
MesCO2H (6)
MesCO2H (6)
MesCO2H (6)
MesCO2H (6)
ꢀ
NaOAc
CsOAc
K2CO3
KO2CMes
a Reaction conditions: 1b (1.50 mmol), 2a (0.50 mmol) [RuCl2(p-
cymene)]2 (2.5 mol %), cocatalyst (30 mol %), K2CO3 (1.00 mmol),
solvent (2.0 mL), 120 °C, 20 h; yields of isolated products.
Scheme 2. Ruthenium-Catalyzed Direct Arylations of Arenes 1
The synthesis of unsymmetrically disubstituted arene
4aab was accomplished through a sequential CꢀH bond
functionalization strategy (Scheme 4).
a Diarylated product 4ea (11%) was also isolated. b[RuCl2(p-cymene)]2
(1.0 mol %).
Scheme 4. Synthesis of Unsymetrically Disubstituted Arene
4aab
The ruthenium(II) carboxylate complex was found to be
broadly applicable and enabled the conversion of both
electron-rich and electron-deficient arenes.12 Generally,
the latter substrates provided higher yields of products 3,
thus rendering a simple SEAr-type mechanism less likely
to be operative. Importantly, a satisfactory result was also
obtained when using a significantly reduced catalyst
loading.
Notably, the ruthenium(II) carboxylate catalyst was not
restricted to the use of aryl bromides 2, but also allowed for
efficient CꢀH bond transformations with less expensive,
yet more challenging aryl chlorides 7 as the arylating
reagents (Scheme 3).
Further, we were pleased to find that the directing group
could easily be removed4b from biaryls 3, thereby yielding
the desired phenols13 8 (Scheme 5).
As to the catalyst’s working mode, an intramolecular
competition experiment with meta-fluoro-substituted
arene 1i preferentially delivered product 3ia00 through
direct functionalization at the kinetically more acidic
(12) The direct arylation of ortho-methoxy-substituted 2-phenoxy-
pyridine with aryl bromide 2a provided the desired product in 38%
isolated yield.
1156
Org. Lett., Vol. 14, No. 4, 2012

Scheme 5. Removal of Directing Group
Scheme 7. Intermolecular Competition Experiments (Ar =
4-MeOC6H4)
Scheme 6. Intramolecular Competition Experiment
In summary, we have reported on the first ruthenium-
catalyzed direct arylation of arenes with organic electrophiles
using removable directing groups. High catalytic efficacy
was ensured by ruthenium(II) carboxylate catalysts, which
allowed for unprecedented ruthenium-catalyzed CꢀH
bond arylations with aryl bromides and chlorides through
six-membered ruthenacycles as the key intermediates.
CꢀH bond (Scheme 6). This observation can be ratio-
nalized with a carboxylate-assisted deprotonative CꢀH
bond ruthenation.
Intermolecular competition experiments with substrates
1 bearing different substituents on the pyridine moiety
revealed that arenes with more electron-rich directing
groups reacted preferentially (Scheme 7a and b). Further-
more, electron-deficient arenes were converted with higher
relative rates (Scheme 7c), which contrasts with previously
made observations in ruthenium-catalyzed direct aryla-
tions with aryl halides.6f
Acknowledgment. Support by the CaSuS PhD program,
the Erasmus Mundus program (fellowship to A.M.), and
the Georg-August-University is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
(13) For the elegant use of rather expensive rhodium or palladium
catalysts for direct arylations of (in situ generated) phenol derivatives,
see: (a) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
Angew. Chem., Int. Ed. 2003, 42, 112–114. (b) Bedford, R. B.; Limmert,
M. E. J. Org. Chem. 2003, 68, 8669–8662. (c) Huang, C.; Gevorgyan, V.
J. Am. Chem. Soc. 2009, 131, 10844–10845. See also: (d) Boebel, T. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534–7535.
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.
Org. Lett., Vol. 14, No. 4, 2012
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