Full text of DOI:10.1021/acs.orglett.7b03387

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium-Catalyzed meta-Carboxylation
Helen L. Barlow, Christopher J. Teskey, and Michael F. Greaney*
School of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
S
* Supporting Information
ABSTRACT: The meta-carboxylation of arenes containing pyridine and other
azine-directing groups is reported. Using carbon tetrabromide as the C1
source, ruthenium(III) trichloride catalysis enables functionalization of the
arene meta-C−H position, affording carboxy methyl ester products after in situ
reaction with methanol.
he meta-functionalization1 of arene C−H bonds using
Truthenium catalysis is a burgeoning area of research,
enabling meta-selective arene bond construction in a very direct
way.2 The principle is set out in Scheme 1 and involves the in
situ formation of ruthenacycle 2 from an arene substrate
featuring a strong directing group such as a pyridine and
ruthenium catalyst (frequently [RuCl2(cymene)]2) capable of
cycloruthenation. Certain classes of electrophiles are then
observed to add para to the C−Ru bond, which upon
protonolysis of the metal complex reveals 1,3-meta-substituted
arene product 4. Initial observations on the reactivity of
stoichiometric complexes 2 with strong electrophiles were
suggestive of simple SEAr chemistry.3 However, subsequent
studies on catalytic meta-alkylation with secondary and tertiary
alkyl halides have identified a radical pathway4 via postulated
electron transfer pathways from Ru(II) species. Successful
meta-functionalizations to date using the Ru method
encompass sulfonylation with sulfonyl chlorides,5 2° and 3°
alkylation with alkyl halides,4,6 benzylation using tolyl
components,7 bromination,8 and nitration.9 Despite these
notable advances, it is clear that several classes of bond
formation remain to be established within the Ru-meta regime.
With this goal in mind, we were interested in exploring a Ru-
catalyzed meta-carboxylation.
Scheme 1. Ruthenium-Catalyzed Carboxylation
The selective carboxylation of arenes is a fundamental
transformation in synthesis frequently used to install a C1
moiety for elaboration into acid, ester, or amide functionalities
that are widely represented in functional molecules (Scheme 1).
Selective meta-carboxylation would introduce a new approach
to these motifs, contrasting favorably with both existing
stoichiometric lithiation processes and classical Friedel−Crafts
acylation chemistry that is not amenable to the 1,3-meta
substitution pattern. Ru-catalyzed carbonylative and acylative
processes are well-established in the ortho series with Murai’s
ortho-carbonylative alkylation of 2-phenylpyridine using CO/
ethylene being formative work in the field of catalytic C−H
activation.10,11 For meta-carboxylation, however, we were
interested in exploiting the electron transfer pathways
implicated in C−C bond formation with alkyl halides.
CO2Me group to benzofurans using iron catalysis and
methanolysis of the incipient tribromomethyl adduct.13 More
recently, Bandini and co-workers used photoredox catalysis to
effect a similar transformation using CBr4 and indoles.12b We
were therefore interested in exploring the SET behavior of this
reagent for meta-carboxylation.
We began our studies using 2-phenylpyridine 1a as the
starting material and limiting reagent with 3 equiv of CBr4 and
5 mol % of [Ru(p-cymene)Cl2]2 in a solvent mixture of
methanol/1,4-dioxane using potassium acetate as a base (Table
1). Pleasingly, under these conditions we achieved a 42%
Mukminov and co-workers have demonstrated the use of
Received: October 31, 2017
CBr4 as a masked carboxylation reagent,12a introducing the
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03387
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Reaction Development
b
entry
catalyst
additive
cosolvent
yield
1
2
3
4
5
6
7
8
9
[Ru(p-cymene)Cl2]2 (5 mol %)
[Ru(p-cymene)Cl2]2 (5 mol %)
Ru3(CO)12 (5 mol %)
KOAc (2 equiv)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMA
42
50
0
RuCl3·xH2O (5 mol %)
RuCl3·xH2O (5 mol %)
RuCl3·xH2O (5 mol %)
RuCl3·xH2O (5 mol %)
RuCl3·xH2O (5 mol %)
RuCl3·xH2O (5 mol %)
RuCl3·xH2O (5 mol %)
RuCl3·xH2O (10 mol %)
50
49
37
15
39
45
c
MeCN
none
MesCO2H (30 mol %)
PPh3 (10 mol %)
1,4-dioxane
1,4-dioxane
1,4-dioxane
10
11
52
d
59
a
Reaction conditions: 2-phenylpyridine (0.50 mmol, 1.0 equiv), CBr4 (1.50 mmol, 3.0 equiv), catalyst (as specified), methanol (0.75 mL), and
b
solvent (0.75 mL) under a nitrogen atmosphere at 85 °C for 16 h in a 5 mL microwave vial. NMR yield using 1,3,5-trimethoxybenzene as the
internal standard. Reaction completed under air atmosphere. Isolated yield.
c
d
conversion of the desired meta-carboxylated product (entry 1),
and removal of the base increased this to 50% (entry 2).
We then investigated the use of alternative ruthenium
catalysts to the commonly employed [Ru(p-cymene)Cl2]2.
Ru3(CO)12 had been successful in meta-nitration as reported by
Zhang;9 however it resulted in no product formation in our
reaction (entry 3). Conversely, the use of ruthenium trichloride
was more successful giving a comparable conversion to [Ru(p-
cymene)Cl2]2 (entry 4). As ruthenium trichloride is a cheaper
catalyst; all subsequent reactions were completed using this
basic ruthenium source. The reaction did not display sensitivity
to air (entry 5) and proceeded with alternative solvents such as
DMA, MeCN, and pure methanol but with lower efficiencies
(entries 6−8). Carboxylate additives, common in Ru-catalyzed
C−H activation, had little impact (entry 9), as did the use of
triphenylphosphine, recently demonstrated to great effect in
meta-difluoroalkylation (entry 10).6c,d An isolated yield of 59%
was recorded upon increasing the catalyst loading to 10 mol %
(entry 11), and control experiments established that no product
formation took place in the absence of ruthenium trichloride.
With the optimized reaction conditions in hand, we sought
to explore the substrate scope (Scheme 2). The reaction
conditions tolerated both electron-donating (6b) and electron-
withdrawing groups (6c−f) in the para position. Halogen
substituents worked well (6c−e), providing the opportunity for
further functionalization via cross coupling reactions. ortho-
Substituents on the phenyl ring were tolerated as demonstrated
by 6g in contrast to our previous work on meta-bromination.8a
However, meta-substituents were not tolerated, giving no
conversion. This is in-line with general reactivity trends in Ru
meta-C−H functionalization, where meta-substituents block
one 3-position and sterically hinder the adjacent ortho-2
Scheme 2. Substrate Scope for meta-Carboxylation
position preventing effective ruthenacycle formation that
a
b
Scale up to 2.5 mmol gave 53% yield after 24 h. MeOH (1.5 mL)
would activate the 5-position. The directing group was
restricted to azine-type nitrogens but was successful for
isoquinolines (6j), purines (6k−n), and pyrimidines (6o).
None of the ortho-carboxy products were detected in this study,
in line with the emerging picture of more sterically encumbered
and 1,4-dioxane (1.5 mL) used as solvent.
carbon-centered radicals preferring the meta mode of
addition.6g The tribromomethyl intermediate (5 in Scheme
B
DOI: 10.1021/acs.orglett.7b03387
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1) was never detected, as it is known to undergo rapid
methanolysis at elevated temperatures.13 Alternative alcohol or
C1 components generally gave poor conversions under the
reaction conditions; for example, ethanol furnished the ethyl
ester product in a very low 18% yield. Formylation with CHCl3
under conventional Ru-meta conditions of [RuCl2(p-cymene)]2
(5 mol %), K2CO3, and Piv-Val-OH (30 mol %) in 1,4-dioxane
did proceed to the analogous aldehyde but only in 22% yield.
Various experiments were conducted to probe the mecha-
nism of the reaction (Scheme 3). Blocking both ortho positions
analogous finding was reported by Huang and Ackermann in
their meta-bromination systems, both of which proceed in the
absence of base.8b,c The use of deuterated methanol gave a
singular product d3-6a, indicating that the methoxy group
results from the methanol present (Scheme 3d). An
intermolecular competition between 2-(4-fluorophenyl)-
pyridine and 2-(4-methoxyphenyl)pyridine, revealed that the
more electron poor substrate was more reactive. This verifies
the supposition that an electrophilic substitution mechanism is
not operative with CBr4 in line with Frost and Ackermann’s
observations on alkyl halide reactivity.4 Finally, addition of 0.5
equiv of product 6a to the reaction leads to reduced
conversions (Scheme 3f), suggesting that product inhibition
may be significant in the reaction due to the creation of an
additional ligation site for ruthenium in 6a. Frost has recently
observed esters acting as effective ancillary coordinating groups
for ruthenium-catalyzed σ-activation of N-pyridyl indoles in this
regard.6f
Scheme 3. Mechanistic Probes
A plausible mechanistic pathway is outlined in Scheme 4
based on these observations and previous studies of Ru-meta
Scheme 4. Mechanistic Pathway
processes in the literature.4−9 As Ru(III)-cyclometalated
complexes are rare in the literature, it is likely that the RuCl3
is a precatalyst to the cyclometalate I familiar to Ru(II) C−H
activation chemistry with in situ reduction taking place with
methanol.14 SET reduction of CBr4 by ruthenium will then
generate the CBr3 radical for SHAr addition. Although the
nature of the Ru species involved in this step remains to be
elucidated, we note that one electron reduction of carbon tri-
and tetrahalides by Ru salts is very well-precedented as the
initiation step in Kharasch-type atom transfer radical addition
chemistry.15 The CBr3 radical then adds para to the Ru−C
bond to give species II. One electron oxidation (in principle by
the Ru(III) but more likely by the CBr4 reagent, which is
present in excess) and proton loss rearomatizes the phenyl-
pyridine to give III. This is followed by a protodemetalation
and methanolysis of 5 to give the product.
a
1H NMR yield using 1,3,5-trimethoxybenzene as an internal standard.
with methyl groups (1p) shut down the reaction, establishing
that ortho-ruthenation is essential and that no background
tribromomethylation takes place without it. The reaction was
also suppressed by the addition of the radical trap TEMPO
consistent with the SET mechanism observed in related
systems. Subjecting 2-(phenyl-d5)pyridine d5-1a to the reaction
conditions afforded d4-2a exclusively, indicating that no H/D
exchange takes place during the reaction (Scheme 3c); an
In summary, we have developed a new meta-C−H
functionalization reaction that introduces the carboxy group.
The reaction exploits the electron transfer character of Ru σ-
activation by using CBr4 as a masked carboxylate moiety,
C
DOI: 10.1021/acs.orglett.7b03387
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. - Eur. J. 2017, 23, 3285. (e) Li, G.; Gao, P. P.; Lv, X. L.; Qu, C.;
Yan, Q. K.; Wang, Ya.; Yang, S. L.; Wang, J. J. Org. Lett. 2017, 19,
2682. (f) Leitch, J. A.; McMullin, C. L.; Mahon, M. F.; Bhonoah, Y.;
Frost, C. G. ACS Catal. 2017, 7, 2616. (g) Paterson, A. J.; Heron, C. J.;
McMullin, C. L.; Mahon, M. F.; Press, N. J.; Frost, C. G. Org. Biomol.
Chem. 2017, 15, 5993. (h) Li, B.; Fang, S.-L.; Huang, D.-Y.; Shi, B.-F.
Org. Lett. 2017, 19, 3950. (i) Li, J.; Korvorapun, K.; Sarkar, S. D.;
Rogge, T.; Burns, D. J.; Warratz, S.; Ackermann, L. Nat. Commun.
2017, 8, 15430. (j) Yuan, C. C.; Chen, X.-L.; Zhang, J. Y.; Zhao, Y. S.
Org. Chem. Front. 2017, 4, 1872.
proceeds with pyridyl, pyrimidyl, and nucleobase directing
groups, and introduces a C1 unit of fundamental synthetic
utility. Further studies on this transformation are underway in
our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03387.
(7) Li, G.; Li, D.; Zhang, J.; Shi, D.-Q.; Zhao, Y. ACS Catal. 2017, 7,
4138.
Experimental procedures, characterization data, and
copies of NMR spectra (PDF)
(8) (a) Teskey, C. J.; Lui, A. Y. W.; Greaney, M. F. Angew. Chem., Int.
Ed. 2015, 54, 11677. (b) Yu, Q.; Hu, L.; Wang, Y.; Zheng, S.; Huang, J.
Angew. Chem., Int. Ed. 2015, 54, 15284. (c) Warratz, S.; Burns, D. J.;
Zhu, C. J.; Korvorapun, K.; Rogge, T.; Scholz, J.; Jooss, C.; Gelman,
D.; Ackermann, L. Angew. Chem., Int. Ed. 2017, 56, 1557.
(9) (a) Fan, Z.-L.; Ni, J.-B.; Zhang, A. J. Am. Chem. Soc. 2016, 138,
8470. (b) Fan, Z.; Li, J.; Lu, H.; Wang, D.-Y.; Wang, C.; Uchiyama, M.;
Zhang, A. Org. Lett. 2017, 19, 3199.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michael.greaney@manchester.ac.uk
ORCID
(10) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997,
62, 2604.
Christopher J. Teskey: 0000-0003-0776-5674
Michael F. Greaney: 0000-0001-9633-1135
Notes
(11) Kochi, T.; Urano, S.; Seki, H.; Mizushima, E.; Sato, M.;
Kakiuchi, F. J. Am. Chem. Soc. 2009, 131, 2792.
(12) (a) Khusnutdinov, R. I.; Baiguzina, A. R.; Mukminov, R. R. Russ.
J. Org. Chem. 2011, 47, 437. (b) Yang, Q. Q.; Marchini, M.; Xiao, W.
J.; Ceroni, P.; Bandini, M. Chem. - Eur. J. 2015, 21, 18052.
(13) Mataka, S.; Liu, G. B.; Sawada, T.; Kurisu, M.; Tashiro, M. Bull.
Chem. Soc. Jpn. 1994, 67, 1113.
(14) Du, W.; Wang, Q.; Wang, L.; Yu, Z. Organometallics 2014, 33,
974.
(15) Munoz-Molina, J. M.; Belderrain, T. R.; Perez, P. J. Eur. J. Inorg.
Chem. 2011, 2011, 3155.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC for funding (Ph.D. studentship to H.L.B,
Doctoral Prize Fellowship to C.J.T.) and Dr Jordi Bures
(University of Manchester) for helpful discussions. Danielle
Bunting (University of Manchester) is acknowledged for
preliminary experimental work.
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DOI: 10.1021/acs.orglett.7b03387
Org. Lett. XXXX, XXX, XXX−XXX