Ruthenium-catalyzed para-selective oxidative cross-coupling of arenes and cycloalkanes

Article abstract of DOI:10.1021/ol202081c

A novel, direct para-selective oxidative cross-coupling of benzene derivatives with cycloalkanes catalyzed by ruthenium was developed. A wide range of arenes bearing electron-withdrawing substituents was functionalized directly with simple cycloalkanes with high para-selectivity; arenes with electron-donating groups were mainly para-functionalized. Benzoic acid can be used directly.

Full text of DOI:10.1021/ol202081c

ORGANIC
LETTERS
2011
Vol. 13, No. 19
4977–4979
Ruthenium-Catalyzed Para-Selective
Oxidative Cross-Coupling of Arenes and
Cycloalkanes‡
Xiangyu Guo and Chao-Jun Li*
Department of Chemistry, McGill University, Montreal, Quebec H3A 2K6, Canada
cj.li@mcgill.ca
Received August 1, 2011
ABSTRACT
A novel, direct para-selective oxidative cross-coupling of benzene derivatives with cycloalkanes catalyzed by ruthenium was developed. A wide
range of arenes bearing electron-withdrawing substituents was functionalized directly with simple cycloalkanes with high para-selectivity; arenes
with electron-donating groups were mainly para-functionalized. Benzoic acid can be used directly.
Regiocontrolled functionalization of aromatic rings has
been an important subject throughout the history of organic
chemistry because of the vital role of aromatic compounds in
materials, fine chemicals, and biological compounds. The
FriedelꢀCrafts-type1 electrophilic substitution of arenes con-
stituted a key pillar of classical synthetic chemistry, leading to
o- andp-aryl CꢀC bonds with electron-donating substituents
and meta-functionalization with electron- withdrawing sub-
stituents. The ortho-lithiation2 and chelation-controlled tran-
sition-metal catalyzed cross-couplings are milestones of
modern achievements in creating alternatives,3 furnishing
ortho-functionalized products regioselectively. Recently, a
significant advance has been made by Gaunt4 and others5
in achieving meta-functionalization of substituted arenes
through transition-metal catalysis. However, the regioselec-
tive transition-metal-catalyzed functionalization of arenes at
the para-position remains virtually unexplored.6
On the other hand, the formation of a carbonꢀcarbon
(CꢀC) bond directly from carbonꢀhydrogen (CꢀH) bonds
via an oxidative cross-coupling has emerged as a powerful
synthetic methodology.7 Such a process will allow the use of
less functionalized starting materials and greatly reduce the
number of synthetic operations.7 For oxidative cross-cou-
pling involving arenes, Fujiwara8 pioneered a palladium-
catalyzed areneꢀalkene oxidative Heck-type coupling, which
has recently been achieved in water by Lipshutz.9 The use
of ruthenium catalyst for such a coupling was achieved
by Milstein.10 Recently, Fagnou11 and others12 reported a
direct areneꢀarene coupling reaction using simple benzene
as reagent. Very recently, the oxidative areneꢀalkyne
coupling13 was also achieved. For the more challenging
(7) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998. (b) Lewis, J. C.;
Bergman, R. G.; Ellman, J. Acc. Chem. Res. 2008, 41, 1013. (c) Newhouse,
T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 2010.
(8) (a) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 8, 1119. (b)
Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S. J. Am.
Chem. Soc. 1969, 91, 7166.
(9) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972.
(10) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001,
123, 337.
(11) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.
(12) (a) Li, R.; Liang, L.; Lu, W. Organometallics 2006, 25, 5973. (b)
Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org.
Lett. 2007, 9, 3137. (c) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2007, 129, 11904. (d) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike,
A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676.
(13) (a) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212. (b)
Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
3478.
‡ Dedicated to Prof. Barry M. Trost on the occasion of his 70th birthday.
(1) Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392.
(2) (a) Kauch, M.; Hoppe, D. Synthesis 2006, 1575. (b) Nguyen, T.-
H.; Castanet, A.-S.; Mortier, J. Org. Lett. 2006, 8, 765. (c) Pena, M. A.;
Sestelo, J. P.; Sarandeses, L. A. J. Org. Chem. 2007, 72, 1271.
(3) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(4) (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (b) Duong,
H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps, R. J.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2010, 50, 463.
(5) For examples on meta-selective CꢀH bond functionalization, see:
(a) Zhou, Y.; Zhao, J.; Liu, L. Angew. Chem., Int. Ed. 2009, 48, 7126. (b)
Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072. (c)
Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 13864–13867.
(6) Amboya, A.; Nguyen, T.; Huynh, H. T.; Brown, A.; Ratliff, G.;
Yonutas, H.; Cizmeciyan, D.; Natarajanb, A.; Garibay, M. A. G. Org.
Biomol. Chem. 2009, 7, 2322.
r
10.1021/ol202081c
2011 American Chemical Society
Published on Web 08/31/2011

transition-metal-catalyzed areneꢀalkane coupling, we pre-
viously reported an ortho-cycloalkylation of phenylpyridine
via chelation control14 (Scheme 1, route a). Herein, we report
an unprecedented direct para-selective oxidative cross-cou-
pling of benzene derivatives with cycloalkanes catalyzed by
ruthenium. A wide range of arenes with both electron-
donating and electron-withdrawing substituents were func-
tionalized directly using simple cycloalkanes with high para-
selectivity, even with the overwhelming strongly ortho-direct-
ing effect of chelating substituents (Scheme 1, route b).
yield slightly (entries 16 and 17). Thus, further studies used 2
equiv of oxidant. Other oxidants such as TBHP, dicumyl
peroxide, benzoic peroxyanhydride, and tert-butyl benzoper-
oxoate gave much lower yields (not shown). The product
yield dropped to 53% with a reduced loading of the catalyst
and ligand (entry 18). Using either more or less ligand
decreased the product yield (entries 19 and 20). Thus, we
chose 10% Ru3(CO)12 together with 5% dppb and 2 equiv of
TBP at 135 °C for 12 h under air as our standard conditions.
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Regioselectivity of Aromatic Substitutions
entry
additives
% NMR yield
1
2
none
35
45
10% Na(OAc)2 þ 10% DMSO
The mechanistic insights on the radical nature of our pre-
vious arene functionalizations14 inspired us to take advantage
of stabilizing the resonance of a radical-charactered inter-
mediate by both electron-donating and electron-withdrawing
groups through FMO interactions,15,16 thereby leading to
selective para-functionalization. To test this hypothesis, we
chose benzoic acid and cyclohexane as the standard sub-
strates for the optimization of the reaction conditions
(Table 1). Di-tert-butyl peroxide (TBP) was used as external
oxidant in this reaction. We found that the desired product 3a
could be generated without any catalyst in a trace amount.
When 10% Ru3(CO)12 wasaddedtothesystem,35%yieldof
the desired product 3a could be obtained (Table 1, entry 1).
We then focused our efforts on changing the ligands.
Sulfinyl groups were found to be good ligands for this
reaction (entries 2 and 3). Phosphine ligands gave similar
results, except for dppb (bis(diphenylphosphino)butane) and
binap (2,20-bis(diphenylphosphino)-1,10-binaphthyl) achiev-
ing 75% and 60% yields, respectively (entries 4ꢀ13). Dppb
oxide gave a similar yield to dppb, and it was found that dppb
(31PNMR δ=ꢀ15.0) was oxidized to dppb oxide (31PNMR
δ = 33.1) after 3 h during the course of the reaction based on
a phosphorus NMR, while the product yield was less than
10%. Therefore, it appears that the real ligand in this reaction
is dppb oxide. Neither a higher or lower temperature
improved the yield (entries 14 and 15). While lowering the
amount of TBP used in this reaction reduced the yield,
increasing the loading of TBP to 4 equiv only increased the
3
5% 1,2-bis(phenylsulfinyl)ethane
55
4
10% Ph3P
50
5
10%/n-Bu3P
5% dppm
35
6
52
7
5% dppe
53
8
5% dppp
53
9
5% dppb
75
10
11
12
13
14
15
16
17
18
19
20
5% dppb oxide
5% binap
75
60
5% 1,2-bis(diphenylphosphino)benzene
3% (Ph2PCH2CH2)2PPh
5% dppb
41
38
38b
70c
77d
61e
53f
48
5% dppb
5% dppb
5% dppb
2.5% dppb
10% dppb
2.5% dppb
55
a Conditions: 1a (0.2 mmol), 2a (0.2 mL, ∼9 equiv), 10% Ru3(CO)12
,
2 equiv of TBP (di-tert-butyl peroxide), 135 °C, 12 h under air. b 120 °C.
c 150 °C. d 4 equiv of TBP. e 1 equiv of TBP. f 5% Ru3(CO)12
.
With the optimized conditions in hand, other benzene
derivatives and cycloalkanes were investigated (Table 2). The
reaction proceeded efficiently for a wide range of benzene
derivatives. Electron-withdrawing group was found to be
efficient for this reaction. Other than benzoic acid, methyl
benzoate worked similarly well and gave a 70% separated
yield (3b). Acetophenone, 2,2,2-trifloroacetophenone, and
cyanobenzene achieved much higher yields (3c, 83%, 3d,
95%, and 3e, 90%). Halobenzenes also reacted smoothly
with cyclohexane in good yields (3g, 75%, and 3h, 72%) with
the halogen group untouched. Fluorobenzene gave a mod-
erate yield, possibly due to the low boiling point of fluor-
obenzene (84 °C), and only a trace amount maybe present in
the catalytic mixture (3f). Iodobenzene gave a complicated
mixture. Amides were also effective, although they gave
moderate yields (3i, 45%, and 3j, 50%). A free NꢀH bond
can be tolerated without any protection during the reaction
(3j). It is interesting to note that even unfunctionalized
(14) (a) Deng, G.; Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47,
6278. (b) Deng, G.; Chen, W.; Li, C.-J. Adv. Synth. Catal. 2009, 351, 353.
(c) Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J. Chem.;Eur.
J. 2009, 15, 333. (d) Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171.
(15) Recently, a number of radical-based arene functionalizations
have been reported; see: (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.;
Itami, K. Org. Lett. 2008, 10, 4673. (b) Liu, W.; Cao, H.; Zhang, H.;
Zhang, H.; Chung, K.-H.; He, C.; Wang, H.; Kwong, F.-Y.; Lei, A.
J. Am. Chem. Soc. 2010, 132, 16737. (c) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu,
M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat.
Chem. 2010, 2, 1044.
(16) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: London, New York, 1976.
4978
Org. Lett., Vol. 13, No. 19, 2011

benzene can be used for this reaction (3k, 45%). Electron-
donating groups such as a methoxyl group on the benzene
ring gave moderate yield (3l). Other cycloalkanes are also
effective in this reaction. The ring size of alkanes had a
dramatic influence on the reaction: while cyclopentane gave a
much lower yield (3m), cycloheptane gave a good yield (3n,
82%, 3w, 41%). In all these reactions, only trace amounts
(about 5%) of the disubstituted products were observed.
Scheme 2. Reaction of 2-Phenylpyridine (Separated Yields
Given)
With the less selective but stronger activating cyano group,
1,3-dicyanobenzene generated dicyclohexyl-substituted
product 4t as the major product with an 81% yield.
Table 2. Cross-Coupling of Benzene Derivatives with
Cycloalkanesaꢀd
Table 3. Cross-Coupling of Disubstituted Benzene Derivatives
with Cyclohexanesa,c,d
a Conditions: 1 (0.2 mmol), 2 (0.2 mL, ∼9 equiv), 10% Ru3(CO)12
,
5% dppb, 2 equiv of TBP (di-tert-butyl peroxide), 135 °C, 12 h under air.
b determined by GC-MS. c Cy = cyclohexyl; d yields are separated yields,
if not otherwise noted; e determined by 1H NMR.
A kinetic isotope study revealed that the reaction
showed a nonisotope effect, with kH/kD = 1.00, when
chlorobenzene and chlorobenzene-d5 were used as the
substrates. These results suggested that the reaction most
likely proceeds via a radical mechanism.
a Conditions: 1 (0.2 mmol), 2 (0.2 mL), 10% Ru3(CO)12, 5% dppb, 2
equiv of TBP (di-tert-butyl peroxide), 135 °C, 12 h under air; yield was
given as a total yield of mixtures of ortho/meta/para products. b Regios-
electivity ratio determined by GCꢀMS. c Cy = cyclohexyl. d Isolated
yield, otherwise noted. e NMR yield. f 72 h.
In summary, we have developed a novel direct para-
selective oxidative cross-coupling of benzene derivatives
with cycloalkanes catalyzed by ruthenium. A wide range
of arenes with electron-withdrawing substituents was func-
tionalized directly with simple cycloalkanes with high para-
selectivity; arenes with electron-donating groups were
mainly para-functionalized. The reaction overwhelmed the
effect of strongly ortho-directing of chelating substituents.
Notably, benzoic acid can be used directly. Further research
on the reaction mechanism is underway in our laboratory.
The reaction proceeded predominately at the para posi-
tion in all cases for monosubstituted benzene derivatives
(3a to 3d, 3i, 3j ,and 3w). However, for benzene derivatives
with a halogen or alkoxy substitutent (3eꢀh, 3l), the
amount of ortho product was increased.
The commonly used 2-phenylpyridine was also tested in
this reaction. We found that the coupling took place
exclusively at the para position (>99%) (Scheme 2).
A small amount of product due to the reaction of the
pyridine ring was also observed.
Disubstituted benzene derivatives were also examined
(Table 3). As methyl benzoate has a very high para-
selectivity, dimethyl terephthalate only gave a low yield
(39%) at the orthoposition because ofthe inaccessibility of
the para-position (3p). By making the para-position avail-
able, excellent yields of the corresponding products were
obtained. (80ꢀ93%). Para selectivity showed a stronger
control than ortho or meta selectivities (3q, 3r, and 3u).
Acknowledgment. We are grateful to the Canada Re-
search Chair (Tier I) Foundation (to C.J.L.), CFI, and
NSERC for support of our research.
Supporting Information Available. Experimental pro-
cedures, characterization data of new compound, and 1H
and 13C NMR data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
4979