Regioselective ortho-arylation and alkenylation of N-alkyl benzamides with boronic acids via ruthenium-catalyzed C-H bond activation: An easy route to fluorenones synthesis

Article abstract of DOI:10.1021/ol3024067

A highly regioselective ruthenium-catalyzed ortho-arylation of substituted N-alkyl benzamides with aromatic boronic acids in the presence of [{RuCl ₂(p-cymene)}₂], AgSbF₆, and Ag₂O is described. Further, ortho-arylated N-alkyl benzamides were converted into fluorenones in the presence of trifluoroacetic anhydride and HCl.

Full text of DOI:10.1021/ol3024067

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regioselective Ortho-Arylation and
Alkenylation of N‑Alkyl Benzamides with
Boronic Acids via Ruthenium-Catalyzed
CꢀH Bond Activation: An Easy Route
to Fluorenones Synthesis
Ravi Kiran Chinnagolla and Masilamani Jeganmohan*
Department of Chemistry, Indian Institute of Science Education and Research,
Pune 411021, India
mjeganmohan@iiserpune.ac.in
Received August 30, 2012
ABSTRACT
A highly regioselective ruthenium-catalyzed ortho-arylation of substituted N-alkyl benzamides with aromatic boronic acids in the presence of
[{RuCl2(p-cymene)}2], AgSbF6, and Ag2O is described. Further, ortho-arylated N-alkyl benzamides were converted into fluorenones in the
presence of trifluoroacetic anhydride and HCl.
The transition-metal-catalyzed heteroatom-directed
ortho-arylation of substituted aromatics with aryl electro-
philes or organometallic reagents by CꢀH bond activation
is one of the most efficient and environmentally friendly
methods to synthesize biaryl derivatives with minimum
waste.1,2 The biaryl structural unit is present in various
natural products, drug and agrochemical molecules, and
also key intermediates in various material syntheses.3 Palla-
dium-, rhodium-, or ruthenium-catalyzed ortho-arylations
of heteroatom group substituted aromatics with aryl
electrophiles such as aryl halides and aryl pseudohalides
have been extensively studied by the groups of Miura,
Daugulis, Yu, Cheng, Sanford, Ackermann, and others.4,5
(4) Reviews: (a) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (b)
Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
(c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792.
(5) Selected papers: (a) Karthikeyan, J.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2011, 50, 9880. (b) Ackermann, L.; Vicente, R.; Potukuchi,
H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032. (c) Wasa, M.; Worrell,
B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 1275. (d) Xiao, B.; Fu,
Y.; Xu, J.; Gong, T. J.; Dai, J. J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010,
132, 468. (e) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H. J. Am.
Chem. Soc. 2010, 132, 8569. (f) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am.
Chem. Soc. 2009, 131, 9886. (g) Ackermann, L.; Vicente, R.; Althammer,
A. Org. Lett. 2008, 10, 2299. (h) Thirunavukkarasu, V, S.; Parthasarathy,
K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2008, 47, 9462. (i) Shabashov,
D.; Maldonado, J. R. M.; Daugulis, O. J. Org. Chem. 2008, 73, 7818. (j)
Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130,
13285. (k) Shabashov, D.; Daugulis, O. Org. Lett. 2006, 8, 4947. (l)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (m) Ackermann, L. Org. Lett. 2005, 7, 3123.
(n) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
(o) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783.
(p) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett.
2000, 41, 2655.
(1) Selected recent reviews: (a) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174. (b) Chen, X.; Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Lyons,
T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (e) Liu, C.; Zhang, H.;
Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (f) Ackermann, L. Chem.
Rev. 2011, 111, 1351.
(2) For oxidative arylation reviews, see: (a) Li, B.-J.; Yang, S.-D.;
Shi, Z.-J. Synlett 2008, 949. (b) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Tetra-
hedron 2012, 68, 5130. (c) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41,
5588. Cross-coupling reaction: (d) Metal-Catalyzed Cross-Coupling
Reactions; Dieterich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998. (e)
Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev.
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(3) MaGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38,
2447 and references therein.
r
10.1021/ol3024067
XXXX American Chemical Society

An alternative strategy such as ortho-arylation by using
aryl organometallic reagents has not been well explored
in the literature. Organoborons, organosilanes, and orga-
nostannanes are commonly used transmetallating agents
in this type of reaction. Among them, organoboron
reagents display multifarious advantages including avail-
ability, air and moisture stability, low toxicity, and easy
removal of boron-derived byproducts unlike other orga-
nometallic reagents.6
acids, addition of boronic acid to the directing groups, and
decomposition of directing groups by in situ generated
proton of boronic acid.10c
Recently, the [{RuCl2(p-cymene)}2] complex has been
widely used as a catalyst in various CꢀH bond activation
reactions due to remarkable reactivity, compatibility, and
the low cost of the complex.11,12 In this communication, we
wish to report a highly regioselective ortho-arylation of
N-alkyl benzamides with substituted aromatic boronic
acids in the presence of [{RuCl2(p-cymene)}2], AgSbF6,
and Ag2O. An ortho-alkenylation of N-alkyl benzamides
with substituted alkenylboronic acids was also shown.
Later, the ortho-arylated N-alkyl benzamides were suc-
cessfully converted into fluorenones in the presence of
(CF3CO)2O and HCl.
In 1998, Oi et al. reported a rhodium-catalyzed direct
arylation of 2-aryl pyridines with arylstannanes.7 In 2003,
Kakiuchi et al. reported a ruthenium-catalyzed direct
arylation of aromatic ketones with aryl boronates.8 Later,
Yu’s group showed several palladium-catalyzed direct
alkylations and arylations of substituted aromatics with
organostannanes and organoboron reagents.9 Subse-
quently, Shi’s group and other research groups demon-
strated palladium-catalyzed arylation of acetanilides and
aromatic oximes with arylboronic acids.10 In most of the
reported CꢀH bond activation reactions, the palladium
complex has been used as a catalyst. In contrast, a ruthe-
nium catalyst was found to be suitable only for CꢀH bond
activation of aromatic ketones. In addition, in most of
the reported reactions, organoboronates have been widely
used as a coupling partner.7,8 The corresponding organo-
boronic acid was not a suitable coupling partner for
the reaction, mainly with ruthenium-catalyzed reactions.
Therefore, hydroxy groups of boronic acid were masked
and the masked reagent was used. Due to the vast avail-
ability and easy preparation of boronic acids, if a new
arylation reaction is developed by an organoboronic
acid, it would be very useful in organic synthesis. However,
the major challenge in this reaction is to suppress other
competitive reactions such as homocoupling of boronic
The reaction optimization was carried out with 4-methoxy
N-methylbenzamide (1a) (1.0 mmol) and phenylboronic
acid (2a) (1.50 mmol) in the presence of [{RuCl2(p-
cymene)}2] (3 mol %) and AgSbF6 (12 mol %) in THF at
110 °C for 16 h. The reaction was first tested with various
terminal oxidants such as Cu(OAc)2, AgOTf, AgBF4,
AgOAc, AgO2CCF3, Ag2O, AgCl, AgBr, Ag2CO3, Ag-
ClO4, and AgF. Among them, Ag2O was very effective for
the reaction, giving 3a in 87% yield. The yield of 3a was
1
determined based on the H NMR integration method
using mesitylene as an internal standard. Ag2CO3, AgOTf,
and AgBF4 were less effective giving 3a in 50%, 40%,
and 21% yields, respectively. The remaining silver salts
AgOAc, AgO2CCF3, Cu(OAc)2, AgCl, AgBr, AgClO4,
and AgF were totally ineffective for the reaction. Next,
the reaction was tested with various solvents such as
1,4-dioxane, DCE, DMF, CH3CN, CH3COOH, THF,
MeOH, tert-BuOH, DMSO, and toluene. Of the solvents
tested, THF was the most effective, affording 3a in 87%
yield. 1,4-Dioxane was also effective, providing 3a in 45%
yield. Other solvents such as DMF and tert-BuOH were less
effective, providing 3a in 25% and 15% yields, respectively.
The remaining solvents such as DCE, CH3CN, CH3COOH,
MeOH and DMSO were totally ineffective. Next, the
reaction was tested with different amounts of Ag2O (0.5,
1.0, 1.5, and 2.0 equiv). The coupling reaction showed a
better yield of 87% in 1.0 equiv of Ag2O. In the remaining
reactions, product 3a was observed only in 75ꢀ55% yields.
Further, the reaction was tested without AgSbF6 and only in
the presence of [{RuCl2(p-cymene)}2] and Ag2O. However,
in this reaction, coupling product 3a was not observed.
The catalytic reaction was also tested with a stoichiometric
amount of AgSbF6 (1.0 equiv) without Ag2O under similar
reaction conditions. In this reaction as well, no coupling
product 3a was observed. These results clearly revealed that
both AgSbF6 (12 mol %) and Ag2O (1.0 equiv) were crucial
for the reaction. The optimization studies revealed that
AgSbF6 (12 mol %) was the best additive, Ag2O (1.0 equiv)
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) (a) Oi, S.; Fukita, S.; Inoue, Y. Chem. Commun. 1998, 2439. (b)
Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229. (c) Vogler, T.;
Studer, A. Org. Lett. 2008, 10, 129.
(8) (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am.
Chem. Soc. 2003, 125, 1698. (b) Kakiuchi, F.; Matsuura, Y.; Kan, S.;
Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936. (c) Ueno, S.; Chatani,
N.; Kakiuchi, F. J. Org. Chem. 2007, 72, 3600.
(9) (a) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J.
Am. Chem. Soc. 2006, 128, 78. (b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J.
Am. Chem. Soc. 2006, 128, 12634. (c) Giri, R.; Maugel, N.; Li, J.-J.;
Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem.
Soc. 2007, 129, 3510. (d) Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J.
Am. Chem. Soc. 2008, 130, 7190. (e) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 17676. (f) Engle, K. M.; Mei, T.-S.; Wasa,
M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (g) Wasa, M.; Engle, K. M.;
Lin, D. W.; Yoo, E. J.; Yu, J.-Q J. Am. Chem. Soc. 2011, 133, 19598.
(10) (a) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129,
6066. (b) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.;
Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (c) Sun, C.-L.; Li, B.-J.;
Shi, Z.-J. Chem. Commun. 2010, 46, 677. (d) Nishikata, T.; Abela, A. R.;
Huang, S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978. (e) Sun,
C.; Liu, N.; Li, B.; Yu, D.; Wang, Y.; Shi, Z. Org. Lett. 2010, 12, 184.
(11) Seleted papers: (a) Ueyama, T.; Mochida, S.; Fukutani, T.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706. (b) Ack-
ermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem., Int. Ed. 2011, 50,
6379. (c) Ackermann, L.; Lygin, A. V.; Hofmann, N. Org. Lett. 2011, 13,
4153. (d) Li, B.; Ma, J.; Wang, N.; Feng, H.; Xu, S.; Wang, B. Org. Lett.
2012, 14, 736. (e) Parthasarathy, K.; Senthilkumar, N.; Jayakumar, J.;
Cheng, C.-H. Org. Lett. 2012, 14, 3478. (f) Hashimoto, Y.; Hirano, K.;
Satoh, T.; Kakiuchi, F.; Miura, M. Org. Lett. 2012, 14, 2058. (g)
Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Org. Lett. 2012, 14,
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Kishor, P.; Jeganmohan, M. Org. Lett. 2012, 14, 1134. (c) Ravi Kiran,
C. G.; Jeganmohan, M. Eur. J. Org. Chem. 2012, 417. (d) Ravi Kiran,
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Commun. 2012, 48, 7140.
B
Org. Lett., Vol. XX, No. XX, XXXX

was the best terminal oxidant, and THF was the best solvent
at 110 °C for 16 h for the present catalytic reaction. Under
the optimized reaction conditions, 1a reacted with 2a
providing coupling product 3a in 81% isolated yield
(Scheme 1).
4-methoxy N-tert-butylbenzamide 1i reacted with 4-hy-
droxyphenylboronic acid (2b) to give the corresponding
ortho-arylated product 3i in 74% yield. A sensitive-free
hydroxy group on the benzene ring of boronic acid 2b
was not affected in the reaction. The coupling reaction
was also tested with various N-phenyl substituted benza-
mides. However, no coupling product was observed in the
reaction.
Scheme 1. Scope of Substituted Amides
We next examined the scope of the regioselectivity of the
present reaction (Scheme 1). Thus, the coupling reaction
was tested with various unsymmetrical benzamides 1jꢀl.
N-Methyl-2-naphthamide (1j) underwent arylation reac-
tion with phenylboronic acid (2a) affording coupling
product 3j in 80% yield in a highly regioselective manner.
In this reaction, there are two ortho CꢀH bonds for
arylation. Regioselectively, arylation takes place at the
sterically less hindered CꢀH bond of 1j. Similarly, 3,4-
dimethoxy N-methylbenzamide (1k) also regioselectively
reacted with 2a at the sterically less hindered CꢀH bond of
the 1k moiety exclusively providing coupling product 3k
in 87% yield. In contrast, 1,3-dioxol group substituted
benzamide 1l reacted with 2a giving coupling product 3l in
77% yield by reverse regiochemistry. In this reaction,
arylation takes place selectively at the sterically hindered
CꢀH bond of the 1l moiety. The catalytic reaction was
also tested with a heteroaromatic group substituted
amide (Scheme 1). Thus, N-methylthiophene-2-carboxa-
mide (1m) underwent couplingwith2ato afford3min75%
yield.
The scope of the present ortho-arylation reaction was
further examined with various substituted aromatic and
heteroaromatic boronic acids (Scheme 2). Thus, electron-
withdrawing group substituted boronic acids such as
4-bromophenylboronic acid (2c), 4-fluorophenylboronic
acid (2d), and 4-acetylphenylboronic acid (2e) reacted
efficiently with 1a or 4-methyl N-methylbenzamide (1b)
providing coupling products 3nꢀp in 77%, 76%, and 65%
yields, respectively. 4-Methoxyphenylboronic acid (2f)
coupled nicely with bulky N-methyl-1-naphthamide (1g)
yielding biaryl derivative 3q in 77% yield. Similarly,
bulkier 1-naphthoboronic acid (2g) also efficiently coupled
with 1a to give the corresponding biaryl derivative 3r in
78% yield. A heteroaromatic boronic acid was also com-
patible for the reaction. Thus, 3-thienylboronic acid (2h)
efficiently participated in the coupling reaction with 1a
affording substituted 3-phenylthiophene derivative 3s in
75% yield. Subsequently, the present coupling reaction
was tested with alkenylboronic acids 2i and 2j (Scheme 2).
Thus, 4-chlorostyrylboronic acid (2i) underwent coupling
with 1a to give the corresponding alkene derivative 3t in
81% yield in a highly E-stereoselective manner. Surpris-
ingly, highly sterically hindered 1-phenylvinylboronic
acid (2j) also efficiently reacted with 1a to yield an alkene
derivative 3u in 78% yield. It is noteworthy to say that
various functional groups such as I, Br, Cl, F, CN, NO2,
OMe, S, COMe, and OH on the amides or boronic acids
were compatible for the present reaction.
Under the optimized reaction conditions, various sub-
stituted N-methyl benzamides 1bꢀh reacted efficiently
with phenylboronic acid (2a) to give the corresponding
ortho-arylated compounds 3aꢀh in good to excellent yields
(Scheme 1). Thus, 4-methyl N-methylbenzamide (1b)
afforded the corresponding ortho-arylated product 3b in
77% yield. Halogen group substituted benzamides such as
4-iodo N-methylbenzamide (1c) and 4-bromo N-methyl-
benzamide (1d) provided coupling products 3c and 3d in
79% and 76% yields, respectively. Interestingly, electron-
withdrawing group substituted benzamides such as 4-nitro
N-methylbenzamide (1e) and 4-cyano N-methylbenzamide
(1f) also efficiently participated in the reaction giving the
corresponding ortho-arylated products 3e and 3f in 73%
and 64% yields, respectively. Bulky N-methyl-1-naphtha-
mide (1g) was also successfully involved in the reaction
providing coupling product 3g in 77% yield. The effect
of changing substituents on the N-group of the benza-
mides to Et and tert-Bu was also tested. Thus, 4-methyl
N-ethylbenzamide (1h) reacted with phenylboronic acid
(2a) to give coupling product 3h in 76% yield. Similarly,
To demonstrate the synthetic utility of ortho-arylated
N-alkylbenzamides 3 in organic synthesis, we carried out
Org. Lett., Vol. XX, No. XX, XXXX
C

On the basis of known metal-catalyzed CꢀH bond
activations, a possible reaction mechanism is proposed to
account for the present ortho-arylation reaction (eq 1). The
first step involves removal of the chloride ligand from the
ruthenium complex by AgSbF6 providing the cationic
ruthenium complex. Coordination of the carbonyl oxygen
of benzamide 1 to the cationic ruthenium species followed
by ortho-metalation gives ruthenacycle intermediate 5.5
Transmetalation of boronic acid 2 into intermediate 5 in
the presence of Ag2O provides intermediate 6. Subsequent
reductive elimination of intermediate 6 in the presence of
Ag2O affords product 3 and regenerates the active ruthe-
nium species for the next catalytic cycle. While the exact
role of Ag2O is unclear, we think Ag2O might play a dual
role in the reaction. It acts as a base to accelerate transme-
talation of boronic acid 2 into intermediate 5. In addition,
the Agþ ion acts as a terminal oxidant to oxidize Ru(0) to
Ru(II).
Scheme 2. Scope of Boronic Acids
Scheme 3. Fluorenones Synthesis
In conclusion, we have described a ruthenium-catalyzed
highly regioselective ortho-arylation of substituted N-al-
kylbenzamides with substituted aromatic and heteroaro-
matic boronic acids in the presence of AgSbF6 and Ag2O.
Later, the observed coupling products were further con-
verted into fluorenones in the presence of trifluoroacetic
anhydride and HCl. Further extension of ortho-arylation
of directing group substituted aromatics with other orga-
nometallic reagents and a detailed mechanistic investiga-
tion are in progress.
intramolecular cyclization of ortho-arylated N-alkylbenza-
mides in the presence of trifluoroacetic anhydride and
HCl (Scheme 3). The intramolecular cyclization of 3h
proceeded smoothly in the presence of (CF3CO)2O at
100 °C for 2 h followed by HCl hydrolysis at 100 °C for
another 2 h yielding fluorenone derivative 4a in 89% yield,
whereas 3b underwent intramolecular cyclization under
similar reaction conditions, giving 4a only in 70% yield.
Similarly, ortho-arylated N-ethyl benzamides of 3e, 3j, and
3k also nicely converted into substituted fluorenone deri-
vatives 4bꢀd in excellent 85%, 82%, and 86% yields,
respectively (Scheme 3). Fluorenone is an important struc-
tural scaffold present in various natural products and
biologically active molecules.5h
Acknowledgment. We thank the DST (SR/S1/OC-26/
2011), Indiaforthesupportof thisresearch. R.K.C. thanks
the CSIR for a fellowship.
Supporting Information Available. General experimen-
tal procedure and characterization details. This material
is available free of charge via the Internet at http://pubs.
acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX