Ru(II)-catalyzed amidation of 2-arylpyridines with isocyanates via C-H activation

Article abstract of DOI:10.1021/ol302000a

An efficient Ru(II)-catalyzed amidation of 2-arylpyridines with isocyanates via C-H bond activation is described.

Full text of DOI:10.1021/ol302000a

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4262–4265
Ru(II)-Catalyzed Amidation of
2‑Arylpyridines with Isocyanates
via CÀH Activation
Krishnamoorthy Muralirajan, Kanniyappan Parthasarathy, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
chcheng@mx.nthu.edu.tw
Received July 18, 2012
ABSTRACT
An efficient Ru(II)-catalyzed amidation of 2-arylpyridines with isocyanates via CÀH bond activation is described.
In recent decades, chelation-assisted CÀH bond activa-
tion and subsequent addition to alkynes, alkenes, and
allenes has attracted increasing attention in metal-
catalyzed organic synthesis.1aÀe These methods have been
broadly applied in the syntheses of natural products,
drugs, and materials.1fÀh Previously, a number of direct
CÀH additions to various polar bonds have been demon-
strated.2 Recently, ortho aromatic CÀH bond activation
and additions across polar unsaturated bonds has been
studied considerably for the construction of substituted
amides and amines at the ortho-position. In this context,
Kuninobu and Takai initially observed a rhenium-
catalyzed addition of aromatic and heteroaromatic aldimine
CÀH to isocyanates leading to the formation of
phthalimidine3a and amidated3b,c derivatives. In 2011, Shi,
Bergman, and Ellman et al. independently developed a
Rh(III)-catalyzed selective CÀH activation and subsequent
addition to N-sulfonyl arylaldimines4 and boc-imines5a
respectively. Very recently, Bergman and Ellman reported
a synthesis of N-acyl anthranilamides and β-enamine amides
via Rh(III)-catalyzed amidation of aryl and vinyl CÀH
bonds with isocyanates.5b However, these methods re-
quired an expensive catalyst or harsh reaction conditions.
Recently, the use of Ru(II) complexes as inexpensive,
readily available, and environmentally friendly catalysts
(4) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.;
Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011, 50, 2115.
(5) (a) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2011, 133, 1248. (b) Hesp, K. D.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 11430.
(6) (a) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem.,
Int. Ed. 2011, 50, 6379. (b) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278. (c) Ackermann, L.; Fenner, S. Org. Lett. 2011,
13, 6548. (d) Ueyama, T.; Mochida, S.; Fukutani, T.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2011, 13, 706. (e) Hashimoto, Y.; Ueyama, T.;
Mochida, S.; Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Lett. 2011, 40, 1165. (f) Kishor, P.; Jeganmohan, M. Org. Lett. 2011, 13,
6144. (g) Ravi Kiran, C. G.; Jeganmohan, M. Eur. J. Org. Chem. 2012, 2,
417. (h) Ravi Kiran, C. G.; Jeganmohan, M. Chem. Commun. 2012, 48,
2030. (i) Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177.
(7) (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett.
2008, 10, 325. (b) Parthasarathy, K.; Cheng, C.-H. J. Org. Chem. 2009,
74, 9359. (c) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-H.
Angew. Chem., Int. Ed. 2008, 47, 9462. (d) Thirunavukkarasu, V. S.;
Parthasarathy, K.; Cheng, C.-H. Chem.;Eur. J. 2010, 16, 1436.
(e) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H. J. Am. Chem. Soc.
2010, 132, 8569. (f) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H.
Angew. Chem., Int. Ed. 2011, 50, 4169. (g) Jayakumar, J.; Parthasarathy,
K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2012, 51, 197. (h) Parthasarathy,
K.; Senthilkumar, N.; Jayakumar, J.; Cheng, C.-H. Org. Lett. 2012, 14,
3478.
(1) (a) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem.;Eur. J. 2002, 8,
2422. (b) Park, Y. J.; Jun, C.-H. Bull. Korean Chem. Soc. 2005, 26, 871.
(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) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212. (f) Johnson,
J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900. (g) Godula,
K.; Sames, D. Science 2006, 312, 67. (h) Tsai, A. S.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6316. (h) Leow, D.; Li, G.;
Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518.
(2) (a) Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
(b) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302.
(c) Fukumoto, Y.; Sawada, K.; Hagihara, M.; Chatani, N.; Murai, S.
Angew. Chem., Int. Ed. 2002, 41, 2779. (d) Hong, P.; Yamazaki, H.;
Sonogashira, K.; Hagihara, N. Chem. Lett. 1978, 535.
(3) (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. J. Am.
Chem. Soc. 2006, 128, 202. (b) Kuninobu, Y.; Tokunaga, Y.; Takai, K.
Chem. Lett. 2007, 36, 872. (c) Kuninobu, Y.; Kikuchi, K.; Tokunaga, Y.;
Nishina, Y.; Takai, K. Tetrahedron 2008, 64, 5974.
r
10.1021/ol302000a
Published on Web 08/08/2012
2012 American Chemical Society

for CÀH activation reactions has attracted considerable
attention.6 Our continuous interest in the metal-catalyzed
CÀH bond activation reactions7 prompted us to explore
the reaction of 2-arylpyridines with isocyanates. Herein,
we wish to report a convenient and mild method for ortho
amidation of 2-arylpyridines via ruthenium-catalyzed
CÀH bond activation. The use of ruthenium(0)8 and
recently [RuCl2(p-cymene)]2-catalyzed6 chelation-assisted
CÀH bond activation reactions have been reported.
We started the amidation reaction using 2-phenylpyr-
idine 1a and phenylisocyanate 2a as the substrates and
[RuCl2(p-cymene)]2 (5 mol %) as the catalyst. The reaction
proceeded in the presence of NaOAc (30 mol %) in
o-xylene at 80 °C for 24 h to give amidation product 3a
in 90% isolated yield (Table 2, entry 1). The structure of 3a
was confirmed by its 1H, 13C NMR and mass data.
To understand the nature of this reaction and to find the
optimal reaction conditions, different additives and sol-
vents were examined. In the absence of any additive, the
[RuCl2(p-cymene)]2-catalyzed reaction gave only a trace of
3a (Table 1, entry 1). The catalytic reaction appears to
requirethe presenceofabaseinordertoproceedsmoothly.
Several bases were tested for the reaction. Among them,
NaOAc gave the best result and afforded 3a in 93% yield
determined by an NMR integration method (Table 1,
entry 2) or 90% isolated yield (Table 2, entry 1). Other
metal acetates including KOAc, CsOAc, Cu(OAc)2, and
AgOAc are less effective giving 3a in 41, 36, 7, and 5%
yield, respectively (Table 1, entries 3À6). The effect of
solvents is also vital to the catalytic reaction. o-Xylene was
found to be the ideal solvent affording 3a in 90% isolated
yield. Other solvents such as benzene, toluene, THF, and
DCE were less effective for the catalytic reaction giving 3a
in 48, 28, 32, and 21% yield, respectively (Table 1, entries
7À10). Alcoholic solvents are not suitable for the catalytic
reaction (entries 11À12). Ruthenium complex [RuCl2-
(p-cymene)]2 is the most effective giving product 3a in 90%
yield. [RuCl2(benzene)]2 is also active forming 3a in 53%
yield (entry 13). Other ruthenium complexes including
Table 1. Optimization Studies for the Ru-Catalyzed Amidation
of 2-Arylpyridines with Isocyanatesa
yield
entry
catalyst
additive
solvent
(%)b
1
[RuCl2(p-cymene)]2
À
o-xylene
trace
2
[RuCl2(p-cymene)]2 NaOAc
o-xylene 93(90)
3
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(benzene)]2
[RuCl2(COD)]n
KOAc
o-xylene
o-xylene
41
36
7
4
CsOAc
5
Cu(OAc)2 o-xylene
6
AgOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
o-xylene
benzene
toluene
THF
5
7
48
28
32
21
0
8
9
10
11
12
13
14
15
16
DCE
MeOH
EtOH
0
o-xylene
o-xylene
o-xylene
o-xylene
53
0
RuCl2(PPh3)3
0
RuCl3 xH2O
0
3
a Unless otherwise mentioned, all reactions were carried out using
2-phenylpyridine 1a (1 mmol), 2a (1.8 mmol), [RuCl2(p-cymene)]2 (5 mol
%), NaOAc (30 mol %), and solvent (2 mL) at 80 °C for 24 h under N2.
b Yields were determined by the 1H NMR integration method; the value
in the parentheses was isolated yield.
(entries 2À6). The above results indicate that both elec-
tron-withdrawing and -donating arylpyridines work well.
Interestingly, 4-formyl- and 4-phenylarylpyridines (1gÀh)
also reacted efficiently with 2a to afford the corresponding
amidation derivatives 3g and 3h in 61 and 76% yield
respectively (entries 7,8). Similarly, the reaction of 2-(2-
methylphenyl)pyridine 1i with 2a proceeded smoothly
to give 3i in 84% yield (entry 9). In addition, 2-(3-
methoxyphenyl)pyridine 1j reacted nicely with 2a to give
3j in 78% yields (entry 10). In the reaction of 3-methox-
yarylpyridine, there are two possible CÀH bond activation
sites at C2 and C6 of 1j, but the CÀH activation occurs
only at C6 likely due to the steric effect of the methoxy
group at C3. In a similar manner, 3-fluoro- and 3-chlor-
ophenylpyridines 1k and 1l gave amidation derivatives 3k
and 3l in 72 and 74% yield, respectively (entries 11,12).
To evaluate the scope of the present catalytic reaction,
we examined the reaction of substrates 1 bearing substi-
tuents on the pyridine ring (1mÀp) with 2a under the
optimized reaction conditions. Thus, 6-methyl (1m),
5-methyl (1n), methoxy (1o), and phenyl (1p) substituted
pyridines underwent CÀH activation and addition reac-
tion effectively with isocyanate 2a affording amidation
products 3mÀp in 82, 87, 82 and 81% yield, respectively
(entries 13À16). 1-Phenylpyrazole (1q) also worked well
with 2a to give 3q in 79% yield (entry 17). In addition to 2a,
[RuCl2(COD)]n, RuCl2(PPh3)3, and RuCl3 xH2O were
3
totally inactive (entries 14À16).
To evaluate the scope of the present catalytic reaction,
we examined the reactions of several substituted 2-arylpyr-
idines (1bÀl) with phenyl isocyanate (2a) under the opti-
mized reaction conditions (Table 2). Thus, 4-methyl,
4-methoxy, 4-bromo-, 4-fluoro-, and 4-cyanophenylpyri-
dines (1bÀf) underwent CÀH activation and an addition
reaction effectively with isocyanate 2a affording the corre-
sponding amidation products 3bÀf in 63À83% yields
(8) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (b) Chatani, N.;
Asaumi, T.; Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi, F.; Murai, S.
J. Am. Chem. Soc. 2000, 122, 12882. (c) Kakiuchi, F.; Kan, S.; Igi, K.;
Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698. (d) Kakiuchi,
F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127,
5936. (f) Martinez, R.; Chevalier, R.; Darses, S.; Genet, J.-P. Angew.
Chem., Int. Ed. 2006, 45, 8232. (g) Martinez, R.; Genet, J.-P.; Darses, S.
Chem. Commun. 2008, 3855. (h) Simon, M.-O.; Genet, J.-P.; Darses, S.
Org. Lett. 2010, 12, 3038. (i) Watson, A. J. A.; Maxwell, A. C.; Williams,
J. M. J. Org. Lett. 2010, 12, 3856. (j) Kakiuchi, F.; Kochi, T.; Mizushima,
E.; Murai, S. J. Am. Chem. Soc. 2010, 132, 17741.
Org. Lett., Vol. 14, No. 16, 2012
4263

isocyanates 2bÀc with 1a gave 3r and 3s in 86 and 82%
yield, respectively (entries 18À19). In a similar manner,
4-bromo- and 4-chlorophenyl isocyanates 2dÀe gave pro-
ducts 3tÀu in 76 and 81% yield, respectively (entries
20À21). The present catalytic reaction can be further
extended to alkyl isocyanates. Thus, cyclohexyl isocyanate
2f reacted with 1a to afford amidation derivative 3v in 72%
yield (entry 22).
Table 2. Results of the Reaction of 2-Arylpyridines with Iso-
cyanatesa
Based on the known chemistry of metal-catalyzed CÀH
bond activation and addition reactions,1,4À9 a possible
mechanism to account for the present catalytic reaction
is proposed (Scheme 1). The catalytic cycle is likely in-
itiated by the dissociation of the [RuCl2(p-cymene)]2 dimer
into the coordinatively unsaturated monomer and the
exchange of acetate with the coordinated chloro ligand
to form an acetate-ligated species.10 Then, the coordina-
tion of the 2-phenylpyridine nitrogen to the ruthenium
center and subsequent ortho CÀH bond activation form a
five-membered ruthenacycle A and the release of an acetic
acid. Selective insertion of isocyanate 2a into the ruthe-
niumÀcarbon bond of intermediate B gives the seven-
membered ruthenacycle C. Protonation of C by acetic acid
affords final product 3a and regenerates the active Ru(II)
species for the next cycle.
Scheme 1. Proposed Mechanism for the Amidation of 2-Aryl-
pyridines with Isocyanates
To support the proposed mechanism, we tried to isolate
the ruthenium catalyst intermediate. Thus, heating 1a in
the presence of 0.10 equiv of [RuCl2(p-cymene)]2 and 0.30
equiv of NaOAc in o-xylene at 80 °C for 10 h led to the
isolation of five-membered ruthenacycle A-OAc in 78%
1
yield which is characterized by its H, 13C NMR and IR
(9) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
(b) Kakiuchi, F. Top. Organomet. Chem. 2007, 24, 1. (c) Ackermann,
L. Top. Organomet. Chem. 2007, 24, 35. (d) Thansandote, P.; Lautens,
M. Chem.;Eur. J. 2009, 15, 5874. (e) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (f) Ackermann,
L.; Vicente, R; Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792.
(g) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211.
(h) Ackermann, L. Chem. Rev. 2011, 111, 1315. (i) Hartwig, J. F. Chem.
a Unless otherwise mentioned, all reactions were carried out with
2-phenylpyridine 1a (1 mmol), 2a (1.8 mmol), [RuCl2(p-cymene)]2
(5 mol %), NaOAc (30 mol %), and o-xylene (2 mL) at 80 °C for 24 h
under N2. b Isolated yields.
€
Soc. Rev. 2011, 40, 1992. (j) Wencel-Delord, J.; Droge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (k) Song, G.; Wang, F.; Li,
X. Chem. Soc. Rev. 2012, 41, 3651. (l) Colby, D. A.; Tsai, A. S.; Bergman,
R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814.
(10) Li, B.; Feng, H.; Xu, S.; Wang, B. Chem.;Eur. J. 2011, 17,
12573.
other isocyanates (2bÀe) were also tested for the reaction.
Thus, treatment of 4-methyl- and 4-methoxyphenyl
4264
Org. Lett., Vol. 14, No. 16, 2012

product 3a in 84% yield (Scheme 2). It is interesting to note
that the reaction of A-OAc with 2a under slightly different
conditions, either in the absence of HOAc or in the pre-
sence of NaOAc, gave product 3a in only a trace amount.
We also successfully isolated A-Cl from [RuCl2(p-cymene)]2
and 1a. However, A-Cl did not react with 2a to give
amidation product 3a under any of the conditions shown
above for A-OAc.
Scheme 2. Structure and Reactivity of Intermediate A
In conclusion, we have demonstrated an easy and con-
venient Ru(II)-catalyzedamidationof 2-arylpyridineswith
isocyanates via CÀH bond activation. This method pro-
vides an opportunity for the synthesis of various amidated
2-arylpyridines under mild reaction conditions. Further
applications of this methodology in natural product synth-
esis are in progress.
Acknowledgment. We thank the National Science
Council of the Republic of China (NSC-100-2119-M-
007-002) for support of this research.
data (Scheme 2). The spectral data are in agreement with
those reported previously.11 As expected, the reaction of
A-OAc with phenylisocyanate 2a in the presence of HOAc
(proton source) in o-xylene at 80 °C for 3 h gave amidation
Supporting Information Available. General experimen-
tal procedure, characterization details, and crystallo-
graphic data (CIF) for 3r. This material is available free
of charge via the Internet at http://pubs.acs.org
(11) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am.
Chem. Soc. 2011, 133, 10161.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
4265