Rh(III)-catalyzed oxidative coupling of N -aryl-2-aminopyridine with alkynes and alkenes

Article abstract of DOI:10.1021/ol1022596

[RhCp*Cl₂]₂ (1-2 mol %) can catalyze the oxidative coupling of N-aryl-2-aminopyridines with alkynes and arylates to give N-(2-pyridyl)indoles and N-(2-pyridyl)quinolones, respectively, using Cu(OAc)₂ as an oxidant. Coupling with styrenes gave mono- and/or disubstituted olefination products.

Full text of DOI:10.1021/ol1022596

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5426-5429
Rh(III)-Catalyzed Oxidative Coupling of
N-Aryl-2-aminopyridine with Alkynes and
Alkenes
Jinlei Chen,‡ Guoyong Song,† Cheng-Ling Pan,† and Xingwei Li*,†
Dalian Institute of Chemical Physics, The Chinese Academy of Sciences,
Dalian, P. R. China 116023 and State Key Laboratory of Theoretical and
Computational Chemistry, Jilin UniVersity, Changchun 130023, P. R. China
xwli@dicp.ac.cn
Received September 20, 2010
ABSTRACT
[RhCp*Cl2]2 (1-2 mol %) can catalyze the oxidative coupling of N-aryl-2-aminopyridines with alkynes and arylates to give N-(2-pyridyl)indoles
and N-(2-pyridyl)quinolones, respectively, using Cu(OAc)2 as an oxidant. Coupling with styrenes gave mono- and/or disubstituted olefination
products.
Transition-metal-catalyzed activation of aromatic C-H bonds
has attracted considerable attention because it enables
efficient synthesis of organic building blocks.1 Oxidative
coupling of arenes and unsaturated molecules represents an
atom-economic method to construct complex molecules, and
this process is highly attractive in that no prior functional-
ization of the arene is necessary.2 Rhodium catalysts are well-
known for C-C coupling reactions that proceed via a C-H
activation pathway owing to broad synthetic utility.1p
However, rhodium-catalyzed oxidative C-H activation has
been less studied. Over the past several years, rhodium(III)
complexes, particularly [RhCp*Cl2]2, have stood out as a
highly efficient catalyst to mediate oxidative C-C, C-N,
and C-O coupling involving alkynes or alkenes.3 This
protocol constitutes an increasingly important strategy to
construct various heterocycles, which has been recently
reviewed.3
Recent studies on the Rh(III)-catalyzed oxidative cou-
pling reaction by Satoh and Miura, Fagnou, Jones, Glorius,
and Zhang reveal that in most cases C-H activation of
arenes requires chelation assistance by a proximal amide,4
† The Chinese Academy of Sciences.
‡ Jilin University.
(1) For reviews on C-H bond functionalization, see: (a) Dyker, G.
Angew. Chem., Int. Ed. 1999, 38, 1698. (b) Kakiuchi, F.; Murai, S. Top.
Organomet. Chem. 1999, 3, 47. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem.
ReV. 2002, 102, 1731. (d) Jun, C.-H.; C. Moon, W.; Lee, H.; Lee, D.-Y. J.
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2002, 35, 826. (f) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219,
212. (g) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (h)
Park, Y. J.; Jun, C.-H. Bull. Korean Chem. Soc. 2005, 26, 871. (i) Kakiuchi,
F. Top. Organomet. Chem. 2007, 24, 1. (j) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. ReV. 2007, 36, 1173. (k) Lewis, J. C.; Bergman, R. G.; Ellman,
J. A. Acc. Chem. Res. 2008, 41, 1013. (l) Kakiuchi, F.; Kochi, T. Synthesis
2008, 3013. (m) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.,
Int. Ed. 2009, 48, 9792. (n) Sun, C. L.; Li, B. J.; Shi, Z. J. Chem. Commun.
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61. (p) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. ReV. 2010,
110, 624. (q) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46,
677.
(2) For reviews on oxidative C-H functionalization, see: (a) Zhang,
M. AdV. Syn. Catal 2009, 351, 2243. (b) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Xu, L.-M.; Li,
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G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318.
(3) (a) Satoh, T.; Miura, M. Chem.sEur. J. 2010, 37, 11212. (b) Satoh.,
T.; Ueura, K.; Miura, M. Pure Appl. Chem. 2008, 80, 1127.
(4) (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou,
K. J. Am. Chem. Soc. 2008, 130, 16474. (b) Guimond, N.; Gouliaras, C.;
Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (c) Rakshit, S.; Patureau,
F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (d) Hyster, T. K.;
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10.1021/ol1022596  2010 American Chemical Society
Published on Web 11/01/2010

pyridyl,5 imine,6 hydroxyl,7 and carboxyl8 group to direct
the C-H functionalization to the ortho position. The
coupling of these substrates with alkynes constitutes an
important method to access heterocycles such as
pyrroles,4c indoles,4a isoquinolines,6a,b isoquinolones,4d,e
and isocoumarins8 (Figure 1). Despite the wide scope of
yield (entry 2, Table 1). Switching the solvent to 1,4-dioxane
or 1,2-dichloroethane led to an increase of the yield to 70%.
Table 1. Screening of Reaction Conditionsa
entry cat. (mol %)b oxidant solvent temp (°C) yield (%)c
1
2
3
4
5
6
7
A (4)
A (4)
A (4)
B (4)
B (2)
B (2)
A (2)
Ag2CO3
PhMe
100
100
100
100
120
120
120
<2
56
70
63
69
96
80
Cu(OAc)2 PhMe
Cu(OAc)2 dioxane
Cu(OAc)2 dioxane
Cu(OAc)2 dioxane
Cu(OAc)2 DMF
Cu(OAc)2 DMF
Figure 1. Previously reported oxidative coupling with alkynes.
substrates that have been studied, it is still necessary to
explore arenes bearing other easily installed directing groups.
We now report the oxidative coupling of N-aryl-2-aminopy-
ridines with alkynes and alkenes. Importantly, quinolones
were readily obtained when acrylates were used as the
coupling partner.
a Reaction conditions: 1a, diphenylacetylene (1.3 equiv), oxidant (1.5
equiv of Ag2CO3 or 2.2 equiv of Cu(OAc)2), catalyst, solvent (3 mL), sealed
tube under nitrogen, 12 h. b A: [RhCp*(MeCN)3](PF6)2. B: [RhCp*Cl2]2.
c Isolated yield.
A comparable yield (63%) was also obtained when the
catalyst was replaced by [RhCp*Cl2]2 (4 mol %) in 1,4-
dioxane at 100 °C. However, no significant improvement of
the yield could be achieved when the reaction was conducted
at a higher temperature (120 °C) if the catalyst loading was
reduced to 2 mol % (entry 5). We were delighted to find
that the combination of [RhCp*Cl2]2 (2 mol %) and
Cu(OAc)2 (2.2 equiv) in DMF at 120 °C afforded product
2a-1 in 96% isolated yield (entry 6), and [RhCp*Cl2]2
showed higher activity than [RhCp*(MeCN)3](PF6)2 (entry
7). For both catalyst systems, essentially no product was
detected when Ag2CO3 was used (entry 1). No coupling
proceeded when Ph2NH was attempted as a substrate under
the optimized reaction conditions, indicating the significance
of the pyridyl directing group.
The scope of this transformation was expanded under these
optimized conditions (Scheme 1). 4-Octyne could be applied,
and the indole product 2a-2 was isolated in 87% yield
(Scheme 1). The scope of the 2-aminopyridines was studied
in detail, and substrates bearing both electron-rich (2d-f,
2j) and electron-poor N-aryl groups (2h, 2i, 2l) can couple
with PhCtCPh in high isolated yield. Furthermore, ortho
substituents (such as Me, Ph, and OMe groups) in both the
N-aryl and the pyridyl groups can be tolerated (2c, 2d, 2i,
2k), indicating the tolerance of the steric bulk of the two
aryl groups in the substrate. However, the N-1-naphthyl
substituent retarded the coupling, and product 2g was
obtained in only 47% yield. To examine the regioselectivity
of this coupling reaction, substrate 1e was applied, and 2e
was obtained in 95% yield as the single isomer, where C-C
coupling occurred at the less hindered position para to the
OMe substituent. This observed selectivity agrees with those
previously reported in Rh-catalyzed oxidative coupling.3a In
contrast, moderate regioselectivity of 2j′:2j (2.3:1) was
observed for substrate 1j, and the major coupling product
We reasoned that N-aryl-2-aminopyridines are suitable
substrates for C-H activation in the N-aryl ring with the
pyridyl being a directing group. Furthermore, the proximal
NH functional group may act as a nucleophile to undergo
further transformations. Indeed, cyclopalladation of N-phen-
yl-2-aminopyridine has been reported,9 and the six-membered
palladacycle can undergo alkyne insertion. However, no
catalytic coupling between N-phenyl-2-aminopyridine and
alkyne or alkene has been reported. In fact, the first example
of intramolecular oxidative C-N coupling of N-phenyl-2-
aminopyridine has not been reported until very recently.10
We initiated our investigation using N-phenyl-2-aminopy-
ridine (1a) and diphenylacetylene as substrates. It has been
shown that [RhCp*(MeCN)3](PF6)2 and [RhCp*Cl2]2 are the
most commonly used Rh(III) catalysts for the oxidative
functionalization of arenes, and Cu(II) and Ag(I) are often
used as oxidants. Our initial screening indicated that the use
of [RhCp*(MeCN)3](PF6)2 (4 mol %) as a catalyst and
anhydrous Cu(OAc)2 (2.2 equiv) as an oxidant in toluene at
100 °C produced the anticipated indole 2a-1 in 56% isolated
(5) (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem.,
Int. Ed. 2008, 47, 4019. (b) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am.
Chem. Soc. 2008, 130, 12414. (c) Guan, Z.-H.; Spinella, S. M.; Yu., S.;
Liang, Y.-M.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 729. (d) Morimoto,
K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2068. (e) Umeda,
N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7094.
(6) (a) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050.
(b) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Commun. 2009, 5141.
(7) (a) Uto, T.; Shimizu, M.; Ueura, K.; Tsurugi, H.; Satoh, T.; Miura,
M. J. Org. Chem. 2008, 73, 298. (b) Mochida, S.; Shimizu, M.; Hirano,
K.; Satoh, T.; Miura, M. Chem. Asian J. 2010, 5, 847.
(8) (a) Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2009, 74, 3478. (b) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
1407.
(9) Maassarani, F.; Pfeffer, M.; Spencer, J.; Wehman, E. J. Organomet.
Chem. 1994, 466, 265.
(10) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem.
Soc. 2010, 132, 13217.
Org. Lett., Vol. 12, No. 23, 2010
5427

Scheme 1
.
Coupling of N-Aryl-2-aminopyridines and Alkynesa
Scheme 2
.
Oxidative Cyclization of N-Aryl-2-aminopyridines
with Benzyl Acrylatea
a Reaction conditions: substrate 1, benzyl acylate (2 equiv), 2.2 equiv
of Cu(OAc)2, 1 mol % of [RhCp*Cl2]2, DMF (3 mL), 100 °C, under
nitrogen, 12 h, isolated yield.
a Reaction conditions: substrate 1, alkyne (1.3 equiv), 2.2 equiv of
Cu(OAc)2, 2 mol % of [RhCp*Cl2]2, DMF (3 mL), under nitrogen, 12 h,
isolated yield.
The formation of the quinolone products most likely
involves the olefination of N-phenyl-2-aminopyridine, fol-
lowed by cyclization. The olefination intermediate is unusual
in that it must be a rare cis-olefin to allow subsequent
cyclization. However, we failed to observe this plausible cis-
olefin intermediate when carrying out this reaction at a lower
temperature. We reasoned that when using electron-neutral
olefins the reaction should stop after the olefination stage.
Indeed, the coupling between N-phenyl-2-aminopyridine and
p-Cl(C6H4)CHdCH2 (1.1 equiv) under the same conditions
gave the monovinylation product 4a (81% yield) with trans
geometry (eq 1). Shifting this olefin to simple styrene caused
differences in product distribution. Both mono- and diviny-
lation products were observed even though only 1 equiv of
styrene was provided. Thus, this divinylation product 4b can
be optimized and was isolated in 72% yield when 10 equiv
of styrene and an excess (4.1 equiv) of Cu(OAc)2 were used,
and it was further characterized by X-ray crystallography.
(2j′) corresponds to C-C coupling at a more hindered
position. This observation is most plausibly ascribed to the
directing effect of the O-atom and/or the electronic effect
of the aryl ring. In addition, halogen substituents in the
substrate can also be tolerated, and indole 2l was obtained
in 84% yield.
To better define the scope of N-aryl-2-aminopyridine in
oxidative coupling, we further applied acylates as the
coupling partners for oxidative Heck reactions. Methyl, ethyl,
and benzyl arylates all readily coupled with N-phenyl-2-
aminopyridines in high yields (80-91%) using 1 mol % of
[RhCp*Cl2]2 and Cu(OAc)2 in DMF (100 °C). The coupled
product was identified as an interesting quinolone on the basis
of IR and NMR spectroscopy. The scope of this reaction
was outlined in Scheme 2. Substrates with both electron-
rich and electron-poor N-aryl groups reacted in high isolated
yield, although relatively lower yields were obtained for those
bearing electron-withdrawing groups (3h, 3l). Analogous to
its coupling with alkynes, the same regioselectivity was
observed for 3e and 3j/3j′. Unlike the tolerance of ortho
substituents in the coupling with alkynes, the introduction
of a methyl group into the ortho position of either the pyridyl
or the N-phenyl ring retarded this reaction (3c, 3k). We noted
that acetanilides can also undergo Rh(III)-4f and Pd(II)11-
catalyzed oxidative coupling with acrylates. However, no
further nucleophilic attack of the amide NH group on the
ester was involved, and the product is a trans-olefin.
To gain insight into the mechanism of this coupling
reaction, an equimolar mixture of 1a and 1a-d5 was heated
(DMF, 100 °C) in the presence of [RhCp*Cl2]2 (2 mol %)
and Cu(OAc)2. H-D exchange occurred at the ortho position
of the N-phenyl ring in these two isotopologues. This result
indicated that the C-H activation is reversible under these
(11) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P.W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586.
5428
Org. Lett., Vol. 12, No. 23, 2010

conditions, which precludes any KIE measurement on the
basis of inter- or intramolecular C-H and C-D competition.
A competition reaction to examine the electronic effect of
the N-aryl ring was carried out using an equimolar mixture
of 1f, 1l, and benzyl acrylate under the standard conditions
(eq 2). NMR analysis of the product mixtures showed that
quinolones 3f and 3l were obtained in 1:0.6 ratio, where an
electron-rich N-aryl group favors this coupling reaction. The
same trend was also observed in the oxidative coupling with
PhCtCPh, and these observation are in sharp contrast to
those in [RhCp*Cl2]2-catalyzed oxidative coupling of N-aryl
benzamides, where the coupling is favored for an electron-
poor N-aryl or benzoyl group.4f In the case of benzamides,
it has been suggested on the basis of electronic perturbation
that metalation at the (deprotonated) NH nitrogen instead of
at the amide oxygen plays a vital role in facilitating the C-H
ortho-metalation.4f The observed electronic effect here seems
inconsistent with the coordination of the (deprotonated) NH
nitrogen. Instead, chelation assistance offered by the pyridine
nitrogen is more likely.
for this Rh(III) alkyl species. Instead, subsequent ꢀ-hydride
elimination occurs to afford a (metal-bound) trans-olefin,
which can isomerize to the cis isomer. Attack of the NH
group on the carbonyl group of this cis intermediate generates
the final product. The catalytic cycle is completed when the
Rh(III) species is regenerated when the Rh(I) intermediate
is oxidated by Cu(II). We have noted that related acid-
catalyzed cyclization of ortho-amino-substituted trans-cin-
namates by the nucleophilic attack of the nitrogen at the ester
carbonyl has been reported to give quinolones (eq 4).13 This
indicates that the isomerization of the trans CdC bond
geometry to the cis one is at least feasible, where annulation
is an apparent driving force.
Two distinct pathways for the coupling between N-aryl-
2-aminopyridines and acrylates can be envisioned. In one
pathway, amidation between the coupling partners might take
place to give the corresponding acylamide, which subse-
quently undergoes catalyzed oxidative C(vinyl)-C(aryl)
coupling to furnish the final product. To test this possibility,
we have synthesized acylamide 5. Subjection of 5 to the
standard conditions gave essentially no coupling product, and
only a small amount of decomposition products was observed
(eq 3). These results suggest that this amidation-oxidation
pathway is unlikely. A more plausible pathway for the
oxidative coupling is thus proposed in Scheme 3. Cyclom-
In summary, we have successfully applied N-aryl-2-
aminopyridine to the oxidative coupling with alkynes and
alkenes using [RhCp*Cl2]2 as a catalyst and Cu(OAc)2 as
an oxidant. The coupling with internal alkynes furnished
N-pyridyl-substituted indoles, and coupling with acrylates
gave N-(2-pyridyl)quinolones as a result of oxidative cy-
clization. Substrates bearing electron-rich N-aryl groups react
preferentially. The reaction between N-aryl-2-aminopyridine
and styrenes under similar conditions afforded mono- and/
or disubstituted trans-olefins, depending on the electronic
effect of the styrene, where an electron-poor styrene favors
the monosubstituted olefin. This methodology proves that
2-aminopyridyl can act as an efficient directing group, and
this method should find important applications in the
synthesis of complex molecules.
Scheme 3
.
Plausible Mechanism for the Formation of
Quinolones
Acknowledgment. We thank the Dalian Institute of
Chemical Physics, Chinese Academy of Sciences, for
financial support.
Supporting Information Available: Synthetic procedures,
characterization data, NMR spectra of all new compounds,
and X-ray crystallographic data of comounds 2a-1, 2g, and
4b. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL1022596
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etalation gives a six-membered Rh(III) intermediate with a
loss of an acid,9,12 which can undergo insertion of an
incoming acylate. Interestingly, no CR-N coupling occurs
Org. Lett., Vol. 12, No. 23, 2010
5429