Synthesis of N-(2-pyridyl)indoles via Pd(II)-catalyzed oxidative coupling

Article abstract of DOI:10.1021/jo1025546

Readily available Pd(II) chloride catalysts can catalyze selective and efficient oxidative coupling between N-aryl-2-aminopyridines and internal alkynes to yield N-(2-pyridyl)indoles. This process involves the ortho C-H activation of N-aryl-2-aminopyridines, and CuCl₂ was used as an oxidant. Compared to our previously reported Rh(III)-catalyzed synthesis of this class of product, this method is advantageous with a wider scope of alkynes and cost-effective Pd(II) catalysts. Molecular oxygen can be used as a terminal oxidant.

Full text of DOI:10.1021/jo1025546

NOTE
pubs.acs.org/joc
Synthesis of N-(2-Pyridyl)indoles via Pd(II)-Catalyzed
Oxidative Coupling
Jinlei Chen,†,‡ Qingyu Pang,‡ Yanbo Sun,† and Xingwei Li*,‡
†State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University,
Changchun 130023, People's Republic of China
‡Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, People's Republic of China
S Supporting Information
b
ABSTRACT: Readily available Pd(II) chloride catalysts can catalyze
selective and efficient oxidative coupling between N-aryl-2-aminopyri-
dines and internal alkynes to yield N-(2-pyridyl)indoles. This process
involves the ortho CꢀH activation of N-aryl-2-aminopyridines, and
CuCl2 was used as an oxidant. Compared to our previously reported
Rh(III)-catalyzed synthesis of this class of product, this method is
advantageous with a wider scope of alkynes and cost-effective Pd(II) catalysts. Molecular oxygen can be used as a terminal oxidant.
ransition metal-catalyzed direct functionalization of CꢀH
bonds via CꢀH activation pathway represents an important
terminal oxidant. Therefore, our objective is to achieve this
reaction with high efficiency using low-cost catalysts such as
palladium(II) complexes that can cover a broader substrate scope
(Chart 1). In fact stoichiometric reactions between N-aryl-2-
aminopyridines and Pd(II) complexes have been reported to give
a cyclometalation product,12 although no catalytic reaction has
been developed. These results make our objective plausible.
We initiated our studies with the coupling between N-phenyl-
2-aminopyridine (1a), and PhCtCPh using Pd(OAc)2 (4 mol %)
as a catalyst in the presence of an oxidant. The desired product 3aa
was isolated in36% yield when Cu(OAc)2 (2.1 equiv) was selected
as an oxidant (entry 1, Table 1). Switching to silver oxidants such
as Ag2CO3 and AgOAc gave essentially no desired product,
although no starting material remained (entry 2). Other solvents
such as acetone (105 °C, sealed tube) turned out to be less
efficient, where the coupled product was obtained in 25% yield.
Compared to Pd(OAc)2 catalysts, a higher isolated yield of 3aa
was obtained when several Pd(II) chloride catalysts were used
(entries 4 and 6ꢀ9). Further screening of catalysts and oxidants
revealed that a combination of inexpensive Pd(MeCN)2Cl2
(4 mol %) and CuCl2 (2.1 equiv) provides optimal conditions,
under which product 3aa was isolated in 89% yield (Conditions A,
entry 8). Importantly, O2 (1 atm) can be used asa terminal oxidant
when 20 mol % of CuCl2 was used as a co-oxidant (conditions B),
although the couple was isolated in slightly lower yield (entry 10).
It is noteworthy that neither O2 nor air can be applied as a terminal
oxidant when [RhCp*Cl2]2 was used as a catalyst and decomposi-
tion of the starting material was observed.
T
and atom-economic strategy to construct complex structures.1
Activation of a CꢀH bond, particularly under chelation assis-
tance, followed by oxidative coupling of unsaturated molecules
has attracted considerable attention because condensed
(hetero)cycles are generated and these structural motifs are
widely present in natural products and pharmaceuticals.2 Re-
cently, Cp*Rh(III) complexes have stood out to catalyze the
oxidative coupling of arenes with alkynes with high efficiency,
and groups of Satoh and Miura, Fagnou, Jones, Glorius, Rovis,
and Li have successfully achieved selective ortho CꢀH activation
of various arenes for the synthesis of condensed heterocycles
such as isoquinolones,3 indoles,4 isoquinolines,5 pyrroles,6
isocoumarins,7 and pyridones.8 Despite the success, convenient
and cost-effective synthetic methods are still necessary.
Palladium catalysts are well-known for their outstanding capa-
city to mediate oxidative CꢀH activation via a CꢀH activation
pathway with high functional group compatibility and low cost,
and this area has been extensively reviewed.2e,9 However,
palladium(II)-catalyzed CꢀH activation followed by oxidative
coupling with alkynes is less well-studied, and only limited
examples have been reported.10 The compatibility of the reaction
conditions for CꢀH activation and for alkyne functionalization
sometimes might pose problems. We recently reported the
oxidative coupling between N-aryl-2-aminopyridines and internal
alkynes for the synthesis of substituted indoles using [RhCp*Cl2]2
as a catalyst.11 In this reaction, the pyridyl ring proved to be an
effective directing group to facilitate the CꢀH activation of the
N-aryl ring. Despite the high selectivity, the alkyne substrates are
limited to symmetrically substituted ones. For example, an
unsymmetrically substituted alkyne such as PhCtCMe failed.
In addition, the high cost of the rhodium catalyst makes it less
competitive. Ideally, it is desirable to use oxygen or even air as a
With the optimized conditions (A and B) in hand, we further
explored the scope of this coupling reaction. As given in Table 2,
coupling of 1a with various symmetrically substituted alkynes
Received: December 23, 2010
Published: March 22, 2011
r
2011 American Chemical Society
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NOTE
Chart 1
Table 2. Palladium-Catalyzed Oxidative Couplinga
Table 1. Screening of Reaction Conditionsa
entry
catalyst
Pd(OAc)2
oxidant
Cu(OAc)2
solvent yield (%)b
1
2
DMF
DMF
acetone
DMF
DMF
DMF
DMF
DMF
DMF
36
0
Pd(OAc)2
Ag2CO3
3
Pd(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
25
57
32
55
72
89
71
75
4
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(COD)Cl2
5
6
7
Pd(CH3CN)2Cl2 Cu(OAc)2
Pd(CH3CN)2Cl2 CuCl2
8
9
Pd(PPh3)2Cl2
CuCl2
10
Pd(CH3CN)2Cl2 CuCl2 (20 mol %), O2 DMF
a Reaction conditions: 1a (0.6 mmol), 2a (0.9 mmol), 1.5 equiv of
Ag2CO3 or 2.1 equiv of CuX2, catalyst (4 mol %), solvent (3.0 mL).
b Isolated yield.
offered indole products in 82ꢀ89% yield under Conditions A
(entries 1ꢀ4 and 7). In addition, heteroaryl-substituted alkyne
(2g) readily undergoes coupling with 1a to give 3ag in high yield
(entry 7). In contrast to the failure of coupling of unsymme-
trically substituted alkynes such as PhCtCMe with 1a using our
previously reported Rh(III) catalysts,11 here a clean reaction was
observed and product 3ae was isolated as a single regioisomer in
71% yield, where the phenyl group in the alkyne unit is disposed
adjacent to the nitrogen atom. When PhCtCPr was applied to
couple with 1a, a mixture of two regioisomers were isolated in 8:1
ratio (entry 6), with the major product (3af) being analogous to
product 3ae. The decreased selectivity is likely ascribed to the
increased steric bulk of the alkyne. Analogously, unsymmetrically
heteroaryl- and alkyl-substituted alkyne 2h undergoes ready
coupling with 1a to give 3ah in 75% yield as a single isomeric
product (entry 8). Here the isolation of 3ah as a single product
highlights the electronic differences between a 2-thiophenyl
group and a phenyl group in terms of the selectivity of alkyne
insertion. Product 3ah is also inaccessible under rhodium(III)-
catalyzed oxidative coupling conditions. The observed regios-
electivity agrees with that in other Rh(III)-catalyzed oxidative
coupling reactions involving alkynes.13 Other N-aryl-2-amino-
pyridines also successfully coupled with PhCtCPh. As given in
Table 2, both electron-donating (entries 9ꢀ11, 13, and 17) and
withdrawing groups (entries 14ꢀ16) at the ortho or para
position of the N-aryl can be tolerated and the coupling products,
a Reaction conditions A: 1 (0.60 mmol), 2 (0.90 mmol), Pd-
(MeCH3)2Cl2 (4 mol %), CuCl2 (2.1 equiv), DMF (3 mL), 105 °C,
12 h. Reaction conditions B: 1 (0.60 mmol), 2 (0.90 mmol), Pd-
(MeCH3)2Cl2 (4 mol %), CuCl2 (0.12 mmol), O2 (1 atm), DMF
(3 mL), 105 °C, 14 h. b Isolated yield, set of conditions after parentheses.
c 8 mol % of Pd(MeCH3)2Cl2 was used.
including 3ja, were isolated in high yield. CꢀH activation of
1e bearing a 3-OMe group (entry 12) occurs exclusively at the
less hindered position as a result of steric effect. It is noteworthy
that for reasons that are unclear 3ja cannot be obtained by
using our reported Rh(III)-catalyzed conditions.11 When ortho
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NOTE
substituents such as Me, OMe, and Ph were introduced into the
N-aryl ring, somewhat lower yields (entries 10, 11, 15, and 18)
were obtained, indicating limited steric tolerance of this reaction.
For these substrates, using 8 mol % loading of the catalyst slightly
increased the yield. Importantly, O2 can be consistently used as a
terminal oxidant and CuCl2 (20 mol %) as a co-oxidant
(conditions B, entries 1, 12, 16, and 20), although the yield is
slightly lower than that obtained by using only CuCl2 as an
oxidant. These results indicate that this reaction can be made eco-
friendly and cost-effective. In contrast, under rhodium(III)-
catalyzed conditions decomposition occurred when O2 was
used as a terminal oxidant and Cu(II) as a co-oxidant. In
addition, when 1l was allowed to react with PhCtCPh
(entry 19), two regioisomers were isolated as a mixture in 5:1
ratio, and the major product corresponds to CꢀH activation at
the more hindered position. This selectivity has been observed
and is most plausibly ascribed to the directing effect of the
oxygen atom.14 With the tethering effect, the ꢀOCH2Oꢀ
group is less sterically bulky compared to a OMe group
(entry 12) and can accommodate CꢀH activation at a more
hindered position.14 Besides pyridine rings, the pyrimidine
(entry 21) and pyrazine ring (entry 24) can also act as an
effective directing group to give 3na and 3qa. In contrast, a
lower yield (52%) of 3na was isolated when rhodium(III)-
catalyzed conditions were used.
Steric bulk at the 3-position in the pyridine ring can be
tolerated when a 3-methyl group is introduced into the pyridine
ring, as evidenced by the isolation of 3ma in 90% yield (entry 20).
However, introduction of a methyl group into the 6-position
significantly retarded this reaction, and the coupled product 3pa
was isolated in only 18% yield. Similarly, using a quinoline
analogue of 1a afforded the coupled product (3oa) in 25% yield
(entry 22). These yields can be somewhat improved when
higher loading (8 mol %) of Pd(MeCN)2Cl2 was applied.
These results suggest that this reaction is sensitive to the steric
bulk around the pyridine nitrogen and in the N-aryl ring.
Coordination of this nitrogen seems to play an important role
in this reaction by assisting the cleavage of the CꢀH bond in the
N-aryl group.
acrylates were used, and only decomposition products were
observed. These results revealed that when properly designed,
Rh(III) and Pd(II) catalysis can be complementary.
In conclusion, we have demonstrated a palladium-catalyzed
oxidative coupling between N-aryl-2-pyridines and alkynes for
the synthesis of substituted indoles. This coupling reaction
readily occurred by using simple Pd(MeCN)2Cl2 catalyst and
no additional ligand is necessary. The CꢀH bond activation is
regioselective, and a broad scope of substrate has been defined.
This synthetic method proved superior to our previously re-
ported Rh(III)-catalyzed version in terms of both substrate scope
and the cost of catalyst. This method has potential applications in
the synthesis of complex structures.
’ EXPERIMENTAL SECTION
A Typical Procedure for the Synthesis of 2,3-Diphenyl-
1-(pyridin-2-yl)-1H-indole (3aa). Compound 1a (102.2 mg, 0.60
mmol), diphenylacetylene (160.5 mg, 0.90 mmol), anhydrous CuCl2
(169.5 mg, 1.26 mmol), and Pd(CH3CN)2Cl2 (6.2 mg, 4 mol %) were
charged into a 10 mL Schlenk tube. After the tube was filled with
nitrogen, anhydrous DMF (3 mL) was added via a syringe and the
mixture was stirred at 105 °C for 12 h. The mixture was diluted with
deionized water then extracted with CH2Cl2 (3 ꢁ 10 mL). The
combined organic layers were dried over Na2SO4. The solvent was
removed under vacuum. Purification of the product was performed by
flash column chromatography on silica gel, using EtOAc and petroleum
ether (1:20). Yield: 184.5 mg (0.53 mmol, 89%), white solid. 1H NMR
(400 MHz, CDCl3): δ 8.61 (d, J = 4.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H),
7.69 (d, J = 8.0 Hz), 7.55 (td, J = 7.6, 1.2 Hz, 1H), 7.30ꢀ7.36 (m, 4H),
7.22ꢀ7.27 (m, 3H), 7.11ꢀ7.20 (m, 6H), 6.82 (d, J = 4.0 Hz, 1H). 13C
NMR (125 MHz, CDCl3): 151.8, 149.1, 137.5, 137.4, 135.9, 134.6,
131.7, 130.9, 130.3, 128.3, 128.2, 128.0, 127.4, 126.1, 123.4, 122.2, 121.6,
121.5, 119.6, 118.2, 111.5. HRMS (ESI) Calcd for [C25H18N2 þ H]þ
347.1548, found 347.1546.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedure and
b
characterization data for new compounds. This material is
A competitive reaction was carried out to probe the electronic
effect of the N-aryl ring. An equimolar mixture of 1f, 1i, and 2a
available free of charge via the Internet at http://pubs.acs.org.
1
was allowed to react under Conditions A (eq 1). H NMR
’ AUTHOR INFORMATION
analysis of the crude products revealed that products 3fa and 3ia
were generated in a 1:3.7 ratio. This result indicates that coupling
is favored for electron-withdrawing groups in this N-aryl ring,
which stands in sharp contrast to the Rh(III)-catalyzed version,11
indicating that they may follow different mechanisms or proceed
with different rate-determining steps.
Corresponding Author
*E-mail: xwli@dicp.ac.cn.
’ ACKNOWLEDGMENT
We thank Dalian Institute of Chemical Physics, Chinese
Academy of Sciences for financial support. This work was
supported by the NSFC (No. 21072188). X.L. conceived and
designed the experiments.
’ REFERENCES
(1) For pertinent reviews on CꢀH bond functionalization, see: (a)
Crabtree, R. H. Chem. Rev. 1985, 85, 245. (b) Kakiuchi, F.; Murai, S. Top.
Organomet. Chem. 1999, 3, 47. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M.
Chem. Rev. 2002, 102, 1731. (d) Labinger, J. A.; Bercaw, J. E. Nature
2002, 417, 507. (e) Miura, M.; Nomura, M. Top. Curr. Chem. 2002,
219, 212. (f) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077.
(g) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (h)
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013.
Our previous studies revealed that N-aryl-2-aminopyridines
can readily couple with various acrylates to give pyridyl-substi-
tuted 2-quinolones under Rh(III) catalysis conditions,11 and
these conditions are essentially the same as those for the rhodium-
(III)-catalyzed coupling with alkynes. However, under the current
Pd(II) catalysis conditions, no such coupling was achieved when
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NOTE
(i) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (j) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (k) Sun,
C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (l) Satoh, T.;
Miura, M. Top. Organomet. Chem. 2007, 24, 61. (m) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(2) For reviews on oxidative CꢀH functionalization, see: (a) Kr€uger,
K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153. (b) Zhang,
M. Adv. Synth. Catal. 2009, 351, 2243. (c) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (d) Xu, L.-M.; Li,
B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (e) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(3) (a) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
Chem. Lett. 2010, 39, 744. (b) Song, G.; Chen, D.; Pan, C.-L.; Crabtree,
R. H.; Li, X. J. Org. Chem. 2010, 75, 7487. (c) Hyster, T. K.; Rovis, T.
J. Am. Chem. Soc. 2010, 132, 10565.
(4) (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474. (b) Wurtz, S.; Rakshit,
S.; Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008,
47, 7230.(c) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am.
Chem. Soc. 2010, 132, 18326.
(5) (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.
(6) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 9585.
(7) (a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. (b)
Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A. J. Am. Chem. Soc. 2009,
131, 18022.
(8) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010,
12, 5462.
(9) (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Chem. Rev. 2007, 107, 5318. (b) Jazzar, R.; Hitce, J.; Renaudat, A.;
Sofack-Kreutzer, J.; Baudoin, O. Chem.—Eur. J. 2010, 16, 2654. (c)
Thansandote, P.; Lautens, M. Chem.—Eur. J. 2009, 15, 5874. (d)
Godula, K.; Sames, D. Science 2006, 312, 67. (e) Wasa, M.; Engle,
K. M.; Yu., J.-Q. J. Am. Chem. Soc. 2010, 132, 3680. (f) Engle, K. M.;
Wang, D. H.; Yu, J. Q. Angew. Chem., Int. Ed. 2010, 49, 1. (g) Li, J.-J.; Mei,
T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452. (h) Li, B.-J.; Tian,
S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115.
(10) (a) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2009, 48, 4572. (b) Shi, Z.; Cui, Y.; Jiao, N. Org.
Lett. 2010, 12, 2908. (c) Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2010,
12, 1540. (d) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed.
2009, 48, 7895. (e) Shi, Z.; Zhang, B.; Cui, Y.; Jiao, N. Angew. Chem., Int.
Ed. 2010, 49, 4036. (f) Wu, Y.-T.; Huang, K.-H.; Shin, C.-C.; Wu, T.-C.
Chem.—Eur. J. 2008, 14, 6697. (g) Yamashita, M.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2009, 11, 2337. (h) Yamashita, M.; Horiguchi, H.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7481.
(11) Chen, J.; Song, G.; Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426.
(12) Maassarani, F.; Pfeffer, M.; Spencer, J.; Wehman, E. J. Organo-
met. Chem. 1994, 466, 265.
(13) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M.
Angew. Chem., Int. Ed. 2008, 47, 4019. (c) Ueura, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2007, 72, 5362.
(14) Wang, F.; Song, G.; Li, X. Org. Lett. 2010, 12, 5432.
3526
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