Palladium-catalyzed regioselective benzylation-annulation of pyridine N -oxides with toluene derivatives via multiple c-h bond activations: Benzylation versus arylation

Article abstract of DOI:10.1021/ol503238a

A palladium-catalyzed cross-dehydrogenative coupling (CDC) reaction of pyridine N-oxides with toluenes has been developed that operates under mild conditions. 2-Benzylpyridines can be obtained directly by this method via a CDC reaction between unactivated toluenes and pyridine N-oxides. In addition, azafluorene N-oxides, of value for future medicinal chemistry applications, can be obtained successfully by this procedure via four tandem C-H bond activations.

Full text of DOI:10.1021/ol503238a

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Regioselective Benzylation−Annulation of
Pyridine N‑Oxides with Toluene Derivatives via Multiple C−H Bond
Activations: Benzylation versus Arylation
Ebrahim Kianmehr,*,† Nasser Faghih,† and Khalid Mohammed Khan‡
†School of Chemistry, College of Science, University of Tehran, Tehran 1417614411, Iran
‡H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi
75270, Pakistan
S
* Supporting Information
ABSTRACT: A palladium-catalyzed cross-dehydrogenative coupling (CDC) reaction of pyridine N-oxides with toluenes has
been developed that operates under mild conditions. 2-Benzylpyridines can be obtained directly by this method via a CDC
reaction between unactivated toluenes and pyridine N-oxides. In addition, azafluorene N-oxides, of value for future medicinal
chemistry applications, can be obtained successfully by this procedure via four tandem C−H bond activations.
ransition-metal-catalyzed cross-coupling reactions have
Temerged as powerful tools for the construction of
carbon−carbon and carbon−heteroatom bonds in the key
step of many natural, unnatural and biologically active products
syntheses. It is a reaction that has become even more applicable
now that C−H bond activation has been developed.1 Recently
Figure 1. Examples of bioactive 2-benzylpyridines.
C−C bond forming reactions from two C−H bonds, under
oxidative conditions (cross-dehydrogenative coupling, CDC),
have gained considerable attention. Tandem oxidation of C−H
palladium-catalyzed reaction with aryl halides for the synthesis
bonds allows the use of simple (i.e., less functionalized)
of the title compounds.10
2-Methylpyridine N-oxides were used by Fagnou for the
reagents and often reduces the number of steps to the target
molecule.2 Despite a number of reports concerning oxidative
synthesis of 2-benzylpyridines via direct arylation of benzylic
coupling between Csp−H and Csp−H,3 Csp−H and Csp2−H,4
Csp3−H bond (Scheme 1) in 2008.11 Decarboxylative cross-
Csp−H and Csp3−H,5 Csp2−H and Csp2−H bonds,6 there are
coupling of 2-(2-pyridyl)acetates with aryl halides, for the
few examples of the construction of C−C bonds between
synthesis of 2-benzylpyridine derivatives, was reported by Liu12
in 2010, and palladium-catalyzed arylation of 2-methylpyridine
with aryl halides is another approach for the synthesis of 2-
benzylpyridines developed by Knochel in 2011.13 Palladium-
catalyzed C−H couplings of pyridine N-oxides with benzyl
chloride derivatives were reported by Mai in 2012.14 (Scheme
1) In all of the above-mentioned methods, prefunctionalization
of at least one of the starting materials was necessary.
Csp3−H and Csp2−H bonds via a CDC reaction.7
The 2-benzylpyridine core structure is present as a key
structural unit in many biologically active compounds
possessing insecticidal, phosphodiesterase inhibiting, antifungal,
antispermatogenic, antifertility, antagonistic, and antiarrhythmic
activities.8 For example, compound 1 has been reported as P2 ×
3 and P2 × 2/3 receptor antagonist, and derivatives of 2 are
known as antiarrhythmic drugs (Figure 1).9 Benzylation of
pyridine and pyridine N-oxide derivatives to construct the 2-
benzylpyridine structural motif has been reported rarely.
Although this class of compounds can be accessed through
addition of benzyl Grignard reagents to suitable pyridyl
compounds, there are only a few new synthetic methodologies
available for construction of 2-benzylpyridines. 2-(2-Pyridyl)-
ethanol derivatives can serve as the starting materials in a
Recently, due to low toxicity, stability, and commercially
availability, toluene and its derivatives have been used in CDC
reactions as ArCOO− and ArCO− surrogates.15
There are only a few examples in which toluene has been
used as a benzyl source and remains intact under the reaction
Received: November 9, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503238a
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Letter
The yield of the reaction was not improved by increasing the
reaction time beyond 18 h. Remarkably, the reaction occurred
in the absence of any additive or ligand.
Scheme 1. Selected Approaches to Synthesis of 2-
Benzylpyridine Derivatives
In the optimization study, we found that the persulfate salts
were of crucial importance for the benzylation reaction, and
when the reaction was performed in the presence of TBHP and
Cu(OAc)2, the monoarylated adduct was obtained exclusively.
Both oxidants, TBHP and Cu(OAc)2, are very important for
the arylation pathway. Omitting TBHP from the reaction
conditions reduces the yield of the reaction to 12% and causes
the lack of regioselectivity, and removing copper salt from the
reaction conditions reduces the yield to 49% (Supporting
Information). A series of 2-arylated pyridine N-oxides, prepared
by this procedure, are shown in Scheme 2. In 2008, Chang et al.
Scheme 2. Palladium-Catalyzed Direct Arylation of Pyridine
a
N-Oxides by Toluenes
conditions without further oxidation.16 To the best of our
knowledge, the synthesis of 2-benzylpyridines via a CDC
reaction, using two unfunctionalized starting materials, has not
been reported. We herein present a simple and practical
palladium-catalyzed CDC process for the direct benzylation of
pyridine N-oxides using nonprefunctionalized and inexpensive
toluene derivatives as the benzyl source and K2S2O8 as the
oxidant. At the outset of our study, we investigated the reaction
of pyridine N-oxide and toluene as a model (eq 1, Table 1). To
Table 1. Optimization of the Reaction Conditions for
Palladium-Catalyzed Coupling of Pyridine N-Oxide with
Toluene
entry
catalyst (mol %)
oxidant (equiv)
temp (°C) yield (%)
1
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Na2S2O8 (1)
(NH4)2S2O8 (1)
TBHP (1)
120
120
120
120
120
120
120
100
80
63
51
trace
75
0
2
3
4
K2S2O8 (1)
5
Ag2CO3 (0.75)
DDQ (0.75)
K2S2O8 (0.75)
K2S2O8 (0.75)
K2S2O8 (0.75)
K2S2O8 (0.75)
K2S2O8 (0.75)
K2S2O8 (0.75)
K2S2O8 (0.75)
K2S2O8 (0.75)
6
0
a
Reaction conditions: pyridine N-oxides (1 mmol), Pd(OAc)2 (3 mol
7
83
56
21
61
0
%), TBHP (2 equiv), Cu(OAc)2.H2O (0.5 equiv) in toluene
derivatives (2 mL) at 120 °C for 18 h.
8
9
10
11
12
13
14
120
120
120
120
120
reported the palladium-catalyzed direct arylation of pyridine N-
oxide derivatives with arenes in the presence of Ag2CO3 as the
oxidant.17 The reaction leads to mono- and diarylated adducts,
the extent of which varies with the substrates employed.
Once the optimized conditions for the desired benzylation
reaction were established, the scope of the reaction was
investigated. A variety of combinations of substrates were
examined, and the results are summarized in Scheme 3.
Pyridine N-oxides with both electron-donating and electron-
withdrawing groups such as methyl or methyl ketone groups
reacted smoothly and resulted in the corresponding 2-
benzylpyridine N-oxides 4a−l in good yields. Pyridine N-
oxide 4a is a sterically disfavored product, but it is formed
preferentially. C−H bond activation in pyridine N-oxides
probably proceeds via a CMD mechanism, and the electronic
Pd(Cl)2 (3)
42
38
79
Cu(Cl)2 (10)
Pd(OAc)2 (10)
optimize the reaction conditions, various catalysts, oxidants,
and temperatures of the reaction were investigated. As shown in
Table 1, a variety of common oxidants were screened in the
reaction, and the best results were obtained with K2S2O8 (0.75
equiv). Under the optimized conditions, 3 mol % of Pd was
sufficient to achieve 83% yield of 2-benzylpyridine N-oxide
(Table1, entry 7). No reaction occurred in the absence of each
catalyst and oxidant. Finally, the reaction temperature was also
varied, and 120 °C gave the best results (Table 1, entries 7−9).
B
DOI: 10.1021/ol503238a
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Letter
Scheme 3. Palladium-Catalyzed Direct Benzylations of
Pyridine N-Oxides by Toluene
Scheme 4. Plausible Mechanism for Palladium-Catalyzed
Benzylation of Pyridine N-Oxide
a
the sulfate radical anion that is produced from the heated
K2S2O8.20 Next, coordination of the palladium complex A with
radical B gives intermediate C which reductively eliminates to
2-benzylpyridine N-oxides (4a−l) and Pd(II) (cycle I). 2-
Substituted pyridine N-oxides with bulky groups may be
involved in another catalytic cycle after benzylation (cycle II in
Scheme 4) to produce azafluorene N-oxides through dual C−H
bond activations. As the results of Scheme 3 show, for
construction of the azafluorene core structure the presence of
an ethyl group on position 2 of the pyridine N-oxide is
necessary (4m−o). It seems that C−H bond activation of the
aryl ring (D to E in Scheme 4) is facilitated by the buttressing
effect of the ethyl group on the pyridine N-oxide ring, which
finally leads to the formation of the azafluorene N-oxide by
heteroarylation through the fourth successful C−H bond
activation and subsequent reductive elimination.
2-Benzylpyridine N-oxides can easily be deoxygenated to
pyridines by reaction with PCl3, making the present route an
attractive approach to 2-benzylpyridine and azafluorene
derivatives (Scheme 5).21
Scheme 5. Deoxygenation of Pyridine N-Oxide by PCl3
a
Reaction conditions: pyridine N-oxides (1 mmol), Pd(OAc)2 (3 mol
%), K2S2O8 (0.75 equiv) in toluene derivatives (20 mmol) at 120 °C
for 18 h.
effect of the methyl group may be effective in the concerted
metalation−deprotonation step.
Gratifyingly, when 2-ethylpyridine N-oxide was used as a
substrate, the reaction led to the formation of the azafluorene
N-oxide derivative through four tandem C−H bond activations
with sequential bond making (Scheme 3, 4m−o).
To prove the role of the K2S2O8 as a radical agent, a control
reaction was performed. When 3a was treated with TEMPO
(2,2,6,6-tetramethylpiperidin-N-oxyl) as a radical inhibitor, no
desired product 4a was detected upon addition of TEMPO.18
On the basis of the above results and previous reports, a
plausible mechanism for the reaction is proposed in Scheme 4.
Initially, an electrophilic palladation occurs preferentially at the
C2-position of the pyridine N-oxide and leads to the formation
of intermediate A.19 Radical intermediate B is generated in situ
by hydrogen-atom abstraction from the toluene facilitated by
In summary, we have demonstrated the first palladium-
catalyzed direct benzylation of pyridine N-oxides for the
synthesis of 2-benzylpyridine N-oxides and azafluorene N-
oxides using K2S2O8 as the oxidant and toluene derivatives as
ideal benzyl sources via multiple C−H bond activations. The
dehydrogenative cross-coupling reaction of the sp3 C−H bond
in toluenes with the sp2 C−H bond in pyridine N-oxides
proceeds smoothly, providing the corresponding products in
good yields. The reaction provides a new, simple, and mild
method for generating the useful 2-benzylpyridine N-oxides
and azafluorene N-oxides of interest for future pharmaceutical
and chemical applications.
C
DOI: 10.1021/ol503238a
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Letter
Polakowski, J.; Cox, B. F.; Kowaluk, E.; Williams, M.; Sullivan, J.;
Faltynek, C. Proc. Natl Acad. Sci. U.S.A. 2002, 99, 17179. (c) Misawa,
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ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and spectral data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(9) Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 65, 7620.
(10) Niwa, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed.
2007, 46, 2643.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: kianmehr@khayam.ut.ac.ir.
(11) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266.
Notes
(12) Shang, R.; Yang, Z.-W.; Wang, Y.; Zhang, S.-L.; Liu, L. J. Am.
Chem. Soc. 2010, 132, 14391.
The authors declare no competing financial interest.
(13) Duez, S.; Steib, A. K.; Manolikakes, S. M.; Knochel, P. Angew.
Chem., Int. Ed. 2011, 50, 7686.
(14) Mai, W.; Yuan, J.; Li, Z.; Yang, L.; Xiao, Y.; Mao, P.; Qu, L.
Synlett 2012, 23, 938.
(15) For recent application of toluenes as ArCOO− and ArCO−
surrogates, see: (a) Bian, Y.-J.; Xiang, C.-B.; Chen, Z.-M.; Huang, Z.-Z.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
Research Council of the University of Tehran and the Iran
National Science Foundation (INSF).
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