Palladium-catalyzed C-H activation/cross-coupling of pyridine N -oxides with nonactivated secondary alkyl bromides

Article abstract of DOI:10.1021/ja3113752

An unexpected C-H activation/C-C cross-coupling reaction has been found to occur between pyridine N-oxides and general nonactivated secondary and even tertiary alkyl bromides. It provides a practically useful approach for the synthesis of alkylated pyridine derivatives. Experimental observations indicated that the C-Br cleavage step involves a radical-type process. Thus, the title reaction provides a rather extraordinary example of Pd-catalyzed cross-coupling of secondary and tertiary aliphatic electrophiles.

Full text of DOI:10.1021/ja3113752

Communication
pubs.acs.org/JACS
Palladium-Catalyzed C−H Activation/Cross-Coupling of Pyridine
N‑Oxides with Nonactivated Secondary Alkyl Bromides
Bin Xiao,†,‡,§ Zhao-Jing Liu,†,§ Lei Liu,‡ and Yao Fu*,†
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Department of Chemistry, Tsinghua University, Beijing 100084, China, and State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, 730000 Lanzhou, China
S
* Supporting Information
Scheme 1. Transition-Metal-Catalyzed Cross-Coupling of
Carbon Electrophiles with Inert C−H Bonds
ABSTRACT: An unexpected C−H activation/C−C
cross-coupling reaction has been found to occur between
pyridine N-oxides and general nonactivated secondary and
even tertiary alkyl bromides. It provides a practically useful
approach for the synthesis of alkylated pyridine derivatives.
Experimental observations indicated that the C−Br
cleavage step involves a radical-type process. Thus, the
title reaction provides a rather extraordinary example of
Pd-catalyzed cross-coupling of secondary and tertiary
aliphatic electrophiles.
ransition-metal-catalyzed intermolecular cross-coupling of
Tinert C−H bonds has recently emerged as a powerful
method for C−C bond formation.1 This approach compares
favorably with conventional cross-coupling reactions using
organometallic reagents in terms of substrate availability2 and
enables the direct functionalization of rather complex molecules
at their otherwise inactive C−H bonds.3 To date, Pd catalysts
have been extensively used in this field because of their
advantages in reaction scope and functional group tolerance.4
Indeed, the past decade has witnessed the development of many
Pd-catalyzed C−H arylation reactions employing various sp2-
carbon electrophiles (e.g., aryl halides).5 These reactions not
only expand the concept and scope of Pd catalysis but also
provide novel tools for the synthesis of pharmaceutically relevant
molecules.6 However, only a few examples of Pd-catalyzed
intermolecular C−H alkylation reactions with nonactivated sp3-
carbon electrophiles have been reported.7 In 2009, Yu and co-
workers reported Pd-catalyzed ortho alkylation/lactonization of
benzoic acids with 1,2-dichloroethane and related halohydro-
carbons.8 In 2010, Shabashov and Daugulis described Pd-
catalyzed C−H activation/alkylation of acylaminoquinolines
with primary (1°) alkyl iodides.9,10 More recently, Bach and co-
workers reported Pd-catalyzed norbornene-mediated alkylation
of indole C−H bonds with 1° alkyl bromides.11 Notably, the
above studies have mainly shown C−H activation/C−C cross-
coupling with 1° alkyl electrophiles,12 whereas very little is
known about alkylation of inert C−H bonds with nonactivated
secondary alkyl halides or pseudohalides (Scheme 1).
cross-coupling of pyridine N-oxides14 with various nonactivated
2° alkyl bromides. This reaction provides a new approach for the
synthesis of diverse 2-alkylpyridine derivatives that may be useful
building blocks in the design of bioactive compounds.15 More
significantly, it adds to the fairly limited number of
intermolecular C−H alkylation reactions with a broad spectrum
of 2° alkyl electrophiles catalyzed by Pd-16,17 or other transition
metals18 In a more general sense, the present work also offers
novel insights into Pd-catalyzed C−C cross-coupling reactions,
as previous studies have established the feasibility of using
primary19 but not yet common secondary20,21 alkyl halides. One
reason for the difficulty of cross-coupling with 2° alkyl halides is
that the Pd-catalyzed SN2 process is sensitive to the steric bulk of
the substrate.22−24 In this regard, it is extraordinary to find that
the new Pd-catalyzed C−H activation/C−C cross-coupling
reaction proceeds through a radical-type process with non-
activated 2° or even tertiary (3°) alkyl bromides.
Our study was instigated by an unexpected observation during
efforts to extend the scope of the Pd-catalyzed C−H
functionalization reaction of pyridine N-oxides pioneered by
Fagnou and co-workers.14 During tests with different cross-
coupling partners, we were surprised to find that cyclohexyl
bromide (1a) reacts with 2-methylpyridine N-oxide (2a), albeit
in a modest yield of 54% (Table 1, entry 1). Other cyclohexyl
halides and pseudohalides gave inferior results (entries 2−4).
Since 2° alkyl bromides are readily accessible substrates in
organic synthesis, we decided to focus on their cross-coupling
reactions with pyridine N-oxides. The yield increased to 82%
A method for C−H alkylation with nonactivated secondary
(2°) alkyl electrophiles would improve the utility of transition-
metal-catalyzed C−H activation/C−C cross-coupling reactions
for the synthesis of compounds with nonplanar structures.13 In
this context, we herein report a Pd-catalyzed intermolecular
Received: November 20, 2012
© XXXX American Chemical Society
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a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope
a
Conditions: 0.5 mmol of 1a and 1.0 mmol of 2a in 1 mL of toluene.
Benzophenone was used as an internal standard.
b
when the base K2CO3 was replaced with Cs2CO3 (entry 5).
Changing the rather simple ligand PCy3 to PMetBu2 did not
improve the yield (entry 6), and bulkier monophosphine ligands
such as PtBu3 and Q-Phos were less efficient (entries 7 and 8).
These observations are consistent with Fu’s previous finding that
monodentate (rather than bidentate) phosphine ligands with
appropriate cone angles are beneficial for Pd-catalyzed cross-
coupling reactions of 1° alkyl halides.19 At this point, it was very
surprising to discover that the bidentate phosphine ligand dppe
also can promote the reaction, affording the desired product in
78% yield (entry 9). A more electron-rich ligand, dcpe, gave a
comparable yield (77%; entry 10), whereas the electron-deficient
ligand dfppe was less effective (27%; entry 11). The optimal
result was obtained when a fairly inexpensive ligand, dppf, was
used (entry 12). We found that the use of a premade
Pd(OAc)2dppf complex gave the highest yield (90%; entry
15). No reaction occurred in the absence of Pd(OAc)2 or dppf
(entries 16 and 17) or when Pd(OAc)2 was replaced with
Pd2(dba)3 (entry 18).
With the optimized conditions in hand, we next examined the
reaction scope (Table 2). Various cyclic and acyclic alkyl
bromides (1b−o), except for cyclopropyl bromide (1f),
underwent this transformation with 2a to generate the desired
products (3ba−ea, 3ga−oa) in modest to good yields (44−
88%). Importantly, NMR analysis of 3ga−oa, 3ra, and 3sa
showed that no rearrangement of the carbon skeleton took place
when nonsymmetric substrates 1 were used. Also, many
synthetically relevant functional groups, including ether (3ia,
3ja), aldehyde (3ja), chloride (3ka), alkene (3la), and protected
amines (3ma−oa) tolerated the reaction conditions. Interest-
ingly, 3° alkyl bromides were smoothly converted in good yields
(3pa, 3qa), whereas 1° alkyl bromides exhibited relatively lower
activity (3ra, 3sa). Furthermore, the reactions of several pyridine
a
Isolated yields. See the Supporting Information for details.
N-oxide derivatives 2b−g with 1a showed very high
regioselectivity, as the alkylation occurred only at the position
ortho to the N-oxide moiety (3ab−ag). Even in the case of
substrate 2g containing a pyridyl group, we did not observe the
alkylation byproduct due to the directing effect of the pyridyl
group.
To explore further the utility of the newly developed reaction
for the synthesis of complex molecules, we tested the C−H
alkylation of quinine N-oxide 2h with 1a (Scheme 2). The use of
1 equiv of 1a was sufficient to generate the desired alkylation
product in 82% yield. Neither the 3° amino nor terminal alkene
group was affected by the alkylation reaction. Furthermore, we
examined the cross-coupling of cinchonine N-oxide 2i with 1-
bromoadamantane (1p), which gave the desired product 3pi in
74% yield. X-ray analysis of 3pi confirmed that the structure of
the cinchonine skeleton was fully maintained under the
alkylation reaction conditions.
To study the stereochemistry of the C−H alkylation process,
we took advantage of the fact that chiral 2° alkyl bromides can
readily be prepared from the corresponding alcohols via SN2
bromination.25 Thus, 2° alkyl bromides 1t and 1t′ were
successfully synthesized from epiandrosterone and androster-
one, respectively. When 1t and 1t′ were reacted with 2a, mixtures
of two diastereomers in ratios of 1.0:2.6 and 1.0:1.9, respectively,
were obtained (Scheme 3). Fortunately, the two isomers could
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Scheme 2. Alkylation of Quinine/Cinchonine N-Oxides
Scheme 5. Substrates Causing Cyclization and Ring Opening
radical-type process. In an 1H NMR experiment, we obtained a
fairly low kinetic isotope effect of 1.38 (Scheme 6). More studies
are needed to understand how the radical-type carbon−halide
activation process is engaged in a Pd-catalyzed C−H
functionalization reaction.
Scheme 3. Cross-Coupling with Steroid Substrates
Scheme 6. Kinetic Isotope Effect
Finally, in a scale-up experiment, we successfully prepared 3aa
in gram quantity with a satisfactory yield of 82% (Scheme 7).
Scheme 7. Gram-Scale Synthesis and Reduction of N-Oxide
easily be separated by column chromatography. X-ray analysis of
the major product revealed that the pyridyl group was placed at
the equatorial position. Furthermore, in the cross-coupling of
either 2a or 2-phenylpyridine N-oxide (2j) with exo-2-
bromonorbornane (1u), we obtained a single product (Scheme
4). X-ray analysis showed that these two reactions proceeded
with retention of configuration.26
This gram-scale reaction could be carried out with a lower
loading of Pd catalyst (2 mol %). Furthermore, 3aa was easily
reduced by Zn to produce the corresponding pyridine derivative,
showing that the new C−H alkylation reaction is practically
useful for the preparation of 2-alkylpyridines.
In summary, we have found an unexpected C−H activation/
C−C cross-coupling reaction of pyridine N-oxides with non-
activated secondary and even tertiary alkyl bromides. This
reaction constitutes a rather rare example of Pd-catalyzed
activation of ordinary 2° or 3° carbon−halide bonds. It shows
good compatibility with many synthetically relevant functional
groups and therefore provides a novel practical tool for the
preparation of alkylpyridine derivatives. The reaction stereo-
chemistry and the observation of cyclization or ring opening with
particular substrates suggested that the C−Br bond cleavage may
proceed through a hybrid organometallic-radical mechanism.
The present results may indicate the existence of more
opportunities for the use of Pd catalysts to handle 2° or even
3° aliphatic electrophiles.
Scheme 4. Cross-Coupling with exo-2-Bromonorbornane
The above observations indicated that the new C−H
alkylation reaction proceeds through a radical-type mechanism.
This proposition distinguishes the present transformation from
most of the previous Pd-catalyzed cross-coupling reactions of
alkyl halides, which have been shown to proceed via an SN2
process. The radical-type mechanism is also consistent with the
observations in Table 2 that 3° alkyl halides can also undergo this
reaction whereas 1° halides are less reactive. Further evidence for
the radical-type mechanism was provided by the reaction of 2a
with 6-bromohex-1-ene (1v), where only the cyclopentylmethy-
lated product was obtained (Scheme 5). Moreover, when
(bromomethyl)cyclobutane (1w) was used, we obtained only
the ring-opening product. These results hinted that the C−Br
bond is activated (presumably with the help of Pd) through a
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
fuyao@ustc.edu.cn
■
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Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131,
3291. (e) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed.
2007, 46, 8872. (f) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc.
2008, 130, 9254. (g) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am.
Chem. Soc. 2009, 131, 13888.
Author Contributions
§B.X. and Z.-J.L. contributed equally.
Notes
The authors declare no competing financial interest.
(15) (a) Tran, L. D.; Daugulis, O. Org. Lett. 2010, 12, 4277. (b) Bagley,
M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459.
ACKNOWLEDGMENTS
■
(16) Sporadic examples of Pd-catalyzed C−H alkylation of inert C−H
bonds with nonactivated 2° alkyl halides were previously reported. For
example, Zhao and Chen10 reported the C−H alkylation of a
picolinamide derivative with i-PrI in 40% yield. Also, Catellani et al.
reported a C−H alkylation with 2-bromopropane over 144 h: Catellani,
M.; Motti, E.; Minari, M. Chem. Commun. 2000, 157. These reactions
have not been shown to be applicable to 2° alkyl halides with any
generality.
(17) In the intramolecular Catellani reaction of 2° alkyl iodides, the
domino process causes C−H bond functionalization of arenes in the
final products: Rudolph, A.; Rackelmann, N.; Lautens, M. Angew. Chem.,
Int. Ed. 2007, 46, 1485.
We thank the 973 Program (2013CB932800), the NNSFC
(20972148), CAS (KJCX2-EW-J02), and the China Postdoc-
toral Science Foundation (2011M500289, 2012T50078).
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̈
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