Nickel-catalyzed reaction of arylzinc reagents with N-aromatic heterocycles: A straightforward approach to C-H bond arylation of electron-deficient heteroaromatic compounds

Article abstract of DOI:10.1021/ja9053509

(Chemical Equation Presented) The reaction of electron-deficient N-heteroaromatic compounds, such as pyridines and quinolines, with arylzinc reagents in the presence of a catalytic amount of a nickel complex affords the arylated products. The reaction is likely to proceed through a formal nucleophilic 1,2-addition, thus exhibiting a reactivity complementary to conventional direct arylation through electrophilic substitution.

Full text of DOI:10.1021/ja9053509

Published on Web 08/10/2009
Nickel-Catalyzed Reaction of Arylzinc Reagents with N-Aromatic
Heterocycles: A Straightforward Approach to C-H Bond Arylation of
Electron-Deficient Heteroaromatic Compounds
Mamoru Tobisu,*,† Isao Hyodo,‡ and Naoto Chatani*,‡
Frontier Research Base for Global Young Researchers, Graduate School of Engineering, and Department of
Applied Chemistry, Faculty of Engineering, Osaka UniVersity, Suita, Osaka 565-0871, Japan
Received June 29, 2009; E-mail: tobisu@chem.eng.osaka-u.ac.jp; chatani@chem.eng.osaka-u.ac.jp
The catalytic direct arylation of aromatic C-H bonds has
emerged as an atom-efficient alternative to conventional cross-
coupling between halides and organometallics for the synthesis of
(hetero)biaryls.1 Despite significant advancement in this method,
C-H bonds in electron-deficient heteroaromatics, such as pyridines
and quinolines, are often not directly applicable.2-5 This serious
limitation of the C-H bond arylation reactions stems from the fact
that the vast majority of them depend on either electrophilic
substitution or concerted metalation/deprotonation mechanisms,6
which inherently restricts the substrates to electron-rich or acidic
C-H bonds, respectively. We report herein an alternate approach
to catalytic C-H bond arylation that is suitable for electron-deficient
heteroaromatics.
the unprecedented 1,2-addition of mild arylating agents toward
pyridines and (2) an oxidant that accommodates the hydride derived
from 3 without inducing undesired reactions, such as oxidative
dimerization of the arylating agent.8
We initiated our study by investigating the reaction of quinoline
with several arylating agents in the presence of an array of catalysts
and oxidants. As a result, we discovered that the use of diphenylzinc
(5) as an aryl donor furnished the desired 2-arylated product 6 in
the absence of an additional oxidant. Although several transition-
metal complexes exhibited catalytic activity, Ni(cod)2/PCy3 proved
to be an optimal catalyst to afford 6 quantitatively (Table 1).9
Table 1. Ni-Catalyzed Arylation of N-Aromatic Heterocycles with 5a
It has long been known that aryllithium and -magnesium reagents
add to pyridines in a 1,2 fashion to afford dihydropyridines 1 after
aqueous workup (Scheme 1a). Oxidation of 1 finally furnishes
2-arylpyridines in low to moderate yields.7 This dearomatizing 1,2-
addition/oxidation approach would be a potentially useful comple-
ment to the direct arylation methods if the reaction could meet the
following criteria: (1) the use of a milder arylating agent, such as
arylzinc or boron compounds and (2) a one-pot operation without
the need for the isolation of the unstable dyhydropyridines 1. We
envisioned a simplified working catalytic cycle that addresses the
above issues (Scheme 1b). The arylmetal species 2 is initially
generated via transmetalation from mild arylating agents. The 1,2-
addition of 2 across a pyridine affords dihydropyridine intermediate
3, which aromatizes to provide the 2-arylpyridine via ꢀ-hydrogen
elimination. The resultant metal hydride 4 is finally oxidized to
regenerate the catalyst.
a Reaction conditions: N-aromatic heterocycle (0.25 mmol), 5 (0.375 mmol),
Ni(cod)2 (0.0125 mmol), and PCy3 (0.025 mmol) in toluene (1.0 mL) for 20 h.
Isolated yields based on the N-heterocycles are shown. b Using 0.50 mmol of 5.
c Using 0.75 mmol of 5. d Using PPh3 instead of PCy3.
Scheme 1. Dearomatizing 1,2-Addition/Oxidation Strategy for
Arylation of Electron-Deficient Heteroaromatics
To probe the generality of this catalytic arylation, we next examined
the reaction of various N-aromatic heterocycles. Isoquinoline, which
contains two possible sites for 1,2-addition, underwent arylation under
our catalytic conditions to afford 1-phenylisoquinoline (7) in excellent
yield and regioselectivity.7b The arylation of a N-heterocycle containing
an extended π system proceeded even at a lower temperature to form
8. As expected on the basis of the reactivity trend in the 1,2-addition
of organolithium to N-aromatics,7a harsher reaction conditions were
required to obtain 2-arylated products 9 and 10 from pyridines.
Interestingly, 2,2′-bipyridine, which is a good chelating ligand for
transition-metal complexes, did not interfere with the catalysis and
efficiently and selectively afforded the monoarylated product 11 even
in the presence of an excess amount of 5.7c Pyrazine served as a
suitable substrate for the catalytic arylation reaction to furnish
monoarylated product 12.
The key to establishing the catalytic process shown in Scheme
1b is the identification of two elements: (1) a catalyst that promotes
† Frontier Research Base for Global Young Researchers.
‡ Department of Applied Chemistry.
9
12070 J. AM. CHEM. SOC. 2009, 131, 12070–12071
10.1021/ja9053509 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ni-Catalyzed Arylation of Quinoline with Various
are notoriously poor substrates in catalytic direct arylation reactions.
Additional scope and mechanistic studies are ongoing.
Arylzincsa
Acknowledgment. We gratefully acknowledge valuable sugges-
tions by the reviewers. This work was conducted by the Program of
Promotion of Environmental Improvement to Enhance Young Re-
searchers’ Independence, the Special Coordination Funds for Promoting
Science and Technology from MEXT, Japan. We also thank the
Instrumental Analysis Center, Faculty of Engineering, Osaka Univer-
sity, for assistance with the 2H NMR and HRMS analyses. I.H. thanks
the GCOE Program of Osaka University.
entry
Ar
yield (%)b
entry
Ar
yield (%)b
1
2
3
phenyl
3,5-Me2C6H3
2-naphthyl
73
71
56
4
5
6
4-(MeO)C6H4
4-(Me2N)C6H4
3-Cl-5-(MeO)C6H3
97
93
51
Supporting Information Available: Detailed experimental proce-
dures and characterization of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: ArB(OH)2 (0.75 mmol) and ZnEt2 (1.05 mmol)
in dioxane (0.5 mL) at 60 °C for 12 h; quinoline (0.25 mmol), Ni(cod)2
(0.0125 mmol), and PCy3 (0.025 mmol) in toluene (1.0 mL) at 130 °C
for 20 h. b Isolated yield based on quinoline.
References
(1) Reviews published after 2008: (a) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett
2008, 949. (b) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (c) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(d) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. ReV., in press.
(2) A notable exception: (a) Berman, A. M.; Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926. Intramolecular
coupling: (b) Basolo, L.; Beccali, E. M.; Borsini, E.; Broggini, G.
Tetrahedron 2009, 65, 3486.
(3) Several transformations other than arylation via catalytic C-H bond
activation of pyridines have been reported. Carbonylation: (a) Moore, E. J.;
Pretzer, W. R.; O’Connell, T. J.; Harris, J.; LaBounty, L.; Chou, L.;
Grimmer, S. S. J. Am. Chem. Soc. 1992, 114, 5888. Alkenylation: (b)
Murakami, M.; Hori, S. J. Am. Chem. Soc. 2003, 125, 4720. (c) Nakao,
Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448.
Alkylation: (d) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2007, 129, 5332. Borylation: (e) Takagi, J.; Sato, K.; Hartwig, J. F.;
Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649. Dimerization: (f)
Kawashima, T.; Takao, T.; Suzuki, H. J. Am. Chem. Soc. 2007, 129, 11006.
(4) The use of N-activated pyridines, such as N-oxides, provides a partial
solution to this issue. For leading references, see: (a) Larivee, A.; Mousseau,
J. J.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 52. (b) Cho, S. H.;
Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. (c) Campeau,
L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.; Villemure, E.;
Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am.
Chem. Soc. 2009, 131, 3291.
We next turned our attention to the scope of arylzinc reagents.
After extensive studies,10 arylzinc reagents prepared by treatment
of readily available arylboronic acids with diethylzinc proved to
be effective aryl donors in this Ni-catalyzed reaction (Table 2).11
Although the reactions required higher temperatures than those using
5, an array of aryl groups could be introduced through this
procedure. Functional groups such as ethers (entry 4), amines (entry
5), and chlorides (entry 6) were tolerated under these conditions.
Moreover, heteroarylzinc reagents prepared by Nakamura’s pro-
cedure12 could also be employed, further demonstrating the utility
of this catalytic arylation (eq 1).
(5) An approach based on the radical process has also been reported, although
it is still in its infancy from the synthetic point of view. For leading
examples, see: (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org.
Lett. 2008, 10, 4673. (b) Li, M.; Hua, R. Tetrahedron Lett. 2009, 50, 1478.
(c) Kobayashi, O.; Uraguchi, D.; Yamakawa, T. Org. Lett. 2009, 11, 2679.
(6) For a comprehensive discussion of these two mechanisms, see: (a) Lie´gault,
B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009,
74, 1826.
(7) (a) Boulton, A. J.; McKillop, A. In ComprehensiVe Heterocyclic Chemistry;
Katrizky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 2,
pp 262-270. (b) Geissman, T. A.; Schlatter, M. J.; Webb, I. D.; Roberts,
J. D. J. Org. Chem. 1946, 11, 741. (c) Pijper, P. J.; van der Goot, H.;
Timmerman, H.; Nauta, W. T. Eur. J. Med. Chem. 1984, 19, 399. (d)
Goldstein, S. W.; Dambek, P. Synthesis 1989, 221.
Although a complete picture of the catalytic cycle remains
elusive, several observations are worth noting. First, treatment of
dihydroquinoline 13 with 5 afforded 6, presumably via zinc amide
14,13 eVen in the absence of a nickel catalyst at room temperature
(eq 2):
(8) For example, see: (a) ArB(OH)2: Yamamoto, Y. Synlett 2007, 1913. (b)
ArZnX: Hossain, K. M.; Kameyama, T.; Shibata, T.; Takagi, K. Bull. Chem.
Soc. Jpn. 2001, 74, 2415.
(9) Yields with other metal complexes in place of Ni(cod)2 in the reaction of
quinoline with 5: Pd(OAc)2, 15%; Cu(OTf)2, 16%; [RhCl(cod)]2, 38%; none,
0%. See the Supporting Information for complete data from the screening
of arylating agents, oxidants, catalysts, and ligands.
(10) The reaction is sensitive to the contaminated metal salts, as is often encountered
in the reaction using organozinc reagents (see the Supporting Information).
(11) Among several protocols, the following one afforded the highest yields: Smith,
S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645.
(12) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Angew. Chem., Int.
Ed. 2006, 45, 944. (b) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E.
Org. Lett. 2006, 8, 2803.
(13) Zinc amides formed by the reaction of diorganozinc and chelating diamines
have been characterized: Hlavinka, M. L.; Hagadorn, J. R. Organometallics
2005, 24, 4116.
This finding suggests that the arylation is initiated by the nickel-
catalyzed dearomatizing 1,2-addition of an arylnickel species,14 as
proposed in Scheme 1b. However, the subsequent aromatization
event is more likely to occur via a zinc amide species similar to
14, which can be formed under the catalytic conditions via
transmetalation between nickel amide 3 (m ) Ni) and 5 rather than
ꢀ-hydrogen elimination of 3 (m ) Ni). Alternatively, zinc amide
14 could also be generated by the reaction of 5 with an azanick-
elacyclopropane intermediate, which can be formed via coordination
of the CdN bond in quinoline to a nickel center.15 Second, a
deuterium substituted at the 2-position of quinoline is finally
incorporated into one of the phenyl groups in 5 to form deuteri-
(14) Although the exact structure of the arylnickel species remains to be clarified,
one possibility is a nickelate complex. For a proposal of a similar nickelate
complex, see: Terao, J.; Nii, S.; Chowdhury, F. A.; Nakamura, A.; Kambe,
N. AdV. Synth. Catal. 2004, 346, 905.
(15) For a proposal of azanickelacyclopropanes from imines, see: Ohashi, M.;
Kishizaki, O.; Ikeda, H.; Ogoshi, S. J. Am. Chem. Soc. 2009, 131, 9161.
(16) In the catalytic arylation reactions and the reaction shown in eq 2, metallic
precipitates were observed upon completion of the reactions. The metallic
precipitates dissolved with gas evolution upon addition of aqueous HCl.
On the basis of these observations, we currently believe that 5 is finally
reduced to metallic Zn(0).
2
obenzene, as was confirmed by H NMR measurements of the
arylation reaction of deuterated quinoline (see eq S1 in the
Supporting Information). This observation indicates that 5 functions
as both an aryl donor and an oxidant.16
In conclusion, we have developed a catalytic 1,2-addition-based
approach to the arylation of electron-deficient heteroaryls, which
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