Nickel-catalyzed chelation-assisted transformations involving ortho C-H bond activation: Regioselective oxidative cycloaddition of aromatic amides to alkynes

Article abstract of DOI:10.1021/ja206850s

Although the pioneering example of ortho metalation involving cleavage of C-H bonds was achieved using a nickel complex (Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544), no examples of catalysis using nickel complexes have been reported. In this work, the Ni-catalyzed transformation of ortho C-H bonds utilizing chelation assistance, such as oxidative cycloaddition of aromatic amides with alkynes, has been achieved.

Full text of DOI:10.1021/ja206850s

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pubs.acs.org/JACS
Nickel-Catalyzed Chelation-Assisted Transformations Involving Ortho
CÀH Bond Activation: Regioselective Oxidative Cycloaddition of
Aromatic Amides to Alkynes
Hirotaka Shiota, Yusuke Ano, Yoshinori Aihara, Yoshiya Fukumoto, and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S Supporting Information
b
Scheme 1
ABSTRACT: Although the pioneering example of ortho
metalation involving cleavage of CÀH bonds was achieved
using a nickel complex (Kleiman, J. P.; Dubeck, M. J. Am.
Chem. Soc. 1963, 85, 1544), no examples of catalysis using
nickel complexes have been reported. In this work, the Ni-
catalyzed transformation of ortho CÀH bonds utilizing
chelation assistance, such as oxidative cycloaddition of
aromatic amides with alkynes, has been achieved.
he development of methods for the direct conversion of
CÀH bonds into CÀC, CÀO, CÀN, and CÀhalogen
T
bonds remains a critical challenge in organic chemistry. Chela-
tion-assisted CÀH bond activation is currently in widespread use
in such transformations of CÀH bonds.1 Various transition-
metal complexes, in particular those of Ru, Rh, Pd, and Ir, have
been used as catalysts in chelation-assisted transformations of
ortho CÀH bonds. The use of Ni, an abundant and low-cost
transition metal, to catalyze the transformation of CÀH bonds
has recently been reported.2 However, to the best of our knowl-
edge, there are still no examples of Ni-catalyzed transformations
of ortho CÀH bonds utilizing chelation assistance,3 although
chelation-assisted ortho CÀH bond activation was achieved by
the cyclometalation of azobenzene with Cp2Ni in a pioneering
study.4 We recently reported the Ru-catalyzed carbonylation of
ortho CÀH bonds of aromatic amides that contain a 2-pyridi-
nylmethylamine moiety, in which coordination of the 2-pyridi-
nylmethylamine moiety to the ruthenium center in an N,N
fashion is involved as a key step and a cyclometalated complex
was proposed as a key intermediate.5a It would be expected that
newly designed directing groups could have the potential for
applications to new catalytic reactions that cannot be achieved
using a conventional directing group.5b Encouraged by the pre-
vious results, we proceeded to explore new types of catalytic re-
actions involving activation of the ortho CÀH bonds of aromatic
amides containing a 2-pyridinylmethylamine structure. We re-
port herein the Ni-catalyzed transformation of such ortho CÀH
bonds utilizing chelation assistance (Scheme 1).
Figure 1. Effect of the directing group.
(0.05 mmol), and PPh3 (0.2 mmol) in toluene (2 mL) at a
temperature of 160 °C for 6 h. Matsubara6 and Murakami7
recently independently reported the Ni-catalyzed synthesis of
isoquinolones with the extraction of CO or N2. Cheng also
reported the Ni-catalyzed reaction of 2-halobenzamides with
alkynes leading to the synthesis of isoquinolones.8 These reac-
tions involve cleavage of reactive chemical bonds that are already
present on the aromatic ring, such as C(O)ÀN, CÀ(NdN), and
CÀhalogen. The reactions described in this report, however,
involve cleavage of ortho CÀH bonds.
We next examined the effect of the directing group on the
efficiency of the reaction (Figure 1). The corresponding benzyl
amide 3 and the one-carbon-shorter amide 4 did not react with
4-octyne under the standard conditions. However, the reaction
of the one-carbon-longer amide 6 with 4-octyne under the
standard conditions gave isoquinolone derivative 7 in 66% yield
along with 15% recovery of 6. Among the directing groups
examined, 2-pyridinylmethylamine gave the best results.
The reaction of amide 1a with 4-octyne in the presence of
Ni(cod)2/PPh3 as the catalyst in toluene at 130 °C for 18 h gave
isoquinolone derivative 2a in 28% isolated yield as a single
product. A longer reaction time (3 days) resulted in an increase
in the product yield to 66%. After optimization of the reaction
conditions, the following conditions were selected as the stan-
dard ones: amide 1a (0.5 mmol), 4-octyne (1.5 mmol), Ni(cod)2
Received: July 29, 2011
Published: August 29, 2011
r
2011 American Chemical Society
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Table 1. Ni-Catalyzed Reactions of Aromatic Amides with
4-Octynea,b
Table 2. Ni-Catalyzed Reactions of Amide 1a with Internal
Alkynesa,b
a Reaction conditions: amide (0.5 mmol), alkyne (1.5 mmol), Ni(cod)2
(0.05 mmol), and PPh3 (0.2 mmol) in toluene (2 mL) at 160 °C for 6 h.
b Isolated yields are shown. Ratios of regioisomers as determined by
NMR analysis are shown in parentheses. c Alkyne (2.5 mmol) was used.
d The reaction was run using Ni(cod)2 (0.075 mmol) for 2 days.
CÀH bond was cleaved to afford 15 and 17, respectively.
However, the reaction took place at the less-hindered CÀH
bond in the reaction of 3,4-dimethoxy-substituted substrate 18.
These results suggest that steric effects are a dominant factor for
this type of reaction but that the electronic nature of the
substituents also can have a significant effect on the regioselec-
tivity of the reaction if they have a lone pair of electrons.
Table 2 shows the results of reactions of 1a with internal
alkynes. Dialkylacetylenes gave the corresponding isoquinolones
in high yields. It was found that diarylacetylenes also participate in
the oxidative cycloaddition. The reaction of 1a with diphenylace-
tylene gave 22 in 71% yield under the reaction conditions used.
The use of 5 equiv of alkyne resulted in an increase in the product
yield to 92%. Unsymmetrical alkynes regioselectively gave the
corresponding isoquinolones 24À26 having the aryl group at-
tached at the carbon adjacent to the nitrogen atom. The conver-
sion of 1a to an isoquinolone requires the release of two hydrogen
atoms, suggesting that the reaction requires a hydrogen acceptor
or an oxidizing agent for a high conversion to be achieved. We
expected that the alkyne would also function as a hydrogen
acceptor as well as a two-component coupling partner. In fact,
stilbene was produced in a yield (81%) comparable to that for 22
(92%) in the reaction of 1a with diphenylacetylene, providing
evidence that the alkyne functions as a hydrogen acceptor.
The reaction with unsymmetrical alkynes was highly regiose-
lective. In the case of phenyl alkyl alkynes, the phenyl group in
the product was attached at the carbon next to the nitrogen atom.
As the size of the alkyl group was increased, the regioselectivity
a Reaction conditions: amide (0.5 mmol), 4-octyne (1.5 mmol), Ni(cod)2
(0.05 mmol), and PPh3 (0.2 mmol) in toluene (2 mL) at 160 °C for 6 h.
b Isolated yields are shown. c The ratio of regioisomers is shown in parentheses.
Some representative results of Ni-catalyzed reactions of aro-
matic amides with 4-octyne are shown in Table 1. Various func-
tional groups, such as methoxy, amino, trifluoromethyl, acetyl,
cyano, and acetal groups, were tolerated under the reaction con-
ditions. Substrates with an electron-donating group were slightly
less reactive than those with an electron-withdrawing group.
Thus, the reaction of 1c and 1d did not proceed to completion
(1c and 1d were recovered in 26 and 28% yield, respectively), but
substrates with an electron-withdrawing group, such as 1e and 1f,
reacted completely. We next examined the regioselectivity of the
annulation using meta-substituted aromatic amides. The reaction
of m-methyl-substituted aromatic amide 8 gave 9 as a single
regioisomer through selective cleavage of the less-hindered CÀH
bond. The same selectivity was observed in the cases of 10 and
12. In sharp contrast, in the case of m-methoxy- and m-dimethyl-
amino-substituted substrates 14 and 16, the more-hindered
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Scheme 2
Scheme 4. Rationale for the Regioselectivity of CÀH Bond
Activation Based on Steric and Electronic Factors
Scheme 3. Proposed Mechanism
Scheme 5. Removal of the 2-Pyridinylmethylamine Moiety
t
also increased (Me < Et < Bu = 13:1 < 16:1 < 28:1). The
concomitant formation of an alkene gives ortho-metalated com-
plex 32. Insertion of the alkyne into complex 329 followed by
reductive elimination results in the formation of an isoquinolone,
with nickel being regenerated. Similar transformations of aro-
matic amides to isoquinolone derivatives using [Cp*RhCl2]2 or
[RuCl2(p-cymene)]2 as the catalyst have been independently
reported by four different groups.10,11 Unlike these reported
examples, the present reaction does not require either an expen-
sive catalyst such as [Cp*RhCl2]2 or [RuCl2(p-cymene)]2 or a
stoichiometric amount of a metal oxidant such as a silver or
copper salt.10a,c,d,11 While the regioselectivity of the reaction has
not been examined extensively in the [Cp*RhCl2]2- and [RuCl2-
(p-cymene)]2-catalyzed reactions reported to date, the reaction
occurred at the less-hindered CÀH bond or a mixture in all cases
examined. In sharp contrast to the present reaction, even the
substitution of a methoxy group at the meta position resulted in
the cleavage of the less-hindered CÀH bond.10c On the basis of
the result that H/D exchange occurs between the ortho CÀH
bond and the NÀH bonds, it is likely that H/D exchange be-
tween 1a and 30 occurs through σ-hydrogen complex 34.
The findings reported herein indicate that the regioselectivity
of reactions using meta-substituted aromatic amides is highly
dependent on the nature of substituent. The substitution of a
methyl or trifluoromethoxy group at the meta position resulted
in the selective cleavage of the less-hindered CÀH bond to give 9
electronic effects of a substituent on the aromatic ring also had a
slight effect on the regioselectivity. Thus, the presence of an
electron-donating group resulted in a slightly increased regios-
electivity (CF3 < H < OMe = 21:1 < 27:1 < 50:1).
We conducted a series of experiments to probe the mechanism
of the reaction. The reaction of a 1:1 ratio of 1a and 1a-d5 was run
for 1 h under otherwise standard reaction conditions (Scheme 2).
1H NMR analysis of the product 2a showed that the 1a reacted
more than 2 times faster than 1a-d5 (0.7/0.3 = 2.3).
In both the product and the recovered starting amide, the
ratios of the protons of the ortho CÀH bonds were slightly
higher than those of the other positions. To determine the pro-
ton source, the reaction of 1a-d5 was conducted in the absence of
4-octyne. When the reaction was carried out in toluene, 1a-d5
was recovered in 95% yield and H/D exchange occurred only at
the ortho position. The same result was obtained when the re-
action was run in toluene-d8, indicating that the source of the
proton is not the solvent but that H/D exchange between the
ortho CÀH bond and the NÀH bonds probably occurs.
A proposed mechanism is shown in Scheme 3. Coordination
of amide 1a to the nickel center as an N,N-donor followed by
activation of the NÀH bond gives nickel hydride complex 30,
and the insertion of the alkyne into the HÀNi bond of 30 affords
vinylnickel complex 31. Cleavage of the ortho CÀH bond with
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or 13, respectively, as shown in Table 1. This can be attributed to
unfavorable steric interactions between a meta substituent and a
ligand on the nickel center, as in 35b and 36b (Scheme 4). In
sharp contrast, the substitution of a methoxy or dimethylamino
group at the meta position favors the cleavage of the hindered
CÀH bond to give 15 or 17, respectively. This reverse selectivity
can be rationalized by the coordination of an oxygen or nitrogen
atom to the nickel center. Thus, the coordination of a heteroatom
stabilizes the cyclometalated complex, as in 37b. In contrast to
the 3-methoxy substrate 14, in the reaction of the 3,4-dimethoxy
substrate 18, the less-hindered CÀH bond underwent cleavage,
probably because of the buttressing effect of the methoxy
group.12 A methoxy group at the 4-position pushes the other
methoxy group at the 3-position away toward the nickel center,
thus creating an unfavorable steric interaction, as in 38b.
(2) For recent selected papers on Ni-catalyzed transformations of
aromatic CÀH bonds, see: (a) Clement, N. D.; Cavell, K. J. Angew. Chem.,
Int. Ed. 2004, 43, 3845. (b) Keen, A. L.; Johnson, S. A. J. Am. Chem. Soc.
2006, 128, 1806. (c) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am.
Chem. Soc. 2006, 128, 8146. (d) Normand, A. T.; Hawkes, K. J.; Clement,
N. D.; Cavell, K. J.; Yates, B. F. Organometallics 2007, 26, 5352.
(e) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed. 2007,
46, 8872. (f) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008,
130, 2448. (g) Nakao, Y; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 16170. (h) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami,
K. Org. Lett. 2009, 11, 1733. (i) Hachiya, H.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2009, 11, 1737. (j) Kobayashi, O.; Uraguchi, D.; Yamakawa,
T. Org. Lett. 2009, 11, 2679. (k) Mukai, T.; Hirano, K.; Satoh, T.; Miura,
M. J. Org. Chem. 2009, 74, 6410. (l) Matsuyama, N.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2009, 11, 4156. (m) Kanyiva, K. S.; L€obermann,
F.; Nakao, Y.; Hiyama, T. Tetrahedron Lett. 2009, 50, 3463. (n) Tobisu,
M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 12070.
(o) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2009, 131, 15996. (p) Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M.
Angew. Chem., Int. Ed. 2010, 49, 2202. (q) Matsuyama, N.; Kitahara, M.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358. (r) Vechorkin,
O.; Proust, V.; Hu, X. Angew. Chem., Int. Ed. 2010, 49, 3061. (s) Nakao,
Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. Angew. Chem., Int. Ed. 2010,
49, 4451. (t) Tsai, C.-C.; Shih, W.-C.; Fang, C.-H.; Li, C.-Y.; Ong, T.-G.;
Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887. (u) Doster, M. E.;
Hatnean, J. A.; Jeftic, T.; Modi, S; Johnson, S. A. J. Am. Chem. Soc. 2010,
132, 11923. (v) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am.
Chem. Soc. 2010, 132, 13666. (w) Hachiya, H.; Hirano, K.; Satoh, T.;
Miura, M. ChemCatChem 2010, 2, 1403. (x) Yao, T.; Hirano, K.; Satoh,
T.; Miura, M. Chem.—Eur. J. 2010, 16, 12307. (y) Shacklady-McAtee,
D. M.; Dasgupta, S.; Watson, M. P. Org. Lett. 2011, 13, 3490.
(3) Although the reaction is limited to indoles, it was reported that
CÀH bonds β to a cyano and ester underwent the addition to alkynes.
However, the authors did not describe the possibility of chelation
assistance. See refs 2c and 2s.
The directing group, a 2-pyridinylmethylamine, can be easily
removed by treatment of 22 with lithium diisopropylamide
(LDA) and then bubbling O2 followed by hydrolysis to give
NH-isoquinolone 39 in good yield (Scheme 5).
In summary, we have reported the development of a new
catalytic system that takes advantage of chelation assistance
by a 2-pyridinylmethylamine moiety.5,13 As a result, the first
example of the Ni-catalyzed transformation of ortho CÀH bonds
utilizing chelation assistance has been achieved. Although the
pioneering example of ortho metalation involving cleavage of
CÀH bonds was achieved using a nickel complex,4 no examples
of catalysis using nickel complexes have been reported even more
than 45 years after the pioneering work appeared in the literature.
Although similar types of transformations using a [Cp*RhCl]2
or [RuCl2(p-cymene)]2 complex as the catalyst have been re-
ported,10,11 it is significant that even less expensive nickel com-
plexes can be used as catalysts for the reaction. To examine the
potential of the newly designed directing group for exploring new
reactions that have not been achieved using a conventional
chelation-assisted system, we are currently testing the system
for its potential for use in a variety of catalytic reactions.
(4) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(5) (a) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am. Chem.
Soc. 2009, 131, 6898. (b) Hasegawa, N.; Charra, V.; Inoue, S.;
Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070.
(6) Kajita, Y.; Matsubara, S.; Kurahashi, T. J. Am. Chem. Soc. 2008,
130, 6058.
’ ASSOCIATED CONTENT
(7) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10, 3085.
(8) Liu, C.-C.; Parthasarathy, K.; Cheng, C.-H. Org. Lett. 2010, 12, 3518.
(9) For a related cyclometalation via activation of a C(sp2)ÀH bond to
form a five-membered nickelacycle, see: Carmona, E.; Palma, P.; Paneque,
M.; Poveda, M. L. J. Am. Chem. Soc. 1986, 108, 6424. Also see: Nakao, Y.;
Morita, E.; Idei, H.; Hiyama, T. J. Am. Chem. Soc. 2011, 133, 3264.
(10) (a) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
Chem. Lett. 2010, 39, 744. (b) Guimond, N.; Gouliaras, C.; Fagnou, K.
J. Am. Chem. Soc. 2010, 132, 6908. (c) Hyster, T.; Rovis, T. J. Am. Chem.
Soc. 2010, 132, 10565. (d) Song, G.; Chen, D.; Pan, C.-L.; Crabtree,
R. H.; Li, X. J. Org. Chem. 2010, 75, 7487. (e) Guimond, N.; Gorelsky,
S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449. (f) Hyster, T. K.;
Rovis, T. Chem. Sci. 2011, 2, 1606.
S
Supporting Information. Experimental procedures and
b
characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
chatani@chem.eng.osaka-u.ac,jp
’ ACKNOWLEDGMENT
(11) (a) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem.,
Int. Ed. 2011, 50, 6379. (b) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278.
This work was supported in part by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” from The Ministry
of Education, Culture, Sports, Science and Technology, Japan.
(12) For a review of the buttressing effect, see: Westheimer, F. H. In
Steric Effects in Organic Chemistry; Newman, M. S., Ed.; Wiley: New York,
1956; Chapter 12, p 552. Also see: Gorecka, J.; Heiss, C.; Scopelliti, R.;
Schlosser, M. Org. Lett. 2004, 6, 4591 and references cited therein.
(13) For papers on catalytic transformations using bidentate direct-
ing groups, see: Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154. Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.-Q.
Organometallics 2008, 27, 1667. Shabashov, D.; Daugulis, O. J. Am.
Chem. Soc. 2010, 132, 3965. Ano, Y.; Tobisu, M.; Chatani, N. J. Am.
Chem. Soc. 2011, 133, 12984.
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