Nickel-Catalyzed Reaction of Benzamides with Bicylic Alkenes: Cleavage of C-H and C-N Bonds

Article abstract of DOI:10.1021/acs.orglett.9b00351

The nickel-catalyzed reaction of aromatic amides that contain an 8-aminoquinoline as a directing group with bicyclic alkenes, such as norbornene and 1,4-dihydro-1,4-epoxynaphthalene, results in the cleavage of both the C-H bond at the ortho-position of th

Full text of DOI:10.1021/acs.orglett.9b00351

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Reaction of Benzamides with Bicylic Alkenes:
Cleavage of C−H and C−N Bonds
Aymen Skhiri and Naoto Chatani*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The nickel-catalyzed reaction of aromatic amides that contain an 8-aminoquinoline as a directing group with
bicyclic alkenes, such as norbornene and 1,4-dihydro-1,4-epoxynaphthalene, results in the cleavage of both the C−H bond at
the ortho-position of the benzene ring and the C(O)−N bond to give methanofluoren-9-one and 1,4-epoxyfluoren-9-one
derivatives. Both Ni(OTf)2 and Ni(cod)2 show a high catalytic activity. The presence of AgOAc is essential for the reaction to
proceed. In the meta-substituted aromatic amides, a less hindered C−H bond is exclusively functionalized.
Scheme 1. Ni-Catalyzed C−H Functionalization of
Benzamides Using an N,N-Bidentate Directing Group
ransition-metal-catalyzed C−H functionalization reactions
Thave emerged as a powerful strategy for the synthesis of a
diverse array of organic compounds.1 Compared with classical
synthetic methods, in which both substrates and reagents are
generally prefunctionalized prior to a coupling step, C−H
functionalization permits simple hydrocarbon moieties to be
converted via an organometallic intermediate to functionalized
products. In this manner, C−H functionalization offers an atom-
efficient approach to chemical synthesis. Various transition-
metal complexes have been used as catalysts in these reactions.
Meanwhile, the use of first-row transition metals, such as nickel
in direct C−H functionalization reactions, has attracted
considerable attention, owing to relatively low cost, abundancy,
and versatile reactivity of such metals.2 Among them, the Ni-
catalyzed C−H functionalization of aromatic amides by taking
advantage of a bidentate directing group,2c such as 2-
pyridinylmethylamine,3 2-pyridinylisopropylamine (PIP),4 8-
aminoquinoline (AQ),5 and triazolylmethylamine,6 has been
extensively studied. Most of the Ni-catalyzed C−H functional-
izations of aromatic amides reported thus far involve reactions
with electrophiles, such as aryl halides, alkynyl halides, alkyl
halides, epoxides, I2, and disulfides (Scheme 1a).2,7 Nucleo-
philes, such as aryl boron reagents, have also been used as a
coupling partner (Scheme 1b).8 The reaction of aromatic
amides with alkynes, leading to the production of naphthalene
derivatives, into which two molecules of an alkyne are
incorporated, is also known (Scheme 1c).9,10 However, to the
best of our knowledge, there are no examples of the Ni-catalyzed
reaction of aromatic amides with alkenes by taking advantage of
a N,N-bidentate directing group. We report herein the Ni-
catalyzed reaction of aromatic amides with bicyclic alkenes,
leading to the production of methanofluoren-9-one and 1,4-
epoxyfluoren-9-one derivatives, the formation of which involves
the cleavage of both C−H and C(O)−N bonds (Scheme 1d).
A similar type of transformation with alkenes and alkynes
involving the cleavage of C−H and C(O)−N bonds catalyzed by
rhodium and cobalt complexes has been reported.11,12 However,
the present reaction is the first example of a Ni-catalyzed
functionalization of nonacidic C−H bonds with alkenes and the
first example of the Ni-catalyzed transformation of aromatic
amides leading to the production of indanone derivatives, the
Received: January 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00351
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formation of which involves the cleavage of both C−H and
C(O)−N bonds.
The reaction of the 2-methyl-N-(quinolin-8-yl)benzamide
(1a) (0.2 mmol) with norbornene 2 (0.6 mmol) in the presence
of Ni(OTf)2 (10 mol %) in toluene (0.8 mL) at 140 °C for 48 h
without AgOAc resulted in no products being formed (entry 1 in
Table 1). However, when 3 equiv of AgOAc was added, product
The substrate scope for aromatic amides containing a variety
of functional groups was examined under the standard reaction
conditions (Scheme 2). Various functional groups, such as
a
Scheme 2. Scope of Benzamides
Table 1. Ni-Catalyzed Reaction of 2-Methyl-N-(quinolin-8-
yl)benzamide (1a) with Norbornene: Optimization of
Reaction Conditions
entry
solvent
toluene
toluene
AgOAc (equiv) temp (°C) NMR yield (%)
a
1
0
3
3
3
3
3
3
3
6
6
6
3
3
140
140
140
140
140
140
140
100
140
140
140
140
140
0
37
58
44
71
21
53
24
91 (71)
97 (81)
79
46
50
a
2
3
4
toluene
a
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
5
b
6
c
7
8
9
10
11
12
13
de
,
f
g
h
a
b
c
No BINAP was used. K2CO3 (2 equiv) was added. PivOH (1
d
e
equiv) was added. Ni(OTf)2 (15 mol %) was used. The reaction
f
was carried out for 60 h. Ni(cod)2 (15 mol %) was used as a catalyst.
g
h
Ni(OAc)2 (10 mol %) was used. [Ni(OAc)2·4H2O] (10 mol %)
was used.
3a was produced in 37% yield (entry 2). In addition, the use of
rac-BINAP as a ligand further improved the product yield to give
3a in 58% (entry 3). The effect of the bases in the reaction was
next examined. Curiously, only AgOAc showed a positive effect,
whereas no product was produced when LiOAc, NaOAc, and
KOAc were used (Table S1). When chlorobenzene was used as a
solvent, the yield was improved slightly to give 3a in 44% (entry
4). We next examined the effect of ligands, including
phosphines, NHCs, and bipyridine derivatives in chlorobenzene
(Table S2). Although product 3a was obtained in 44% yield,
even in the absence of a ligand, all of the above ligands slightly
accelerated the reaction. Among the ligands examined, rac-
BINAP gave the best results. The reaction in the presence of a
base, such as K2CO3, or an acid, such as PivOH, decreased the
efficiency of the reaction (entries 6 and 7). When the reaction
was carried out at 100 °C, the yield of 3a dramatically decreased
(entry 8). Use of 6 equiv of AgOAc increased the product yield
to 91% (entry 9). Curiously, Ni(cod)2 also showed a catalytic
activity comparable to that of Ni(OTf)2 (entries 5 and 11).
Ni(OAc)2 and [Ni(OAc)2·4H2O] as a catalyst showed catalytic
activity lower than that of Ni(OTf)2 (entries 5, 13, and 14).
Finally, the following reaction conditions were determined as
the standard conditions: 1a (0.2 mmol), norbornene 2 (0.6
mmol), Ni(OTf)2 (15 mol %), rac-BINAP (10 mol %), and
AgOAc (1.2 mmol) in chlorobenzene (0.8 mL) at 140 °C for 60
h (entry 10).
a
b
Number in parentheses is the recovery of 1. On 1 mmol scale.
c
Isolated by GPC.
methoxy, trifluoromethyl, ester, fluoride, chloride, bromide, and
even iodide groups, were tolerated in the reaction. The tolerance
of bromide and iodide functionalities is crucial given their
potential for use in late functionalization reactions. A 1 mmol
scale was carried out using 3j. In the reaction of ortho-methoxy-
and phenyl-substituted benzamides, the starting amides were
recovered in 48 and 34% yields, respectively, whereas the
starting amides were completely consumed when other ortho-
substituted substrates were used as a substrate. This can be
attributed to steric effects because the reaction of meta- and
para-methoxy-substituted benzamides reached completion to
give the corresponding products in good yields. Most
importantly, only less hindered C−H bonds reacted in the
case of meta-substituted substrates, irrespective of the nature of
substituents (3g−3l). Cheng and co-workers reported a similar
transformation of aminoquinline amides using Co(OAc)2 as a
catalyst.12 However, the regioselectivity in the case of meta-
methoxy-substituted aromatic amides was 3:1, in favor of
B
DOI: 10.1021/acs.orglett.9b00351
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Letter
hindered C−H functionalization. In sharp contrast, the
regioselectivity was perfect in our system, irrespective of the
nature of the substituent. In addition, the reaction proceeded
with a high degree of diastereoselectivity, and C−C bond
formation took place from the exoface of the norbornene, which
was unambiguously confirmed by X-ray crystallographic
analyses of 3ac. It was found that a 2-naphthyl group showed
high selectivity, with 3aa being formed in 81% yield. The
reaction of 2-methyl-N-(quinolin-8-yl)benzenesulfonamide also
gave the desired product 3ab in 79% yield. Flavonoids have
various bioactive effects, making them useful for preparing drugs
with anticancer properties.13 The reaction of flavone results in
the formation of 3ac in 76% isolated yield.
Scheme 5. Control Experiments
The reaction was also applicable to 1,4-dihydro-1,4-
epoxynaphthalene (4) as an alkene coupling partner (Scheme
3). The reaction again showed a high functional tolerance. In
fact, even bromide and iodide groups remained intact to give 5c,
5d, and 5f in reasonably good yields.
a
Scheme 3. Scope of 1,4-Dihydro-1,4-epoxynaphthalene
quinolin-8-amine with 3 equiv of AgOAc resulted in N-
acetylation to give the amide in high yields irrespective of
whether or not Ni(OTf)2 was present (Scheme 5c,d), suggesting
that one of the roles of AgOAc is to remove the quinolin-8-
amine from the reaction system, which retards the catalytic
activity of Ni(OTf)2. A similar negative effect by an 8-
aminoquinoline was also observed by Cheng.12 The reaction
of 1a with TEMPO (1 equiv) gave 3a in 70% yield, indicating
that a radical species is not involved in the reaction (Scheme 5e).
To gain additional insights into the mechanism for the
reaction, deuterium labeling experiments were carried out
(Scheme 6). The reaction of 1a-d7 gave 3a-d6 with 82 and 18%
of the starting amide being recovered, in which a very low level of
H/D (0.07H) exchange was detected at the ortho-C−H bonds
when the reaction was carried out at 140 °C (Scheme 6a). It is
also interesting to note that no H/D exchange took place when
the reaction was carried out at 100 °C in the absence of
norbornene (Scheme 6b). In a previously reported reaction,12
the ratio of H/D exchange at the ortho-position was also
reported to be low. In the case of meta-substituted aromatic
amides, only a less hindered C−H bond was selectively
functionalized, irrespective of the electronic nature of the
substituent, as shown in Schemes 1 and 2. The result shown in
Scheme 6c indicates that H/D exchange also did not occur at the
2-position in 1g-d7, which is a sterically hindered position. The
intermolecular kinetic isotopic effect (KIE) for the reaction of an
equimolecular amount of 1a and 1a-d7 with 2 under the standard
conditions was determined to be kH/kD = 2.8 (Scheme 6d). In
addition, the intermolecular KIE (1.8) was obtained when the
reaction was carried out in a parallel reaction (Scheme 6e). The
obtained value suggests that the cleavage of the C−H bond is a
rate-determining step.
a
Number in parentheses is the recovery of 1.
It is known that tetrahydro-1,4-epoxynaphthalene derivatives
can be converted into naphthalene derivatives under various
reaction conditions.14 The reaction of 1ad with 4 with a higher
catalyst loading, a higher reaction temperature, and a longer
reaction time gave 6 in a one-pot reaction in 57% isolated yield,
which is produced by the ring opening of a primary product
followed by aromatization (Scheme 4).
Scheme 4. One-Pot Synthesis
The reaction requires excess amount of AgOAc to proceed
efficiently, although the reaction essentially does not include
oxidation steps. To gain insights into the role of AgOAc, a series
of control experiments under different conditions were
conducted (Scheme 5). The addition of 1 equiv of quinolin-8-
amine quenched the reaction, resulting in the desired product 3a
not being formed (Scheme 5a). The reaction of quinolin-8-
amine with 20 mol % of Ni(OTf)2 did not result in any
transformation (Scheme 5b). In contrast, the reaction of
Based on the results obtained in control experiments and
deuterium labeling experiments and on the previously reported
studies, a mechanism is proposed (Scheme 7). The abstraction
of a proton from an amide 1 after the coordination of a N(sp2)
C
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C bond in B gives the seven-membered nickelacycle D. An
intramolecular nucleophilic cyclization promoted by AgOAc
generates intermediate E. Product 3 is formed from E, with
elimination of an aminoquinoline moiety F, which is converted
to N-(quinolin-8-yl)acetamide.
Scheme 6. Deuterium Labeling Experiments
In summary, we report the Ni(II)-catalyzed reaction of
aromatic amides with bicyclic alkenes to generate a variety of
useful products, such as methanofluorenones and epoxybenzo-
fluorenones in good to excellent yields. Chemoselectivity was
high. A variety of substituent groups on aromatic amides
remained intact even in the case of C−Br and C−I bonds. We
were able to selectively produce the desired products,
particularly for meta-substituted benzamide derivatives that
contain two possible sites that could be functionalized at the less
hindered ortho-position. Mechanistic studies were carried out in
a series of deuterium labeling experiments and control
experiments.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00351.
Experimental procedures for the reaction, synthesis of
new starting materials, optimization of additives and
ligands, and characterization of new compounds (PDF)
Accession Codes
CCDC 1870109 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chatani@chem.eng.osaka-u.ac.jp.
ORCID
Scheme 7. Proposed Mechanism
Naoto Chatani: 0000-0001-8330-7478
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grant in Aid for Specially Promoted
Research by MEXT (No. 17H06091). We are thankful to the
Instrumental Analysis Center, Faculty of Engineering, Osaka
University, for their assistance with HRMS analysis.
REFERENCES
■
(1) (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012,
112, 5879−5918. (b) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.;
Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236−10254. (c) Rouquet,
G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726−11743.
(d) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040−1052.
(e) Wei, Y.; Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017, 117, 8864−
8907. (f) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; Dong, G. Chem.
Rev. 2017, 117, 9333−9403. (g) Nairoukh, Z.; Cormier, M.; Marek, I.
Nat. Rev. Chem. 2017, 1, 0035. (h) Hummel, J. R.; Boerth, J. A.; Ellman,
J. A. Chem. Rev. 2017, 117, 9163−9227. (i) Shang, R.; Ilies, L.;
Nakamura, E. Chem. Rev. 2017, 117, 9086−9139. (j) He, J.; Wasa, M.;
Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754−8786.
(k) Crabtree, R. H.; Lei, A. Chem. Rev. 2017, 117, 8481−8482.
atom to a Ni(II) species gives complex A. The cleavage of the
ortho-C−H bond gives the nickelacycle B,10 which is followed by
the coordination of norbornene to give complex C in the first
step of ligand exchange. The insertion of norbornene into a Ni−
D
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(l) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer, N. Chem. Rev.
́
2017, 117, 8908−8976. (m) Wang, C.-S.; Dixneuf, P. H.; Soule, J.-F.
Chem. Rev. 2018, 118, 7532−7585. (n) Chatani, N.; Rej, S. Angew.
Chem., Int. Ed., 2018 DOI: 10.1002/anie.201808159.
(2) (a) Dixneuf, P. H.; Doucet, H. C-H. Bond Activation and Catalytic
Functionalization II; Springer International Publishing Switzerland,
Switzerland, 2015, 19−46. (b) Tasker, S. Z.; Standley, E. A.; Jamison, T.
F. Nature 2014, 509, 299−309. (c) Castro, L. C. M.; Chatani, N. Chem.
Lett. 2015, 44, 410−421.
(3) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc.
2009, 131, 6898−6899.
(4) Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.;
Shi, B.-F. Chem. Sci. 2013, 4, 4187−4192.
(5) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 13154−13155.
(6) Gu, Q.; Al Mamari, H. H.; Graczyk, K.; Diers, E.; Ackermann, L.
Angew. Chem., Int. Ed. 2014, 53, 3868−3871.
(7) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308−
5311. (b) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2014, 136, 898−901.
(c) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, 1789−1792.
(d) Song, W.; Lackner, S.; Ackermann, L. Angew. Chem., Int. Ed. 2014,
53, 2477−2480. (e) Landge, V. G.; Shewale, C. H.; Jaiswal, G.; Sahoo,
M. K.; Midya, S. P.; Balaraman, E. Catal. Sci. Technol. 2016, 6, 1946−
1951. (f) Yokota, A.; Aihara, Y.; Chatani, N. J. Org. Chem. 2014, 79,
11922−11932. (g) Iyanaga, M.; Aihara, Y.; Chatani, N. J. Org. Chem.
2014, 79, 11933−11939. (h) Lin, C.; Li, D.; Wang, B.; Yao, J.; Zhang, Y.
Org. Lett. 2015, 17, 1328−1331. (i) Aihara, Y.; Wuelbern, J.; Chatani,
N. Bull. Chem. Soc. Jpn. 2015, 88, 438−446. (j) Reddy, V. P.; Qiu, R.;
Iwasaki, T.; Kambe, N. Org. Biomol. Chem. 2015, 13, 6803−6813.
(k) Khan, B.; Kant, R.; Koley, D. Adv. Synth. Catal. 2016, 358, 2352−
2358. (l) Uemura, T.; Yamaguchi, M.; Chatani, N. Angew. Chem., Int.
Ed. 2016, 55, 3162−3165. (m) Aihara, Y.; Chatani, N. ACS Catal. 2016,
6, 4323−4329.
(8) Liu, B.; Zhang, Z.-Z.; Li, X.; Shi, B.-F. Org. Chem. Front. 2016, 3,
897−900.
(9) Misal Castro, L. C.; Obata, A.; Aihara, Y.; Chatani, N. Chem. - Eur.
J. 2016, 22, 1362−1367.
(10) He, Z.; Huang, Y. ACS Catal. 2016, 6, 7814−7823.
(11) (a) Wang, X.; Tang, H.; Feng, H.; Li, Y.; Yang, Y.; Zhou, B. J. Org.
Chem. 2015, 80, 6238−6249. (b) Yang, X.-F.; Hu, X.-H.; Loh, T.-P.
Org. Lett. 2015, 17, 1481−1484. (c) Ikemoto, H.; Yoshino, T.; Sakata,
K.; Matsunaga, S.; Kanai, M. J. Am. Chem. Soc. 2014, 136, 5424−5431.
(d) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Angew. Chem., Int. Ed.
2012, 51, 3948−3952.
(12) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Angew. Chem., Int. Ed.
2016, 55, 4308−4311.
(13) (a) Zhang, H.-W.; Hu, J.-J.; Fu, R.-Q.; Liu, X.; Zhang, Y.-H.; Li, J.;
Liu, L.; Li, Y.-N.; Deng, Q.; Luo, Q.-S.; Ouyang, Q.; Gao, N. Sci. Rep.
2018, 8, 11255. (b) Batra, P.; Sharma, A.-K. Biotech 2013, 3, 439−459.
(c) Chahar, M.-K.; Sharma, N.; Dobhal, M.-P.; Joshi, Y.-C. Pharmacogn.
Rev. 2011, 5, 1−12.
(14) (a) Blank, D.-H.; Gribble, G.-W. Tetrahedron Lett. 1997, 38,
4761−4764. (b) Suzuki, H.; Manabe, H.; Enokiya, R.; Hanazaki, Y.
Chem. Lett. 1986, 15, 1339−1340. (c) Best, W. M.; Collins, P. A.;
McCulloch, R. K.; Wege, D. Aust. J. Chem. 1982, 35, 843−848.
E
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