Nickel-Catalyzed C-F/N-H Annulation of Aromatic Amides with Alkynes: Activation of C-F Bonds under Mild Reaction Conditions

Article abstract of DOI:10.1021/jacs.0c08512

The Ni-catalyzed reaction of ortho-fluoro-substituted aromatic amides with alkynes results in C-F/N-H annulation to give 1(2H)-isoquinolinones. A key to the success of the reaction is the use of KOtBu or even weak base, such as Cs2CO3. The reaction proceeds in the absence of a ligand and under mild reaction conditions (40-60 °C). DFT calculations suggest that the pathway for this Ni-catalyzed C-F/N-H annulation involves N-H deprotonation, oxidative addition of a C-F bond, migratory insertion of an alkyne, and reductive elimination to form 1(2H)-isoquinolinone derivatives.

Full text of DOI:10.1021/jacs.0c08512

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Communication
Nickel-Catalyzed C-F/N-H Annulation of Aromatic Amides with
Alkynes: Activation of C-F Bonds under Mild Reaction Conditions
Itsuki Nohira, Song Liu, Ruopeng Bai, Yu Lan, and Naoto Chatani
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c08512 • Publication Date (Web): 27 Sep 2020
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Nickel‐Catalyzed C‐F/N‐H Annulation of Aromatic Amides with Al‐
kynes: Activation of C‐F Bonds under Mild Reaction Conditions
Itsuki Nohira,1 Song Liu,2 Ruopeng Bai,2 Yu Lan,2* and Naoto Chatani1*
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1Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565‐0871 (Japan)
2School of Chemistry and Chemical Engineering, and Chongqing Key Laboratory of Theoretical and Computational
Chemistry, Chongqing University, Chongqing 400030, P. R. China.
ABSTRACT: The Ni‐catalyzed reaction of ortho‐fluoro‐substituted aromatic amides with alkynes results in C‐F/N‐H annu‐
lation to give 1(2H)‐isoquinolinones. A key to the success of the reaction is the use of KOBut or even weak base, such as
Cs2CO3. The reaction proceeds in the absence of a ligand and under mild reaction conditions (40‐60 °C). Competition
experiments and DFT calculations suggest that the pathway for this Ni‐catalyzed C‐F/N‐H annulation involves NH depro‐
tonation, oxidative addition of C‐F bond, migratory insertion of an alkyne, and reductive elimination pathway to form
1(2H)‐isoquinolinone derivatives.
The use of reactive chemical bonds has long been the pri‐
mary focus of organic synthesis. However, various unreac‐
tive chemical bonds, such as C‐H,1 C‐C,2 and C‐O3 bonds
are now beginning to be used in organic transformations,
thus providing new possibilities for developing new syn‐
thetic methodologies. C‐F bonds are an example of such
unreactive chemical bonds that have great potential.4 In
fact, a variety of Ni‐catalyzed cross‐coupling reactions of
aryl fluorides with nucleophiles have been reported thus
far,5 however the reaction patterns including C‐F bond ac‐
tivation as a key step are still limited mainly to cross‐cou‐
pling reactions. In this context, C‐F bond activation still re‐
mains a relatively undeveloped area of research and there
is considerable room for the subject to continue to evolve.
Herein, we report the Ni‐catalyzed C‐F/N‐H annulation of
ortho‐fluoro‐substituted aromatic amides with alkynes,
leading to the production of isoquinolin‐1(2H)‐ones, the
formation of which involves the activation of a C‐F bond
(Scheme 1).11
Table 1. Ni‐Catalyzed C‐F/N‐H Annulation of Aromatic
Amide 1a with Diphenylacetylene (2a)
NMR yields
3aa / 1a (%)
97 / trace
97 / 3
deviations from the
reaction conditionsa
entry
base
solvent
1
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOMe
dioxane
dioxane
dioxane
toulene
xylene
DMF
dtbbpy 0.05 mmol
PPh3 0.05 mmol
2
3
88 / trace
41 / 63
4
5
70 / 22
Scheme 1. Ni‐Catalyzed C‐F/N‐H Annulation of Aromatic
Amides with Alkynes
6
99 / trace
87 / trace
99/ trace
no reaction
no reaction
68 / 22
7
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
8
KOtBu
9
K2CO3
10
11
12
13
14
15
16
no base
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
Ni(OAc)2
60 °C
89 / 7
99 / trace
99 / trace
no reaction
97 / 3%
In various pharmaceuticals, natural products and biologi‐
cally active molecules, isoquinolin‐1(2H)‐one serves as a
key structural unit that is crucial to their bioactivities and
their derivatives are also widely used as key intermediates
in various organic transformations.6 A number of synthetic
methods for the construction of an isoquinolin‐1(2H)‐one
core have been developed over the past few decades.7 One
straightforward method includes Ni‐catalyzed C‐I/N‐H an‐
nulation with alkynes.8 More atom‐economical methods
involving C‐H/N‐H annulation with alkynes including C‐H
bond activation have also been extensively studied.9,10
DMF
40 °C, 6 h
no catalyst
60 °C, 14 h
DMF
Cs2CO3
DMF
aReaction conditions: 1a (0.25 mmol), 2a (0.3 mmol),
Ni(cod)2 (0.025 mmol), base (0.25 mmol), solvent (0.25 mL),
100 °C for 14 h.
The reaction of 2‐fluoro‐N‐(4‐methoxyphenyl)benzamide
(1a) with diphenylacetylene (2a) in the presence of
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Ni(cod)2 and 4,4'‐di‐tert‐butyl‐2,2'‐dipyridyl (dtbbpy) in
were tolerated in the reaction. Remarkably, a boryl group
was also tolerated in the reaction, which allowed further
elaboration to produce useful and complex molecules by
cross‐coupling reactions. Even sterically hindered sub‐
strates, such as 1t and 1u reacted with 2a to give 3ta and
3ua in high yields. These types of products cannot be ob‐
tained through C‐H/N‐H oxidative annulation because the
less hindered C‐H bonds are selectively activated in most
cases.
1,4‐dioxane at 100 °C gave 2‐(4‐methoxyphenyl)‐3,4‐diphe‐
nylisoquinolin‐1(2H)‐one (3aa) in 97% NMR yield (entry 1
in Table 1). Curiously, 3aa was obtained in high yield, even
when the reaction was carried out in the absence of a lig‐
and (entry 3). Among the solvents examined, 1,4‐dioxane
and DMF gave 3aa in high yield (entires 3 and 6). No reac‐
tion took place when the reaction was carried out in the
presence of K2CO3 or in the absence of a base (entries 9 and
10). It was found that Ni(OAc)2 also shows a catalytic activ‐
ity (entry 11). Interestingly, the reaction in 1,4‐dioxane,
even at 60 °C gave 3aa in 89% yield, along with 7% of 1a
being recovered (entry 12). Because the amide was only
sparingly soluble in dioxane, DMF was used as a solvent
(entry 13). Gratifyingly, it was found that the reaction pro‐
ceeds smoothly, even at 40 °C in DMF for 6 h (entry 14).
Interestingly, the use of 1 equiv of a weak base, such as
Cs2CO3, also gave 3aa in 97% NMR yield (entry 16).12 Finally,
we determined the reaction conditions shown in entries 14
and 16 as standard reaction conditions. We previously re‐
ported the Ni‐catalyzed oxidative C‐H/N‐H annulation of
aromatic amides with alkynes.10 However, such a reaction
was not observed in all cases. If the ortho C‐H bond in 1a
could be activated, the product would be 3ia (see Scheme
3). However, only 3aa was produced in all cases.
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Scheme 3. Scope of Amides in the Ni‐Catalyzed C‐F/N‐H
Annulation of Aromatic Amides 1 (Ar = 4‐MeOC6H5) with
Diphenylacetylene (2a)a
Scheme 2. Effect of N‐substituents
The effect of substituents on the amide nitrogen was ex‐
amined under the optimized conditions (entry 14 in Table
1). The scope of N‐substituents was wide and aryl groups
containing both electron‐donating (OMe) and electron‐
withdrawing (CF3) groups gave the corresponding isoquin‐
olinones, 3aa and 3ca in high yields. The presence of an
alkyl group, such as benzyl, hexyl, and tert‐butyl groups
also gave the corresponding products, 3da, 3ea, and 3fa.
The scope of this annulation reaction was investigated with
respect to the 2‐fluoro‐N‐(4‐methoxyphenyl)benzamide
derivatives (Scheme 3). It was found that the reaction of
ortho‐substituted substrates required a slightly higher re‐
action temperature, i.e. 60 °C. While nickel complexes are
known to activate C‐O,3 C‐F,4,5 and CN bonds,2b these
bonds did not react, as in 3ga, 3ia, 3la, 3na, 3ta, 3va, 3wa,
and 3xa because the present reaction proceeds smoothly,
even at a low temperature. The reaction shows a high func‐
tional group compatibility. Even free NH2 and OH groups
aReaction conditions: amide 1 (0.25 mmol), diphenylacety‐
lene (2a) (0.3 mmol), Ni(cod)2 (0.025 mmol), KOtBu (0.25
mmol), and DMF (0.25 mL) at 40 °C for 6 h. bThe reaction was
carried out at 60 °C for 14 h. cCs2CO3 (2 equiv), DMF (0.5 mL)
at 100 °C for 24 h. dAt 100 °C for 14 h. eKOtBu (2 equiv).fAt 80 °C
for 24 h.
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The scope of alkynes was also investigated (Scheme 4).
Various diarylacetylenes, including diarylacetylenes and
1,2‐di(thiophen‐2‐yl)ethyne reacted readily to give the cor‐
responding isoquinolinones, 3ab‐3ae. Alkyl‐substituted al‐
kynes, such as 3‐hexyne also participated in the reaction to
give 3af in high yield. The reaction with unsymmetrical al‐
kynes, such as 1‐phenylpropyne gives the corresponding
1(2H)‐isoquinolinones in a regioselective manner.
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Scheme 4. Scope of Alkynes in Ni‐Catalyzed C‐F/N‐H An‐
nulation of Aromatic Amide 1a with Alkynesa
We next examined the electronic effects of a substituent
on alkynes in the reaction of 1a. In the case of the methoxy‐
substituted alkyne 2b, the reaction was very fast and
reached completion within 20 min under the standard
conditions. the reaction was then carried out using a lower
catalyst loading (5 mol % Ni(cod)2). It was found that the
presence of an electron‐rich methoxy group resulted in a
significant acceleration in the reaction (Scheme 6).
Scheme 6. Electronic Effects: Alkynes
aReaction conditions: amide 1a (0.25 mmol), alkyne (0.3
mmol), Ni(cod)2 (0.025 mmol), KOtBu (0.25 mmol), and DMF
b
(0.25 mL) at 40 °C for 6 h. Isolated yield. The reaction was
carried out at 60 °C for 14 h.
To gain mechanistic insights into the reaction, competi‐
tion experiments using 1a, 1k and 1m were examined
(Scheme 5). An electron‐withdrawing group dramatically
decelerates the reaction, suggesting that C‐F bond activa‐
tion appears not to be a rate‐determining step.
Scheme 5. Electronic Effects: Aromatic Amides
A proposed mechanism for the above reaction is shown in
Scheme 7, based on the results of competition experiments.
The base abstracts the NH proton of the amide 1 to gener‐
ate the amidate anion A, which reacts with Ni(0) followed
by C‐F activation to give the nickelacycle C through the
nickel ate complex B.10c,13 The insertion of an alkyne into
the C‐Ni bond in C gives the seven‐membered nickalacycle
D. Reductive elimination gives the isoquinolinone 3 with
the regeneration of Ni(0). As shown in Scheme 5, the pres‐
ence of an electron‐donating group on an aromatic ring ac‐
celerates the reaction, suggesting that C‐F bond cleavage is
not involved in the rate‐determining step, instead the in‐
sertion of the alkyne appear to be the rate‐determining
step.
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Scheme 7. Proposed Reaction Mechanism
In TS1, the lengths of the breaking C‐F bond and the form‐
4
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ing C‐Ni bond are 1.59 and 2.02 A, respectively. KF is then
released from the Ni(II) center in CP4 to yield CP5 with an
endothermal energy of 6.5 kcal/mol. The subsequent mi‐
gratory insertion of the C‐C triple bond into Ni‐C(aryl)
bond with the coordination of the diphenylacetylene 2a to
the Ni(II) center gives the alkenyl‐Ni(II) intermediate CP6
via the transition state TS2 with an energy barrier of 19.9
kcal/mol. Structural information regarding TS2 shows that
the lengths of the forming C‐C bond and the breaking the
C‐Ni bond are 2.05 and 1.95A, respectively. The calcula‐
tions indicate that the migratory insertion step is the rate‐
determining step in the catalytic cycle, which is consistent
with the results of competition experiments shown in
Scheme 5, and the overall activation free energy for this re‐
action is 30.4 kcal/mol. It should also be noted that the free
energy difference between TS1 and TS2 is small, which
would result in the rate‐determining step of this reaction
being changed depending on the effect of the substituent
on 1a and the alkyne being used. The calculations indicate
that the migratory insertion step without the coordination
of an extra diphenylacetylene to the Ni(II) center occurs
via the transition state TS4 with an overall free energy of
activation of 37.6 kcal/mol, which is 7.2 kcal/mol higher
than that of TS2. The vinyl‐Ni(II) intermediate CP6 would
isomerize into the seven‐membered vinyl‐Ni(II) interme‐
diate CP7. The C(vinyl)‐N reductive elimination takes
place via the transition state TS3 with an energy barrier of
only 10.9 kcal/mol to give the η3‐coordinated Ni(0) species
CP8. In TS3, the length of the forming C‐N bond is 1.95 A.
The ligand exchange of 1a’ with the isoquinoline product
3aa gives the active catalytic intermediate CP2, thus com‐
pleting the catalytic cycle.
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A detailed computational study was performed to investi‐
gate the mechanism for this Ni‐catalyzed C‐F/N‐H annula‐
tion of aromatic amides with alkynes. The calculated Gibbs
energy profiles for oxidation addition, migratory insertion
and reductive elimination pathway are shown in Figure 1,
where the Ni(0) species CP1 was set as the relative zero
point.14 Ligand exchange of the deprotonated substrate 1a’
with the cyclooctadiene moiety in CP1 gives the amido‐
Ni(0) complex CP2 with an endothermal energy of 5.9
kcal/mol. The C‐F bond in 1a is then activated by coordi‐
nation with the Ni(0) center in CP3. The subsequent oxi‐
dative addition of the C‐F bond onto Ni(0) occurs via the
transition state TS1 with an energy barrier of 18.7 kcal/mol,
in which the five‐membered nickelacycle CP4 is generated.
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Figure 1. Free energy profiles for oxidation addition, migratory insertion and reductive elimination pathway of the Ni‐
catalyzed C‐F/N‐H annulation of aromatic amides with alkynes.
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(2015), 575‐619, John Wiley & Sons, Inc. (b) Nakao, Y. Cat‐
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In summary, we report herein on the Ni‐catalyzed C‐F/N‐
H annulation of ortho‐fluoro‐substituted aromatic amides
with alkynes, leading to the production of 1(2H)‐isoquino‐
linones, in which activation of C‐F bond is a key step.15 The
reaction proceeds in the absence of a ligand and under
mild reaction conditions (40‐60 °C). The new methodology
reported herein, such as the amidate‐promoted activation
of C‐F bonds is applicable to the activation of other unre‐
active bonds. Studies of the use of this methodology are
currently underway and will be reported in due course.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free charge at http://pubs.acs.org.
Experimental procedure, synthesis of starting materials, and
characterization of compounds. Computational Studies.
X‐ray structural information of 3wa (CCDC‐2009074).
Watanabe,
Y.;
Hosoya,
T.
Ni/Cu‐Catalyzed
AUTHOR INFORMATION
Defluoroborylation of Fluoroarenes for Diverse C‐F Bond
Functionalizations. J. Am. Chem. Soc. 2015, 137, 14313‐14318.
(d) Ogawa, H.; Yang, Z.‐K.; Minami, H.; Kojima, K.; Saito,
T.; Wang, C.; Uchiyama, M. Revisitation of Organoalumi‐
num Reagents Affords a Versatile Protocol for C‐X (X = N,
O, F) Bond‐Cleavage Cross‐Coupling: A Systematic Study.
ACS Catal. 2017, 7, 3988‐3994. (e) Harada, T.; Ueda, Y.;
Iwai, T.; Sawamura, M. Nickel‐Catalyzed Amination of
Aryl Fluorides with Primary Amines. Chem. Commun.
2018, 54, 1718‐1721. (f) Li, J.; Wu, C.; Zhou, B.; Walsh, P. J.
Nickel‐Catalyzed C(sp3)‐H Arylation of Diarylmethane
Derivatives with Aryl Fluorides. J. Org. Chem. 2018, 83,
2993‐2999. (g) Ho, Y. A.; Leiendecker, M.; Liu, X.; Wang,
C.; Alandini, N.; Rueping, M. Nickel‐Catalyzed Csp2‐Csp3
Bond Formation via C‐F Bond Activation. Org. Lett. 2018,
20, 5644‐5647. (h) Zhao, X.; Wu, M.; Liu, Y.; Cao, S.
LiHMDS‐Promoted Palladium or Iron‐Catalyzed ipso‐
Defluoroborylation of Aryl Fluorides. Org. Lett. 2018, 20,
5564‐5568. (i) Lim, S.; Song, D.; Jeon, S.; Kim, Y.; Kim, H.;
Lee, S.; Cho, H.; Lee, B. C.; Kim, S. E.; Kim, K. Cobalt‐Cat‐
alyzed C‐F Bond Borylation of Aryl Fluorides. Org. Lett.
2018, 20, 7249‐7252. (j) Tian, Y.‐M.; Guo, X.‐N.; Kuntze‐
FechnerIvo, M. W.; Krummenacher, I.; Braunschweig, H.;
Radius, U.; Steffen, A.; Marder, T. B. Selective Photocata‐
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Corresponding Author
*E‐mail: chatani@chem.eng.osaka‐u.ac.jp
ORCID
Ruopeng Bai: 0000‐0002‐1097‐8526
Yu Lan: 0000‐0002‐2328‐0020
Naoto Chatani: 0000‐0001‐8330‐7478
Notes
There are no conflicts to declare.
ACKNOWLEDGMENT
This work was supported by Grant in Aid for Specially Pro‐
moted Research by MEXT (No. 17H06091).
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Synthesis of 1(2H)‐Isoquinolones by the Nickel‐Catalyzed
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Nickel‐Catalyzed Dimerization and Alkylarylation of 1,3‐
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14. See the supporting information in detail.
15. During the preparation of the manuscript, Ackermann,
Ribas, and coworkers reported the Ni‐catalyzed reaction
of ortho‐fluoro‐aromatic amides with alkynes using an 8‐
aminoquinoline directing group. Capdevila, L.; Meyer, T.
H.; Roldan‐Gomez, S.; Lius, J. M.; Ackermann, L.; Ribas, X.
ACS Catal. 2019, 9, 11074‐11081. In this study, the reaction
required high reaction temperature (140 °C) and a mixture
of double‐alkyne‐insertion homologation or alkyne mono‐
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annulation (1(2H)‐isoquinolinones) products were formed.
Only when an electron‐deficient alkynes are used, 1(2H)‐
isoquinolinones were selective obtained.
8. Liu, C.‐C.; Parthasarathy, K.; Cheng, C.‐C. Synthesis of
Highly Substituted Isoquinolone Derivatives by Nickel‐
Catalyzed Annulation of 2‐Halobenzamides with Alkynes.
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A. Cobalt‐catalyzed electrooxidative C‐H/N‐H [4+2] an‐
nulation with ethylene or ethyne. Nat. Commun. 2018, 9,
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less Hydrazides for Cobalt‐Catalyzed Electro‐Oxidative
C−H/N−H Activation with Internal Alkynes J. Am. Chem.
Soc., 2018, 140, 7913‐7921.
10. For papers from this laboratory on the Ni‐catalyzed C‐
H/N‐H coupling with alkynes, see: (a) Shiota, H.; Ano, Y.;
Aihara, Y.; Fukumoto, Y.; Chatani, N. Nickel‐Catalyzed
Chelation‐Assisted Transformations Involving Ortho C‐H
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255. (d) Obata, A.; Sasagawa, A.; Yamazaki, K.; Ano, Y.;
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11. Xie, H.; Xing, Q.; Shan, Z.; Xiao, F.; Denga, G.‐J. Nickel‐
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