Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling Involving C?O Bond Activation

Article abstract of DOI:10.1002/hlca.202100089

An efficient Suzuki-Miyaura cross-coupling reaction of ortho-phenoxy-substituted aromatic amides with aryl boronates is described. The use of LiO^tBu is crucial for the success of the reaction. An amidate anion, which is formed through deprotonation of the amide NH bond by LiO^tBu, functions as a directing group to activate a C?O bond.

Full text of DOI:10.1002/hlca.202100089

doi.org/10.1002/hlca.202100089
COMMUNICATION
Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling Involving CÀ O Bond
Activation
Aoi Morishige,a Yasuaki Iyori,a and Naoto Chatani*a
a
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan,
e-mail: chatani@chem.eng.osaka-u.ac.jp
Dedicated to Professor E. Peter Kündig on the occasion of his 75th birthday.
An efficient Suzuki-Miyaura cross-coupling reaction of ortho-phenoxy-substituted aromatic amides with aryl
boronates is described. The use of LiOtBu is crucial for the success of the reaction. An amidate anion, which is
formed through deprotonation of the amide NH bond by LiOtBu, functions as a directing group to activate a
CÀ O bond.
Keywords: amides, CÀ O activation, nickel, organoboron, Suzuki-Miyaura cross-coupling.
in the formation of isoquinolinone derivatives
Introduction
(Scheme 1, X=H).[7] A key to the success of this
Organic synthesis involves the breaking of an existing reaction is the use of a base, which functions to
bond and the formation of a new one to convert abstract a proton from an aromatic amide to form an
simple, small compounds into large and complex amidate anion species, which acts as a chelation-
organic molecules by CÀ C bond and CÀ heteroatom assisted directing group. The amidate anion coordi-
bond formation. The use of reactive chemical bonds
has long been the primary focus of organic synthesis.
However, reactions of various unreactive chemical
bonds, such as CÀ H, CÀ C, CÀ F, CÀ O, and other bonds
are now beginning to be the focus of interest in
organic transformations, thus providing new possibil-
ities for developing new synthetic methodologies.
Chelation assistance is one of the more reliable
strategies for the activation of CÀ H bonds.[1–5] A wide
variety of chelation-assisted systems has been de-
signed and have been used in developing new trans-
formations involving CÀ H activation.[6] Chelation sys-
tems that are applicable to the activation of various
unreactive bonds, however, such as CÀ O, CÀ N, CÀ F,
and other unreactive bonds continue to be an
undeveloped area. In 2017, we reported that the Ni-
catalyzed CÀ H/NÀ H annulation of aromatic secondary
amides with alkynes in the presence of KOtBu results
Scheme 1. Ni-catalyzed transformations involving the activation
of unreactive bonds.
Supporting information for this article is available on the
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Helv. Chim. Acta 2021, 104, e2100089
nates to the Ni(0) complex to give the nickel ate
species A in which the nickel center is located in close
proximity to the ortho CÀ H bond, which is selectively
activated.[8] Encouraged by this reaction, we were
prompted to apply this protocol to the activation of
other unreactive bonds. Surprisingly, the strategy was
found to be applicable to the activation of other
unreactive bonds, such as CÀ F,[9] CÀ O, CÀ S, and
CÀ CN.[10] In all cases, no ligand was required. We also
recently applied this protocol to the Ni-catalyzed
cross-electrophile coupling of 2-fluoro-substituted ar-
omatic amides with aryl chlorides[11] and the Ni-
catalyzed Suzuki-Miyaura coupling reaction of 2-fluoro-
substituted aromatic amides with aryl boronates.[12] In
all cases, anionic nickel ate species A appears to be a
key species. We wish to report herein the Ni-catalyzed
Suzuki-Miyaura cross-coupling reaction of ortho-
phenoxy-substituted aromatic amides with aryl boro-
nates, which involve the activation of CÀ O
bonds.[13–17]
Results and Discussion
We first carried out the reaction of 2-phenoxy-N-
phenylbenzamide (1a) with tolylboronic acid neo-
pentylglycol ester 2a (3 equiv.), Ni(cod)2 (10 mol-%),
Scheme 2. Ni-catalyzed reaction of reaction of 1a with 2a and
the possible pathways for the formation of byproduct 5a.
Me4Phen
(3,4,7,8-tetramethyl-1,10-phenanthroline:
5 mol-%), KOtBu (1 equiv.), and CsF (1 equiv.) in DMF
°
(1 mL) at 100 C for 20 h. The reaction gave the
expected arylation product 3a in 59% GC yield, along
with 4a in 6% and 5a in 16% yields as byproducts
(Scheme 2). The formation of 5a appears to proceed
through an SNAr mechanism. Thus, the KOtBu abstracts
a proton from 1a to generate an amidate anion B. The
nitrogen anion in B then attacks at the ipso-carbon to
give the Meisenheimer intermediate C, from which a
phenyl group migrates from an O-atom to a N-atom to
gives D. The protonation of D then gives 5a. An
alternative pathway involves the oxidative addition of
a PhÀ O bond in E give F, which gives 5a through
reductive elimination followed by protonation.
Scheme 3. Ni-catalyzed Suzuki-Miyaura coupling reaction of 1b
with 2a.
To suppress possible side reaction through an
SNAr-like mechanism to give the undesired product 5a,
an electron-donating group such as 4-meth-
oxyphenoxy group was used as a leaving group as in proceeded, even in the absence of CsF (58% yield).
1b in place of a phenoxy group. As expected, the The use of PPh3 (20 mol-%) in place of Me4Phen also
reaction of 1b with 2a gave the desired arylated gave 3a in 70% yield.
product 3a in 85% GC yield and 5b was not formed
The scope of this arylation was investigated with
(Scheme 3). Among the bases that were examined, respect to amides and boronates (Figure 1). To exam-
LiOtBu gave a slightly higher product yield compared ine electronic effects, the reaction of meta-substituted
to NaOtBu (76% yield) and KOtBu (59%). The reaction aromatic amides that contain a 4-methoxyphenoxy
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a CÀ F bond remained unreactive, as in 3d, indicating
that chelation-assistance is involved in the activation
of the CÀ O bond. It was found that N-aryl-substituted
amides gave the corresponding products 3b, 3o and
3p in good yields.
A proposed mechanism for the cross-coupling
reaction is shown in Scheme 4. Deprotonation of the
amide 1 by LiOtBu forms the amidate anion G, which
coordinates to Ni(0) to give the Ni(0) ate complex H.1
Activation of the CÀ OAr bond in H gives the five-
membered azanickelacycle I with the elimination of
LiOAr. Transmetalation between complex I and the
arylboronic ester 2 gives the Ni intermediate J. An
arylated product K is then obtained by reductive
elimination from J with the regeneration of Ni(0) and
the final product 3 is then obtained after workup. The
addition of CsF was not crucial for the reaction to
proceed since LiOAr, which can activate an aryl
boronate in place of CsF, is generated during the
reaction.
Figure 1. Scope of products of the Ni-catalyzed Suzuki-Miyaura
coupling reaction of 1 with 2. Reaction conditions: amide 1
(0.5 mmol), arylboronate 2 (1.5 mmol), Ni(cod)2 (0.05 mmol),
Me4Phen (0.025 mmol), LiOtBu (0.5 mmol), and CsF (0.5 mmol)
°
in DMF (1 mL) at 100 C for 20 h. Yields after isolation with
MPLC are given.
group as a leaving group was examined. The use of an
electron-withdrawing group gave the arylated prod-
ucts in higher yields (3c–3e). We next examined the
scope of arylboronic esters using 1b as a substrate.
The presence of an electron-donating group on the
arylboronic esters showed a higher reactivity, irrespec-
tive of the position of the substituents. Thus, methoxy-
substituted arylboronic esters gave higher product
yields, as in 3g and 3j compared to trifluoromethyl-
substituted arylboronic esters, as in 3i and 3m.
Although a CÀ OMe bond is known to participate in
Suzuki-Miyaura cross-coupling reactions,[13–19] the
CÀ OMe bond remained intact under the reaction
conditions employed, as in 3g, 3j, and 3o. In addition,
Scheme 4. A proposed mechanism.
1 A similar nitrogen-based Ni(0) ate complex was
proposed.[20] An alkoxy anion-substituted Ni(0) ate com-
plex, which facilitates the rate determining CÀ O activa-
tion step, was proposed as a key catalytic species in the
Ni-catalyzed hydrogenolysis of aryl ethers.[21]
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References
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Experimental Section
General Procedures
To an oven-dried 5 mL screw-capped vial in a glove
box, Ni(cod)2 (14.0 mg, 0.05 mmol), Me4Phen (6.0 mg,
0.025 mmol), and DMF (0.5 mL) were added in this
order and the mixture was stirred at room temperature
for 2 min. LiOtBu (40.0 mg, 0.5 mmol), CsF (77.1 mg,
0.5 mmol), 2-(4-methoxyphenoxy)-N-phenyl-5-(trifluo-
romethyl)benzamide (195.1 mg, 0.5 mmol), 4-(5,5-
dimethyl-1,3,2-dioxaborinan-2-yl)methylbenzene (2a,
306.7 mg, 1.5 mmol), and DMF (0.5 mL) were then
added in sequential order. The mixture was stirred at
°
100 C for 20 h and then cooled to room temperature.
The resulting mixture was washed with 5 M NaOH aq.
(20 mL) and then 1 M HCl aq. (20 mL), and extracted
with AcOEt. The combined organic layers were filtered
through an alumina column and the filtrate concen-
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(Medium-pressure Liquid Chromatography: eluent: 9%
AcOEt in hexane) to afford the product 3e (140.4 mg,
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Acknowledgements
This work was supported by a Grant in Aid for
Specially Promoted Research by Ministry of Education,
Culture, Sports, Science and Technology, Japan (MEXT)
(No. 17H06091).
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experiments and analyzed the data. A. M., Y. I., and N.
C. discussed the results and N. C. wrote the manu-
script. A. M. performed the experiments described in
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Received June 9, 2021
Accepted July 1, 2021
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