Nickel-Catalyzed Benzylation of C?H Bonds in Aromatic Amides with Benzyltrimethylammonium Halides

Article abstract of DOI:10.1002/ijch.201700044

Nickel-catalyzed benzylation reactions of C?H bonds in aromatic amides with benzyltrimethylammonium halides are developed by using a 5-chloro-8-aminoquinoline derivative as a bidentate directing group. Benzylation occurs selectively at the ortho-C?H bonds in aromatic amides, and no methylation was detected. The presence of a 5-chloro-8-aminoquinoline moiety is essential for the success of this reaction, in which a variety of functional groups can be tolerated.

Full text of DOI:10.1002/ijch.201700044

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DOI: 10.1002/ijch.201700044
Nickel-Catalyzed Benzylation of CÀH Bonds in Aromatic
Amides with Benzyltrimethylammonium Halides
[a]
[a]
[a]
[a]
Akane Sasagawa, Mao Yamaguchi, Yusuke Ano, and Naoto Chatani*
Dedicated to Professor Robert G. Bergman on the occasion of his receipt of the 2017 Wolf Prize in Chemistry
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Abstract: Nickel-catalyzed benzylation reactions of CÀH no methylation was detected. The presence of a 5-chloro-8-
bonds in aromatic amides with benzyltrimethylammonium aminoquinoline moiety is essential for the success of this
halides are developed by using a 5-chloro-8-aminoquinoline reaction, in which a variety of functional groups can be
derivative as a bidentate directing group. Benzylation occurs tolerated.
selectively at the ortho-CÀH bonds in aromatic amides, and
Keywords: CÀH activation · Chelation assistance · Nickel · Benzylation · Benzyltrimethylammonium halide
[
15]
The transition metal-catalyzed cross coupling reactions are
generally considered to be one of the most reliable and diverse
tion, arylation, alkynylation, and carbonylation. We recently
reported on the development of the Ni-catalyzed direct
[
1]
[16]
[17]
[18]
CÀC bond forming methods in the field of organic synthesis.
arylation, alkylation, and oxidative annulation of CÀH
bonds in aromatic amides by utilizing the bidentate directing
group. This newly developed chelation system using a
bidentate directing group in conjunction with a nickel catalyst
allowed to significantly expand the substrate scope, which had
Considerable advances have been achieved in this area and a
wide variety of electrophiles can now be used in place of aryl
halides in catalytic cross coupling reactions. Aryltrimethylam-
monium salts have been found to serve as useful electrophilic
partners in a wide variety of Ni-catalyzed cross coupling
[
19]
been limited to acidic CÀH bonds. Furthermore, we quite
[
2]
reactions, such as the Kumada-Tamao-Corriu reaction, the
recently found that the Ni-catalyzed methylation of aromatic
[3]
[4]
+
À
Suzuki-Miyaura reaction, the Negishi reaction, the Migita-
amides with PhMe N I as an effective methylation re-
agent. On the basis of these results, we postulated that the
3
[5]
[6]
[20]
Kosugi-Stille reaction, the a-arylation of ketones, amina-
[7]
[8]
[9]
tion, borylation, and reduction. Aryltrimethylammonium
benzylation of CÀH bonds aromatic amides could be achieved
+
salts have also been used in the Pd-catalyzed CÀH arylation of
with benzylammonium salt being used in place of PhMe N
3
[
10]
À
azoles.
Likewise, benzyltrimethylammonium salts have
I . To verify this hypothesis, the reaction of an aromatic amide
bearing a 5-chloro-8-aminoquinoline moiety as a directing
group 1a and 2 equivalents of BnMe N Br was
examined in the presence of Ni(OTf) (10 mol%) and Na CO
3
(2 equiv) in toluene at 1408C, with a reaction time of 20 h
(Scheme 1). As a result, the ortho-benzylation product 2a was
produced in 99% isolated yield. Importantly, the formation of
the ortho-methylation product 3a was not observed. Screening
of reaction conditions revealed that other Ni sources were less
effective for the benzylation: Ni(OAc)2 89% NMR yield,
Ni(OAc) ·4H O 54%, and NiBr (dme) 51%. The addition of
been used as benzylation reagents in place of benzylic halides.
Cs a´ k y¨ reported the Rh(I)-catalyzed cross coupling of (in-
dolylmethyl)trimethylammonium iodide with aryl boronic
[
17b,21,22]
+
À
3
2
2
[
11]
acids.
In addition, benzyltrimethylammonium salts have
been exploited in Ni-catalyzed coupling reactions with, not
[12]
[5]
only aryl boronic acids,
but aryl stannanes, carbon
[
13]
[14]
dioxides, and diboronates as well. We report herein the
Ni-catalyzed benzylation of CÀH bonds in aromatic amides
with benzyltrimethylammonium salts.
The catalytic transformation of CÀH bonds into CÀC
bonds has emerged as a powerful and straightforward method-
ology for constructing frameworks of organic compounds.
Both the chemo- and regioselectivity of CÀH bonds are
important tasks for direct CÀC bond formation because of the
ubiquity of CÀH bonds. The use of a directing group has
emerged as an effective and widely employed strategy for the
regioselective transformation of CÀH bonds. The proximity
effect based on the coordination of a directing group to a
metal center can often overcome the inherent reactivity of
CÀH bonds. To date, enormous efforts have been devoted to
realizing the catalytic transformation of CÀH bonds into
various types of CÀC bonds, including alkylation, alkenyla-
2
2
2
PPh as a ligand had no effect on product yield. On the other
hand, the nature of the benzylammonium salt used had an
impact on the efficiency of this benzylation. When BnMe N
Cl was used, benzylation was quantitative, as observed by
3
+
3
À
+
À
NMR. In contrast, BnMe N OTf was ineffective for this
3
[
a] A. Sasagawa, M. Yamaguchi, Dr. Y. Ano, Prof. Dr. N. Chatani
Department of Applied Chemsitry, Faculty of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
E-mail: Chatani@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ijch.201700044
Isr. J. Chem. 2017, 57, 1–5
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Ni-catalyzed benzylation of aromatic amides with benzyltri-
[a]
metylammonium bromide.
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Scheme 1. Benzyltrimethylammonium bromide as a CÀH benzyla-
tion reagent in the Ni-catalyzed reaction of aromatic amides.
CÀH benzylation, which resulted in the formation of 2a in 4%
NMR yield, along with 1a being recovered in 94% yield. 2a
was not formed when the benzylation was carried out with
+
À
+
À
BnH N Cl . We selected BnMe N Br as a preferred
3
3
benzylation reagent because of its ease of handling in
+
À
comparison with the hygroscopic BnMe N Cl .
3
The scope of the aromatic amide for this CÀH benzylation
was investigated under standard conditions (Table 1). Aro-
matic amides bearing an ortho-substitutent, as in 1b and 1c
reacted vigorously in this benzylation. The ortho-fluorine
group of 1c remained intact under the standard conditions.
Other functional groups, including dimethylamino, methoxy,
chlorine, trifluoromethyl, and acetyl groups, were compatible
in this benzylation. Benzylation took place selectively at the
less hindered CÀH bond when meta-substituted aromatic
amides 1d–i were used, as was stated in our previous report on
the use of aryltrimethylammonium salt in Ni-catalyzed
[20]
methylation reactions.
Relatively electron-deficient aro-
matic amides 1h and 1i reacted efficiently, with higher yields
of benzylation products 2h and 2i, respectively, compared to
the more electron-rich amides 1e and 1f. In contrast, the 3,4-
dimethoxy substituted amide 4 served as a suitable substrate,
providing a regioselective benzylation product 5 in 92% yield.
The electron-rich thiophene 6 could also successfully em-
ployed in this protocol. However, all of pyridinecarboxamide
substrates did not react.
We next surveyed a series of substituted benzyltrimethy-
lammonium salts for the this Ni-catalyzed CÀH benzylation
[Eq (1)]. It is noteworthy that, when the reaction of 1a with o-
methylbenzyltrimethylammonium bromide was performed
under standard conditions, the corresponding benzylation
product 8 was obtained in 97% isolated yield, without any
inhibition by the steric hindrance of o-tolylmethyl group. Both
m- and p-methylbenzyltrimethylammonium salts were also
tolerated, providing 9 and 10 in 96% and 97% yields,
respectively. However, the introduction of a diphenylmethyl
group into 1a was unsuccessful in this catalysis.
[
a] Reaction conditions: amide (0.3 mmol), BnMe NBr (0.6 mmol),
3
Ni(OTf) (0.03 mmol), Na CO (0.6 mmol), toluene (1 mL) at 1408C
2
2
3
for 20 h. [b] Yield of isolated product. [c] 2,5-Dibenzylation product
was obtained in 1% NMR yield. [d] Isolated by GPC after column
chromatography. [e] 2,5-Dibenzylation product was obtained in 5%
NMR yield. [f] 2,5-Dibenzylation product was obtained in 2% NMR
yield.
To obtain insights into the reaction mechanism, we carried
out several experiments, as outlined below. When the
benzylation of 1a was performed in the presence of 2
equivalents of TEMPO as a radical scavenger, 2a was obtained
in 50% isolated yield and the O-benzylated TEMPO 11 was
Isr. J. Chem. 2017, 57, 1–5
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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produced in 23% isolated yields (based on TEMPO), along
with 1a being recovered in 48% yield [Eq (2)]. While a
detailed mechanism has not been elucidated at this time, this
result supports the conclusion that it is unlikely that a free-
radical species is formed as an intermediate in this CÀH
investigation of our previous report on Ni-catalyzed CÀH
[17,20,21] II IV
functionalization,
a Ni /Ni catalytic cycle appears to
[
25]
be involved in this benzylation.
The coordination of the
II
quinoline nitrogen of I to the Ni species followed by ligand
exchange gives the bidentate complex II. The reversible
cleavage of the ortho CÀH bond in the aromatic amide assisted
by Na CO takes place, providing a five-membered nickela-
[
23]
benzylation system.
2
3
+
À
II
cycle III. The oxidative addition of BnMe N Br to the Ni
center leads to the formation of the Ni intermediate IV. The
successive reductive elimination and protonation of V gives
3
IV
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II
the benzylation product along with the regeneration of the Ni
species.
This benzylation proceeds efficiently, even in the absence
of a phosphine ligand, despite the fact that the presence of
PPh3 is required for Ni-catalyzed CÀH methylations with
+
À [20]
Considering our previous report on Ni-catalyzed CÀH
alkylations with alkyl halides, it is possible that benzyl
PhMe N I . We predict that two possible factors play a role
3
[17a]
in this result. One is the electronic nature of the electrophilic
+
À
bromide could function as an actual benzylation reagent. In
coupling partner. The high electrophilicity of BnMe N Br
3
+
À
fact, benzyl bromide can be generated from BnMe N Br
would be preferable for the efficient oxidative addition process
3
[24]
+
À
under the reaction conditions. To examine this issue further,
in comparison with that of PhMe N I . The other involves the
3
we examined the reaction of 1a with benzyl bromide being
steric demand associated with eliminating substituents from
+
À
IV
used in place of BnMe N Br for 3 h. As shown in Eq (3), 2a
the Ni species. The presence of a sterically bulky benzyl
3
was produced in 39% NMR yield along with the 57% 1a
group would be expected to accelerate the reductive elimi-
nation step. On the other hand, in the case of Ni-catalyzed
being recovered. However, the addition of Et N (2 equivalents)
3
improved the yield of 2a to 72%. In addition, the use of BnEt
N Br gave the benzylation product 2a in a yield comparable
CÀH methylation, the presence of PPh can result in ligand
3
3
+
À
2
exchange with a quinoline sp nitrogen on the Ni complex,
to that obtained when a combination of benzyl bromide and
which would be expected to provide a suitable active species
for both the oxidative addition and reductive elimination steps.
In summary, we report on the Ni-catalyzed CÀH benzyla-
tion of aromatic amides using benzyltrimethylammonium salts
as effective benzylation reagents. The use of an 8-amino-5-
chloroquinoline directing group is essential for an efficient,
ortho-selective reaction. Various functionalized aromatic
amides are acceptable for this benzylation. Further investiga-
tions of this reaction are currently in progress.
Et N was used. These results suggest that benzylammonium
3
salt appears to a greater role in this transformation than benzyl
bromide alone.
A plausible mechanism for the Ni-catalyzed benzylation is
shown in Scheme 2. On the basis of the mechanistic
Experimental Section
To an oven-dried 5 mL screw-capped vial, N-(5-chloroquinolin-8-yl)-
2
0
-methylbenzamide (1a, 90.4 mg, 0.3 mmol), BnMe NBr (138.7 mg,
3
.6 mmol), Ni(OTf)2 (10.5 mg, 0.03 mmol), Na CO (65 mg,
2
3
0.6 mmol) and toluene (1 mL) were added in a glove box. The mixture
was stirred for 20 h at 1408C followed by cooling. The reaction
mixture was washed with aq. HCl (6.25 mM, 16 mL), and the aqueous
layer was extracted with EtOAc (33 5 mL). The combined organic
layers were dried over Na SO , filtered, and concentrated in vacuo.
2
4
The residue was purified by column chromatography on silica gel
eluent: hexane/EtOAc=20/1) to afford the desired benzylated product
(
2a (116.7 mg, 99%) as a white solid.
Acknowledgements
This work was supported by the JST Strategic Basic Research
Programs “Advanced Catalytic Transformation Program for
Scheme 2. A plausible catalytic cycle.
Isr. J. Chem. 2017, 57, 1–5
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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+
À
23] The reaction of BnMe N Br with 2 equivalents of TEMPO in
3
the absence of 1a, Ni(OTf) , and Na CO in toluene-d at 1408C
2
2
3
8
for 20 h also led to the formation of benzylated TEMPO 11, but
the yield of 11 could not be determined in this case due to the
formation of various unidentified by-products.
2
017, 28, 350–353. The Ni-catalyzed cross coupling reaction of
alkyl pyridinium salts with aryl boronic acids was recently
reported, see: d) C. H. Basch, J. Liao, J. Xu, J. J. Piane, M. P.
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coupling have been reported with Pd catalysts: e) H. J. Davis,
M. T. Mihai, R. J. Phipps, J. Am. Chem. Soc. 2016, 138, 12759–
+
À
[24] When BnMe
N Br was heated in toluene-d at 1408C for 20 h,
3
8
benzyl bromide was obtained in 27% NMR yield, along with
dibenzylmethylamine, as detected by GCMS. This result suggests
that both benzyl and methyl bromide were formed by the thermal
+
À
decomposition of BnMe N Br under the standard conditions.
3
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2762; f) T. Wang, S. Yang, S. Xu, C. Han, G. Guo, J. Zhao, RSC
[
25] Quite recently, Liu reported on a computation study of the Ni(II)-
catalyzed CÀH functionalization. According to their DFT
calculations, CÀH arylation and alkylation with aryl and alkyl
Adv. 2017, 7, 15805–15808.
[
[
13] T. Moragas, M. Gaydou, R. Martin, Angew. Chem. Int. Ed. 2016,
5
5, 5053–5057; Angew. Chem. 2016, 128, 5137–5141.
14] a) H. Zhang, S. Hagihara, K. Itami, Chem. – Eur. J. 2015, 21,
6796–16800; b) C. H. Basch, K. M. Cobb, M. P. Watson, Org.
Lett. 2016, 18, 136–139.
halides proceeds via
a concerted metalation-deprotonation
(
CMD) mechanism, an oxidative addition, and reductive elimi-
1
nation mechanism involving a Ni(IV) intermediate. H. M. Omer,
P. Liu, J. Am. Chem. Soc. 2017, 139, 9909–9920.
[15] For recent selected reviews on the use of directing groups in the
transition-metal catalyzed functionalization of CÀH bonds, see:
a) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res.
Received: May 24, 2017
Accepted: September 4, 2017
Published online on && &&, 0000
2
012, 45, 788–802; b) D. A. Colby, A. S. Tsai, R. G. Bergman,
J. A. Ellman, Acc. Chem. Res. 2012, 45, 814–825; c) S. R.
Isr. J. Chem. 2017, 57, 1–5
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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COMMUNICATION
A. Sasagawa, M. Yamaguchi, Dr. Y.
Ano, Prof. Dr. N. Chatani*
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Nickel-Catalyzed Benzylation of
CÀH Bonds in Aromatic Amides
with Benzyltrimethylammonium
Halides
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