Phenyltrimethylammonium Salts as Methylation Reagents in the Nickel-Catalyzed Methylation of C-H Bonds

Article abstract of DOI:10.1002/anie.201511197

Methylation of C(sp²)-H bonds was achieved through the Ni^II-catalyzed reaction of benzamides with phenyltrimethylammonium bromide or iodide as the source of the methyl group. The reaction has a broad scope and shows high functional-g

Full text of DOI:10.1002/anie.201511197

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International Edition: DOI: 10.1002/anie.201511197
German Edition: DOI: 10.1002/ange.201511197
À
C H Activation
Phenyltrimethylammonium Salts as Methylation Reagents in the
À
Nickel-Catalyzed Methylation of C H Bonds
Takeshi Uemura, Mao Yamaguchi, and Naoto Chatani*
2
À
Abstract: Methylation of C(sp ) H bonds was achieved
through the NiII-catalyzed reaction of benzamides with phenyl-
trimethylammonium bromide or iodide as the source of the
methyl group. The reaction has a broad scope and shows high
arylation, alkylation, amination, hydroxylation, halogenation,
thionylation, borylation, and silylation, has been reported to
À
date. However, examples of the methylation of C H bonds
still remain rare compared to other extensively studied types
À
functional-group compatibility. The reaction is also applicable
of C C bond formation, such as arylation, alkylation, and
3
À
to the methylation of C(sp ) H bonds in aliphatic amides.
allylation reactions, although methylation is fundamental in
medicinal chemistry; the biological and physical properties of
a drug can be greatly affected by the addition of just one
methyl group to a lead compound.[11] In 1984, Tremont
reported the PdII-mediated reaction of acetanilides with MeI,
T
he transition-metal-catalyzed cross-coupling reaction has
À
emerged as one of the most reliable and versatile C C bond-
forming methods in organic synthesis.[1] Aryltrimethylammo-
nium salts were recently found to be applicable as an
electrophilic coupling partner in place of the extensively
used aryl halides or their pseudohalides in various catalytic
cross-coupling reactions as arylation reagents, especially in
Ni-catalyzed cross-coupling reactions (Scheme 1). Wenkert
and co-workers have reported Ni-catalyzed Kumada–Tamao
which results in methylation at the ortho position.[12]
A
catalytic version using MeI as the methylation reagent was
subsequently reported by several groups.[13,14] Organometallic
reagents, such as Me4Sn,[15] MeB(OH)2,[16] MeMgCl,[17]
Me3Al,[18] Me2Zn,[19] peroxides,[20] and others,[21] can also be
used in the methylation of C H bonds. The development of
a methylating reagent that is easy to use and is not sensitive to
air continues to be a significant challenge. The present
À
reaction involves the first reported use of aryltrimethylam-
[22]
À
monium salts in catalytic transformations of C H bonds.
Reaction of the aromatic amide 1a with 2 equivalents of
PhMe3N+IÀ (mp 2278C (subl.)) in the presence of Ni(OTf)2
and PPh3 in toluene at 1608C for 14 h gave the methylation
product 2a in 88% yield of isolated product (97% NMR
yield; Scheme 2). No arylation product (3) was detected.
When the reaction was carried out in the absence of PPh3, 2a
was obtained in 37% NMR yield. The reaction was signifi-
cantly affected by the nature of the base used: NaHCO3 gave
92% NMR yield, Li2CO3 0%, K2CO3 40%, NaOtBu 0%, and
no base 0%. When the reaction was carried out at 1408C, 2a
was obtained in 88% NMR yield, along with recovered 9%
1a. It was found that PhMe3N+BrÀ showed comparable
reactivity; using PhMe3N+BrÀ gave 2a in 90% yield of
isolated product, along with a small amount of recovered 1a.
Scheme 1. Cross-coupling reactions with aryltrimethylammonium salts.
coupling with aryltrimethylammoinium iodide.[2] Later, Ni-
catalyzed Suzuki–Miyaura coupling,[3] Negishi coupling,[4]
amination,[5] and borylation[6] with aryltrimethylammonium
salts were reported. Quite recently, aryltrimethylammonium
À
triflates have been used as C H arylation reagents in the Pd-
catalyzed arylation of azoles.[7] Benzyltrimethylammonium
salts have also been used as benzylating reagents in cross-
coupling reactions.[6,8] However, the use of ammonium salts as
methylation reagents in cross-coupling reactions has never
been reported (Scheme 1).[9] We report herein the Ni-
À
catalyzed methylation of C H bonds in aromatic amides
No reaction occurred when PhMe3N+PF6 was used. Curi-
À
with phenyltrimethylammonium salts, which function as
methylation reagents.
ously, tetramethylammonium iodide also showed no reactiv-
ity.
À
The transition-metal-catalyzed functionalization of C H
bonds to other chemical bonds has great significance in
synthetic chemistry because of its high efficiency.[10] A wide
À
variety of direct functionalizations of C H bonds, including
[*] T. Uemura, M. Yamaguchi, Prof. Dr. N. Chatani
Department of Applied Chemistry, Faculty of Engineering
Osaka University
2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)
E-mail: chatani@chem.eng.osaka-u.ac.jp
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201511197.
À
Scheme 2. Phenyltrimethylammonium iodide as the C H methylation
reagent in the Ni-catalyzed reaction of aromatic amides.
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Table 1: Ni-catalyzed methylation of C H bonds with phenyltrimethyl-
The scope of this methylation reaction with respect to the
amides was investigated (Table 1). The reaction shows
a broad substrate scope and high functional-group tolerance.
A wide variety of functional groups, such as methoxy,
benzyloxy, siloxy, acetoxy, fluoride, chloride, iodide, ketone,
and trifluoromethyl groups, were tolerated. In the case of
ammonium iodide.[a]
Amide
Product[b]
À
meta-substituted aromatic amides, the less hindered C H
bond was methylated exclusively.
The present system was applicable to the methylation of
3
À
C(sp ) H bonds (Scheme 3). The addition of MesCOOH
resulted in an increased product yield. The reaction of 20 gave
the methylation product 21 in 68% yield of isolated product,
along with 4% dimethyl isomer 22 and 14% recovered 20.
The phenylation product 23 was not formed.
À
Scheme 3. Phenyltrimethylammonium iodide as the C H methylation
reagent in the Ni-catalyzed reaction of aliphatic amide 20.
The deuterated amide 1a-d7 was reacted with PhMe3NI
for 0.5 h under otherwise standard reaction conditions
À
(Scheme 4). As observed in the case of C H alkylation and
arylation reactions,[14,23,24] a significant amount of H/D
exchange occurred at the ortho position (52%H) in the
recovered amide, even after 0.5 h. This result indicates that
À
cleavage of the C H bonds is fast and reversible and thus
unlikely to be the rate-determining step in the reaction.
The reaction is not completely inhibited by the addition of
the radical trapping reagent TEMPO. When 1 equivalent of
TEMPO was used, 2a was produced in 53% yield along with
19% recovered 1a. Even when 3 equivalents of TEMPO were
used, 2a was obtained in 16% yield along with 31%
recovered 1a. In both cases, the methyl TEMPO ether was
not detected and an as yet unidentified product was formed in
small amounts. The results suggest that an intermediate free-
[a] Reaction conditions: amide (0.3 mmol), PhMe3NI (0.6 mmol), Ni-
(OTf)2 (0.03 mmol), PPh3 (0.06 mmol), Na2CO3 (0.6 mmol) in toluene
(1 mL) at 1608C for 14 h. [b] Yield of isolated product. [c] Isolated by GPC
after column chromatography. [d] At 1408C. [e] For 24 h.
Scheme 4. H/D exchange when using 1a-d7.
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radical species does not appear to be involved in this
methylation system.
A proposed mechanism involving a NiII/NiIV catalytic
cycle is shown in Scheme 5, which is essentially the same as
À
that proposed for C H alkylation and arylation reac-
tions.[14,23,24] The coordination of the N(sp2) atom to the NiII
complex followed by ligand exchange on the N(sp3) atom
Scheme 6. Hydrolysis of the methylation product.
À
gives complex B. Cleavage of the ortho C H bonds gives the
nickelacycle C, and this step is accelerated by Na2CO3.
Oxidative addition of PhMe3NI, followed by reductive
elimination to give E, which undergoes protonation, results
in the formation of the methylation product with regeneration
of the NiII species.
phenyltrimethlammonium bromide or iodide as the methyl-
ation reagent. A combination of a NiII catalyst and an 8-
aminoquinoline directing group facilitates the reaction. The
reaction displays a broad substrate scope and high functional-
group tolerance.
Experimental Section
2-methyl-N-(8-quinolyl)benzamide
(1a,
78.7 mg,
0.3 mmol),
PhMe3NI (158 mg, 0.6 mmol), Ni(OTf)2 (10.7 mg, 0.03 mmol), PPh3
(15.7 mg, 0.06 mmol), Na2CO3 (63.6 mg, 0.6 mmol) and toluene
(1 mL) were added to an oven-dried 5 mL screw-capped vial in
a glove box. The mixture was stirred for 14 h at 1608C followed by
cooling. The resulting mixture was filtered through a celite pad and
the filtrate concentrated in vacuo. The residue was purified by column
chromatography on silica gel (eluent: hexane/EtOAc = 20:1) to
afford the desired methylated product 2a (73.1 mg, 88%) as a white
solid.
Acknowledgements
This work was supported, in part, by a Grant-in-Aid for
Scientific Research on Innovative Areas “Molecular Activa-
tion Directed toward Straightforward Synthesis” from The
Ministry of Education, Culture, Sports, Science and Technol-
ogy, and by JST Strategic Basic Research Programs
“Advanced Catalytic Transformation Program for Carbon
Utilization (ACT-C)” from Japan Science and Technology
Agency.
Scheme 5. Proposed mechanism.
The most curious issue is why phenylation does not take
place in this system, since aryltrimthylammonium salts are
known to serve as arylation reagents in various cross-coupling
reactions with the aid of a Ni catalyst.[2–6] Our experimental
results indicate that phenylation did not take place under the
reaction conditions when using the NiII complex as the
catalyst precursor, and the reported fact that phenyltrime-
thylammonium salts function as phenylation reagents in
various cross-coupling reactions when using Ni0 complexes
suggest that Ni0 is not a key catalytic species in the present
À
Keywords: C H activation · chelation assistance · methylation ·
nickel · phenyltrimethylammonium iodide
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3162–3165
Angew. Chem. 2016, 128, 3214–3217
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À
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À
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Received: December 3, 2015
Published online: January 28, 2016
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