Selective Methylation of Arenes: A Radical C?H Functionalization/Cross-Coupling Sequence

Article abstract of DOI:10.1002/anie.201804628

A selective, nonchelation-assisted methylation of arenes has been developed. The overall transformation, which combines a C?H functionalization reaction with a nickel-catalyzed cross-coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late-stage methylation of small-molecule pharmaceuticals.

Full text of DOI:10.1002/anie.201804628

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Accepted Article
Title: Selective Methylation of Arenes via Radical C-H Functionalization
Cross-Coupling Sequence
Authors: Fabien Serpier, Fei Pan, WonSeok Ham, Jerome Jaqc,
Christophe Genicot, and Tobias Ritter
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804628
Angew. Chem. 10.1002/ange.201804628
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10.1002/anie.201804628
Angewandte Chemie International Edition
COMMUNICATION
Selective Methylation of Arenes via Radical C–H Functionalization
Cross–Coupling Sequence
Fabien Serpier,[a] Fei Pan,[a] Won Seok Ham,[a], [b] Jérôme Jacq,[c] Christophe Genicot,[c] and Tobias
Ritter[a], [b]*
Abstract: A selective, non-chelation-assisted methylation of arenes
has been developed. The overall transformation, which combines a
C–H functionalization reaction with a nickel-catalyzed cross-coupling,
offers rapid access to methylated arenes with high para selectivity.
The reaction is amenable to late-stage methylation of small molecule
pharmaceuticals.
The methyl group is the simplest organic substituent, yet it
plays a central role in many biological processes such as DNA
replication.[1] In drug design, methyl groups can impart dramatic
improvements on small molecule pharmaceutical candidates, an
3]
influence that has been termed the magic methyl effect.[2,
Today, the origins of the magic methyl effect are largely
understood, for example, through conformational changes
induced by appropriately positioned methyl groups, an IC50 value
decrease by more than three orders of magnitude has been
observed (Scheme 1a).[4] Aromatic C–H functionalization is an
attractive strategy to install methyl groups on arenes,[5]
especially if such a transformation is performed selectively and
late-stage. Innate C–H methylation of heteroarenes has been
developed successfully.[6-10] Useful, direct carboaryl methylation
reactions are, however, currently limited to arenes that bear
coordinating directing groups.[11-16] Selective reactions for non-
chelation assisted C–H methylation are challenging. Here, we
report a method that can convert arenes into the corresponding
methylated arenes through a C–H functionalization-methylation
sequence that does not rely on coordinating directing groups.
Our protocol combines a novel radical C–H TEDAylation with
Selectfluor-II, which proceeds with high and predictable
selectivity, with a methylation reaction of the resulting dicationic
arylammonium salts. The sequence constitutes a para-selective,
Scheme 1. Magic methyl effect.
late-stage methylation of arenes, as illustrated by the synthesis
of the nonsteroidal anti-inflammatory drug celecoxib (Scheme
1c).
Substantial progress has been made in C–H methylation of
heteroarenes since the early work by Minisci, directed at
studying the addition of nucleophilic carbon-based alkyl radicals
to electron-deficient heterocycles.[17] In 2014, a group at Merck
led by DiRocco reported an efficient late-stage heterocycle
derivatization through the addition of
generated via photoredox catalysis from tert-butylperacetate. At
the same time, the Baran group published practical
heteroarene methylation reaction through phenylsulfonyl
a
methyl radical,[6]
[a]
[b]
[c]
Dr. F. Serpier, Dr. F. Pan, W. Ham, Prof. Dr. T. Ritter
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: ritter@mpi-muelheim.mpg.de
W. Ham, Prof. Dr. T. Ritter
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street, Cambridge, MA 02138 (USA)
Dr. J. Jacq, Dr. C. Genicot
a
a
methylation-reduction sequence[7] that made use of Baran zinc
sulfinate chemistry.[18] Shortly thereafter, MacMillan published a
photoredox catalysis approach for the methylation of
heteroarenes with methanol as the methyl source.[8] In contrast,
undirected C–H methylation of carboarenes is largely absent
from the literature. Methylation of carboarenes through cross-
coupling reactions is efficient,[19] but requires pre-
Global Chemistry, UCB Medicines, UCB Biopharma
Braine-L’ Alleud, 1420 (Belgium)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201804628
Angewandte Chemie International Edition
COMMUNICATION
functionalization. Installation of a functional group, for example
via halogenation, often proceeds well for simple substrates, but
mixtures of constitutional isomers, according to electrophilic
aromatic substitution reactivity, are often observed. Since the
seminal work of Tremont in the 1980s on the directed ortho-
alkylation of acetanilides,[11a] several C–H methylation reactions
of carboarenes have been reported relying on directing groups
such as amides,[11] oxazolines,[12] pyridines,[13] carboxylic
acids,[14] and sulfonamides.[15] To date, para-selective C–H
methylation of carboarenes has not been reported.
Table 1. Reaction optimization:a, b
Yield
[%]c
Yield
[%]c
Yield
[%]c
Yield
[%]c
change of reaction conditions
None
71
8
8
<1
<1
10
<1
<1
10
<1
<1
<1
<1
<1
<1
<1
21
No additive
90
43
85
18
<1
<5
TBABr instead of TBACl
TBAPF6 instead of TBACl
LiCl instead of TBACl
Me2Zn instead of MeZnCl
nBuZnCl instead of MeZnCl
33
14
<5
40
<1d
a
Reaction conditions: 3a (0.05 mmol), NiCl2(PCy3)2 (5 mol%), TBACl (3.1
equiv.), MeZnCl 1M in THF (1.5 equiv.) in THF/NMP 1:1 ([C] = 0.17 M), at 50
Scheme 2. Cross coupling with Ar-TEDA electrophile.
b
°C for 20 h.
TBACl: tetra-n-butylammonium chloride, NMP: N-methyl-2-
c
pyrrolidinone. 1H-NMR yield determined using dichloromethane and ethyl
acetate as internal standards. d n-Butyl rather than methyl.
In 2016, our group reported a para-selective C–H amination
of arenes featuring a palladium (II) catalyst and Selectfluor (F-
TEDA-BF4).[20] Single-electron reduction of the N–F reagent by
the palladium catalyst generates a dicationic N-centered radical
(TEDA2+·), which adds to arenes in predictable and high
selectivity, generally >99:1. However, we could not identify any
synthetically useful cross-coupling reaction using aryl-TEDA I
(Ar-TEDA I) generated from an arene and Selectfluor (Scheme
2). Herein, we present a related, but different C–H TEDAylation
reaction with Selectfluor II and its successful application to
cross-coupling with methylzinc chloride. The absence of the
chloromethyl substituent of Selectfluor enables successful
methylation of the unusual dicationic aryl electrophile under
specific conditions.
addition of organic or inorganic halide sources is known to
promote the in situ formation of higher-order zincates RZnX32- (R
= alkyl, X = halide), which facilitate the transmetalation.[24]
Among the tested halide sources, however, only TBACl
furnished the corresponding methylated arene in high yield, and
suppressed the formation of byproducts. Addition of other
halides resulted in precipitates, which we believe to be Ar-TEDA
complexes 3a´ that may exit the catalytic cycle via counteranion
exchange,[25] or formation of aryl piperazine 5. Expansions to
other alkyl cross-coupling reactions, for example n- or t-
butylation reactions, were not promising. Functional groups
including esters (4a, 4c), nitrile (4d), ethers (4b–d), ketones (4b,
4l), sulfonamides (4p, 4q), amide (4r) and chloro (4x) are
tolerated in the C–H methylation of arenes (Table 2). Several
electron-rich amines, however, are not suitable due to their
incompatibility with Selectfluor. The two-step transformation
proved to be compatible with N-heteroaromatic compounds (4h,
4i, 4m–o, 4v) as well as thiophenes (4j, 4k). In a small number
of cases, lower yields were obtained due to the low solubility of
certain Ar-TEDA compounds. The issue was addressed by
replacement of TBACl with TBAPF6 (4g, 4h, 4k). Both electron-
rich and -neutral substrates react smoothly. When more than
We identified desired methylation reactivity during the
evaluation of known cross-coupling reaction conditions.[21] Our
starting point was informed by the cross-coupling reactions of
aryltrimethylammonium salts.[22-23] But the dicationic Ar-TEDA
electrophiles exhibited different reactivity compared to more
conventional aryltrimethylammonium salts, and we observed
several side reactions with the original reaction conditions (Table
1). The specific methyl source MeZnCl and the chloride additive
tetra-n-butylammonium chloride (TBACl) were crucial. The
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10.1002/anie.201804628
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COMMUNICATION
Table 2. Methylation of Ar-TEDA IIsa
a Reactions performed with Ar-TEDA II (0.25 mmol), NiCl2(PCy3)2 (5 mol%), TBACl (3.1 equiv.), MeZnCl 1 M in THF (1.5 equiv.) in THF/NMP 1:1 ([C] = 0.17 M), at
50 °C for 20 h. Yields refer to isolated analytically pure compounds. b TBACl (4 equiv.) was used, with NiCl2(PCy3)2 (10 mol%) and MeZnCl 1 M in THF (2 equiv.).
c
d
TBAPF6 (3.1 equiv.) was used instead of TBACl. TBAPF6 (4 equiv.) was used instead of TBACl, with NiCl2(PCy3)2 (10 mol%) and MeZnCl (2 equiv.). e Major
f
g
isomer (7:2:1 ratio, see SI). NiCl2(PCy3)2 (10 mol%), TBACl (4 equiv.) and MeZnCl 1 M in THF (4 equiv.) were used. NiCl2(PCy3)2 (5 mol%), TBACl (4 equiv.)
and MeZnCl 1 M in THF (1.0 equiv.) were used.
one arene is present, the most electron-rich arene is methylated
selectively (4n, 4o). Electron-deficient arenes, such as methyl
benzoate, are insufficiently reactive and undergo low or no
conversion in the first step. The methylation of 2,4-
utility of the transformation through late-stage functionalization of
small molecule pharmaceuticals (4s-x). For example, the 4’
position of flurbiprofen methyl ester (4t) was methylated
selectively in 66% yield. The position, susceptible to metabolic
diphenylpyridine was successfully performed on gram-scale (4o), oxidation,[26] can be protected by the introduction of the methyl
with no notable decrease in yield. We further demonstrated the
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10.1002/anie.201804628
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COMMUNICATION
group.[27] Our approach was also applied to the synthesis of
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The cross-coupling was extended to the cyclopropyl
substituent, which can improve pharmacological properties, such
as brain permeability and metabolic stability.[29] Under the
reaction conditions developed for methylation, (hetero)arenes
reacted smoothly with commercially available cyclopropylzinc
bromide (Table 3).
[5]
[6]
[7]
Table 3. Cyclopropylation of Ar-TEDAsa
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In conclusion, we have developed a selective methylation of
arenes based on
a
C–H functionalization–cross-coupling
sequence. Our transformation does not require a pre-installed
coordinating group on the starting materials, and therefore
allows access to an enlarged substrate scope in comparison to
previously reported methods.
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́
Acknowledgements
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We thank the Max-Planck-Institut für Kohlenforschung and UCB
Pharma for funding. W. H. thanks the Kwanjeong Educational
Foundation for funding.
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Keywords: methylation• arene• C–H functionalization • nickel•
cross-coupling
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COMMUNICATION
Fabien Serpier,[a] Fei Pan,[a] Won Seok
Ham,[a],[b] Jérôme Jacq,[c] Christophe
Genicot,[c] and Tobias Ritter[a],[b]*
Selective Methylation of Arenes via
Radical C–H Functionalization Cross-
Coupling Sequence
A selective, non-chelation-assisted methylation of arenes has been developed. The
overall transformation, which combines a C–H functionalization reaction with a
nickel-catalyzed cross-coupling, offers rapid access to methylated arenes with high
selectivity, e.g. exclusive para-selectivity for mono-substituted arenes. The reaction
is amenable to gram-scale synthesis, and is applicable to late-stage methylation of
small molecule pharmaceuticals.
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