Modular Dual-Tasked C-H Methylation via the Catellani Strategy

Article abstract of DOI:10.1021/jacs.9b07857

We report a dual-tasked methylation that is based on cooperative palladium/norbornene catalysis. Readily available (hetero)aryl halides (39 iodides and 4 bromides) and inexpensive MeOTs or trimethylphosphate are utilized as the substrates and methylating reagent, respectively. Six types of "ipso" terminations can modularly couple with this "ortho" C-H methylation to constitute a versatile methylation toolbox for preparing diversified methylated arenes. This toolbox features inexpensive methyl sources, excellent functional-group tolerance, simple reaction procedures, and scalability. Importantly, it can be uneventfully extended to isotope-labeled methylation by switching to the corresponding reagents CD₃OTs or ¹³CH₃OTs. Moreover, this toolbox can be applied to late-stage modification of biorelevant substrates with complete stereoretention. We believe these salient and practical features of our dual-tasked methylation toolbox will be welcomed by academic and industrial researchers.

Full text of DOI:10.1021/jacs.9b07857

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Article
A Modular Dual-Tasked C-H Methylation via the Catellani Strategy
Qianwen Gao, Yong Shang, Fuzhen Song, Jinxiang Ye, Ze-
Shui Liu, Lisha Li, Hong-Gang Cheng, and Qianghui Zhou
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07857 • Publication Date (Web): 12 Sep 2019
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Qianwen Gao, Yong Shang, Fuzhen Song, Jinxiang Ye, Ze-Shui Liu, Lisha Li, Hong-Gang Cheng, Qi-
anghui Zhou1,2,*
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1Sauvage Center for Molecular Sciences, Engineering Research Center of Organosilicon Compounds & Materials (Ministry
of Education), College of Chemistry and Molecular Sciences, Wuhan University, 430072, Wuhan, P. R. China.
2The Institute for Advanced Studies, Wuhan University. 430072, Wuhan, P. R. China.
ABSTRACT: We report a dual-tasked methylation based on cooperative palladium/norbornene catalysis. Readily available (het-
ero)aryl halides (39 iodides and 4 bromides) and inexpensive MeOTs or trimethylphosphate are utilized as the substrates and meth-
ylating reagent, respectively. Six types of ipso terminations can modularly couple with this ortho C-H methylation to constitute a
versatile methylation toolbox for preparing diversified methylated arenes. This toolbox features inexpensive methyl sources, excellent
functional-group tolerance, simple reaction procedures, and scalability. Importantly, it can be uneventfully extended to isotope-la-
beled methylation by switching to the corresponding reagents CD3OTs or 13CH3OTs. Moreover, this tool-box can be applied to late-
stage modification of bio-relevant substrates with complete stereo-retention. We believe these salient and practical features of our
dual-tasked methylation toolbox will be welcomed by academic and industrial researchers.
Retail Sales in 20183 shows that more than 47% of small-mole-
cule drugs contain at least one methyl group, with typical ex-
Extensive studies have revealed that the introduction of a me-
thyl group can modulate the solubility, hydrophilicity, and con-
formation of a drug candidate, thus leading to a profound im-
pact on its biological activity, pharmacokinetic profile, as well
as physical properties, which is called the “magic methyl effect”
in medicinal chemistry.1 For example, in a recent report, the re-
markable advantage that the methylation can have on potency
(over 2000-fold boost) has been demonstrated (Figure 1A).2 A
survey of Njarðarson’s Top 200 Pharmaceutical Products by
amples presented in Figure 1B. In addition, the introduction of
trideuteriomethyl (CD3) group has also been widely attempted
during the optimization of drug candidates,4 and several clini-
cally important deuterated compounds have been developed. For
instance, Austedo4c is a marketed antichorea drug approved by
FDA in 2017, CTP-7864d and SD-5604e are now in clinical trials
(Figure 1C). Therefore, (deuterated)methylation has become
one of the most widely used strategies to modify bioactive com-
pounds in medicinal chemistry.1,5 Efficient methods for selec-
tive methylation, particularly C-H bond methylation, are highly
desirable.1b,6
Until now, substantial progress has been made for installing
methyl groups on (hetero)arenes.6,7-21 Since the early work by
Minisci,7 the radical-type innate C-H methylation of het-
eroarenes has been developed successfully due to the efforts of
Baran,8 DiRocco,9 Macmillan,10 Li11 and others.12 Meanwhile,
transition-metal-catalyzed methylation of a C-H or C-X bond
involving the use of methyl organometallic reagents (lithium13,
magnesium,14 tin,15 boron,16 zinc,17 aluminum,18 silicon19 etc),
methyl electrophiles20 or others21 has also boomed in the past
two decades. Despite powerful, these methods possess some
limitations, including: a) the requirement of a directing
group;18b,20c,20d b) narrow substrate scope;13 c) harsh reaction
conditions (high temperature, strong base and oxidants).20h-j In
addition, due to the very limited availability and high cost of
CD3-containing organometallic reagents,13,20f these methods
have a pronounced limitation when the installation of a CD3
group is desired. Moreover, these methods are commonly sin-
gle-tasked: the operations only lead to sheer methylations (Fig-
ure 2A).
Figure 1. The Importance of Methylation in Pharmaceutical
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CH3OTs (2A) (other methyl sulfonates were also screened, see
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Table S1), while employing tert-butyl acrylate (3) as the Heck-
type terminating reagent.25a Through extensive reaction condi-
tions optimization (see Table S2 of Supporting Information for
details), it was identified that the desired methylated product 4a
was obtained with the highest yield (95%) while running the
reaction with Pd2(dba)3 (5 mol%) as the catalyst, TFP (11 mol%)
as the ligand, the cyano derivative of NBE (N2, 2.0 equiv)32 as
the mediator, and Cs2CO3 (2.5 equiv) as the base in MeCN (0.2
M) at 80 °C (Table 1, Standard Condition A). It is noteworthy
that significant ligand effect was observed for this transfor-
mation. When the bulky ligand XPhos was employed, the poor
yields of 4a were obtained. In contrast, the use of small TFP as
the ligand dramatically increased the yield to 99% (95% iso-
lated yield) (Table S2).
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Figure 2. Strategies for Arene Methylation
The cooperative palladium/norbornene (NBE) catalysis
(namely the Catellani reaction)22 is a powerful strategy that al-
lows the expeditious synthesis of highly substituted arenes,
through sequential ortho C-H functionalization and ipso termi-
nation of aryl iodides.23,24 Hence, based on this chemistry, we
surmise whether a dual-tasked methylation can be developed by
coupling the ortho-C-H methylation with the diversified ipso-
cross coupling reactions of aryl iodides (Figure 2B). We believe
such a method will possess huge synthetic potential to access
more diversified methylated arenes, thereby meet the increasing
needs from medicinal chemists.1b,25a However, Catellani-type
ortho C-H methylations with methyl halides (or pseudohalide)
have been rarely reported.25 Only the group of Lautens25b, Wil-
son25a and Dong25c successively reported the ortho-C-H-meth-
ylation of (hetero)aromatic iodide with iodomethane as the
methylating reagent, albeit just one example each was showed
respectively. This deficit probably owes to the high volatility
and reactivity of methyl halides under the Catellani-type reac-
tion conditions.25b,c Thus, we thought the incorporation of other
methylating reagents with a lower reactivity might enable this
dual-tasked methylation. After careful evaluation, we treated
CH3OTs as the promising candidate, based on the following
reasons. First, CH3OTs indeed exhibits a lower reactivity since
the dissociation energy of the C-O bond in CH3OTs is signifi-
cantly higher than the C-I bond in iodomethane.26 Second, io-
dide ion27 can readily react with CH3OTs to slowly release io-
domethane and maintain a low concentration, thereby the po-
tential side reactions could be significantly reduced.28 Third,
CH3OTs is an inexpensive reagent, and the isotope labeled ver-
sion CD3OTs is also commercially available.29 Actually,
CH3OTs and CD3OTs have already been utilized as the methyl-
ation reagent in transition-metal catalyzed cross-coupling30 and
C-H functionalization reactions.28
With the standard reaction condition in hand, we began to ex-
plore the reaction scope with respect to the aryl iodides. Grati-
fyingly, a large variety of aryl iodides were able to undergo
methylation with CH3OTs (2A) and 3 to furnish the desired
products 4 in moderate to excellent yields (47–96%) (Table 1).
In principle, aryl iodides containing electron-withdrawing, elec-
tron-donating and electron-neutral substituents all proved to be
competent substrates. The reaction also exhibited high
chemoselectivity: various functional groups, including fluoro
Table 1. Scope of Aryl Iodides that Undergo Methylation with
CH3OTs or PO(OMe)3.a
Herein, we report a dual-tasked ortho C-H methylation of
aryl iodides enabled by cooperative palladium/NBE catalysis. It
features an inexpensive methyl source, excellent functional-
group tolerance, simple reaction procedure, and scalability. Im-
portantly, six types of ipso terminations can modularly couple
with this ortho C-H methylation to provide a versatile methyla-
tion toolbox for preparing diversified methylated arenes. More-
over, this strategy can be uneventfully extended to isotope-la-
beled methylation by switching to the corresponding reagents
CD3OTs and 13CH3OTs31 (Figure 2B).
aAll reactions were performed on a 0.2 mmol scale. Isolated yields
were reported. Condition A: Pd2(dba)3 (5 mol%), TFP (11 mol%),
N2 (2.0 equiv), 2A (2.0 equiv), Cs2CO3 (2.5 equiv), MeCN (0.2 M),
o
80 C; Condition B: Pd(OAc)2 (10 mol%), TFP (22 mol%), N1
(2.0 equiv), 2B (2.0 equiv), Cs2CO3 (2.5 equiv), DMA (0.1 M), 80
oC. bCondition A was applied. cCondition B was applied. dAryl bro-
mide was used instead of aryl iodide with Pd(OAc)2 (10 mol%) as
the catalyst, 1,4-dioxane as the solvent, while other reaction pa-
rameters were the same as Condition A. eThe reaction was per-
formed on a 5.0 mmol scale. fReaction temperature was increased
to 100 oC. g4.0 equiv of 2A was applied.
To develop the promising dual-tasked ortho C-H methylation
of aryl iodides through palladium/NBE cooperative catalysis,
we first studied the reaction of 2-ethyliodobenzene (1a) with
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(4j, 4l and 4q), chloro (4t and 4C), bromo (4m, 4z and 4K),
Due to the value of labeled methyl groups in medicinal chem-
istry,4 we examined whether this approach could be applied to
introduce CD3 to arenes, utilizing commercially available
CD3OTs (2A′)29 as the methylation reagent. To our delight, 2A′
showed very similar reactivity as 2A under Standard Condi-
tion A (Table 2). The cross-coupling of 2A′ with ortho substi-
tuted aryl iodides (1) and olefin (3) afforded the corresponding
deuterated methylation products (4a′–4j′) in good to excellent
yields (70-96%). The structure of 4f′ was unambiguously as-
signed by X-ray crystallographic analysis (CCDC 1935063).
For aryl iodides without ortho substituents, the corresponding
deuterated dimethylation product 4k′–4n′ were obtained in 52–92%
yields. Given the availability and low cost of 2A′, our method pro-
vides a practical and affordable access to CD3-functionalized
arenes.4
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methoxy (4h, 4s, 4t, 4B, 4D, 4J and 4M), benzyloxy (4c, 4i, 4u
and 4v), TBS-protected hydroxy (4d), nitro (4n), trifluorome-
thyl (4g and 4G), carbonyl (4H), ester (4e, 4f, 4o, 4u, 4v and
4I), and amide (4p and 4L) groups, were compatible with the
reaction conditions. Notably, the acidic α-CH of the carbonyl
group in 1e and 1H as well as NH in aryl amides 1p and 1L
(which were nucleophilic under basic conditions to react with
MeI)28 were well tolerated in the reaction. In addition, the use
of densely functionalized aryl iodides 1t and 1u as starting ma-
terials led to penta-substituted aromatics 4t–u in excellent
yields. As to 1v, since the acetonalide-embeded lactone motif
was unstable under basic conditions, the corresponding penta-
substituted arene 4v was only isolated in 47% yield. Importantly,
various heteroaryl iodides (1A–D) were also suitable substrates
to this methylation process. Notably, this procedure was scala-
ble as demonstrated by the methylation of 1-iodonaphthalene
(1y), which was successfully performed on a 5.0 mmol scale to
afford the product 4y in 92% yield (1.23 gram) (Table 1A). It is
worth mentioning that the reactions of aryl iodides without or-
tho substituents (1E–M) led to the dimethylation products (4E–
M), while 4.0 equiv of 2A should be used correspondingly (Ta-
ble 1B). For example, iodobenzene (1E) and 3-methoxy iodo-
benzene (1M) reacted with 2A and 3 smoothly to provide the
bis-methylated products 4E and 4M in 79% and 78% yields,
respectively. More importantly, besides the success of ortho C-
H methylation of aryl iodides, aryl bromides were also identi-
fied as the suitable substrates for this transformation, eg. 4y, 4A,
4E and 4K. This is an intriguing and practical feature since such
kind of Catellani reactions were rarely reported.25c
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Following the success of terminating the methylation-in-
volved Catellani procedure through a Heck reaction, we pro-
ceeded to examine other types of termination methods, there-
fore expanding the utility of this methylation strategy. Consid-
ering the wide accessibility of arylboronic acids and their deriv-
atives, we investigated the Suzuki–Miyaura termination.33 Just
through minor modifications of the previous Heck termination
Standard Condition A of Table 1 (see Table S3 of Supporting
Information for details), we found a large group of pinacol ar-
ylborates (5a–u) could be utilized to react with 1-iodonaphtha-
lene (1y) and 2A, providing the ortho-methylated unsymmet-
rical biaryls (6a–u) in moderate to good yields (45–89%) (Table
3). It is noteworthy that this procedure possessed excellent func-
tional group tolerance as to pinacol arylborates. For example,
chloro (6b), methoxy (6c, 6h and 6n), vinyl (6d), trimethylsilyl
(6e), ester (6f), morpholino (6g) and methylthio (6l) groups
were compatible with the reaction conditions. More importantly,
various pinacol heteroarylborates (5m–u) were also proved to
be suitable terminating reagents, which include thiophene, pyr-
idine, quinoline, benzothiophene, dibenzothiophene, benzofu-
Besides 2A, we found that another inexpensive methylation
reagent trimethylphosphate (PO(OCH3)3, 2B)20k was also com-
petent for this transformation, as exemplified by the formation
of methylated products 4d, 4f–j, 4n, 4q, 4r, 4w, 4x, and 4A–C
in 41–90% yields (Table 1A). Especially for heteroaryl iodides
1B and 1C, the methylated products (4B and 4C) were obtained
in excellent yields while applying 2B as the methylating reagent.
Nevertheless, a modification of the reaction condition was re-
quired when 2B was used instead of 2A, which included apply-
ing Pd(OAc)2 (10 mol%) as the catalyst, TFP (22 mol%) as the
ligand, NBE (N1, 2.0 equiv) as the mediator, and DMA as the
solvent (0.1 M) (Table 1A, Standard Condition B).
Table 3. Catellani-type Methylation Terminated by Suzuki
Coupling.a
Table 2. Scope of Aryl Iodides that Undergo Methylation
with CD3OTs.a
aAll reactions were performed on a 0.2 mmol scale. Isolated yields
were reported. bThe reaction was performed on a 4.0 mmol scale.
aAll reactions were performed on a 0.2 mmol scale. Isolated
yields were reported. b4.0 equiv of 2A′ was applied.
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ran, and indole motifs that are ubiquitous and essentially im-
Table 5. Methylation Terminated by Cyanation.a
portant in small molecule drug discovery.34 Meanwhile, the
scope of aryl iodide (1) was further probed, with 2A and aryl-
borate 5u as the methylating and terminating reagent, respec-
tively. Just as expected, eight different aryl iodides including
one hetero-aryl iodide reacted with 2A and 5u smoothly to pro-
vide the corresponding ortho-methylated unsymmetrical biaryls
(6v–6C) in moderate to good yields (42–86%). It is worthwhile
mentioning that the deuterated version of methylation was
tested on arylborates 5h and 5u, with 1y and 2A′ as the reaction
partners. Again, the reactions took place uneventfully to afford
the products d3-6h and d3-6u in 84% and 83% yield, respec-
tively (Table 3). Notably, a scale-up operation (4.0 mmol) of
this methylation procedure was successfully performed to ob-
tain 0.89 gram of product 6h (80% yield), with no notable de-
crease in yield.
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were reported.
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Table 6. Methylation Terminated by Borylation.a
Next, we investigated this Catellani-type methylation process
using Sonogashira coupling as the ipso-termination process.35
As shown in Table 4, various aryl iodides 1 could react
soomthly with 2A and the terminating reagent (triisopropylsi-
lyl)acetylene (7a) under slightly modified reaction conditions
compared to Standard Condition A of Table 1 (see Table S4
of Supporting Information for details), that included the switch
to a medium strong base K2CO3, an increase of the reaction tem-
aAll reactions were performed on a 0.2 mmol scale. Isolated yields
were reported.
Table 7. Methylation Terminated by Hydrogenation.a
o
perature to 100 C and lowering the reaction concentration. A
series of ortho-methylated phenylacetylenes (8a–j) were ob-
tained in good to excellent yields (61–93%). Besides 7a, t-butyl
acetylene (7b)35c and 2-methyl-4-phenylbut-3-yn-2-ol (7c)35b
were also suitable termination reagents, providing the corre-
sponding products (8k–n) in 51–75% yields. Notably, while 7c
was used, the stronger base Cs2CO3 should be employed to pro-
mote the reaction efficiency.
Table 4. Catellani-type Methylation Terminated by
Sonogashira Coupling.a
aAll reactions were performed on a 0.2 mmol scale. Isolated yields
were reported.
termination, (Bpin)2 (11)37 was chosen as the reagent. Similarly,
modification of the reaction conditions was required to promote
this transformation (see Table S6 of Supporting Information for
details). Under the microwave-driven conditions, aryl iodides
(1) reacted with 2A and 11 to deliver the ortho-methylated pi-
nacol arylborates (12a–d) in 43–70% yields (Table 6). Remark-
ably, the incorporated Bpin function in 12a–d would enable
them to access a diverse range of important aromatics.37a As to
ipso-hydrogenation termination, sodium formate (HCO2Na,
13)38c was identified as the optimal hydride donor. After minor
modifications of standard condition A of Table 1, including
the employment of the novel mediator N339 and a solvent change
to DME (see Table S7 of Supporting Information for details),
aryl iodides (1) reacted smoothly with 2A and 13 to deliver the
desired meta-methylated arenes (14a–d) in moderate to good
yields (52–72%). Correspondingly, when 2A′ was used as the
methylating reagent, the meta-trideuteriomethylated arenes d3-
14b and d3-14c were obtained in 53% and 80% yield, respec-
tively (Table 7).
aAll reactions were performed on a 0.2 mmol scale. Isolated yields
b
were reported. 2-methyl-4-phenylbut-3-yn-2-ol was applied as
the terminating reagent, and Cs2CO3 was used as the base corre-
spondingly.
Additionally, the more challenging ipso-cyanation,25b,36 ipso-
borylation37 and ipso-hydrogenation38 terminations were also
demonstrated applicable to this ortho-methylation approach
(Table 5–7). As to ipso-cyanation termination, Zn(CN)2 (9)36
was identified as the ideal reagent. After a careful modification
of the reaction conditions (see Table S5 of Supporting Infor-
mation for details), aryl iodides (1) were able to react with 2A
and 9 to deliver the desired ortho-methylated benzonitrile prod-
ucts (10a–e) in 35–57% yields (Table 5). For ipso-borylation
The inherent value of our dual-tasked C-H methylation strat-
egy was showcased by its applicability to bio-relevant sub-
strates (Table 8 and Scheme 1). As depicted in Table 8, when
the derivative of enantiopure 4-iodophenylalanine 15 (99% ee)
was subjected to these aforementioned protocols, six bismeth-
ylated derivatives of phenylalanine (16a–e and d6-16a) were
readily prepared in 38–83% yields. For example, 15 reacted
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We have developed a dual-tasked methylation based on pal-
Table 8. Methylation of Biologically Important Substrate.a
1
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ladium/NBE cooperative catalysis. Readily available (het-
ero)aryl iodides and inexpensive MeOTs or trimethylphosphate
are utilized as the substrates and the methylating reagent, re-
spectively. Six types of ipso terminations including Heck, Su-
zuki, Sonogashira, cyanoation, borylation and hydrogenation,
can modularly couple with this ortho C-H methylation, thereby
constituting a versatile methylation toolbox for preparing diver-
sified methylated arenes. This strategy features inexpensive me-
thyl sources, excellent functional-group tolerance, simple reac-
tion procedures, and scalability. Importantly, it can be unevent-
fully extended to isotope-labeled methylation by switching to
the corresponding reagents CD3OTs or 13CH3OTs. Moreover,
this toolbox can be applied to late-stage modification of bio-rel-
evant substrates with complete stereo-retention. These salient
and practical features of our dual-tasked methylation toolbox
will undoubtedly be welcomed by academic and industrial re-
searchers.
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aAll reactions were performed on a 0.2 mmol scale, and 4.0 equiv
of methylating reagent was applied. Isolated yields were reported.
well with 2A or deuterated 2A′ or 13C labeled 13CH3OTs (2A′′)
31 to afford 16a as well as its isotope labeled siblings d6-16a and
16b in good yields, while using olefin 3 as the terminating rea-
gent. In addition, Suzuki and Sonogashira coupling could also
be applied as the termination strategies to further diversify the
bismethylated phenylalanine, as exemplified by the formation
of 16c–e in moderate to good yields. It is noteworthy that these
reactions proceeded with complete stereo-retention to afford the
corresponding products (16c and 16e) with 99% ee, which is
very important for future applications of these novel unnatural
α-amino acid derivatives in biological and medicinal studies.
Supporting Information. Experimental details, spectra, and X-ray
crystallography. This material is available free of charge via the
Internet at http://pubs.acs.org.
qhzhou@whu.edu.cn
Furthermore, we applied this dual-tasked C-H methylation
toolbox for late-stage functionalization40 of medicinal agents.
Aryl iodides 17 (from antihyperlipidemic drug fenofibrate
"Tricor")41 and 18 (from antiatherosclerosics drug ezetimibe
"Zatia")41 were selected as the representatives for modification
(Scheme 1). Three bis-methylated derivatives (19–21) and one
deuterated bis-methylated derivative (22) were readily gener-
ated in 31%–61% yields, using Heck (with 3) or Suzuki (with
5m or 5u) termination. These examples revealed the potential
and modularity of our method in bioactive molecules late-stage
functionalization and diversity-oriented synthesis42 to quickly
generate a wide variety of ortho-methylated bioactive arenes,
which will surely facilitate the related structure–activity rela-
tionship (SAR) study in drug discovery.
We are grateful to the National Natural Science Foundation
of China (Grants 21602161, 21871213, and 21801193), the
start-up funding from Wuhan University, and the China Post-
doctoral
Science
Foundation
(2016M602339
and
2018M642894) for financial support. We thank Dr. Hengjiang
Cong and Ms Wei Yan for X-ray crystallographic analysis.
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