Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-Release Mechanism for the Methylation of Arylboronic Esters

Article abstract of DOI:10.1021/jacs.8b10076

A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules. Typical methods to form a methylarene involve strong nucleophiles or strong and often toxic electrophiles. We report a strategy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl- and heteroarylboronic esters with the mild, nontoxic reagent trimethylphosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases tested in yields that are higher than those of analogous copper-catalyzed reactions of MeOTs or MeI. The combination of C-H borylation and this methylation with trimethylphosphate provides a new approach to the functionalization of inert C-H bonds and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol scale demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide by reaction of PO(OMe)₃ with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low concentration of the reactive electrophile enables selective reaction with an arylcopper intermediate, rather than nucleophilic groups on the arylboronate, and binding of tert-butoxide to the boronate inhibits reaction of the electrophile with the tert-butoxide activator to form methyl ether.

Full text of DOI:10.1021/jacs.8b10076

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Article
Trimethylphosphate as a Methylating Agent for Cross Coupling: A
Slow-release Mechanism for the Methylation of Arylboronic Esters
Zhi-Tao He, Haoquan Li, Alexander M Haydl, Gregory T Whiteker, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10076 • Publication Date (Web): 12 Nov 2018
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Journal of the American Chemical Society
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Trimethylphosphate as a Methylating Agent for Cross Coupling: A Slow-
release Mechanism for the Methylation of Arylboronic Esters
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Zhi-Tao He,†,§ Haoquan Li,†,§ Alexander M. Haydl,† Gregory T. Whiteker,‡ and John F. Hartwig†*
†Department of Chemistry, University of California, Berkeley, California 94720, United States.
‡Process Chemistry, Dow AgroSciences, 9330 Zionsville Rd., Indianapolis, Indiana 46268, United States
ABSTRACT: A methyl group on an arene, despite its small size, can have a profound influence on biologically active molecules.
Typical methods to form a methylarene involve strong nucleophiles or strong and often toxic electrophiles. We report a strat-
egy for a new, highly efficient, copper and iodide co-catalyzed methylation of aryl and heteroaryl boronic esters with the mild,
non-toxic trimethylphosphate, which has not been used previously in coupling reactions. We show that it reacts in all cases
tested in yields that are higher than those of analogous copper-catalyzed reactions of MeOTs or MeI. The combination of C-H
borylation and this methylation with trimethylphosphate provides a new approach to the functionalization of inert C-H bonds,
and is illustrated by late-stage methylation of four medicinally active compounds. In addition, reaction on a 200 mmol-scale
demonstrates reliability of this method. Mechanistic studies show that the reaction occurs by a slow release of methyl iodide
by reaction of PO(OMe)3 with iodide catalyst, rather than the typical direct oxidative addition to a metal center. The low con-
centration of the reactive electrophile enables selective reaction with an arylcopper intermediate, rather than nucleophilic
groups on the arylboronate and binding of t-butoxide to the boronate inhibits reaction of the electrophile with the t-butoxide
activator to form methyl ether.
possible that substrates containing basic functional groups
or heteroaryl groups would undergo uncatalyzed methyla-
tion to form undesired side products.
INTRODUCTION
A methyl group is the smallest non-polar substituent in
organic chemistry and is inert towards most organic trans-
formations. Many studies have shown that a methyl group
modulates the solubility, hydrophilicity, and conformation
of a drug, thus leading to the term “magic methyl effect”.1 In
addition, isotopically labelled methyl groups are important
for medicinal chemistry. For example, Austedo®, an FDA-
approved drug for the treatment of chorea, contains a deu-
terated methyl group to attenuate the drug metabolism and
improve tolerability by reducing adverse events related to
peak plasma concentrations.2 Attesting to this profound ef-
fect of a methyl group, a survey by Njardarson shows that
over 67% of the top 200 selling small-molecule drugs in
2011 contain at least one methyl group.1c Hence, efficient
methods for selective installation of methyl groups, partic-
ularly installation at the position of a C-H bond are highly
desirable.3
A reliable method for the methylation of arylboronic es-
ters with broad scope could be valuable for many applica-
tions, particularly the overall conversion of an aryl or het-
eroaryl C-H bond to the corresponding aryl or heteroaryl-
methane (Scheme 1). However, to be applicable for such
processes, the reaction must meet several requirements.
First, the methylation process must occur with pinacol-sub-
stituted aryl and heteroaryl boronates because this class of
arylboronates is formed by the borylation of C-H bonds.6
Second, a higher tolerance for basic and heteroaryl moieties
must be realized than that of reactions of aryl and het-
eroaryl boronates with MeI or MeOTs. Presumably, this
higher tolerance would require a milder source of methyl
electrophile than has been used previously for the coupling
with arylboronates. Finally, for the most practical applica-
tions, a methyl electrophile should be used that is inexpen-
sive, available on large scale, and less mutagenic than the
standard highly reactive methyl halides, sulfates, and sul-
fonates.7
Arylboronic acids are versatile reagents and can be ac-
cessed by numerous synthetic methodologies.4 Direct meth-
ylation of arylboronic acids or derivatives of them would be
a convenient method to introduce a methyl group into
widely-existing aromatic structures in biologically active
molecules. However, reports of methods to couple aryl-
boronic acids or esters with a methyl electrophile are
scare.5 In 2004, Gooßen developed a Pd-catalyzed cross-
coupling reaction of ArB(OH)2 with MeI as the methyl elec-
trophile.5a More recently, Liu reported the methylation of
two arylboronic neopentanediolate esters (ArBneop) with
MeOTs as the electrophile in the presence of a Cu catalyst.5b
In both cases, the substrate scope is limited. Because MeI
and MeOTs are highly reactive methyl electrophiles, it is
We report the copper and iodide co-catalyzed methyla-
tion of a wide range of aryl and heteroaryl pinacolboronates
with trimethylphosphate as a new methylating agent in cou-
pling reactions.8 Detailed mechanistic analysis of the pro-
cess shows that the phosphate does not react directly with
the copper catalyst. Instead, the conditions developed lead
to a slow release of MeI that reacts rapidly with an aryl-
copper species. By this slow-release mechanism, the reac-
tion occurs with a wide range of both aryl and heteroaryl
boronates in yields that are much higher than the analogous
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copper-catalyzed reactions with MeI, MeOTs, or Me2SO4.
Studies on the combined borylation and methylation of me-
dicinally active compounds show that this process is suita-
ble for the site-selective methylation of biologically active
compounds and reactions on 200 mmol of arylboronate
show that this methylation process should be suitable for
process scale.
Page 2 of 7
(entry 6). The presence of iodide in the system seemed cru-
cial. Reactions with copper catalysts lacking iodide oc-
curred in much lower yield than those catalyzed by CuI, and
reactions catalyzed by CuI with added LiI occurred in a
much higher yield (entry 1, 93%) than that in the absence
of LiI (entry 7, 29%). Because the reactions with and with-
out LiI also contain LiOtBu, the iodide in the LiI is important.
To exclude the potential requirement that the reaction re-
quires CuI, other types of copper sources were tested. In the
absence of added catalytic amount of LiI, CuBr·Me2S was the
only complex of five tested that gave product, and this cata-
lyst gave the product in a low 36% yield; none of the reac-
tions catalyzed by CuOAc, CuCl, CuTc and Cu(MeCN)4PF6
gave methylated product 2a (entry 8). However, product 2a
was observed in over 60% yield from reactions initiated
with all of these catalyst precursors when the reactions con-
tained 20 mol% of LiI (entry 9). The precise role of each of
the reaction components was elucidated by mechanistic
studies described in the final section of this paper.
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Scheme 1. Research design
PO(OMe)3
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Ar-Bpin
Ar-Me
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Slow_release methylation
C-H
Borylation
One-pot process
Ar-H
Late_stage C-H Methylation
RESULTS AND DISCUSSION
Reaction Development. To develop the methylation of
aryl pinacolboronates, we studied the reactions of 1-naph-
thyl-Bpin (1a) as the model substrate, in part because of the
high boiling point of the product and ability to detect the
protodeboronation product. A series of experiments
showed (See SI for details) that the methylated product 2a
was obtained in 93% yield with a copper catalyst, iodide co-
catalyst, LiOtBu as the base, and PO(OMe)3 as the source of
methyl group in DMI solvent at 50 oC (Table 1, standard con-
dition).
Scope of Arylboronic Esters that Undergo Methylation
with PO(OMe)3. The scope of the methylation of a group of
arylboronic esters with PO(OMe)3 was assessed, and the re-
sults are summarized in Scheme 2. Electron-withdrawing
substituents, such as Cl, Br and I, were well tolerated, afford-
ing the corresponding methylarene in 70−85% yield
(2b−2d). These reactions occur without any interference
from the halides or reaction between the boronate unit and
a halide. Arylboronic esters containing electron-donating
groups (1e, 1h) also were suitable for the methylation with
PO(OMe)3, providing product 2e and 2h in 69% and 58%
yield respectively. Reaction of the electron-rich ferrocenyl-
boronate 1i afforded the methylated product 2i in 79%
yield. An ortho-substituent did not inhibit the process; ra-
ther product 2g formed in a high 97% yield. Substrates con-
taining ester, amide or OTBS functionality also underwent
methylation, in this case to form 2f, 2j and 2k in 68−76%
yield. Finally, the methylation process was applied to com-
plex molecules 1l and 1m; the methylation of these com-
pounds occurred in 71% and 68% yield respectively.
Table 1. Standard Reaction Condition and Control Ex-
periments
Me
Bpin
CuI (5 mol%), LiI (20 mol%)
PO(OMe)3 (1.1 equiv)
LiOtBu (1.1 equiv)
DMI, 50 oC 16 h
1a
2a
(0.2 mmol)
Standard condition
Entry
Variation from the standard condi-
tions
Yielda
93%b
24%
54%
23%
n.d.
n.d.
29%
0−36%
To assess whether PO(OMe)3 was a more effective agent
for methylation than more commonly used MeOTs or MeI,
we tested these reactions with the copper catalyst and
alkoxide activator with these two reagents. These data are
included in Scheme 2. These data show that methylation of
each substrate occurred in higher yield with PO(OMe)3 than
with MeI or MeOTs. For example, product 2b was obtained
in 85%, 33% and 10% yield from the copper-catalyzed re-
actions with PO(OMe)3, MeOTs and MeI, respectively. Like-
wise, the simple 2-methylbiphenyl product 2g formed in
97% yield with PO(OMe)3 but only 33% yield with MeOTs
and 27% yield with MeI. For all of the cases in scheme 2, the
advantage of using PO(OMe)3 was obvious on the reaction
efficiency.
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none
MeI instead of PO(OMe)3
MeOTs instead of PO(OMe)3
Me2SO4 instead of PO(OMe)3
CO(OMe)2 instead of PO(OMe)3
Without CuI
Without LiI
Other [Cu] sources instead of CuI, no
LiI
Other [Cu] sources instead of CuI, with 61−85%
LiI
9
[Cu]: CuOAc CuCl CuBr·Me2S CuTc Cu(MeCN)4PF6
No LiI: n.d.
With LiI: 61% 70%
aDetermined by crude 1H NMR spectroscopy with CH2Br2 as the
internal standard. bIsolated yield. DMI: 1,3-dimethyl-2-imidaz-
olidinone. n.d., not detected.
trace
36%
85%
n.d.
75%
n.d.
75%
Scope of Heteroarylboronic Esters that Undergo Meth-
ylation with PO(OMe)3. Heteroaromatic moieties are ubiq-
uitous in biologically active molecules, but cross-couplings
of heteroarenes are usually more challenging to achieve
than those with less polar and less basic arenes. Substrates
containing a basic nitrogen could be a particular challenge
for reactions with an electrophilic methyl group, due to the
The series of experiments shown in Table 1 reveal the im-
portance of each component. Conventional methylation re-
agents, like MeI, MeOTs, Me2SO4 and CO(OMe)2 reacted in
much lower yield (table 1, entry 2−5, 0−54% vs 93%). Re-
actions in the absence of CuI formed no methylated product
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Scheme 2. Scope of Arylboronic Esters that Undergo
Methylation with PO(OMe)3
96% and 67% yield, respectively. Due to the labelled methyl
group valuable in medicinal area, the reactions of 3d and
3m with commercially available PO(OCD3)3 were also
tested, giving d3-4d and d3-4m in high isolated yields (75%
and 89%, respectively).
a
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Scheme 3. Scope of Heteroarylboronic Esters that Un-
dergo Methylation with PO(OMe)3
a
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aConditions: 1 (1.0 equiv), PO(OMe)3 (1.1 equiv), CuI (5-10
mol%), LiI (20 mol%), LiOtBu (1.1 equiv), DMI (0.66M), 50 °C.
Isolated yields are reported. For cases of MeOTs and MeI, yields
were determined by crude 1H NMR or 19F NMR. bDetermined by
crude 1H NMR.
aConditions: 3 (1.0 equiv), PO(OMe)3 (1.1 equiv), CuI (10
mol%), LiI (20 mol%), LiOtBu (1.1 equiv), DMI (0.66M), 50 °C.
b
Isolated yields are reported. Reaction performed at 2 mmol
scale. cCuI (20 mol%) was used.
potential of uncatalyzed methylation and the potential to
sequester the unligated copper catalyst.
As for the copper-catalyzed methylation of arenes, we
tested the copper-catalyzed methylation of heteroarenes
with MeOTs and MeI as methylating agents. Again, the
yields were uniformly higher for reactions with trime-
thylphosphate than with MeOTs or MeI. For example, indole
3a reacted with PO(OMe)3 in 62% yield while it reacted with
both MeOTs and MeI in less than 5% yield; For other sub-
strates, the yields of reactions of MeOTs and MeI were
16−57% lower than those of the reactions of PO(OMe)3.
Nevertheless, the results in Scheme 3 showed that the
methylation occurred with a broad range of heteroaryl pi-
nacolboronic esters. Nitrogen-containing heterocycles like
indole, pyrazole, pyrimidine and carbazole were well toler-
ated and produced the corresponding methylated het-
eroarenes in 62−90% yield (4a−4e, 4g). A sterically hin-
dered pyridine 3h afforded 4h in moderate yield. Reaction
of the heteroarylboronates, which contain oxygen and sul-
fur heterocycles (3f, 3j−3l, 3m, 3o), gave the corresponding
methyl-heteroarenes in 78−99% yield. Likewise, reactions
of benzoxazole and benzothiazole (3i, 3n), as representa-
tive heteroarenes containing multiple heteroatoms, af-
forded the corresponding methyl-heteroarenes 4i and 4n in
A robustness test9 was also conducted to provide more
general information on the tolerance of the process for a se-
ries of functional groups and potential limitation of
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PO(OMe)3 as a methylating agent (See SI for detailed re-
Page 4 of 7
high yield (5a, 79%). A similar one-pot process enabled the
late-stage site selective methylation of loratadine, sold as
Claritin® for the treatment of allergies,14 in moderate yield
(5b). The benzothiazole-based heterocycle, PMX-610,15
which has exhibited high antitumor activity in breast-can-
cer cell lines, was modified by a stepwise borylation and
methylation in 54% overall yield (5c). Finally, this methyla-
tion also was tested for the modification of the hydrocarbyl
natural product guaiazulene which possesses anti-inflam-
matory and anti-oxidative activity,16 providing methylated
guaiazulene or CD3-guaiazulene in 42% and 49% yield re-
spectively (5d, d3-5d).
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sults). Reactions with added unprotected amine, alcohol or
amide occurred in low to moderate yield because methyla-
tion of the functional groups in these additives was more
facile than methylation of the arylboronate, and competitive
protodeboronation of the aryl boronate occurred. In con-
trast, high yields were observed when reactions were run
with analogous additives in which the free N-H or O-H
groups were protected by Boc, TIPS or TBS groups. Like-
wise, the methylation reactions conducted with an added
secondary dialkylamine, tertiary amine, allylic ester, epox-
ide, pyridine, pyridine 1-oxide, nitrile, alkene, ketone, imine
or aldehyde all gave the methylarene product in high yield.
The methylation reaction with a terminal alkyne as additive
gave only 7% yield, but the reaction with an internal alkyne
occurred in high yield.
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Results with Reactions on 1000-Fold Larger Scale. The
feasibility of this coupling reaction for process scale was as-
sessed by conducting the reaction on a 200 mmol scale
(Scheme 5). This reaction afforded 2a in 88% isolated yield in
92% purity after simple extraction. This yield is nearly identi-
cal to that obtained with the same substrate on a smaller scale
(0.2 mmol scale for 93% yield).
Late-stage Site Selective C-H Methylation of Biologi-
cally Active Molecules. The current methods for the meth-
ylation of unactivated C-H bonds are limited to N-contained
heteroaromatic compounds or arenes containing directing
groups. Published methods include Minisci reactions with
acetic acid as the methyl source,10 the addition of methyl
radicals to heteroarenes under both thermal and photore-
dox conditions,11 and Pd- or Fe-catalyzed methylation of C-
H bonds in arenes containing a directing group.12
Scheme 5 Reaction with 200 mmol of Arylboronate
Due to the limited methods to realize the methylation of
inert C-H bonds,10-12 particularly an undirected methylation
of a C-H bond, we tested the combination of the methylation
of arylboronates with the borylation of aryl and heteroaryl
C-H bonds.6 Four medicinally active compounds were cho-
MECHANISTIC STUDIES
Uncovering the Role of PO(OMe)3 and Iodide. Methyl
electrophiles typically react with organometallic complexes
by oxidative addition5a or SN2 substitution5b. To determine
whether trimethylphosphate reacted by one of these path-
ways, we conducted mechanistic studies.
sen to test this tandem process (Scheme 4). Clopidogrel,13
a
medication for heart disease and stroke known as Plavix®,
Scheme 4. Late-stage Site Selective C-H Methylation of
Biologically Active Moleculesa
The transmetallation of aryl boronates to form arylcopper
complexes is well precedented.17 Thus, to understand how
an arylcopper complex would undergo methylation in this
system, we first studied reactions of Mes-Cu with PO(OMe)3
and MeI (Scheme 6a). The reaction of Mes-Cu with
PO(OMe)3 gave no product after 20 h, but the reaction with
MeI afforded Mes-Me in 20% yield after 5 h at 40°C and 58%
yield after 42 h. The analogous reactions also were con-
ducted with the less hindered PhCu, which is not isolable
but can be generated in situ.18 The reaction of this species
with PO(OMe)3 gave no detectable product after 10 min; in
contrast, the reaction with MeI occurred with a half-life of
less than two minutes. These results fit our observation that
the catalytic methylation reaction proceeds only in the pres-
ence of halide (Table 1, entry 8−9). These results suggest
that the combination of LiI and trimethylphosphate gener-
ate MeI in the reaction system.
B2(pin)2
PO(OMe)3
Me
Ar-
Ar-H
C-H borylation
Methylation
(One-pot process)
Cl
Me
Cl
S
Me
N
N
H
O
O
N
O
OEt
From Clopidogrel
From Loratadine
5a
5b
79%
42%
Me
OMe
OMe
F
N
S
D3C/Me
Me
To assess this hypothesis, we studied the reaction of LiI
with PO(OMe)3 under conditions related to those of the cat-
alytic process (Scheme 6b). This reaction was too slow to
occur in the catalytic system; but a trace of MeI was ob-
served after 24 h at 40 °C. We considered that the Li+ of Li-
OtBu in the catalytic system could act as a Lewis acid to in-
crease the electrophilicity of the methyl group of PO(OMe)3.
Indeed, the reaction of LiI with PO(OMe)3 in the presence of
an additional equimolar amount of LiBF4 released MeI much
faster than the reaction without LiBF4; 66% of MeI formed
Me
Me
Me
From PMX-610
5c
From Guaiazulene
5d -5d
49%
54%
42%; d3
aSee Supporting Information for details.
underwent the one-pot, Ir-catalyzed borylation and copper-
catalyzed methylation with PO(OMe)3 to install a methyl
group selectively at the 2-position of the thiophene ring in
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after 2 h. The same reaction at 50 °C reached equilibrium
after 1.5 h to generate MeI in 80% yield, based on the iodide
added.
Kinetic Studies. To reveal the step that controls the over-
all rate of the reaction, we conducted kinetic studies
(Scheme 7). The reaction was first order in both [I-] and
[PO(OMe)3]. In contrast to most catalytic processes, the re-
action was zero-order in [CuI] at the concentrations of the
preparative reactions. These data indicate that the genera-
tion of active methyl electrophile is the rate-determining
step. The importance of the lithium cation generated from
LiOtBu and the ArBpin was supported by observing a first-
order dependence of the rate on the concentration of both
of these two components. The importance of Li+ was also
supported by the separate observation of a first-order de-
pendence of the reaction rate on Li+BF4. These data imply
that thereaction of the methyl electrophile with copper and
formation of the methylarene are faster than generation of
MeI. As described previously in this section, the reaction of
[I-] with [PO(OMe)3] occurs on the timescale of hours at
40 °C, whereas the reaction of MeI with PhCu occurs within
minutes.
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Although this experiment showed that Li+ accelerates the
reaction, the lithium cations are associated with iodide and
alkoxide in the true reaction system. The Li+ added to the
system is not associated with a non-coordinating anion,
-
such as BF4 , and if methyl iodide is formed, one might ex-
pect it to react with the t-butoxide in the system because the
reaction of MeI with LiOtBu to give methyl tert-butyl ether
occurs in quantative yield after 10 min at room tempera-
ture. To solve this paradox about how Li+ could accelerate
the formation of MeI and why MeOtBu did not form from re-
action of LiOtBu and MeI in the catalytic reactions, we con-
sidered the role of the arylboronic ester. LiOtBu reacted
with the ArBpin reagent to form Li[ArB(pin)OtBu], as deter-
mined by the 11B NMR and 19F NMR resonance of the reac-
tion of these two reaction components alone. This borate
was also the major form of the boron reagent in the catalytic
system, as determined by the similarity of the 11B NMR and
19F NMR resonances of the catalytic reaction to those of the
borate generated separately (Scheme 6c).19 The lithium cat-
ion in this boronate complex is more loosely bound than
that in LiOtBu and can act as the Lewis acid to catalyze for-
mation of MeI. Moreover, the alkoxide unit in this borate
complex is much less nucleophilic than that in LiOtBu and
does not react with MeI.20
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Scheme 7. Kinetic Order of the Methylation Reaction
[Cu], LiI
Me
Bpin
Me
PO(O
LiOtBu,
DMI, 40 °C
[Cu] = CuI or CuOtBu
)
3
1a
2a
1st order in [I-]
1st order in [Li+]
•
•
•
•
•
•
Scheme 6. Stoichiometric reactions potentially occur-
ring in the catalytic system
1a
]
1st order in [PO(OMe)3]
Zero order in [Cu]
1st order in [
1st order in [LiOtBu]
a)
PO(OMe)3 (1 equiv)
DMF, 50 °C
Proposed Mechanism. Based on these results, a mechanism
for the methylation of arylboronates with Cu(I) as catalyst and
iodide as co-catalyst is depicted in Scheme 8. In a rate-deter-
mining step external to the catalytic cycle, iodide reacts with
PO(OMe)3 to release MeI. The slowly-released MeI rapidly re-
acts with the arylcopper intermediate generated from the com-
bination of CuI, LiOtBu and ArBpin, either from reaction of
CuOtBu with ArBpin or reaction of CuI with [ArBpin(OtBu)]-.
The -OtBu does not react with MeI because it is sequestered by
the arylboronate, and the low concentration of MeI ensures
that the MeI in the system reacts with the arylcopper species
over many basic groups on the arylboronate reagent.
Mes-Me
0% ( 20 h)
MesCu
MeI (1 equiv)
DMF, 40 °C,
Mes-Me
20% (5 h)
58%(42 h)
PO(OMe)3 (1 equiv)
DMI, 40 °C
Ph-Me
0% ( 10 min)
[PhCu]
(Generated
In-situ)
MeI (1 equiv)
DMI, 40 °C
Ph-Me
58% (2 mins)
81% (11 mins)
Scheme 8. Proposed Reaction Mechanism
b)
LiI (1 equiv)
DMI, 40 °C
PO(OMe)3
(5 equiv)
MeI + Li[OP(O)(OMe) 2
]
No additive, trace (24 h)
With 5 equiv LiBF4, 66% (2 h)
With 5 equiv LiBF4, 50 oC, 80% (1.5 h)
c)
LiOtBu
DMI, RT
O
B
F
Bpin
Li
O
OtBu
F
11 B NMR: 6.7 ppm
19F NMR: -121.2 ppm
(Observed in catalytic reaction as well)
a) Reactivity comparison of MeI and PO(OMe)3 with ArCu. b)
MeI generation from PO(OMe)3 and LiI. c) Reaction of 4-
FPhBpin with LiOtBu.
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CONCLUSION
̈
1
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4
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8
In summary, we reveal an approach based on slow-re-
lease of MeI for the methylation of arylboronates with tri-
methylphosphate. This reagent is inexpensive and non-
toxic, but has not been used previously as a source of a me-
thyl group in coupling chemistry. By this unusual mecha-
nism, the yields for methylation with PO(OMe)3 are higher
than those of the more reactive methyl electrophiles MeOTs
and MeI. Although the mechanism involves a web of on-cy-
cle and off-cycle steps that make the reaction occur in high
yield, it is amenable to large scale and to the late-stage func-
tionalization of pharmaceutical intermediates. The reaction
with 200 mmol of arylboronate occurred the same as reac-
tions on 0.2 mmol, and four medicinally active compounds
were converted selectively into the methyl analogs. The for-
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limiting, and steps on the catalytic cycle, including the reac-
tion of MeI with the arylcopper species were fast. Overall,
this process shows an approach to using a methylating
agent that does not react directly with the metal center and
is reminiscent of the use of MeOH with HI for rhodium- and
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Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
Experimental details and procedures, spectra for all unknown
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*jhartwig@berkeley.edu
ORCID
John F. Hartwig: 0000-0002-4157-468X
Zhi-Tao He: 0000-0003-2375-9557
Haoquan Li: 0000-0002-8636-1979
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Pharmacol. 1997, 49, 938−942.
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Layfield, R. A.; Ingleson, M. J. Chem.– Eur. J., 2017, 23, 15889–
15893.
20. The reaction of o-tol-Bpin(OtBu) generated in situ with an
equimolar amount of MeI at 40 °C led to 38% conversion of the o-
tol-Bpin(OtBu) after 1 h, which is significantly slower than the re-
action of ArCu with MeI (half life < 2 minutes).
Author Contributions
§Z.-T. H. and H. L contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Dow AgroSciences for support of this work and the
DAAD for a Postdoc Fellowship to A.M.H.
REFERENCES
1. (a) Bazzini, P.; Wermuth, C. G., Chapter 20 - Substituent
Groups. In The Practice of Medicinal Chemistry (Third Edition), Ac-
ademic Press: New York, 2008; pp 429−463. (b) Barreiro, E. J.;
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Bpin
Me
PO(OMe)3
Slow_release methylation
200 mmol
(50.9 grams)
88% yield
92% purity after
simple extraction
10
11
12
13
14
15
16
17
18
19
20
21
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23
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40
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60
Cl
Cl
S
S
Late_stage
C-H Methylation
H
Me
N
O
N
O
79%
O
O
7
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