ACS Catalysis
Research Article
further experiments on the use of cosolvents for catalytic HIE
due to the insolubilities of 12 and 13 in CH3OD. We found that
the developed silver catalyst is active for exchange of the C−H
bonds with CH3OD in a range of polar and nonpolar solvents,
including dimethylformamide, dimethyl sulfoxide, tetrahydro-
furan, and dichloromethane (see SI for further details). Thus,
the syntheses of [2H]12−[2H]13 were performed with THF or
CH2Cl2 as cosolvent, respectively.
Ag2CO3 and di-tert-butylphenylphosphine, respectively. This
protocol led to deuteration of 16, with relative rates of reaction
at the 2-, 4-, and 5-positions that follow the trend C2 > C4 > C5.
Indoles and pyrroles are important electron-rich heterocycles.
However, isotopic labeling of these nitrogen heterocycles to
high levels has required directing groups that enable C−H
activation.19 In contrast, our silver-catalyzed method enabled
high levels of incorporation of deuterium into 17 and 18 at the
positions α and β to the nitrogen atom with the silver complex of
JohnPhos as catalyst in air at 80 °C. Other fused heterocycles
including benzofuran (19), benzothiophene (20), benzoxazole
(21), benzothiazole (22), and caffeine (23) also underwent
deuteration with a high level of deuterium incorporation at the
most acidic C−H bond with the silver complex of JohnPhos as
catalyst in air.
The scope of the silver-catalyzed method with a series of
different classes of five-membered aromatic heterocycles is
shown in Scheme 3. Thiazoles, imidazoles, and 1,2,4-triazoles
Scheme 3. Scope of Five-Membered Heterocycles That
a
Undergo Selective C−H Deuteration
Deuteration of Pharmaceuticals. The broad functional
group tolerance and the site selectivity of the silver-catalyzed
method complementary to that of existing methodologies20
prompted us to examine its applicability to the deuteration of
C−H bonds in pharmaceuticals by conducting reactions with a
series of active pharmaceutical ingredients. As shown in Scheme
4, pharmaceuticals containing xanthine heterocycles, namely,
doxofylline (24) and pentoxyfilline (25), underwent high levels
of incorporation of deuterium at the most acidic sp2 and sp3 C−
H bonds at 50 °C after 24 h. The labeling of sp3 C−H bonds in
25 resulted from the facile enolization of the hydrogen atoms α
to the carbonyl group. Etomidate (26), an anesthetic agent, and
flumazenil (27), a GABA-antagonist, developed by Roche
underwent deuteration at the imidazole core, while trace
amounts of isotopic incorporation also were observed at the
sp3 C−H bonds of the benzodiazepine ring of 27. It is important
to note that 26 and 27 were deuterated with commercially
available CH3CH2OD to avoid transesterification with CH3OD.
Antifungal drugs, such as clotrimazole (28) and tioconazole
(29), which contain imidazole and thiophene, underwent C−H
bond deuteration in these heterocycles at 65 °C after 48 h. In
addition, partial isotopic incorporation at one position of the
benzene ring of 29 was observed, which presumably resulted
from the moderate acidity of the labeled C−H bond. The
antidepressant (S)-duloxetine (30) and the antiplatelet drug
ticlopidine (31) both underwent selective deuteration at the
thiophene heterocycle. Finally, fluconazole (32) and tebucona-
zole (33), an antifungal and agrochemical agent, respectively,
underwent selective deuteration at the most acidic position of
their triazole units in excellent yield and isotopic incorporation.
Mechanistic Investigation. Having demonstrated the
synthetic applications of the silver-catalyzed HIE, we performed
a series of experiments to gain insight into the reaction
mechanism. We first examined whether C−H bond cleavage
was involved in the rate-determining step of the reaction. To do
so, we measured the initial rates of deuterium and protium
incorporation in parallel reactions of 34 and [2H]34 in separate
vessels. As shown in Scheme 5a, a large primary kinetic isotope
effect (KIE) of 4.8 0.3 was measured from experiments with
2.5 mol % of Ag2CO3 and 5 mol % of JohnPhos at 40 °C under
air. The large value of the measured KIE strongly suggested that
C−H cleavage occurs during the rate-determining step.
a
b
Performed over two reaction cycles (see SI for details). With di-tert-
c
butylphenylphosphine under nitrogen. With CH2Cl2 as cosolvent.
are electron-poor five-membered heterocycles found in modern
antibiotics, antifungal drugs, and agrochemicals.9a Despite this
prevalence, homogeneous catalysts for isotopic exchange with
these heterocycles without directing groups are lacking.7a,c Our
data show that methyl thiazole-4-carboxylate (14) undergoes
high deuterium incorporation at the 2- and 5-positions, and N-
benzyl-1,2,4-triazole (15) undergoes selective deuteration at its
most acidic C−H bond under the conditions we developed with
the silver catalyst.
N-Benzyl-imidazole (16) proved less reactive than other
heteroarenes under the standard conditions. However, 16
underwent C−H deuteration at faster reaction rates when di-
tert-butylphenylphosphine was used as ligand in place of
JohnPhos (see SI for details). Therefore, the deuteration of 16
was performed after two reaction cycles over a period of 48 h at
65 °C under nitrogen in the presence of 10 and 20 mol % of
To gain additional kinetic data on the silver-catalyzed C−H
deuteration, we measured the dependence of the reaction rate
on the concentration of benzothiophene (34), silver catalyst,
and CH3OD under air at 40 °C by the method of initial rates
(Scheme 5b). The obtained data showed a first-order depend-
ence on the concentration of 34 and on the concentration of the
1122
ACS Catal. 2021, 11, 1119−1127