Trideuteromethylation Enabled by a Sulfoxonium Metathesis Reaction

Article abstract of DOI:10.1021/acs.orglett.8b03641

A conceptually novel sulfoxonium metathesis reaction between TMSOI and cost-effective DMSO-d₆ is developed for the efficient generation of a new trideuteromethylation reagent TDMSOI. The new reagent TDMSOI is produced highly efficiently by simply heating a mixture of TMSOI and DMSO-d₆ and directly used for subsequent trideuteromethylation in a "one-pot" operation. The preparative power of the new versatile reagent and the "one-pot" protocol is demonstrated by its use to install the ?CD₃ moiety into broad functionalities including phenols, thiophenols, acidic amines, and enolizable methylene units in high yield and at a useful level of deuteration (>87% D).

Full text of DOI:10.1021/acs.orglett.8b03641

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Trideuteromethylation Enabled by a Sulfoxonium Metathesis
Reaction
Zuyuan Shen,† Shilei Zhang,‡ Huihui Geng,† Jiarui Wang,† Xinyu Zhang,† Anqi Zhou,† Cheng Yao,†
Xiaobei Chen,*,† and Wei Wang*,†,§
†State Key Laboratory of Bioengineering Reactor, and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East
China University of Science & Technology, Shanghai 200237, China
‡Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, 199 Ren’ai
Road, Suzhou, Jiangsu 215123, China
§Department of Pharmacology and Toxicology, and BIO5 Institute, University of Arizona, 1703 East Mabel Street, P.O. Box 210207,
Tucson, Arizona 85721-0207, United States
S
* Supporting Information
ABSTRACT: A conceptually novel sulfoxonium metathesis
reaction between TMSOI and cost-effective DMSO-d6 is
developed for the efficient generation of a new trideuter-
omethylation reagent TDMSOI. The new reagent TDMSOI is
produced highly efficiently by simply heating a mixture of
TMSOI and DMSO-d6 and directly used for subsequent
trideuteromethylation in a “one-pot” operation. The preparative power of the new versatile reagent and the “one-pot” protocol
is demonstrated by its use to install the −CD3 moiety into broad functionalities including phenols, thiophenols, acidic amines,
and enolizable methylene units in high yield and at a useful level of deuteration (>87% D).
he potential for the use of deuterium across multiple
applications is bolstered by its safety profile, its proven
capacity to improve drugs, and the predictability of its effects
on small molecule properties.1 However, the limited
availability of deuterated compounds is a major barrier that
inhibits the use of deuterium in biomedical research and drug
discovery.2
T
The methyl group, one of the most commonly occurring
moieties in bioactive compounds, occupies an unrivaled
position in medicinal chemistry because of the “magic methyl
effect”.3 XCH3 (X = O, N, S, et al.) are also well-known groups
that are easy to metabolize. Therefore, effort has been devoted
to the development of trideuteromethylation analogues for
these methyl-containing pharmaceuticals to improve their
metabolic stability.4 Notably, the FDA has approved Austedo
(deutetrabenazine) as the first deuterated product for the
treatment of chorea associated with Huntington’s disease in
2017 (Figure 1).5 The other representative molecules, such as
SD-254, CTP-518, AVP-786, deuterated glyburide, and
deuterated urapidil, currently are in clinical trials.
Despite its proved improved properties in drug discovery
and structural simplicity, the methods for introducing −CD3
into the target molecules of interest remains elusive owing to
the paucity of practically useful methods and reagents.6 CD3I
and (CD3)2SO4 are widely used trideuteromethylation
reagents but with the carcinogenic and cost concerns.7 The
lower toxicity and/or more cost-effectiveness of CD3OD and
DMSO-d6 make them appealing trideuteromethylation alter-
natives. Nonetheless, their application in drug discovery is
hampered by a very limited number of available synthetic
Figure 1. Drugs containing trideuteromethyl group.
methods. The introduction of a CD3O− group into aromatics
for the synthesis of ArOCD3 has been achieved by using the
established palladium-catalyzed coupling of alcohols (e.g.,
CD3OD) with aryl halides (Scheme 1a).8 An interesting metal-
free CF3CO2H- mediated radical process with aryl triazenes is
9
̈
also realized by Brase and co-workers (Scheme 1b). The
synthesis of the carbon−CD3 bond has been developed
recently by Antonchick et al. via an elegant radical process
using DMSO-d6 as deuterium source (Scheme 1c).10
No doubt, a broad applicable trideuteromethylation method
for the alkylation of various functional groups such as OH,
NH, SH, etc. will significantly facilitate drug discovery. Toward
this end, herein we report a new, general trideuteromethylation
strategy (Scheme 1d). A sulfoxonium metathesis11 is
Received: November 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
0, 1, 2, 4, 8, and 16 h. The studies revealed that as time went
on (Figure 2), (1) the content of DMSO and CD3SOCH3
Scheme 1. Methods for Introducing the CD3 Group
Figure 2. Monitoring the new sulfoxonium metathesis progress.
continued to increase, while TMSOI kept decreasing and (2) a
noticeable amount of CH3I was generated initially and then
gradually disappeared. Therefore, the process involves the
initial reversible decomposition of TMSOI to give DMSO and
CH3I, and the latter reacts with DMSO-d6 to form a new
deuterated sulfoxonium (2). The second decomposition of 2
releases CD3SOCH3 (3) and CD3I, and eventually the
combination of CD3I and DMSO-d6 furnishes deuterated
TDMSOI (1).
implemented between trimethyl sulfoxonium iodide (TMSOI)
and readily accessible and less toxic DMSO-d6 and enables the
efficient generation of trideuteromethyl sulfoxonium iodide
(TDMSOI, 1) as a new, cost-effective trideuteromethylation
reagent. The studies demonstrate that TDMSOI serves as a
versatile trideuteromethylation reagent with a broad substrate
scope and high efficiency in a “one-pot” operation. Structurally
diverse phenols, carboxylic acids, thiophenols, anilines, and
enolizable carbons can be trideuteromethylated with the
reagent in high yield and at a useful level of deuteration
(>87% D).
Recently, we initiated a program aimed at developing
practically applicable deuteration reagents and reactions for the
synthesis of synthetically and medicinally valued deuterated
building blocks and functional groups. To engineer the “magic
methyl effect” deuterated version CD3 moiety into organic
molecules, we harness the synthetic power of metathesis12 to
create a new trideuteromethylation reagent. We envision that
the sulfoxonium metathesis between trimethyl sulfoxonium
iodide (TMSOI) and DMSO-d6 might produce fully
deuterated TDMSOI (1, Scheme 1d), which could be directly
utilized for trideuteromethylation of various functionalities.
The realization of the process can afford new safer and cheaper
trideuteromethylation reagent than commonly used CD3I and
(CD3)2SO4. However, implementing the metathesis strategy
must overcome the challenge that the control of intrinsic
reversibility enables to manipulate the equilibrium to achieve
synthetically useful yields of the desired product. Inspired by
Le Chatelier’s principle,13 we propose to explore the strategy of
combining a thermodynamic approach with the use of one of
the reaction components (e.g., DMSO-d6) in a large excess.
The combined force drives the reaction forward to favor
formation of the desired product (Scheme 1d).
Having proved the feasibility of the new sulfoxonium
metathesis for the generation of 1 by simply heating the
mixture of TMSOI and DMSO-d6, we next set out to optimize
the metathesis and subsequent alkylation reaction conditions.
A model trideuteromethylation with 4-nitrophenol 4a was
probed (Table 1 and Tables S1−5). In the initial attempt, the
formation of 1 was carried out using 30 equiv of DMSO-d6
(relative to TMSOI) at 80 °C for 4 h (Table 1, entry 1), and
then 4a (0.9 equiv) and K2CO3 (1.0 equiv) were added. The
mixture was stirred at 65 °C for 18 h to afford aryl ether in
high yield, but the degree of deuterium incorporation was poor
(36%). This may be attributed to incomplete exchange
between TMSOI and DMSO-d6. Le Chatelier’s principle
suggests that higher temperature and longer heating time
drives the reaction forward to favor formation of the desired
product.12 Indeed, enhancing these parameters could remark-
ably improve the deuterium incorporation, whereas it had an
adverse effect on the reaction yield (entries 2−8). The best
choice for further screening was the reaction conditions
identified in entry 6 (120 °C, 2 h). When the loading of 1 was
increased to 2 equiv, to our delight, a quantitative yield of 5a
was furnished (entry 10). Next, adjusting the ratio of TMSOI/
DMSO-d6 from 30 to 40 times slightly enhanced the
deuterium incorporation to 96% (entry 12). Eventually, a
variety of bases were evaluated, all leading to inferior
deuterium incorporations compared with K2CO3 (entries
14−18 vs 12). Nevertheless, it was found that the choice of
a base for a specific substrate highly depended on the
electronic nature of the substrate. Therefore, different bases
were used in probing the substrate scope of the process. It is
noteworthy that the role of TMSOI could be replaced by the
same molar MeI in the metathesis reaction (entry 19). Owing
to the absence of DMSO-h6, the desired deuterated product 5a
was eventually generated with higher deuterium incorporation
(98%) albeit in lower yield (89%).14
To test the hypothesis, a reaction of TMSOI (0.5 mmol)
with DMSO-d6 (15 mmol) was heated at 80 °C. The
1
metathesis reaction progress was monitored by H NMR at
B
DOI: 10.1021/acs.orglett.8b03641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a−c
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Phenol as Substrates
b
c
entry temp (°C) time (h) 1/4a
base
yield (%) (% D)
1
2
3
4
5
6
7
8
80
100
120
130
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
4
4
4
4
3
2
1.5
1
2
2
2
2
2
2
2
2
2
2
2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.7
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOH
94
87
49
45
56
58
62
66
74
99
99
99
99
91
90
88
99
91
89
36
75
94
93
94
94
91
89
94
94
94
96
96
91
71
84
93
85
98
9
10
11
12
13
14
15
16
17
18
19
d
e
d
d
d
d
d
t-BuOK
NaHCO3
K3PO4
K2CO3
df
,
a
Reaction conditions: unless otherwise specified, TMSOI (0.5 mmol)
was dissolved in DMSO-d6 (15 mmol, 30 equiv) and stirred at 80−
130 °C in sealed tube for specified time. To the reaction mixture were
added 4a (0.45−0.20 mmol) and base (1 mmol), and the resulting
b
solution was stirred at 65 °C in sealed tube for 18 h. Isolated yield.
c
d
Deuterium incorporation was determined by 1H NMR. 40 equiv of
e
f
DMSO-d6 was used. 50 equiv of DMSO-d6 was used. MeI (0.5
mmol) was used instead of TMSOI.
a
Reaction conditions: unless otherwise specified, TMSOI (0.5 mmol)
was dissolved in DMSO-d6 (20 mmol) and stirred at 120 °C in sealed
tube for 2 h. To the reaction mixture were added 4 (0.25 mmol) and
base (1 mmol), and the resulting solution was stirred at 65 °C in a
With the optimal reaction conditions in hand, the scope of
the reactions was probed with a wide range of phenol
substrates (Scheme 2). The results showed that the protocol
served as a general strategy for the synthesis of structurally
diverse aryl trideuteromethyl ethers. A variety of phenols,
containing electron-withdrawing (4a−p) or -donating sub-
stituents (4q−v), could efficiently participate in the process to
give products 5 with good to excellent yields and good
deuterium incorporations. Furthermore, a similar trend was
observed for naphthol 4w and heterocyclic phenols 4x−ac.
The reaction was also applicable to double and triple
trideuteromethylations of polyphenols (4ad−af), albeit with
slightly decreased deuterium incorporations. Notably, the
broad applicability of this methodology enabled the convenient
access to trideuteromethyl versions of valuable drug and
natural product targets (agomelatine 5ag, Ts-protected
melatonin 5ah, and xanthotoxin 5ai) from their phenol
precursors with satisfactory results.
Encouraged by the successful trideuteromethylation of
phenols, we then turned our attention to other types of
substrates (Scheme 3). Remarkably, when the optimized
protocol was applied to carboxylic acids, whether they were
connected with aromatic or alkyl moieties, they could be
readily converted into the corresponding trideuteromethyl
esters 7a−k in 62−99% yields with uniformly high deuterium
incorporations (96%). Significantly, when hydroxyl and
carboxylic groups presented in the same molecule, both of
them were well trideuteromethylated (7l). Thiophenols, the
b
c
sealed tube for 18 h. Isolated yield. Deuterium incorporation was
d
determined by 1H NMR. TMSOI (1 mmol) and DMSO-d6 (40
e
mmol) were used. TMSOI (1.5 mmol) and DMSO-d6 (60 mmol)
were used.
analogues of phenols, were also proved to be effective
substrates, providing the desired products 7m−r even without
affecting the NH2 group in 7r.
The methylation of nitrogen-containing moieties is a highly
useful method. It was demonstrated that phthalimide, indole,
and indoline all could be transformed into their corresponding
trideuteromethylated products (7s−u). Finally, when active
methylene compounds were treated with 1, one or two
trideuteromethyl groups were efficiently introduced as
illustrated in the formations of 7v−aa (see the optimization
reaction conditions in Tables S6 and S7). Thus, the strategy
serves as a versatile approach to the construction of O-CD3, S-
CD3, N-CD3, and C-CD3.
In conclusion, in the study described here we developed a
new, versatile trideuteromethylation reagent TDMSOI and a
“one-pot” method for facile installation of the pharmaceutically
relevant CD3 moiety into various functionalities in high yields
and with a useful level of deuteration. Notably, a sulfoxonium
metathesis reaction between TMSOI and DMSO-d6 is
implemented for the synthesis of deuteration reagents by
taking advantage of ready availability and cost effectiveness of
C
DOI: 10.1021/acs.orglett.8b03641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of Carboxylic Acid, Thiol, Amine and
Active Methylene as Substrates
ACKNOWLEDGMENTS
■
a−c
Financial support of this research from the program of the
National Natural Science Foundation of China (21572055 and
21738002, W.W., and 21702058, X.C.) and the National
Institutes of Health (1R01GM125920-01, W.W.) is gratefully
acknowledged.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03641.
Experimental procedures, analytical data, and NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: xiaobei@ecust.edu.cn.
*E-mail: wwang@pharmacy.arizona.edu.
ORCID
Shilei Zhang: 0000-0001-8169-0098
Wei Wang: 0000-0001-6043-0860
Notes
The authors declare no competing financial interest.
D
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(14) It should be noted that it is impossible for this method to be
completely trideuteromethylated. In addition, in comparison with
other methods, such as direct reaction with CD3I, it is difficult to
separate the nondeuterated “byproduct” from the desired D
analogues.
E
DOI: 10.1021/acs.orglett.8b03641
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