CF2DSO2Na: An Effective Precursor Reagent for Deuteriodifluoromethylthiolation and Deuteriodifluoromethylation

Article abstract of DOI:10.1021/acs.orglett.1c01882

Deuteriodifluoromethythio (SCF2D) and deuteriodifluoromethyl (CF2D) are important functional groups in pharmaceutical and agrochemical compounds, and the introduction of these functional groups remains a challenging. We herein report a robust reagent for deuteriodifluoromethylthiolation and deuteriodifluoromethylation. Its potentials were successfully showcased by deuteriodifluoromethylation and deuteriodifluoromethylthiolation of indoles with high-level deuterium incorporation. The reagent also has potential for deuteriodifluoromethylation and deuteriodifluoromethylthiolation of wide range of other natural or synthetic bioactive molecules.

Full text of DOI:10.1021/acs.orglett.1c01882

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Letter
CF DSO Na: An Effective Precursor Reagent for
2
2
Deuteriodifluoromethylthiolation and Deuteriodifluoromethylation
Junqing Liang, Gangao Wang, Lefeng Dong, Xiwen Pang, Jiawei Qin, Xiaoyong Xu, Xusheng Shao,
and Zhong Li*
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ABSTRACT: Deuteriodifluoromethythio (SCF D) and deuterio-
2
difluoromethyl (CF D) are important functional groups in
2
pharmaceutical and agrochemical compounds, and the introduc-
tion of these functional groups remains a challenging. We herein
report a robust reagent for deuteriodifluoromethylthiolation and
deuteriodifluoromethylation. Its potentials were successfully
showcased by deuteriodifluoromethylation and deuteriodifluor-
omethylthiolation of indoles with high-level deuterium incorpo-
ration. The reagent also has potential for deuteriodifluoromethylation and deuteriodifluoromethylthiolation of wide range of other
natural or synthetic bioactive molecules.
ompared with the C−H bond, the C−D bond needs
(deuterofluoromethyl)silane derived from the Ruppert−
C
more bond dissociation energy to be unlinked. Thus
Prakash reagent is the most recognizable example; however,
replacing the C−H bond with the C−D bond greatly enhances
the properties, including the metabolism and pharmacoki-
netics, while preserving the performance and selectivity of the
drug molecule. Deuterium-labeling methods have been
extensively applied in mechanistic studies, organic synthesis,
this reagent was also reported to transfer a deuterium atom
5
instead of the “CF D” group. Sulfoximine, is another reagent,
2
but the deuterium binding level of the “CF D” group of the
2
6
reagent is too low to be used. Nevertheless, there is only one
exception of 19-deutero-19,19-difluoroandrost-4-3,17-dione
1
7
drug metabolism analysis, and structure determination. In
synthesis to explore the mechanism of aromatase inactivation.
2
017, deutetrabenazine was authorized by the U.S. Food and
Therefore, there is a need for an efficient reagent for
introducing “CF D/SCF D” (Figure 1b). In 2016, Billard’s
Drug Administration (FDA) for the treatment of tardive
2
2
2
dyskinesia and Huntington’s disease (Figure 1a).
group successfully synthesized the molecule with SCF D
2
8
The modification of fluorine or fluorine-containing func-
tional groups into bioactive molecules can significantly
through a two-step synthesis (Figure 1c). In 2020, Yi’s group
reported a mild and transition-metal-free method for the one-
optimize their lipophilicity, metabolic stability, and bioavail-
pot preparation of deuterated difluoromethyl thioethers in high
3
9
ability. In particular, the difluoromethylthio group (SCF H)
2
yield with a high deuterium incorporation level (Figure 1d).
and the difluoromethyl group (CF H) are superior fluoro-
2
Colby’s group synthesized ketones and sulfones with CF D by
2
containing groups for this purpose. They are lipophilic
hydrogen-bond donors and can be used as biological isosteres
with high metabolic stability toward biological thiols, amines,
releasing trifluoroacetate from highly fluorinated gem glycol
10
(
Figure 1e). In 2020, Jamison’s group reported the use of the
continuous-flow method to produce deuteriodifluoromethy-
lated products by reacting chlorodifluoromethane gas with
aldehydes in high yields with a high deuterium incorporation
4
and alcohols. Interestingly, the simultaneous incorporation of
both deuterium and fluorine atoms into a bioactive molecule
has rarely been reported. We envisage that this could be a
general method for drug development, and −SCF D/−CF D
11
level (Figure 1f). Recently, Yan’s group reported the
2
2
hydrogen−deuterium (H/D) exchange reaction of difluor-
are two very attractive yet challenging functional groups. To
our knowledge, no effective precursor reagent has been
developed for this transformation.
omethylarenes in DMSO-d solution by t-BuOK catalysis
6
12
(
Figure 1g). Given the superior metabolic stability of the C−
A review of the literature reveals that there are few methods
to introduce CF D and SCF D into molecules directly, and
these functional groups are still challenging functional groups
because of the unavailability of precursor reagents and the
Received: June 7, 2021
Published: July 7, 2021
2
2
difficult deuterium incorporation. The two “CF D” reagents
2
were derived from trifluoromethylation reagents, replacing one
fluorine atom with a deuterium atom. Typically, trimethyl-
©
2021 American Chemical Society
https://doi.org/10.1021/acs.orglett.1c01882
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Scheme 1. Methods for the Preparation of CF DSO Na (1)
2
2
difluoromethylsulfinate (CF DSO Na) was obtained in a
2
2
high overall yield of 72% (for a total of five steps) with a
high level of deuterium incorporation (97% D). It is a white
powder that is insensitive to light but prone to moisture.
With this novel reagent in hand and considering that indole
is a common structure in medicines and natural products, we
reacted it with various electron-rich aromatics, for example,
indoles, and checked if Friedel−Crafts-type deuteriodifluor-
omethylation could occur. It was observed that the reaction of
indole with reagent 1 under the presence of 2.0 equiv of
TMSCl and 3.0 equiv of (EtO) P(O)H proceeded smoothly to
2
afford product 3a in a 87% yield with 95% deuterium
incorporation. Likewise, different indoles were screened for
the deuteriodifluoromethylthiolation reaction to investigate the
reaction scope. As illustrated in Scheme 2, indoles with
multifarious functional groups such as methyl (3b, 3l),
methoxy (3c, 3i, 3k), alkoxy (3h, 3j), halogen (3f), ester
Figure 1. (a) Examples of deuterated drugs and fluorine-containing
drugs. (b) Notable compounds displaying a ‘‘CF D” group. (c)
2
Billard’s work. (d) Yi’s work. (e) Colby’s work. (f) Jamison’s work.
(g) Yan’s work. (h) This work.
(
3e), trifluoromethyl (3g), and formyl (3d) groups were
D bond, CF D- and SCF D-containing compounds have
compatible with this reagent and furnished the corresponding
products in moderate to high yields (49−91%) with high levels
of deuterium incorporation (94−96%). The reaction of
multisubstituted indoles (3m−o) also formed the correspond-
ing deuteriodifluoromethylthiolation compounds in high yield
(79−92%) with a high level of deuterium incorporation. In
general, indoles equipped with electron-donating groups have
higher yields than those with electron-withdrawing groups. N-
Substituted indoles (3p, 3q) also reacted to obtain the desired
product in 91 and 64% yield with high levels of deuterium
incorporation under the conditions. Remarkably, 5,6-dihydro-
4H-pyrrolo[3,2,1-ij]quinolone was also compatible with the
reaction conditions, giving the product 3r in a moderate yield
(75%) with high levels of deuterium incorporation (95%).
Meanwhile, we also carried out a gram-scale reaction that gave
product 3a in a high yield of 82%, and the level of deuterium
incorporation did not change.
Inspired by the successful introduction of the deuteriodi-
fluoromethylthiol group at the C-3 position of N-pyrimidyl
indoles, we next set our sights on the scope of different indole
motifs during the process of this direct C-2 deuteriodifluor-
omethylation. As presented in Scheme 3, different positions of
the N-pyrimidine indoles can undergo deuteriodifluoromethy-
lation at the C-2 position. It is noteworthy that this
transformation was proved to be dramatically compatible
2
2
potential for drug discovery. We aim to synthesize building
blocks for introducing CF D and SCF D groups and further
2
2
showcase their potential in modifying bioactive molecules of
natural or synthetic origins.
CF HSO Na is a useful reagent for difluoromethylation and
2
2
13−23
difluoromethylthiolation.
Therefore, we hypothesize that
replacing the hydrogen atom of the reagent with a deuterium
could be a viable approach to develop reagents for the
introduction of CF D and SCF D groups into heterocyclic
2
2
molecules. The starting material for the preparation of
CF DSO Na is BTSCF D. First, we adopted the method of
2
2
2
Hu’s group by using difluorocarbene reagent to react with 2-
benzothiazolyl mercaptan in deuterium aqueous solution
containing 20% KOH (weight percentage). The deuteration
rate of TMSCF Br was 92%, and that of CF BrP(O)(OEt)
2
2
2
24
was 89% (Scheme 1, route 1). Presumably, the hydrogen on
mercaptan affects the deuterium incorporation of the product;
therefore, bromoketone was instead used first followed by
fluorination and benzoyl removal to introduce deuteration
(
Scheme 1, route 2). The result shows that the fluorination
step was difficult. A limited yield of 41% was achieved by using
.5 equiv of Selectfluor. Then, we changed the sequence and
2
did the fluorination first, followed by a substitution (Scheme 1,
route 3). This time, the desired deuterated sodium
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Letter
Scheme 2. Deuteriodifluoromethylthiolation and
Deuteriodifluoromethylation of Indoles
Scheme 3. Late-Stage Deuteriodifluoromethylation and
a
Deuteriodifluoromethylthiolation of Drugs and Natural
a
Products
a
Reaction conditions: 6a and 6b (0.2 mmol), CF DSO Na (0.8
2
2
mmol), Ph PCl (0.8 mmol), Me SiCl (0.3 mmol), 90 °C, CH CN (2
2
3
3
b
mL), under Ar, 12 h. Isolated yields. Reaction conditions: 8a and 8b
(
(
0.2 mmol), CF DSO Na (0.3 mmol), CuCl (10 mol %), K S O
2 2 2 2 2 8
0.6 mmol), CH CN (2 mL), 50 °C, 36 h, under air. Isolated yields.
3
PPh Cl/Me SiCl system, thymol (6a) generated the corre-
2
3
sponding SCF D product 7a in satisfactory yields with 95%
2
deuterium incorporation. The pesticide fipronil 6b furnished
the SCF D product 7b in 73% yield with 94% deuterium
2
incorporation. In addition, the direct deuteriodifluoromethy-
lation of drug molecules and natural products, such as
melatonin (8a) and auxin (8b), can react smoothly under
the standard conditions, and the corresponding products 9a
and 9b were obtained in good yields with high levels of
deuterium incorporation (94%).
In summary, we developed an effective precursor reagent for
deuteriodifluoromethylthiolation and first deuteriodifluorome-
thylation. This reagent achieved deuteriodifluoromethylation
and deuteriodifluoromethylthiolation at the C-2 and C-3
positions of indoles, with a high deuteration incorporation.
This reagent can be used to introduce SCF D and CF D to
2
2
drug molecules and natural products, providing a unique and
powerful strategy for drug discovery and modification.
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01882.
Spectral data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Zhong Li − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China; orcid.org/0000-
0001-6665-5040; Email: lizhong@ecust.edu.cn
a
Reaction conditions: 2 (0.4 mmol), 1 (0.2 mmol), (EtO) P(O)H
2
(
0.6 mmol), TMSCl (0.4 mmol), toluene (1 mL), 85 °C, 3 h. Isolated
Authors
b c
yields. 5 mmol scale. Reaction conditions: 4 (0.3 mmol), 1 (0.2
Junqing Liang − Shanghai Key Laboratory of Chemical
Biology, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, China
Gangao Wang − Shanghai Key Laboratory of Chemical
Biology, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, China
Lefeng Dong − Shanghai Key Laboratory of Chemical
Biology, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, China
Xiwen Pang − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
mmol), CuCl (10 mol %), K S O (0.6 mmol), CH CN (2 mL), 50
2
2
2
8
3
°C, 36 h, under air. Isolated yields.
with the indole 4a, providing the desired product 5a in 82%
yield. Additionally, the substituted indoles of C-3, C-4, C-5,
and C-6 likewise reacted well. Among them, C-2 deuteriodi-
fluoromethylation products were smoothly gained in moderate
to good yields (5b−l).
Finally, we tried to introduce deuteriodifluoromethylation
and deuteriodifluoromethylthiolation into pharmaceutical
molecules and natural products. By using the CF DSO Na/
2
2
5
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Letter
Jiawei Qin − Shanghai Key Laboratory of Chemical Biology,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
Xiaoyong Xu − Shanghai Key Laboratory of Chemical
Biology, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, China;
orcid.org/0000-0001-9679-3153
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Colby, D. A. Conversion of methyl ketones and methyl sulfones into
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The work was financially supported by the Innovation Program
of Shanghai Municipal Education Commission
201701070002E00037) and the Fundamental Research
Funds for Central Universities, National Key Research
Program of China (2017YFD0200505).
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