Bunte Salt CH2FSSO3Na: An Efficient and Odorless Reagent for Monofluoromethylthiolation

Article abstract of DOI:10.1021/acs.orglett.8b02753

A practical and efficient monofluoromethylthiolation that employs the typical Bunte salt, sodium S-(fluoromethyl) sulfurothioate, as the sulfur source is described. This reagent reacts readily with a variety of aryl amines and aryl thiols. The high tolerance of functional groups demonstrates the potential of this reaction. In addition, this method is suitable for the late-stage monofluoromethylthiolation of complex bioactive molecules.

Full text of DOI:10.1021/acs.orglett.8b02753

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Bunte Salt CH FSSO Na: An Efficient and Odorless Reagent for
2
3
Monofluoromethylthiolation
Fanmin Liu, Lvqi Jiang,* Huangyao Qiu, and Wenbin Yi*
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing, 210094, China
*
S Supporting Information
ABSTRACT: A practical and efficient monofluoromethylth-
iolation that employs the typical Bunte salt, sodium S-
(
fluoromethyl) sulfurothioate, as the sulfur source is
described. This reagent reacts readily with a variety of aryl
amines and aryl thiols. The high tolerance of functional
groups demonstrates the potential of this reaction. In
addition, this method is suitable for the late-stage monofluoro-
methylthiolation of complex bioactive molecules.
ver the past few decades, the selective introduction of
In response to the growing demand in life and material
science, organic chemists have developed several reagents and
methods for the introduction of fluoroalkylthio groups into
O
fluorine atom(s) into organic molecules has attracted
increased attention in the fields of agrochemicals and
pharmaceuticals, since fluorine has been described as a crucial
element to modify the chemical and physical properties of the
8
,9
aromatic rings. Nevertheless, methods for the introduction of
a monofluoromethylthio group are still lacking, with the
monofluoromethylthioester being the least understood. There-
fore, strategies to synthesize organic molecules containing the
monofluoromethylthio group have emerged as an active field in
organic chemistry. The typical method for the synthesis of
monofluoromethyl sulfides focuses on the monofluoromethyla-
tion of thiols (Scheme 1). For example, electrophilic
monofluoromethylation of thiols with chlorofluormethane or
1
original compounds. Among numerous fluorinated compounds
known to date, fluoroalkylthio groups (such as SCF , SCF H,
3
2
and SCH CF ) are often encountered in biologically active
2
3
molecules such as antibiotics, antiulcers, antibacterials, and
2
pesticides. However, there are few studies on the monofluor-
omethylthio group, mainly due to the lack of monofluoro-
3
methylthiolating reagents and instability of some compounds.
As one of the strategic fluorine-containing substituents, the
monofluoromethylthio group is widely used by the pharma-
ceutical industry in many drugs and drug candidates. Well-
Scheme 1. Strategies for the Preparation of
Monofluoromethylthioester
4
known examples include antiflammatory drug Androstanes and
5
Fluticasone, nonsteroidal antiflammatory agent fluoro-ana-
6
7
logues of Sulindac, and cathepsin K inhibitors (Figure 1).
Figure 1. Monofluoromethylthioester based drugs and bioactive
molecules.
Received: August 28, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
S-(monofluoromethyl)diarylsulfonium tetrafluoroborate has
been applied to construct these compounds. Later, Hu’s
mechanism of the Sandmeyer reaction and the recent advances
in this field, we wondered if it was possible to apply the unique
property of Bunte salt 1 to develop a similar Sandmeyer-type
monofluoromethylthiolation reaction.
10
group developed PhSO(NTS)CH F as a radical monofluoro-
2
methylating reagent to introduce the monofluoromethyl moiety
3
a
to thiols. Yet, smelly and unstable thiol derivatives might be a
restriction for further application in more complicated
molecules. Alternative approaches involved the fluorination of
aromatic thioethers with an electrophilic fluorination agent or
Initially, we chose available p-nitroaniline and tert-butyl nitrite
as an aryl diazonium salt precursor and Bunte salt 1 as sulfur
sources, 10 mol % CuSO ·5H O as the catalyst, and 10 mol %
4
2
2,2-bipyridine as the ligand in MeOH/H O (Table 1, entry 1).
2
11
halogen exchange reaction with chloromethyl phenyl sulfides.
a
However, these strategies suffer from some limitations, such as
harsh reaction conditions, use of toxic or hazardous reagents,
and narrow functional group tolerance. The first direct
electrophilic monofluoromethylthiolating reagent, S-(fluoro-
methyl) benezenesulfonothioate, was developed by Shen and
Table 1. Optimization of Reaction Conditions
b
12
entry
catalyst
CuSO ·5H O
CuI
CuCl
CuBr
ligand
solvent
MeOH/H O
yield (%)
co-workers in 2017. This reagent was smoothly synthesized by
treatment of easily available PhSO Na with CH FI in two steps.
1
2
3
4
5
6
7
8
9
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Phen
−
−
23
−
38
16
17
22
−
16
71
trace
−
−
16
−
68
56
25
4
2
2
2
2
MeOH/H O
The reagent is shelf-stable and has substrate generality, which
enables reaction with a variety of aryl boronic acids to form
monofluoromethylthioester. Despite this progress, the discovery
of new, readily accessible, and solid monofluoromethylthiolating
reagents that are effective with a broad range of substrates is still
highly desirable. Interestingly, we find that the stable and easy-
to-handle Bunte salt has a similar scaffold with this reagent. 13
Historically, Bunte salts, reported by Hans Bunte in 1874,
2
MeOH/H O
2
MeOH/H O
2
CuSO4
MeOH/H O
2
CuCl2
MeOH/H O
2
Cu(OAc)2
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
MeOH/H O
2
MeOH/H O
2
Et N
MeOH/H O
2
3
14
10
11
12
13
14
15
16
17
18
19
−
MeOH/H O
have been proven to be valuable synthetic intermediates. Due
to the masked effect and their high stability and being odorless,
they have been widely used in the development of sulfides as
2
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
MeOH
H O
2
1
5
DMF
DMSO
sulfur sources. Inspired by these seminal works and our
continuous research interests in fluorine-containing sodium
1
6
CH CN
salts, we decided to disclose a typical Bunte salt, sodium S-
fluoromethyl) sulfurothioate, that could be a potential
3
THF
(
c
MeOH
MeOH
MeOH
monofluoromethylthiolating reagent.
d
e
According to the previous report, Bunte salt can be
conveniently prepared by the reaction of odorless and
17
a
inexpensive sodium thiosulfate with alkyl halides. Similarly,
Reaction conditions: p-nitroaniline (0.2 mmol), Bunte salt 1 (0.3
t
mmol), catalyst (10 mol %), ligand (10 mol %), BuONO (1.5 equiv)
sodium S-(fluoromethyl) sulfurothioate 1 was efficiently
b
19
18
in solvent (1.0 mL) at 80 °C for 5 h. Yield determined by F NMR
synthesized by mixing fluoromethyl iodide with sodium
c
d
using PhCF as an internal standard. 20 mol % CuSO was used. Ar.
3
4
thiosulfate in MeOH/H O (Scheme 2). Subsequently, the
2
e
2
.0 equiv NaCl were used.
Scheme 2. Preparation of Sodium S-(Fluoromethyl)
Sulfurothioate 1
To our disappointment, only deamination occurred to give the
corresponding p-nitrobenzene without the formation of the
desired monofluoromethylthiolated product. In order to
improve its activities, various copper salts, such as CuI, CuCl,
CuBr, CuSO , CuCl , and Cu(OAc) , were evaluated (entries
4
2
2
2
−7). Fortunately, when using CuSO as the catalyst, the
4
monofluoromethylthiolated product, 2a, was formed in 38%
yield. Subsequently, we screened the reaction conditions with
different ligands and found that 2,2-bipyridine served as an
optimal ligand (entries 8−10). The effect of different solvents
was also tested, and the results showed that MeOH was superior
to the other solvents such as H O, DMF, DMSO, CH CN, and
reaction was scaled up to over 5.0 g, and the desired product was
isolated as a crystalline white solid in 66% yield and fully
1
13
19
characterized by H, C, and F NMR spectroscopies. The
compound 1 decomposes without melting at 170 °C. The
reagent is fairly stable without deterioration when stored in a
refrigerator for a month. Around 20% of detectable decom-
position was observed after storage at room temperature after a
week.
2
3
THF (entries 11−16). Finally, some control experiments were
carried out. For example, increasing the amount of copper salt to
20 mol % or performing the reaction under a Ar atmosphere did
not afford the product with higher yields (entries 17−18). It is
noteworthy that the lower yield of product was obtained when
NaCl were added, which was previously proven to be necessary
Aromatic amines are cheap and readily available substrates,
and they can serve as a versatile motif, which can be converted
15d
for the coupling of aryl amines with Bunte salts (entry 19).
19
into various functional groups. More recently, Sandmeyer-
type trifluoromethylthiolation, difluoromethylthiolation,
pentafluoroethylthiolation, and trifluoromethylselenolation of
With the optimized conditions in hand, we next explored the
scope of the substrates, and the results are summarized in
Scheme 3. In general, a variety of aryl-substituted amines were
applicable and moderate to excellent isolated yields of the
20
aryl diazonium salts have also been developed. Inspired by the
B
DOI: 10.1021/acs.orglett.8b02753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of the Monofluoromethylthiolation of Aryl
Amines
To further demonstrate the utility of this reagent in late-stage
modification, we applied it to the monofluoromethylthiolation
of sulfonamides, an antibacterial drug, which has been used for a
,
a b
21
few decades (Scheme 4). Satisfyingly, sulfamethoxazole and
Scheme 4. Late-Stage Monofluoromethylthiolation of Drug-
,
a b
like Aryl Amines
a
Reaction conditions: aryl amine (0.4 mmol), Bunte salt 1 (0.6
t
mmol), CuSO (10 mol %), 2,2-bipyridine (10 mol %), BuONO (1.5
equiv) in MeOH (2.0 mL) at 80 °C for 5h. Yield of isolated product.
4
b
sulfadimidine were also good candidates for this transformation,
thus giving the products in moderate yields (2aa−2ab). These
results encourage the application of this method to more
complex small molecules. For example, mosapride, which is a
22
gastroprokinetic agent that acts as a selective 5HT agonist,
4
was selectively converted at the amino group to give the
monofluoromethylthiolated product 2ac in 44% yield.
With the successful development of methods for the
preparation of C-monofluoromethylthiolated compounds, we
next sought to investigate the reaction of heteroatom
monofluoromethylthiolation (Scheme 5). The results for thiols
a
Reaction conditions: aryl amine (0.4 mmol), Bunte salt 1 (0.6
t
mmol), CuSO (10 mol %), 2,2-bipyridine (10 mol %), and BuONO
4
b
(
1.5 equiv) in MeOH (2.0 mL) at 80 °C for 5 h. Yield of isolated
product.
products were achieved (2a−z). Substrates bearing different
electron-withdrawing or -donating groups at a different position
in the aromatic ring were all compatible with this reaction. A
series of common functional groups, such as nitro, halogen,
cyano, ketone, ester, amide, trifluoromethyl, and alkyl, were all
well-tolerated, thus indicating the generality of the reaction
conditions. In particular, the product 2b, containing a bromine
Scheme 5. Scope of the Monofluoromethylthiolation of Aryl
Thiols
,
a b
3a
moiety, which was proven to be unstable, was also applicable to
this reaction, giving the corresponding product in moderated
isolated yield. In addition, m- and o-substituted nitroaniline gave
the corresponding products in moderate yields, which shows the
position of substituents on the phenyl ring has some effect on
this reaction (2j−k). The sterically hindered aryl amines with o-
substituted groups could also afford the desired products in
moderate to good yields (2k−o). Moreover, disubstituted
amines could be converted to the desired product through this
reaction (2l−q). The structure of 2o was unambiguously
confirmed by single-crystal X-ray diffraction analysis. Note that a
sensitive coupling precursor, such as a terminal alkyne, was also
amenable to this method, generating the monofluoromethyl-
thiolated product 2r in 51% yields. Remarkably, substrates
containing sulfanilamide, 4-perfluorooctyl, Indane, and phtha-
limide were successfully reacted with Bunte salt 1, providing the
corresponding products in moderate yields (2s−v). Interest-
ingly, amines with heteroaryl moieties such as pyridine,
benzothiazole, benzoxazole, and benzimidazole were also
suitable for the current reaction, enabling the synthesis of
more useful biologically relevant molecules (2w−z).
a
Reaction conditions: aryl thiol (0.4 mmol) and Bunte salt 1 (0.6
b
mmol) in methanol (2.0 mL) at 50 °C for 12 h. Yield of isolated
product.
show that this reaction is compatible with both electron-
donating and -withdrawing aryl thiols (3a−m). Owing to the
mild conditions, aryl thiols possessing many functional groups,
including fluoro, chloro, bromo, ether, and ester, were also good
coupling partners, providing products in good yields. The
monofluoromethylthiolation of ortho- and meta-substituted
thiols occurred in moderate to good yields (3h−k). The
connection position had a negligible effect on the yield of the
reaction (3i−j). Di- or multisubstituted monofluoromethyl
C
DOI: 10.1021/acs.orglett.8b02753
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
thiolated thiols could also be obtained through this trans-
formation (3l−m).
(4) Ashton, M. J.; Lawrence, C.; Karlsson, J.-A.; Stuttle, K. A. J.;
Newton, C. G.; Vacher, B. Y. J.; Webber, S.; Withnall, M. J. J. Med.
Chem. 1996, 39, 4888.
In summary, a new monofluoromethylthiolating reagent,
sodium S-(fluoromethyl) sulfurothioate, has been reported.
This reagent can be efficiently synthesized in one step from
cheap and available starting materials. Furthermore, it could
react with amines and thiols to afford the corresponding
monofluoromethylthiolated products in moderate to good
yields. Beneficial factors such as ready availability, ease of
handing, good functional group compatibility, broad substrate
scope, and applicability in late-stage functionalization of drug-
like compounds make this reagent a general agent for the
synthesis of a variety of monofluoromethylthio-containing
compounds. We believe that this reagent may find wider
application in the near future.
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ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02753.
6
(
3, 10569.
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Experimental details and copies of H NMR, 13C NMR,
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Proced. Int. 1994, 26, 605. (c) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.;
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1
9
and F NMR spectra of all products (PDF)
Accession Codes
(
12) Zhao, Q.; Lu, L.; Shen, Q. Angew. Chem., Int. Ed. 2017, 56, 11575.
(13) Bunte, H. Ber. Dtsch. Chem. Ges. 1874, 7 (1), 646.
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15) (a) Qiao, Z.; Ge, N.; Jiang, X. Chem. Commun. 2015, 51, 10295.
CCDC 1843537 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(
(
(
(b) Qi, H.; Zhang, T.; Wan, K.; Luo, M. J. Org. Chem. 2016, 81, 4262.
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8
AUTHOR INFORMATION
Corresponding Authors
■
(16) (a) Jiang, L.; Qian, J.; Yi, W.; Lu, G.; Cai, C.; Zhang, W. Angew.
Chem., Int. Ed. 2015, 54, 14965. (b) Yan, Q.; Jiang, L.; Yi, W.; Liu, Q.;
Zhang, W. Adv. Synth. Catal. 2017, 359, 2471. (c) Wang, R.; Jiang, L.;
Yi, W. J. Org. Chem. 2018, 83, 7789.
*
E-mail: lvqi.jiang@njust.edu.cn.
E-mail: yiwb@njust.edu.cn.
*
(17) (a) Reeves, J. T.; Camara, K.; Han, Z. S.; Xu, Y.; Lee, H.; Busacca,
ORCID
C. A.; Senanayake, C. H. Org. Lett. 2014, 16, 1196. (b) Ogura, F.;
Yamaguchi, H.; Otsubo, T.; Nakano, T.; Saito, T. Bull. Chem. Soc. Jpn.
Wenbin Yi: 0000-0003-4606-7668
Notes
1
(
983, 56, 1257.
18) Hu, J.; Gao, B.; Li, L.; Ni, C.; Hu, J. Org. Lett. 2015, 17, 3086.
(19) (a) Xing, B.; Ni, C.; Hu, J. Angew. Chem., Int. Ed. 2018, 57, 9896.
b) Danoun, G.; Bayarmagnai, B.; Grunberg, M. F.; Gooßen, L. J.
The authors declare no competing financial interest.
(
̈
Angew. Chem., Int. Ed. 2013, 52, 7972. (c) Bayle, A.; Cocaud, C.;
Nicolas, C.; Martin, O. R.; Poisson, T.; Pannecoucke, X. Eur. J. Org.
Chem. 2015, 2015, 3787. (d) Lishchynskyi, A.; Berthon, G.; Grushin, V.
V. Chem. Commun. 2014, 50, 10237. (e) Bayarmagnai, B.; Matheis, C.;
Risto, E.; Goossen, L. J. Adv. Synth. Catal. 2014, 356, 2343. (f) Danoun,
̈
G.; Bayarmagnai, B.; Grunberg, M. F.; Matheis, C.; Risto, E.; Gooßen,
L. Synthesis 2014, 46, 2283.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21776138, 21476116), Fundamental
Research Funds for the Central Universities (30916011102,
0918011314), Natural Science Foundation of Jiangsu
BK20180476), Qing Lan and Six Talent Peaks in Jiangsu
3
(
Province, and Priority Academic Program Development of
Jiangsu Higher Education Institutions.
(20) (a) Danoun, G.; Bayarmagnai, B.; Gruenberg, M. F.; Goossen, L.
J. Chem. Sci. 2014, 5, 1312. (b) Bayarmagnai, B.; Matheis, C.; Jouvin, K.;
Goossen, L. J. Angew. Chem., Int. Ed. 2015, 54, 5753. (c) Wu, J.; Gu, Y.;
Leng, X.; Shen, Q. Angew. Chem., Int. Ed. 2015, 54, 7648. (d) Matheis,
C.; Bayarmagnai, B.; Jouvin, K.; Goossen, L. Org. Chem. Front. 2016, 3,
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DOI: 10.1021/acs.orglett.8b02753
Org. Lett. XXXX, XXX, XXX−XXX