Trifluoromethyl aryl sulfonates (TFMS): An applicable trifluoromethoxylation reagent

Article abstract of DOI:10.1016/j.tetlet.2019.04.033

Fluorine is probably another favorite hetero-atom for incorporation into small molecules after nitrogen. Among many fluorine-containing groups, trifluoromethyl aryl ethers (ArOCF₃) have unique properties in drug design and are difficult to be synthesized, and many different methods were developed to prepare them. A novel one-pot synthesis of o-iodine-aryl trifluoromethyl ethers (ArOCF₃I) was described by the reaction of trifluoromethoxylation and iodination with trifluoromethyl aryl sulfonates (TFMS) in this manuscript. The reaction conditions were optimized by screening different solvents, crown ethers, substrates and the ratios and the yields of products were in moderate to high yields (up to 86%).

Full text of DOI:10.1016/j.tetlet.2019.04.033

Accepted Manuscript
Trifluoromethyl aryl sulfonates (TFMS): an applicable trifluoromethoxylation
reagent
Meng Lei, Hang Miao, Xueyuan Wang, Wen Zhang, Chengjian Zhu, Xiaqiang
Lu, Jian Shen, Yanru Qin, Haoyang Zhang, Sijia Sha, Yongqiang Zhu
PII:
S0040-4039(19)30382-X
https://doi.org/10.1016/j.tetlet.2019.04.033
TETL 50748
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 February 2019
16 April 2019
23 April 2019
Please cite this article as: Lei, M., Miao, H., Wang, X., Zhang, W., Zhu, C., Lu, X., Shen, J., Qin, Y., Zhang, H.,
Sha, S., Zhu, Y., Trifluoromethyl aryl sulfonates (TFMS): an applicable trifluoromethoxylation reagent,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.033
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Trifluoromethyl aryl sulfonates (TFMS): an applicable
trifluoromethoxylation reagent
Meng Leia,*, Hang Miaoa, Xueyuan Wangb, Wen Zhangb, Chengjian Zhub, Xiaqiang
Lub, Jian Shenc, Yanru Qind, Haoyang Zhangb, Sijia Shaa, Yongqiang Zhub,*
a
College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing
210037, PR China
b
College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing
210046, PR China
c
College of Chemistry and Materials Science, Nanjing Normal University, No. 1
Wenyuan Road, Nanjing 210046, PR China
d
School of Bio-engineering, Qilu University of Technology (Shandong Academy of
Sciences), No. 3501 Daxue Rd. Changqing District, Jinan, 250353, PR China
ABSTRACT
Fluorine is probably another favorite hetero-atom for incorporation into small
molecules after nitrogen. Among many fluorine-containing groups, trifluoromethyl aryl
ethers (ArOCF3) have unique properties in drug design and are difficult to be
synthesized, and many different methods were developed to prepare them. A novel one-
pot synthesis of o-iodine-aryl trifluoromethyl ethers (ArOCF3I) was described by the
reaction of trifluoromethoxylation and iodination with trifluoromethyl aryl sulfonates
(TFMS) in this manuscript. The reaction conditions were optimized by screening
different solvents, crown ethers, substrates and the ratios and the yields of products
were in moderate to high yields (up to 86%).
Keywords: Organofluorine compounds; Trifluoromethylation; Arenes
Tel.:+86 25 85891591.
E-mail address: zhyqscu@hotmail.com (Y. Zhu)
Tel.:+86 25 85427621.
E-mail address: hk-lm@163.com (M. Lei)

Introduction
In recent years, fluorinated organic compounds had played increasingly important
roles in pharmaceuticals, materials and other scientific fields.1 One or more fluorine
atoms substituted at a particular position in an organic compound could significantly
alter their chemical and biological properties, such as solubility, metabolism and
1c,2
oxidative stability, lipophilicity and bioavailability.
Fluorination of organic
compounds had become a new method for the design of novel drugs, which attracted
many interests of research on the synthesis of fluorine-containing compounds and made
the methodology of organic fluorine a very popular field of organic synthesis. Among
many fluorine-containing groups, trifluoromethyl aryl ethers (ArOCF3) had unique
properties1c,3 and were difficult to be synthesized. Thus, the reactions to prepare these
molecules had become focus for the development of synthetic methods. However,
despite this particular interest, the synthesis of ArOCF3 compounds was challenging.
Several strategies for the preparation of trifluoromethyl aryl ethers had been published.4
However, the one-pot synthesis of o-iodine trifluoromethyl ethers with functional
iodine atoms was rarely reported.5
Traditional methods for the synthesis of trifluoromethyl ethers, such as
chlorine/fluorine exchange of chlorinated precursors6 and deoxyfluorination of
fluoroformates,7 were restricted by few substrates and reaction conditions. Recently,
Ngai and co-workers developed intramolecular OCF3 migration to prepare
trifluoromethylation products.8 Ritter and co-workers reported a silver-mediated cross
coupling of aryl stannanes and aryl boronic aids with tris(dimethylamino)sulfonium
trifluoromethoxide (TASOCF3),9 which was a method of generating trifluoromethyl
ethers from transition metals. In addition, chemists also developed a series of
trifluoromethylation reagents for the synthesis of trifluoromethoxy compounds, but
these reagents also had various problems. Fluoroxytrifluoromethane (FMT) was used
for trifluoromethylation through free radical reaction, but it was toxic and was difficult
to be operated.10 Trifluoromethyl triflate (TFMT) had been known since its preparation
by Noftle and Cady, but it was a volatile liquid with the boiling point of only 19 °C,
which limited its applications.11 The 2,4-dinitrotrifluoromethoxybenzene (DNTFB)

developed by Langlois showed poor reactivity and narrow substrate ranges.12 In 2017,
Tang group developed a new trifluoromethoxylation reagent, trifluoromethyl aryl
sulfonates (TFMS).13 Hu and co-workers reported the trifluoromethyl benzoate (TFBz)
in 2018.5 However, the synthesis of this compound required the application of COF2,
which was a highly toxic reagent.5 In 2018, Ngai and co-workers reported the direct
C-H aryl trifluoromethylation by the OCF3 radical mechanism under photocatalysis or
redox-active catalyst.14 Togni and co-workers designed highly electrophilic N-O
pyridinium reagents capable of undergoing facile single-electron reduction to afford
trifluoromethoxyl radicals under catalytic conditions in 2018.15 Up to now, only several
methods for the synthesis of trifluoromethoxylated aromatics had been reported in the
past decades (Scheme 1). Compared with other trifluoromethoxyl reagents, TFMS was
much easier to be prepared and operated. Furthermore, TFMS had good thermal
stability and reactivity. In this manuscript, we reported one-pot synthesis of o-iodine
trifluoromethyl ethers in moderate to high yields with functional iodine atoms by the
employment of benzene-acetylene precursor as a substrate and TFMS as a
trifluoromethoxyl reagent.
Togni (2008) - direct, electrophilic radical o-trifluoromethylation of phenols：
OH
OH
OCF3
CF3
+
CF3
Ritter (2011) - silver-mediated synthesis of trifluoromethoxylated arynes:
X
OCF3
silver salts
R
OCF3
R
+
or
TMSCF3
X=OH, B(OH)2, or SnBu3
Hu (2018) –trifluoromethoxylation-halogenation of arynes:
O
KF (4.5 equiv)
X
TMS
cis-DCy-18-C-6 (4.5 equiv)
OCF3
+
+
R
R
" X "
EtOAc
OCF3
OTf
TFBz
X = Cl, Br, I

This work-one pot synthesis of o-iodine trifluoromethyl ethers:
KF (4.0 equiv)
cis-DCy-18-C-6 (2.0 equiv)
C4F9I (6.0 equiv)
O
O
TMS
OTf
S
I
OCF3
+
R
R
DMC
OCF3
TFMS
Scheme 1. Synthesis of trifluoromethoxylation reagents and related trifluoro-
methoxylated aryl ethers.
Results and discussion
We initiated our investigation with 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonate 1 as model substrate to screen different trifluoromethyl p-toluenesulfonates
(TFMS) 2 (Table 1), which were trifluoromethoxyl reagents.
Table 1. Investigation of different substituted trifluoromethyl aryl sulfonates
(TFMS)
TMS
OTf
I
KF, 24-C-8, C4F9I
TFMS
2
+
+
℃
OCF3
CH CN,
, 12 h
60
OCF3
3
1
3
4
O
O
O
O
OCF3
O
OCF3
O
OCF3
O
OCF3
O
S
S
S
S
O
2c
2a
2b
2d
2h
O
OCF3
O
O
O
O
S
OCF3
O
OCF3
O
OCF3
O
S
S
S
F3C
O2N
F
2g
2e
2f
Entry
1
2
Yield (3, %)
Yield (4, %)
2a
2b
2c
48
10
2
3
40
38
6
7

4
5
6
7
8
2d
2e
2f
40
45
35
40
41
7
9
4
9
6
2g
2h
Conditions: 1 (0.05 mmol), 2 (2.0 equiv), KF (4.0 equiv), 24-crown-8 (24-C-8, 2.0 equiv), C4F9I (6.0 equiv), CH3CN
(0.3 mL), 60 °C, 12 h. Yields were determined by 19F NMR with PhCF3 as the internal standard.
It was interestingly found that all the reactions produced 3 in moderate yields and
by-products 4 in low yields. Trifluoromethoxyl reagent 2a gave final product 3 in the
highest yield (Table 1, entry 1). Other trifluoromethoxyl reagents with electron
withdrawing groups (phenyl of 2e, trifluoromethyl of 2f, fluoro of 2g, nitro of 2h) and
substituents with steric hindrance (2c and 2d) give products 3 in lower yields, which
showed that there were stereo and electronic effects on this reaction. Then we checked
the effects of different ratios of 2/1 and it showed that the yields of 3 were nearly the
same when the ratio of 2/1 was varied from 2 to 4 equivalents (Table 2, entries 1-3).
However, when the ratio of 2 was increased to 5 and 6 equivalents, the yields of 3 were
greatly decreased (Table 2, entries 4-5), which was probably due to more -OCF3 to
attack the arynes intermediate to give other byproducts.
Table 2. Investigation of different ratios of trifluoromethyl aryl sulfonate reagents
O
S
OCF3
O
TMS
OTf
I
KF, 24-C-8, C4F9I
+
+
℃
CH CN,
, 12 h
60
3
OCF3
OCF3
1
2
3
4
Entry
1
Ratio (2/1)
Yield (3, %)
Yield (4, %)
2
42
5
2
3
3
4
40
42
7
4

4
5
5
6
25
11
1
1
Conditions: 1 (0.05 mmol), KF (4.0 equiv), 24-C-8 (2.0 equiv), C4F9I (6.0 equiv), CH3CN (0.3 mL), 60 °C, 12 h.
Yields were determined by 19F NMR with PhCF3 as the internal standard.
Crown ethers were good phase-transfer catalysts (PTC) in the presence of metal
ions.16 We investigated the effect of different types of crown ethers on the formation of
3 and found that 18-crown-6 (18-C-6) was more favorable to the yield of 3 than 24-C-
8 (Table 3, entries 1-2). As to different solvents in the presence of 18-C-6, the highest
yield was obtained in ethyl acetate (EA) and byproducts 4 were not determined in EA
and dimethyl carbonate (DMC) (Table 3, entries 3-4). Finally, the reaction was carried
out in EA, dimethoxy ethane (DME) and DMC, respectively with the cis-
dicyclohexano-18-C-6 (cis-Dcy-18-C-6) as the PTC, and the results showed that high
yields of 3 were obtained without byproducts 4 in EA and DMC (Table 3, entries 5-6).
However, DME only gave 3 in 21% yield (Table 3, entry 7). As can be found in Table
3, hydrophilic solvent CH3CN resulted in the formation of by-product 4, while
hydrophobic solvents, such as EA, DMC and DME only gave products 3.
Table 3. Effects of different crown ethers and solvents
O
S
OCF3
O
I
TMS
OTf
KF, crown ether, C4F9I
+
+
℃
, 12 h
60
OCF3
OCF3
1
2
3
4
Entry
Additives
24-C-8
Solvents
CH3CN
Yield (3, %)
Yield (4, %)
1
2
3
4
5
6
37
5
18-C-6
18-C-6
CH3CN
EA
44
60
54
62
64
2
0
0
0
0
18-C-6
DMC
EA
cis-DCy-18-C-6
cis-DCy-18-C-6
DMC

7
cis-DCy-18-C-6
DME
21
0
Conditions: 1 (0.05 mmol), 2 (2.0 equiv), additives (2.0 equiv), KF (4.0 equiv), C4F9I (6.0 equiv), solvents (0.3 mL),
60 °C, 12 h. Yields were determined by 19F NMR with PhCF3 as the internal standard.
How did different fluorides and iodides affect the reaction? The results showed
that only KF could produce 3 in the presence of C4F9I (Table 4, entry 1). However,
NaF, AgF and no fluoride did not give expected products 3 (Table 4, entries 2-4), which
was probably due to lack of proper crown ethers. Finally, we investigated the effect of
different iodides on the yields of 3 in the presence of KF. The results showed that I2,
NIS and CsI did not give expected products 3 (Table 4, entries 5-7). In contrast, product
3 could be obtained in 58% of yields in the presence of tetrabutylazanium iodide (Table
4, entry 8).
Table 4. Investigation of different fluoride salts and iodides
O
S
OCF3
O
fluoride, iodide,
cis-DCy-18-C-6
I
TMS
OTf
+
+
℃
DMC,
, 12 h
60
OCF3
OCF3
1
Entry
1
2a
3
4
Fluoride salts
KF
Iodide
C4F9I
Yield (3, %)
Yield (4, %)
64
0
2
3
4
5
6
7
8
NaF
AgF
-
C4F9I
C4F9I
C4F9I
I2
0
0
0
0
0
0
0
0
0
0
KF
KF
KF
KF
0
NIS
CsI
0
0
tetrabutylazanium
iodide
58
Conditions: 1 (0.05 mmol), fluoride salts (4.0 equiv), cis-DCy-18-C-6 (2.0 equiv), Iodide (6.0 equiv), DMC (0.3
mL), 60 °C, 12 h. Yields were determined by 19F NMR with PhCF3 as the internal standard.

With the optimized conditions, we explored the scope of substrates with different
substituents on the aryl rings. Substituted phenyl rings (3a-3m) smoothly underwent
trifluoromethoxylation and iodination to give the corresponding products in moderate
to high yields (Table 5). In all cases, no byproducts of fluorination,
trifluoromethoxylation-protonated and 4 were observed. In cases of unsymmetrical
aryls with 4-substituent, low to moderate regioselectivities were observed, which might
be dependent on the electronic characteristics of the substituents (3b-3j). Functional
groups such as methoxyl (3h, 3l, 3m), fluoride (3g), phenyl (3i) and alkyl (3c-3f, 3j,
3k) were well tolerated in this reaction.
Table 5. Investigation of different substratesa
O
S
OCF3
O
TMS
OTf
I
KF, cis-DCy-18-C-6,C4F9I
R
R
+
R
+
h
DMC, 60 ℃, 12
OCF3
OCF3
2
1
3
4
I
a
b
OCF3
OCF3
OCF3
a
b
OCF3
a
a OCF3
I
I
I
b
b
I
b
b
3a
3b
3c
3d
3e
, 66%
, 86%
, 71%
, 57%
, 53%
(ab/ba = 1.94:1)c
(ab/ba = 1.54:1)c
(ab/ba = 1.55:1)c
(ab/ba = 3.02:1)c
OCF3
I
a
b
b
a
F
I
O
b
a
I
a OCF3
a OCF3
OCF3
OCF3
b
I
b
I
b
3f
3g
3h
3i
3j
, 53%
, 66%
, 64%
, 68%
, 60%
(ab/ba = 1.58:1)c
(ab/ba = 2.78:1)c
(ab/ba = 5.6:1)c
(ab/ba = 1.1:1)c
(ab/ba = 1.52:1)c
OCF3
O
O
OCF3
OCF3
O
O
I
I
I
3k
3l
3m
, 62%
, 44%
, 45%
a Conditions: 1 (0.5 mmol), 2 (2.0 equiv), iodides (6.0 equiv), cis-DCy-18-C-6 (2.0 equiv), KF (4.0 equiv), DMC
(0.3 mL), 60 °C, 12 h. Unless otherwise noted, isolated yields were given. For structures of 1, see SI. b Yields were
determined by 19F NMR with PhCF3 as the internal standard. c The ratio of regioisomers was determined by 19F
NMR spectroscopy prior to isolation.
In conclusion, we developed a useful method of one-pot synthesis of o-iodine aryl
trifluoromethyl ethers with functional iodine atoms in moderate to high yields through

the reaction of trifluoromethoxylation and iodination with TFMS. The functional
building blocks could be used in drug design and synthesis.
Acknowledgments
This work was supported by the following grants: National Natural Science
Foundation of China (21877061), Natural Science Foundation of Jiangsu Province
(BK20171448), National and Local Joint Engineering Research Center of Biomedical
Functional Materials and Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD).
Supplementary data
Supplementary data associated with this article can be found in the SI file.
References
1. (a) Müller, K.; Faeh, C.; Diederich, F. Sci. 2007, 317, 1881-1886; (b) Berger, R.; Resnati, G.; Metrangolo, P.;
Weber, E.; Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496-3508; (c) Jeschke, P. ChemBioChem. 2004, 5, 570-589.
2. (a) Hiyama, T.; Yamamoto, H. In Organofluorine Compounds; Springer Berlin Heidelberg: Berlin, Heidelberg.
2000, 137-182; (b) Swallow, S. In Progress in Medicinal Chemistry. 2015, 54, 65-133; (c) Liang, T.; Neumann,
C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214-8264; (d) Wang, J.; Sánchez-Roselló, M.; Aceña, L.;
Pozo, C.; Sorochinsky, A.; Fustero, S.; Soloshonok, V.; Liu, H. Chem. Rev. 2014, 114, 2432-2506.
3. (a) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827-856; (b) Jeschke, P.; Baston, E.; Leroux,
F. R. Mini-Rev. Med. Chem. 2007, 7, 1027-1034; (c) Leroux, F. R.; Manteau, B.; Vors, J. P.; Pazenok, S. Beilstein
J. Org. Chem. 2008, 4, 13; (d) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214-
8264; (e) Xu, X. H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731-764; (f) Xing, L.; Blakemore, D. C.;
Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. ChemMedChem. 2015, 10,
715-726.
4. (a) Chen, C.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2015, 137, 15648-15651; (b) Fantasia, S.; Welch, J. M.; Togni,
A. J. Org. Chem. 2010, 75, 1779-1782; (c) Chen, C.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2015, 137, 15648-
15651; (d) Tomita, R.; Al-Maharik, N.; Rodil, A.; Bühl, M.; O'Hagan, D. Org. Biomol. Chem. 2018, 14, 1113-
1117.
5. Zhou, M.; Ni, C.; Zeng, Y.; Hu, J. J. Am. Chem. Soc. 2018, 140, 6801-6805.
6. Yagupol’skii, L. M. Dokl. Akad. Nauk. SSSR. 1955, 105, 100-102.
7. Sheppard, W. A. J. Org. Chem. 1964, 29, 1-11.
8. (a) Hojczyk, K. N.; Feng, P.; Zhan, C.; Ngai, M. Y. Angew. Chem. Int. Ed. 2014, 53, 14559-14563; (b) Feng, P.;
Lee, K. N.; Lee, J. W.; Zhan, C.; Ngai, M. Y. Chem. Sci. 2016, 7, 424-429; (c) Lee, K. N.; Lei, Z.; Morales-
Rivera, C. A.; Liu, P.; Ngai, M. Y. Org. Biomol. Chem. 2016, 14, 5599-5605.
9. Huang, C.; Liang, T.; Harada, S.; Lee, E.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 13308-13310.
10. (a) Noftle, R. E.; Cady, G. H. Inorg. Chem. 1965, 4, 1010-1012; (b) Taylor, S. L.; Martin, J. C. J. Org. Chem.
1987, 52, 4147-4156.
11. Rooj, S.; Das, A.; Thakur, V.; Mahaling, R. N.; Bhowmick, A. K.; Heinrich, G. Mater. Design. 2010, 31, 2151-
2156.
12. Marrec, O.; Billard, T.; Vors, J. P.; Pazenok, S.; Langlois, B. R. Adv. Synth. Catal. 2010, 352, 2831-2837.

13. Guo, S.; Cong, F.; Guo, R.; Wang, L.; Tang, P. Nat. Chem. 2017, 9, 546-551.
14. (a) Zheng, W.; Lee, J. W.; Morales-Rivera, C. A.; Liu, P.; Ngai, M. Y. Angew. Chem. Int. Ed. 2018, 57, 13795-
13799; (b) Zheng, W.; Morales-Rivera, C. A.; Lee, J. W.; Liu. P.; Ngai, M. Y. Angew. Chem. Int. Ed. 2018, 57,
9645-9649.
15. Jelier, B. J.; Tripet, P. F.; Pietrasiak, E.; Franzoni, I.; Jeschke, G.; Togni, A. Angew. Chem. Int. Ed. 2018, 57,
13784-13789.
16. Shirakawa, S.; Maruoka, K. Angew. Chem. Int. Ed. 2013, 52, 4312-4348.
Highlights:
(1) A novel one-pot synthesis of o-iodine-aryl trifluoromethyl ethers (ArOCF3I) with
an excellent handle (the iodine atom).
(2) A benzene-acetylene precursor was used as a substrate and a high performance
TFMS was used as a trifluoromethyloxy reagent.
(3) The reaction was carried out in mild and robust conditions and gave the expected
products in moderate to high yields.
17.
A new one-pot synthesis of trifluoromethyl ethers with an excellent handle
(the iodine atom) in moderate to high yields was developed.
O
S
OCF3
O
C4F9I, KF
cis-DCy-18-C-6
TMS
OTf
I
R
R
+
DMC, 60 C/12 h
OCF3
1
2
3
18.