A highly stable and versatile heterobifunctional fluoroalkylation reagent for preparation of fluorinated organic compounds

Article abstract of DOI:10.1039/c6ob00637j

A highly stable heterobifunctional fluoroalkylation reagent, 1-azido-2-chloro-1,1,2-trifluoro-2-iodoethane (ACTI) has been prepared in high yield for the first time by a new method. Moreover, the reactivity of both the azido group and the iodine atom of t

Full text of DOI:10.1039/c6ob00637j

Organic &
Biomolecular Chemistry
View Article Online
View Journal
COMMUNICATION
A highly stable and versatile heterobifunctional
fluoroalkylation reagent for preparation of
fluorinated organic compounds†
Cite this: DOI: 10.1039/c6ob00637j
Received 24th March 2016,
Accepted 18th April 2016
Jingwen Dai, Zili Li, Taisheng Wang and Ruke Bai*
DOI: 10.1039/c6ob00637j
www.rsc.org/obc
A
highly stable heterobifunctional fluoroalkylation reagent,
So far, most of the fluoroalkylation reagents reported in the
1-azido-2-chloro-1,1,2-trifluoro-2-iodoethane (ACTI) has been literature are monofunctional fluoroalkyl compounds, which
prepared in high yield for the first time by a new method. More- have been successfully used to prepare end-capped fluorinated
over, the reactivity of both the azido group and the iodine atom of organic compounds. However, very few bifunctional fluoroalkyl
the reagent was systematically investigated and the results demon- reagents available have been reported up to now.12 Note that
strate that this compound is a very versatile and useful new fluoro- the bifunctional fluoroalkyl reagents reported usually consist
alkylation reagent for preparation of fluorinated organic of two reactive groups with a tetrafluoroethylene-bridging
compounds.
linker (R–CF2CF2–R′), which can be used as a fluorinated
building block to incorporate into organic compounds. There-
fore, bifunctional fluoroalkyl reagents are undoubtedly very
useful for preparation of new fluorinated organic compounds.
Dibromo- and diiodo-perfluoroalkanes are the most common
bifunctional fluorinated reagents.13 In particular, 1,2-dibromo-
tetrafluoroethane (BrCF2CF2Br) is commercially available and
widely used to prepare fluorinated organic compounds or poly-
mers.14 However, the two bromine atoms show the same reac-
tivity in the reaction, in other words, the reaction proceeds
with no selectivity between the two bromine atoms. Thus it is
not convenient to synthesize heterobifunctional fluorinated
organic compounds through a substitution reaction of the two
bromine atoms in dibromo perfluoroalkanes. Recently, Ogoshi
prepared 2-aryl-1,1,2,2-tetrafluoroethyl copper complexes by
the carbocupration of tetrafluoroethylene (TFE), and demon-
strated that it could be used as a fluoroalkylation reagent for
the preparation of 1,2-difunctionalized-1,1,2,2-tetrafluoro-
ethanes in high yields.15 Since heterobifunctional fluoroalkyl
reagents can selectively undergo more diversified reactions,
compared to homobifunctional fluoroalkyl reagents, they are
more suitable and useful for preparing fluorinated organic
compounds with an asymmetric molecular structure. There-
fore, it is highly desired to develop new heterobifunctional
fluoroalkylation reagents.
Over the past few decades, an increasing attention has been
paid to the synthesis of the fluorine atom or perfluoroalkyl
groups-containing organic compounds because fluorinated
compounds show potential applications in various fields, such
as agrochemicals, medicines, and functional materials.1 For
example, CF3-containing drugs usually show high efficacy,
high stability to oxidation, and good membrane permeability.
Currently, about 30% of the agrochemicals and 25% of the
drugs contain one or more fluorine atoms.2 Consequently,
various new methods for fluorination and fluoroalkylation of
organic compounds have been developed. In the fluoroalkyla-
tion reaction, the fluoroalkylation reagent plays a very impor-
tant role. Therefore, more and more investigations have been
focused on the exploration of new fluoroalkylation reagents for
preparation of new fluorinated organic compounds. We
noticed that a number of fluoroalkylation reagents had been
reported, such as the Ruppert–Prakash reagent (MeSiCF3),3 the
Langlois reagent (CF3SO2Na),4 the Umemoto reagent,5 the
Togni reagent,6 and perfluoroalkyl iodides.7 Among their
counterparts, fluoroalkyl iodides are commonly used in fluoro-
alkylation reactions, and the reactions can be achieved by
different approaches, such as radical,8 nucleophilic,9 trans-
metal catalysis10 and photochemical strategies.11
Here we report a new heterobifunctional fluoroalkylation
reagent, 1-azido-2-chloro-1,1,2-trifluoro-2-iodoethane (ACTI).
To the best of our knowledge, this is the first highly stable and
versatile heterobifunctional fluoroalkylation reagent as a new
fluoro building block for preparation of fluorinated organic
compounds. Regarding ACTI, there is only one paper pub-
lished by Banks and McGlinchey in 1971, and in this one-page
CAS Key Laboratory of Soft Matter Chemistry and Department of Polymer Science
and Engineering, University of Science and Technology of China, Jinzhai Road 96,
Hefei, Anhui Province, People’s Republic of China. E-mail: bairk@ustc.edu.cn
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/c6ob00637j
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
Table 1 Screening of catalysts for CuAACa
Scheme 1 Preparation of ACTI. Reagents and conditions (yield): ICl,
NaN3, chlorotrifluoroethylene (CTFE), −30 °C, CH3CN, 24 h (83%).
Additive
[mol%]
Time Yieldb
Entry Cu [mol%]
Solvent
[h]
[%]
1
2
3
4
5
6
7
8
9
CuSO4·5H2O (2)
CuBr (5)
Cu(PPh3)3Br (5)
CuBr (5)
Cu(PPh3)2NO3 (2.5)
Cu(OAc)2 (5)
Cu2O (5)
CuI (5)
CuI (5)
CuI (5)
NaAsc (10)
PPh3 (10)
—
PMDETA (10) THF
—
H2O/t-BuOH
CH3CN
CH3CN
8
12
12
12
12
24
12
16
16
4
0
0
0
<10
0
0
paper, the authors briefly reported the synthesis of ACTI via
the addition of iodine azide to chlorotrifluoroethylene (CTFE),
but unfortunately the yield was low (19%).16 We carefully and
thoroughly investigated the reaction and developed a new
facile method for preparation of ACTI (Scheme 1). Through
this new facile method, ACTI could be obtained in a high yield
of 83% (ESI Table 1†). Moreover, ACTI could be separated and
purified conveniently. There is very limited information avail-
able on the properties of ACTI in the literature, therefore, the
stability of ACTI was examined by 19F NMR spectroscopy. The
result indicates that ACTI is a fairly stable liquid with a light
red color at room temperature in the dark. No detectable
decomposition was observed after storage in a glass vial for six
months at room temperature.
Then, the reactivity of the azido group in ACTI was investi-
gated. It is well known that the Cu(ι)-catalyzed azide–alkyne
cycloaddition (CuAAC) reaction has been studied widely, which
is commonly described as “click reaction” in the synthesis of
organic compounds, polymers, and biomaterials.17 In general,
functional groups directly attached to perfluoroalkanes show
quite different reactivities from those in non-perfluoroalkanes.
Note that there is no report on Cu(ι)-catalyzed azide–alkyne
cycloaddition between a perfluoroalkyl azide and an alkyne in
the literature. In order to understand the reactivity of the azido
group in ACTI with an alkyne, the azide–alkyne cycloaddition
reaction was performed in aqueous t-BuOH using CuSO4/
Toluene
Toluene
H2O
CH2Cl2
CH2Cl2
CH2Cl2
PPh3 (10)
—
0
NEt3 (10)
NEt3 (100)
NEt3 (10),
HOAc (10)
TBAA (10)
TBAA (5)
TBAA (6)
TBAA (14)
TBAA (10)
TBAA (10)
TBAI (10)
TBAN (10)
TBAA (10)
TBAA (10)
TBAA (10)
TBAA (10)
TBAA (10)
TBAA (10)
TBAA (10)
19
15
76
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CuI (5)
CuI (5)
CuI (3)
CuI (7)
CuCl (5)
CuBr (5)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
EtOAc
THF
4
4
4
89
63
39
88
20
42
0
4
12
12
4
4
4
4
4
4
4
0
92
87
79
82
73
36
55
Acetone
DMSO
EtOH
4
4
H2O
a The reaction was carried out using ACTI (1.5 mmol) and 1a (1 mmol)
in the presence of a catalyst in the solvent (1 ml) at room temperature
under an N2 atmosphere. b Yields refer to isolation after
chromatography.
However, we found that when a catalytic amount of HOAc
NaAsc as a catalyst, which was generally used in the click reac- was added to the system of CuI/NEt3, the yield of the product
tion (Table 1, entry 1).18 Phenylacetylene (1a) was chosen as a was significantly improved up to 76% (entry 10). Encouraged
reactant for the model reaction and the reaction was con- by this positive result, we conducted the reaction using tetra-
ducted at room temperature in the dark. Unfortunately, the butyl ammonium acetate (TBAA) instead of NEt3. To our
expected target product was not obtained. The reason may be delight, the combination of CuI and TBAA was demonstrated
attributed to the low reactivity of fluoroalkyl azido groups com- to be a quite effective catalyst system for the reaction, and the
pared to common alkyl azido groups, which was reported by product could be obtained with yield as high as 89% (entry
K. Christe.19 Therefore, it is necessary to find a suitable and 11). The optimal molar ratio between CuI and TBAA was found
highly efficient catalyst for the cycloaddition reaction of ACTI to be 1 : 2 and excellent yield could be obtained when 0.05
with alkynes.
equiv. of CuI was added (entries 12–14). Further screening of
Subsequently, we examined the catalytic activities of Cu sources disclosed that the catalytic activity of Cu(I) halides
different Cu salts and Cu complexes and the results are shown increased in the following order: CuCl < CuBr < CuI (entries 15
in Table 1. It was demonstrated that most of the salts and com- and 16). Besides TBAA, other ammonium salts, such as tetra-
plexes (entries 2–7) showed very low or even no catalytic activity butylammonium nitrate (TBAN) or tetrabutylammonium
for the reaction, although they were normally used as catalysts iodide (TBAI) were also investigated (entries 17 and 18).
in the cycloaddition of common alkyl azides and alkynes.20
No product could be detected in the reaction when TBAN or
Fortunately, when CuI/NEt3 was used as a catalyst for the reac- TBAI was used as a catalyst. Obviously, the acetate ion
tion, the desired product 2a could be obtained in 19% yield (CH3COO−) should play a crucial role in the reaction. In order
(entry 8). Inspired by this success, we tried to improve the to optimize the conditions of the reaction, the influence of
efficiency of the catalyst by tuning the amount of NEt3, but the different solvents on the reaction was studied. The results
result was disappointing (entry 9).
revealed that the efficiency of the catalyst was highly depen-
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Communication
Table 2 Substrate scope of alkynes for CuAACa,b
dent on the nature of the solvents. The yield of the product
was higher than 85% (entries 19 and 20) when the solvents
with moderate polarity, such as PhCH3 and EtOAc were used.
The highest yield of 92% was obtained in PhCH3. However, the
yield decreased slightly in the highly polar solvents like THF,
acetone, and DMSO (entries 21–23). When the protic solvents,
such as EtOH and H2O were used, the yield decreased signifi-
cantly (entries 24 and 25).
Interestingly, we observed that a bright yellow color solid
was formed at the beginning of the reaction and then it dis-
appeared gradually. Fortunately, in the absence of ACTI, the
yellow color solid was isolated from the reaction of CuI/TBAA
and 1a. The solid was assumed to be PhCuCCu based on its
IR spectrum and elemental analysis (ESI Fig. 1†), which was in
accordance with that reported in the literature.21 We noticed
that no reaction occurred between PhCuCCu and ACTI
without addition of HOAc, and thus HOAc plays a vital role for
the reaction of the intermediate PhCuCCu with ACTI to form
2a successfully. On the other hand, Hu22 reported the same
phenomenon and result using CuOAc as a catalyst for the
azide–alkyne cycloaddition. Therefore, the reaction route of
ACTI with phenylethyne was proposed and is shown in
Scheme 2. The catalyst CuI/TBAA firstly reacted with phenyl-
ethyne to quickly form PhCuCCu, while an equimolar
amount of HOAc was produced in situ. Although the inter-
mediate PhCuCCu was not active, its cycloaddition with ACTI
could efficiently proceed in the presence of the in situ-formed
HOAc. Actually, in this catalytic reaction, TBAA not only acts as
a The reaction was carried out using ACTI (1.5 mmol) and 1 (1 mmol)
in the presence of CuI (0.05 mmol) and TBAA (0.1 mmol) in 1 ml
toluene at room temperature under an N2 atmosphere in the dark for
4 hours. b Yields refer to isolation after chromatography.
bonds, therefore, these functional groups can be conveniently
incorporated into fluorinated compounds.
a
base and ligand, but also provides the acetate ion
Finally, we focused our attention on the reactivity of the
iodine atom in the fluoroalkylated compounds. 2a as a model
reactant of the fluoroalkylated compounds was investigated
and the reactions are illustrated in Scheme 3. The experi-
mental result demonstrated that the fluoroalkyl iodide 2a
could be transformed into sodium fluoroalkane sulfinate 4
under ambient conditions in the presence of NaS2O4/NaHCO3
(Scheme 3A).23 It is well known that fluoroalkyl iodides are
sensitive to light, thus they are generally used as photoreactive
reagents in photochemistry. Actually, 2a could successfully
react with a mercaptan to form fluorinated sulfur ethers 5 in a
moderate yield at room temperature under visible-light
irradiation (Scheme 3B).24 In addition, 2a could also react with
(CH3COO−) to promote the CuAAC reaction. It is worth point-
ing out that the stability of CuI is much higher than that of
CuOAc in air, thus it is more convenient to use CuI/TBAA as a
catalyst for the click reaction of alkynes and azides.
To understand the effect of the alkyne structure on the
cycloaddition reaction of the azide group in ACTI, various
alkynes as substrates were investigated. The results are shown
in Table 2, and based on the yields of the products, it can be
seen that the aromatic alkynes with electron-rich groups have
higher reactivities than those with electron-withdrawing
groups (2b–2f). Moreover, aliphatic alkynes were also proved to
be suitable substrates and the corresponding products were
obtained in high yields (2g–2i). It is necessary to mention that
the reaction has high tolerability to the functional groups,
such as aldehyde, bromo, t-butyl, hydroxyl, and CvC double
Scheme 2 Proposed mechanism of the CuAAC reaction.
Scheme 3 Representative reactions of 2a.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Communication
Organic & Biomolecular Chemistry
alkenes, such as 3-buten-1-ol, to obtain a fluoroalkylated com-
pound 6 by visible-light photoredox catalysis (Scheme 3C).25
In summary, we developed a new facile method for prepa-
ration of ACTI and obtained ACTI in high yield for the first
time. As a heterobifunctional fluoroalkylation agent, the reac-
tivity of ACTI was investigated for the first time. The results
indicated that the azide group could react with different
alkynes with aromatic and aliphatic structures to give the pro-
ducts in high yields using CuI/TBAA as a catalyst. Moreover,
46, 754; (c) M. S. Wiehn, E. V. Vinogradova and A. Togni,
J. Fluorine Chem., 2010, 131, 951.
7 N. O. Brace, J. Fluorine Chem., 1999, 93, 1.
8 (a) Y. Takeyama, Y. Ichinose, K. Oshima and K. Utimoto,
Tetrahedron Lett., 1989, 30, 3159; (b) N. O. Brace, J. Fluorine
Chem., 2001, 108, 147.
9 (a) T. Billard, B. R. Langlois and M. Medebielle, Tetrahedron
Lett., 2001, 42, 3463; (b) C. Pooput, W. R. Dolbier and
M. Medebielle, J. Org. Chem., 2006, 71, 3564.
the iodine atom can also chemically or photochemically react 10 (a) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang,
with different reagents. To the best of our knowledge, ACTI is
the first highly stable and versatile heterobifunctional fluoro-
alkylation agent. Therefore, it will be very useful for prepa-
ration of new functional fluorinated organic compounds, or
functional fluorinated polymers, such as medicines and
D. A. Watson and S. L. Buchwald, Science, 2010, 328, 1679;
(b) I. Popov, S. Lindeman and O. Daugulis, J. Am. Chem.
Soc., 2011, 133, 9286; (c) H. Morimoto, T. Tsubogo,
N. D. Litvinas and J. F. Hartwig, Angew. Chem., Int. Ed.,
2011, 50, 3793.
pharmaceutics. In addition, the strategy for ACTI may also be 11 (a) J. D. Nguyen, J. W. Tucker, M. D. Konieczynska and
used for the synthesis of ICF2CF2N3 from tetrafluoroethylene
and its application in the preparation of fluorinated organic
compounds. Further investigation is underway in our laboratory.
C. R. J. Stephenson, J. Am. Chem. Soc., 2011, 133, 4160;
(b) N. Iqbal, S. Choi, E. Kim and E. J. Cho, J. Org. Chem.,
2012, 77, 11383.
This research was supported financially by the National 12 (a) C. P. Zhang, Q. Y. Chen, Y. Guo and J. C. Xiao, Tetra-
Natural Science Foundation of China (no. 21174136).
hedron, 2013, 69, 10955; (b) E. Schmitt, B. Rugeri,
A. Panossian, J.-P. Vors, S. Pazenok and F. R. Leroux, Org.
Lett., 2015, 17, 4510; (c) E. Schmitt, G. Landelle, J.-P. Vors,
N. Lui, S. Pazenok and F. R. Leroux, Eur. J. Org. Chem.,
2015, 6052.
Notes and references
1 (a) P. Kirsch, in Modern Fluoroorganic Chemistry, Wiley- 13 (a) C. D. Bedford and K. Baum, J. Org. Chem., 1980, 45, 347;
VCH, Weinheim, 2004; (b) T. Umemoto, J. Fluorine Chem.,
2000, 105, 211; (c) J. A. Ma and D. Cahard, Chem. Rev.,
2008, 108, 1; (d) L. Chu and F. L. Qing, J. Am. Chem. Soc.,
(b) H. P. Cao and Q. Y. Chen, J. Fluorine Chem., 2007, 128,
1187; (c) J. Zhu, B. Wang and D. Liu, Green Chem., 2013, 15,
1042.
2012, 134, 1298; (e) S. B. Vallejo and A. Postigo, Eur. J. Org. 14 (a) O. Ruff, O. Bretschneider and Z. Anorg, Allg. Chem.,
Chem., 2012, 1889; (f) T. Furuya, A. S. Kamlet and T. Ritter,
Nature, 2011, 473, 470; (g) P. Kirsch, Modern Fluoro-organic
1933, 210, 173; (b) H. Thomassen, S. Samdal and
K. Hedberg, J. Am. Chem. Soc., 1992, 114, 2810.
Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, 15 H. Saijo, M. Ohashi and S. Ogoshi, J. Am. Chem. Soc., 2014,
Weinheim, 2013; (h) S. Purser, P. R. Moore, S. Swallow and 136, 15158.
V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320; (i) J. Wang, 16 R. E. Banks and M. J. McGlinchey, J. Chem. Soc. C, 1971,
M. S. Rosello, J. L. Acena, C. Delpozo, A. E. Sorochinsky, 23, 3971.
S. Fustero, V. A. Soloshonok and H. Liu, Chem. Rev., 2014, 17 (a) V. D. Bock, H. Hiemstra and J. H. van Maarseveen,
114, 2432. Eur. J. Org. Chem., 2006, 51.
2 (a) D. O’Hagan, J. Fluorine Chem., 2010, 131, 1071; 18 (a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and
(b) C. Alonso, E. M. Marigorta, G. Rubiales and F. Palacios,
Chem. Rev., 2015, 115, 1847.
3 (a) I. Ruppert, K. Schlich and W. Volbach, Tetrahedron Lett.,
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596;
(b) T. Hiramatsu, Y. Guo and T. Hosoya, Org. Biomol.
Chem., 2007, 5, 2916.
1984, 25, 2195; (b) G. K. S. Prakash, R. Krishnamurti and 19 K. Christe and C. J. Schack, Inorg. Chem., 1981, 20, 2566.
G. A. Olah, J. Am. Chem. Soc., 1989, 111, 393.
20 (a) S. Lal and S. D. Gonzalez, J. Org. Chem., 2011, 76, 2367;
(b) W. H. Binder and C. Kluger, Macromolecules, 2004, 37,
9321; (c) D. Wang, N. Li, M. Zhao, We. Shi, C. Ma and
B. Chen, Green Chem., 2010, 12, 2120; (d) K. Wang, X. Bi,
S. Xing, P. Liao, Z. Fang, X. Meng, Q. Zhang, Q. Liu and
Y. Ji, Green Chem., 2011, 13, 562; (e) Z. Gonda and
Z. Novak, Dalton Trans., 2010, 39, 726; (f) L. Y. Wu,
Y. X. Xie, Z. S. Chen, Y. N. Niu and Y. M. Liang, Synlett,
2009, 1453.
4 (a) B. R. Langlois, E. Laurent and N. Roidot, Tetrahedron
Lett., 1991, 32, 7525; (b) A. T. Parsons, T. D. Senecal and
S. L. Buchwald, Angew. Chem., Int. Ed., 2012, 51, 2947;
(c) C. Chen, Y. Xie, L. Chu, R. W. Wang, X. Zhang and
F. L. Qing, Angew. Chem., Int. Ed., 2012, 51, 2492.
5 (a) T. Umemoto, S. Ishihara and K. Adachi, J. Fluorine
Chem., 1995, 74, 77; (b) S. Noritake, N. Shibata, Y. Nomura,
Y. Huang, A. Matsnev, S. Nakamura, T. Torua and
D. Cahard, Org. Biomol. Chem., 2009, 7, 3599.
21 K. Jouvin, J. Heimburger and G. Evano, Chem. Sci., 2012, 3,
756.
6 (a) P. Eisenberger, I. Kieltsch, R. Koller, K. Stanek and
A. Togni, Org. Synth., 2011, 88, 168; (b) I. Kieltsch, 22 (a) C. Shao, G. Cheng, D. Su, J. Xu, X. Wang and Y. Hu, Adv.
P. Eisenberger and A. Togni, Angew. Chem., Int. Ed., 2007,
Synth. Catal., 2010, 352, 1587; (b) Q. Zhang, X. Wang,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Communication
C. Cheng, R. Zhu, N. Liu and Y. Hu, Org. Biomol. Chem., 24 N. J. W. Straathof, B. J. P. Tegelbeckers, V. Hessel, X. Wang
2012, 10, 2847. and T. Noel, Chem. Sci., 2014, 5, 4768.
23 (a) B. N. Huang, W. Y. Huang and C. M. Hu, Acta Chim. 25 C. J. Wallentin, J. D. Nguyen, P. Finkbeiner and
Sin., 1981, 39, 481; (b) B. N. Huang, W. Y. Huang and
C. M. Hu, J. Fluorine Chem., 1983, 23, 193.
C. R. J. Stephenson, J. Am. Chem. Soc., 2012, 134,
8875.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.