Expedient and efficient one pot synthesis of trifluoroethyl ethers from metal free 2,4,6-tris-(2,2,2-trifluoro-ethoxy)-[1,3,5] triazene

Article abstract of DOI:10.1039/c5ra00618j

An efficient synthesis of fluorinated alkyl and aryl ethers was achieved by the use of s-triazene derived fluorinated reagent 2,4,6-tris-(2,2,2-trifluoro-ethoxy)-[1,3,5] triazene (TriTFET). The procedure offers a very attractive alternative for the synthesis of fluorinated motifs that are found in various bioactive molecules. Moreover, TriTFET is a synthetic non-toxic, non-ozone depleting and stable reagent. All compounds were characterized by ¹H, ¹³C and ¹⁹F NMR.

Full text of DOI:10.1039/c5ra00618j

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: S. K. Mangawa,
C. Sharma, A. K. Singh and S. K. Awasthi, RSC Adv., 2015, DOI: 10.1039/C5RA00618J.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 5
RSC Advances
View Article Online
DOI: 10.1039/C5RA00618J
163x41mm (300 x 300 DPI)

RSC Advances
Page 2 of 5
View Article Online
DOI: 10.1039/C5RA00618J
Journal Name
RSCPublishing
COMMUNICATION
Cite this: DOI: 10.1039/x0xx00000x
Expedient and Efficient One Pot Synthesis of
Trifluoroethyl Ethers From Metal Free 2,4,6-tris-
(2,2,2-Trifluoro-Ethoxy)-[1,3,5] Triazene
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
Shrawan Kumar Mangawa, Chiranjeev Sharma, Ashawani kumar Singh and Satish K.
Awasthi*
www.rsc.org/
of amino groups.8 Trifluoroethanol (TFE) can be used as an efficient
substitute for fluorous protecting groups. It is also used in the total
synthesis of Vinigrol proposed by Njardarson et al.9
An efficient synthesis of fluorinated alkyl and aryl ethers was
achieved by the use of -triazene derived fluorinated reagent
s
2,4,6-tris-(2,2,2-trifluoro-ethoxy)-[1,3,5] triazene (TriTFET).
The procedure offers a very attractive alternative for the
synthesis of fluorinated motifs that are found in various
bioactive molecules. Moreover, TriTFET is a synthetic non-
toxic, non-ozone depleting and stable reagent. All compounds
were characterized by 1H, 13C and 19F NMR.
Fluorinated ethers (FEs) are one of the most important classes of
organic compounds.1 It is well known that trifluoroethoxy
(CF3CH2Oꢀ) group increase metabolic stability and lipophilicity.2
High molecular weight fluorinated ethers are extensively used in
industry as lubricants, dielectric fluids, diffusion pump oils.3 Due to
high O2 solubility of fluorinated ethers these are also used as blood
substitute.4 Low molecular weight fluorinated ethers such as
Desflurane, Enflurane and Sevofluoraane are used as anaesthetics.
Further, some blockbuster drugs viz., Lansoprazole (used as
antibacterial), Silodosin (treatment of benign prostatic hyperplasia)
and Flecainide (introduced into the treatment of arrhythmias in
Figure 1. Example of drugs which have fluorous motifs
Generally, fluorinated ethers are prepared by nucleophilic addition
of alcohols and fluorinated substrates using strong base.10 Other
choice for synthesizing fluorinated ethers are direct fluorination of
chlorinated ethers with fluorine gas,11a 2,2,2ꢀtrifluorodiazoethane,11b
Cobalt trifluoride,12 alkenes under the catalysis of boron
tetrafluordiethyl ether complex catalyst13a or by electrochemical
methods.13b Williamson etherification is the most simple and
convenient method for preparing fluoroethers using alcohols and
alkyl halides.14 However, these fluorinated alkyl halides are
responsible for ozone layer depletion. Another simple method is
the pediatric population) bearing
a
trifluoroethyl aryl ether
pharmacophore are commercially available (figure 1).5 Fluorinated
ethers (FEs) have a lower ozone depletion potential (ODP) and low
global warming potential (GWP).6 Chlorofluorocarbons (CFCs),
hydrochlorofluorocarbons (HCFCs), hydrofluorocarbon (HFCs) and
perfluorocarbons (PFCs) are replaced by fluorinated ethers due to
their vast industrial applications such as use in cleaning solvents,
heat transfer agents, refrigeration and carrier fluids.7
etherification
i.e,
alkoxylation
of
tosylate
esters
The popular fluorous analogues tꢀbutyl, benzyl, and
fluorenylmethyloxycarbonyl groups are used for fluorous protection
(perfluoroalkanesulfonate) with alkoxide (phenoxide) anions.15
Fluorinating reagent, fluorous silanes, THP, ethoxylethyl ether
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 1

Page 3 of 5
COMMUNICATION
RSC Advances
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA00618J
acetals, fluorous methoxymethyl ether (FMOM) fluorous benzyl in acetonitrile was found to be the optimum condition for the
groups and acyclic polyfluoro siloxanes are also used for fluorous synthesis of fluorinated ethers (Table 1) and all reaction were
protection of alchohols.16 In these reports, reactions proceed at carried out in this conditions.
elevated temperature in high boiling point solvents. Few research
articles have also reported the synthesis of trifluoroethyl aryl/alkyl
ethers, in which harsh conditions were used in the presence of
aryl/alkyl halides at high temperatures.10 However, there is still need
for mild and efficient reaction conditions. In this context, we now
report a general process for the synthesis of an acid catalyzed
fluorinated alkylating reagent and its use in the synthesis of
alkyl/aryl TFE ethers.
Table 1. Optimization of reaction conditions for the synthesis of
fluorinated ethers using TriTFET.
Entry
Solvent
TriTFET
(Equiv)
0.6
Yielda
1
2
CH2Cl2
CH2Cl2
20
10
94
68
78
60
52
40
84
72
45
32
0.4
0.6
0.4
0.6
0.4
0.6
0.4
0.6
0.4
0.6
0.4
3
CH3CN
CH3CN
DMF
4
5
6
DMF
7
AcOEt
8
AcOEt
9
1,4ꢀDioxane
1,4ꢀDioxane
Toluene
Toluene
10
11
12
Figure 2. Procedure for the synthesis of fluorinated ethers.
Synthesis of fluorinated alkylating reagent TriTFET (2,4,6ꢀTrisꢀ
(2,2,2ꢀtrifluoro ethoxy)ꢀ[1,3,5] triazene) is shown in scheme 1.
Chang et al17 in 1961 introduced the reactions of cyanuric chloride
with several electronegative substituted primary alcohols in which
the electronegative substituents were fluoro, bromo, nitro, or nitroxy
groups. Here we report the synthesis of TriTFET with slight
modification in previously reported methods using the
trifluoroethanol and NaOH as base. The side product cyanuric acid
can be easily removed by filtration because of its low solubility in
organic solvents. Further, during the synthesis and using TriTFET,
we did not observe any irritating properties in our laboratory while
its precursor cyanuric chloride is harmful, corrosive to skin and
irritating to the respiratory tract. These features classify this reagent
as an ecoꢀ and user friendly. TriTFET was characterized by 1H
NMR, 13C NMR and 19F NMR. In 1H NMR spectra only one
multiplet is observed at 4.8 due to –OCH2ꢀ protons. 13CNMR spectra
shows one singlet at δ 172 due to triazene carbons, quartet at δ 126ꢀ
118 is due to ꢀCF3 carbon and multiplet at δ 64 is due to ꢀCH2
carbons. 19FNMR show a singlet at δ ꢀ73 is due to fluorine atom of –
CF3 groups.
aExperimental yield determined by 1H NMR. All reactions carried at room
temperature, TsOH; pꢀtoluenesulphonic acid
19F NMR of TriTFET and all synthesized fluorinated ethers
showed identical peaks at ca. ꢀ73 ppm, which can be attributed
to the presence of –OCH2CF3 group (see supporting
information). The scope of the use of TriTFET for fluorinated
alkylation was investigated with various substrates. (Table 2).
Simple alcohols such as primary and secondary alcohols (Table
2, entries 1ꢀ7) gave desired TFE protected ethers 1a-7a in
excellent yields. Propargyl alcohol also yielded corresponding
TFE ether in good yield (82%, Table 2, entry 8). Benzyl and
benzil alcohols also provided TFE protected ethers in moderate
yields (Table 2, entries 9ꢀ11). Interestingly, reaction of
αꢀ
hydroxyacetophenones, phenols, biologically active hydroxy
coumarin and natural product menthol also afforded
corresponding TFE protected ethers in moderate to good yields
(62ꢀ94%, table 2, entries 12ꢀ17). Further, α and βꢀnaphthols
also undergo TFE etherification with TriTFET, although the
yields are lower than hydroxy acetophenones (Table 2, entries
15 and 16). It is noteworthy that our method is more superior
and economic for fluorinated ether synthesis in comparison
with the other results reported earlier in literature because in
our method no metal and aryl/alkyl halides are used.
TriTFET is protonated with the help of pꢀtoluenesulphonic acid
Scheme 1. Synthesis of TriTFET
(PTSA) to form the trifluoroethyl cation, which reacts with
1
alcohols via SN mechanism to form trifluoroethane ethers.
To optimize the reaction conditions for fluorinated
etherification, we choose different equivalents (0.4 and 0.6) of
TriTFET in different solvents using nꢀbutanol as substrate
Further, the final concomitant leaving group isocyanuric acid is
obtained and easily removed by filtration. However, reaction
did not proceed in the absence of PTSA. Mechanistic results
were rationalized on the basis of previous reports,18 which is
shown in following plausible mechanism (Figure 2).
(scheme 2). We found that 0.6 equivalent of TriTFET gave the
optimum yield. Further, while performing this reaction in
different solvents viz. ACN, AcOEt, DMF, 1,4ꢀdioxane and
toluene, the best result was obtained in CH3CN. Thus, the
reaction of nꢀbutanol in the presence of 0.6 equivalent TriTFET
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

RSC Advances
Page 4 of 5
View Article Online
Journal Name
COMMUNICATION
DOI: 10.1039/C5RA00618J
Table 2. Scope of various alcohol and phenols for the synthesis of fluorinated
ethers using TriTFET
TriTFET
RꢀOH
RꢀOCH2CF3
TsOH (0.2 eq)
ACN, rt
S.
NO.
1
Substrate (R-OH) Prod- TriTFET Time Yielda
uct
1a
2a
0.6
0.6
4h
4h
94
96
2
3
4
5
3a
4a
5a
0.6
0.6
0.6
4h
4h
4h
90
94
80
6
6a
0.6
4h
89
Figure. 2 Reaction Mechanism of TFE alkylation using TriTFET
7
8
7a
8a
0.6
0.6
4h
4h
88
82
OH
Conclusions
9
9a
0.6
4h
78
In conclusion, the present study introduces the 1,3,5ꢀtriazine
based TriTFET as a new reagent for the synthesis of various
fluorinated ethers in higher yield. The inexpensive and easily
available cyanuric chloride and 2,2,2ꢀtrifluoroethanol in one
step gives TriTFET. Its use in the protection of alcohol and
phenols by TFE group allows the synthesis of fluorinated ethers
without using a large amount of halogenated alkyl halides as
previously reported. Thus it is an expedient and ecoꢀfriendly
approach. Further, TriTFET is also suitable for the conversion
of sterically hindered secondary hydroxyl groups and converts
menthol into the corresponding fluorinated ether.
10
10
0.6
5h
80
11
12
11a
12a
0.6
0.6
4h
4h
86
92
Acknowledgement
13
13a
0.6
4h
94
SKM, CS, AKS are thankful to CSIR and UGC, India for providing
fellowship. SKA acknowledges the University of Delhi, Delhi, India
for financial support. Authors are thankful to USIC, University of
Delhi for spectral data.
14
15
14a
15a
0.6
0.6
6h
3h
79
83
Notes and references
aChemical Biology Laboratory, Department of Chemistry, University of
HO
O
O
Delhi,
India.
Emailꢀawasthisatish@yahoo.com;
skawasthi@chemistry.du.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
16
17
16a
17a
0.6
0.6
3h
5h
85
78
1
2
3
4
M. Hudlicky, in: E. Horwood (Ed), Chemistry of Organic
fluorine Compounds, 2nd Edition, Wiley, New York, 1976.
F. Leroux, P. Jeschke, M. Schlosser, Chemical Reviews, 2005,
105, 827ꢀ856.
J. Pacansky, M. Miller, W. Halton, B. Liu, A. Scheiner. J.
Am. Chem. Soc. 1991, 113, 329ꢀ343.
aExperimental yield determined by 1H NMR; Solvent acetonitrile; TsOH= pꢀ
toluenesulphonic acid
Lawson, D. D.; Moacanin, J.; Scherer, K. V., Jr.; Terranova, T.
F.; Ingham, J. D. J. Fluorine Chem. 1978, 12, 221.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 3

Page 5 of 5
COMMUNICATION
RSC Advances
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA00618J
5
6
(a) P. Jeschke, E. Baston, F. R. Leroux, Mini-Reviews in
Medicinal Chemistry, 2007, , 1027ꢀ1034.
7
(a) I. Bravo, DiazꢀDeꢀMera, Y. Aranda, K. Smith, K. P. Shine,
G. Marston, Phys. Chem. Chem. Phys. 2010, 12, 5115ꢀ5125.
(b) D. A. Good, J. S. Francisco, j. Geophy. Res., 1998, 103
28,181ꢀ28,186.
,
7
8
A. Sekiya, S. Misaki, J. Fluorine Chem., 2000, 101, 215ꢀ221.
(a) Z. Y. Luo, J. Williams, R. W. Read, D. P. Curran, J. Org.
Chem. 2001, 66, 4261ꢀ4266. (b) D. P. Curran, M. Amatore, D.
Guthrie, M. Campbell, E. Go, Z. Y. Luo, J. Org. Chem. 2003,
68, 4643ꢀ4647. (c) D. V. Filippov, D. J. Van Zoelen, S. P.
Oldfield, G. A. Vander Marel, H. S. Overkleeft, J. W.
Drijfhout, J. H. Van Boom. Tetrahedron Lett. 2002, 43, 7809ꢀ
7812.
9
Q. Yang, C. Draghici, J. T. Njardarson, F. Li, B. R. Smith and
P. Das. Org. Biomol. Chem. 2014, 12, 330ꢀ344.
10 (a) Q. Yang and J. T. Njardarson. Tetrahedron Lett. 2013, 54
,
7080ꢀ7082. (b) C. E. Morelli, L. Duri, A. Saludino, G.
Speranza, P. Manitto. Synthesis, 2004, 18, 3005ꢀ3010. (c) P. V.
Ramachandran and A. Chatterjee. Organic Letters, 2008, 10,
1195ꢀ1198.
11 (a) S. Akira, U. Kunimasa, Chemistry Letters, 1991, 8, 1421ꢀ
1424. (b) K. L. Koller, H. C. Dorn, Anal. Chem. 1982, 54, 529ꢀ
533.
12 (a) S. Kurosawa, T. Arimura, A. Sekiya, j. of Fluorine Chem.,
1997, 88, 111ꢀ114. (b) J. Burdon, L. Garwer, R. L. Powell, J.
Chem. Soc. Perkin Trans, 1996,
2, 625ꢀ631. (c) D. D.
Moldavskii, G. G. Furin, L. V. Shkul’ttskaya, B. Y. Eifman,
Russian J. of Applied Chem., 2002, 75, 959ꢀ961.
13 (a) D. F. Shellhamer, R. P. Callahan, V. L. Heasley, M. L.
Druelinger, R. D. Chapman. Synthesis, 1997, 1056ꢀ1060. (b) J.
H. Simmons (Ed.), Fluorine Chemistry, Vol. 1, Academic
Press, New York, 1950, 1, pp. 414ꢀ420.
14 P. Tarrant, J. A. Young, J. Am. Chem. Soc. 1952, 75, 932ꢀ934.
15 Q.ꢀY. Chen, R.ꢀX. Zhu, Z.ꢀZ. Li, S.ꢀD. Wang, W. X. Huang,
Acta Chem. Simica. 1982, 40, 337ꢀ352.
16 (a) A. Studer, S. Hadida, R. Ferritto, S.ꢀY. Kim, P. Jeger, P.
Wipf, D. P. Curran. Science, 1997, 275, 823ꢀ826. (b) D. P.
Curran, T. Furukawa, Org. Lett. 2002, 4, 2233ꢀ2235. (c) D. P.
Curran, C. Ogoe, QSAR Comb. Sci. 2006, 25, 732ꢀ735. (d) N.
R. Patel, J. Chen, Y. F. Zhang, R. L. Kirchmeier, J. M.
Shreeve. Inorg. Chem. 1994, 33, 5463ꢀ5470.
17 A. J. Matuszko; M. S. Chang. J. Org. Chem. 1962, 77, 677.
18 K. Yamada; H. Fujita; M. Kunishima. Org. Lett. 2012, 14
,
5026ꢀ5029.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012