Base mediated deprotection strategies for trifluoroethyl (TFE) ethers, a new alcohol protecting group

Article abstract of DOI:10.1016/j.tetlet.2013.10.097

A trifluoroethyl (TFE) ether is specifically introduced as a protecting group in organic chemistry. Its first strategic application and removal in the total synthesis of vinigrol is discussed. Two lithium base mediated deprotection strategies for its removal are presented in this Letter. In one deprotection approach, the trifluoroethyl ether is converted to a difluorovinyl ether and then catalytically cleaved using osmium tetraoxide, while in the second approach a difluorovinyl anion is formed and trapped with an electrophilic oxygen reagent (MoOPH) to form a labile difluoroacetate. To further aid the reader, a summary of approaches for forming trifluoroethyl ethers is included as well as a discussion of alternate deprotection strategies.

Full text of DOI:10.1016/j.tetlet.2013.10.097

Tetrahedron Letters 54 (2013) 7080–7082
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Base mediated deprotection strategies for trifluoroethyl (TFE) ethers,
a new alcohol protecting group
⇑
Qingliang Yang, Jon T. Njardarson
Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A trifluoroethyl (TFE) ether is specifically introduced as a protecting group in organic chemistry. Its first
strategic application and removal in the total synthesis of vinigrol is discussed. Two lithium base
mediated deprotection strategies for its removal are presented in this Letter. In one deprotection
approach, the trifluoroethyl ether is converted to a difluorovinyl ether and then catalytically cleaved
using osmium tetraoxide, while in the second approach a difluorovinyl anion is formed and trapped with
an electrophilic oxygen reagent (MoOPH) to form a labile difluoroacetate. To further aid the reader, a
summary of approaches for forming trifluoroethyl ethers is included as well as a discussion of alternate
deprotection strategies.
Received 11 October 2013
Revised 19 October 2013
Accepted 21 October 2013
Available online 26 October 2013
Keywords:
Trifluoroethyl ether
Difluorovinyl
Ó 2013 Elsevier Ltd. All rights reserved.
Deprotection
Dihydroxylation
Electrophilic oxygen
In our recent total synthesis of vinigrol1 we required a unique
alcohol protecting group that needed to serve several critical roles
(Scheme 1). We needed a small group that would not interfere
with and survive a challenging Dakin oxidation. This same group
was then expected to be electron withdrawing enough to guide
an oxidative dearomatization reaction to the more hindered ether.
In this same key step, the protecting group also needed to
deactivate the resulting enol ether to allow a key intramolecular
Diels Alder reaction to proceed while hindering unproductive
ortho-quinone formation.2 This protecting group was then
expected to survive a plethora of metal-catalyzed, oxidative,
reductive, nucleophilic, acidic and basic reactions all the way to
the final step of the synthesis. Finally, a successful deprotection
of the protected tertiary alcohol was expected to deliver vinigrol.
Remarkably, we did find a protecting group that delivered the
specific size and electronic functions we required. It also survived
an amazing array of reactions and could be selectively deprotected
in the final step. The group we identified as being optimal for all
these tasks was a trifluoroethyl (TFE) ether.
From what we gather from the literature, this is the first exam-
ple that a trifluoroethyl ether is used strategically as protecting
group in target oriented synthesis.3 The aim of this Letter is to edu-
cate the reader about this unique new protecting group. Current
state of the art approaches for protecting alcohols with a TFE ether
will first be summarized followed by a discussion of current and
proposed deprotection approaches inspired by our vinigrol
synthetic pursuit. Finally, the results from two successful base
mediated deprotection strategies we have developed are
presented.
How are trifluoroethyl ethers synthesized? Current state of the
art approaches are summarized in Scheme 2. In addition to what
one would consider classic nucleophilic displacement approaches
O
O
O
O
O
CF3CH2OTf
Cs2CO3. 85 °C
CH3CN
I
I
OMe
OMe
98%
HO
Stable strongly electron withdrawing
protecting group needed!
CF3
PhI(OAc)2, MeOH
2,6-lutidine
CF3CH2OH
-40 °C then
toluene, 60 °C
64%
H2O2, B(OH)3
10 M H2SO4
THF, 50 °C
81%
O
HO
I
OMe
TFEO
O+
O
O
O
O
I
OMe
I
OMe
TFEO
TFEO
LDA
then
OsO4
70%
O
O
OH
OH
OMe
steps
OH
OH
I
O
O
O
TFE
OH
vinigrol
TFE
⇑
Corresponding author.
E-mail address: njardars@email.arizona.edu (J.T. Njardarson).
Scheme 1. Trifluoroethyl ether protecting group in total synthesis.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.097

Q. Yang, J. T. Njardarson / Tetrahedron Letters 54 (2013) 7080–7082
7081
OH
acetylenic ether, which could be transformed to an ester upon
treatment with an appropriate acid and hydrolyzed or reductively
cleaved to afford the alcohol. For our vinigrol total synthesis,
method A was shown to be successful albeit with the use of
stoichiometric amounts of osmium tetroxide.14
Lg
HO
OH
R
SN2
R
R
CF3
HO
Mitsunobu
SN
2
Lg
base
PBu3
CF3
F3C
base
I
CF3
HO
We were eager to learn if the deprotection conditions (Method
A) we had developed for vinigrol could be further improved
(employing catalytic instead of stoichiometric osmium) and to
explore the feasibility of Method B as an alternative TFE ether
deprotection strategy. We were delighted to learn that the inter-
mediate difluorovinyl ether could indeed be cleaved using catalytic
amounts of osmium (Table 1).15,16 The eight substrates shown in
Table 1 can all be deprotected using this approach (Method A) with
the exception of entry 4, which cleanly affords the intermediate
difluorovinyl ether but in our hands does not undergo the oxidative
cleavage reaction. TFE ether protected adamantane alcohol 7
required a slight procedural modification in the form of a stronger
base (t-BuLi). Yields range from moderate to very good for this
deprotection approach. For our second base mediated deprotection
approach, we wanted to explore the feasibility of trapping the vinyl
anion of the intermediate difluorovinyl ether in situ with an elec-
trophilic oxygen reagent (Method B). We were inspired by recent
success from the Wood laboratory, wherein such a strategy (t-BuLi,
O2) had been applied to an extremely challenging deprotection of a
benzyl protected amine.17 These conditions failed in our hands to
deprotect TFE ether. Using LDA as a base we screened what we
considered based on the literature to be the most promising
sources of electrophilic oxygen (O2,18 Davis oxaziridine,19
MoOPH,20 and peroxides21). Our studies revealed that MoOPH
was far superior to all other electrophilic oxygen trapping agents22
in affording the desired intermediate difluoroacetate, which was
hydrolyzed during workup. This new deprotection approach
affords the alcohol product in modest to very good yields (Table 1,
Method B).
Lg = leaving
O
CF3
CuI, ligand
base
R
group
R
ylide
cross coupling
Ph3P(OCH2CF3)2
HBF4
N2
ligand
O
=
F3C
acid
OH
O
insertion
SN
1
CF3
OH
R
OEt
OH
R
R
HO
Scheme 2. How to synthesize trifluoroethyl ethers.
(SN2 or SN1),4 several intriguing trifluoroethyl ether forming reac-
tions have been developed. Because of the strong inductive effects
of the trifluoroethyl groups more strategies are available than
otherwise would be for normal alkyl ethers. For example, Mitsun-
obu reactions are feasible with trifluoroethanol5 as a nucleophile as
are copper catalyzed cross-couplings.6 A particularly interesting
approach is the conversion of alcohols to TFE protected alcohols
employing bis(fluoroalkoxy)triphenyl phosphoranes.7 Finally, it
has been shown that trifluorodiazo ethane can be treated with a
mild acid in the presence of an alcohol as a way to access TFE
protected alcohol products.8
Not surprisingly, since TFE ether has not been used purposefully
as a protecting group, there is not much literature dedicated to
cleaving it. In 1980, inspired by the uniquely attractive solvolysis
properties of trifluoroethanol Sargent decided to evaluate condi-
tions for deprotecting these solvolysis products (TFE protected
alcohols). He found that sodium naphthalene was suited for this
deprotection task.9 In his studies of diamondoid fluorides, Schrein-
er has shown that adamantane type trifluoroethyl ethers can be
subjected to refluxing trifluoroacetic thus affording trifluoroace-
tate products.10 Neither one of these deprotection approaches were
suitable for the last step in our vinigrol synthesis, which meant we
needed to develop new solutions to cleave the TFE ether. We were
drawn to two key clues from the literature (Scheme 3). It has been
known for some time, from the work of Nakai, that lithium bases
could be used to transform trifluoroethyl ethers into difluorovinyl
ethers.11,12 The same authors soon thereafter revealed that treat-
ment with excess alkyllithium forms acetylenic ethers from trifluo-
roethyl ethers.13 We proposed that the intermediate difluorovinyl
ether provided two different deprotection options for accessing
the free alcohol. It could be oxidatively cleaved with reagents such
as osmium tetraoxide (Method A), or alternatively, it could be
deprotonated and the resulting vinyl anion trapped with an
electrophilic oxygen (Method B) reagent to afford a base labile
difluoroacetate product. A more aggressive approach would be to
use Nakai’s conditions to convert the trifluoroethyl ether to an
Trifluoroethyl (TFE) ether is a new small and robust alcohol
protecting group capable of surviving an incredible array of organic
reactions. In this Letter we have demonstrated two new base
Table 1
Two new TFE ether base-mediated deprotection approaches
Entry
1
Method A (%)
73
Method B (%)
41 (66)
O
CF3
1
O
CF3
2
3
42 (49)a
50
29a
2
C8H17
O
CF3
34 (53)
3
O
CF3
4
5
80b
68
4
BnO
O2N
O
CF3
CF3
49 (60)
54 (75)
5
O
F
F
O
CF3
O
O
"O+"
6
34 (44)
71 (83)
6
RLi
RLi
F
F
R
R
R
Li
Method
B
63 (67)
(t-BuLi used)
7
O
excess
RLi
7
8
75b
Method A
CF3
F
cat.
OsO4
O
HO-
O
OH
8
F
R
O
CF3
R
44 (79)
28 (88)
O
R
Ph
Ph
R
reductive
or acidic
cleavage
Method A: LDA then catalytic OsO4. Method B: LDA followed by in situ MoOPH
trapping. Isolated yields, with numbers in parentheses representing yields based on
recovered starting material.
H3O+
O
HO-
R
O
CF3
R
R
O
a
Volatile product.
b
Yield of difluorovinyl ether.
Scheme 3. Base mediated TFE ether deprotection approaches.

7082
Q. Yang, J. T. Njardarson / Tetrahedron Letters 54 (2013) 7080–7082
mediated deprotection strategies. Both take advantage of the low
pKa of the trifluoroethylether protons and remarkably rapid
b-elimination of HF to afford a difluorovinyl ether we then show
can be either oxidatively cleaved or converted into a labile diflu-
oroester. These new deprotection strategies are complementary
to the reductive approach developed by Sargent. The strong elec-
tron withdrawing properties of the TFE ether provide opportunities
for achieving additional synthetic goals beyond protection as
highlighted in our total synthesis of vinigrol wherein the TFE ether
also played a critical enabling role in a Dakin oxidation and oxida-
tive dearomatization steps. It is our hope that the chemistry and
strategies detailed in this Letter will inspire and catalyze new
investigations into target oriented applications of the TFE ether.
Supplementary data
Supplementary data (experimental procedures are provided as
well as spectral data for all new compounds) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.10.097.
References and notes
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8648–8651; For our earlier attempts towards vinigrol, see: (a) Morton, J. G. M.;
Draghici, C.; Kwon, L. D.; Njardarson, J. T. Org. Lett. 2009, 11, 4492–4495; (b)
Morton, J. G. M.; Kwon, L. D.; Freeman, J.; Njardarson, J. T. Tetrahedron Lett.
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2. In our earlier studies we had demonstrated that tosylates (Ts) and benzoates
(Bz) were effective in accomplishing the electronic tasks associated with the
oxidative dearomatization/Diels-Alder step. These groups did however not
survive or hinder the Dakin oxidation reaction, which led us on a quest for a
more robust protecting group with strong electron withdrawing
characteristics.
Representative experimental conditions for Methods A and B
Method A: n-BuLi (2.5 M in hexanes, 0.59 mL, 1.47 mmol) was
added dropwise to
a solution of diisopropylamine (0.23 mL,
3. Baldwin and Tomesch used trifluoroethanol as a solvent for cationic cyclization
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formation of a trifluoroethyl ether. Baldwin, S. W.; Tomesch, J. C. J. Org. Chem.
1980, 45, 5052–5057. This trifluoroethyl ether was found to be resistant to
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1.60 mmol) in THF (2.8 mL) at À78 °C. The reaction was further
stirred at À78 °C for 15 min, and then warmed to 0 °C and stirred
for 15 min. The resultant LDA solution was cooled back to À78 °C
and 1 (100.0 mg, 0.458 mmol) in THF (1.0 mL) was added over
30 min. After the addition was completed, the stirring was
continued for 45 min at À78 °C. The reaction solution turned from
colorless to dark yellow. The reaction was then quenched with
saturated NH4Cl solution at À78 °C and warmed to rt, diluted with
ethyl acetate, washed with brine, dried over anhydrous Na2SO4,
and concentrated. Purification by a silica gel plug (5% ethyl
acetate/hexanes) and careful evaporation of solvent afforded the
difluorovinyl ether with trace residual hexanes. The ether was then
dissolved in t-butanol (2.5 mL) and water (2.5 mL). Potassium
ferricyanide (452.4 mg, 1.37 mmol), potassium carbonate
(189.9 mg, 1.37 mmol), potassium osmium (VI) oxide dihydrate
(3.0 mg, 0.00824 mmol), and pyridine (0.10 mL) were then added.
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(0.5 g) was added and stirred for 30 min. The mixture was diluted
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Jarvi, E. T.; Burkhart, J. P. Tetrahedron Lett. 1985, 26, 2861–2864; (b) Lee, J.;
Tsukazaki, M.; Snieckus, V. Tetrahedron Lett. 1993, 34, 415–418; (c) Patel, S. T.;
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added dropwise to
a solution of diisopropylamine (0.06 mL,
0.400 mmol) in THF (1.0 mL) at À78 °C. The reaction was further
stirred at À78 °C for 15 min then warmed to 0 °C and stirred for
15 min. The resultant LDA solution was cooled back to À78 °C
and 4 (25.0 mg, 0.0886 mmol) in THF (0.5 mL) was added over
30 min. Stirring was then continued for 2 h at À78 °C at which
point MoOPH (192.4 mg, 0.443 mmol) was added. Following two
additional hours of stirring at À78 °C, the reaction was quenched
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(12.0 mg, 68% yield). Note: Depending on substrates, if the basic
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those were not successful.
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Acknowledgements
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22. Davis oxaziridine was shown to be the second best of the trapping agents
although far less successful than MoOPH.
We would like to thank the NIH-NIGMS (RO1 GM 086584) for
supporting our complex molecule synthesis program, which
opened led to the science presented in this Letter.