Download Full-Text PDF

molecules
Article
Evaluation of Efficient and Practical Methods
for the Preparation of Functionalized Aliphatic
Trifluoromethyl Ethers
Taras M. Sokolenko 1 , Maya I. Dronkina 1,† , Emmanuel Magnier 2 , Lev M. Yagupolskii 1,‡
and Yurii L. Yagupolskii 1,3, *
1
2
3
*
†
‡
Institute of Organic Chemistry, NAS of Ukraine, Murmans’ka St. 5, Kiev 02660, Ukraine; [email protected]
Bâtiment Lavoisier, Université de Versailles-Saint-Quentin, 45 Avenue des Etats-Unis,
Versailles 78035, France; [email protected]
Enamine Ltd, A. Matrosova str. 23, Kiev 01103, Ukraine
Correspondence: [email protected]; Tel.: +380-44-559-03-49
Retired.
Passed away.
Academic Editor: Thierry Billard
Received: 28 April 2017; Accepted: 11 May 2017; Published: 14 May 2017
Abstract: The “chlorination/fluorination” technique for aliphatic trifluoromethyl ether synthesis was
investigated and a range of products with various functional groups was prepared. The results were
compared with oxidative desulfurization-fluorination of xanthates with the same structure.
Keywords: fluorination; chlorination; oxidative desulfurization-fluorination; antimony trifluoride;
hydrogen fluoride; trifluoromethyl ethers
1. Introduction
Fluorine is one of the most favorite heteroatoms for incorporation into small molecules in life
science-oriented research. In particular, commercial pharmaceuticals and agrochemicals frequently
contain single fluorine atoms or trifluoromethyl groups [1–4]. Nevertheless, growing interest in
emergent fluorinated substituents, like α-fluorinated ethers, has been observed within recent years [5–8].
While aromatic trifluoromethyl ethers, since their first publication [9] in 1955, have been extensively
studied and widely used as pharmaceuticals and crop protection agents, as well as critical components
for liquid crystals design [3–6,10], aliphatic trifluoromethyl ethers are less studied. Only a few practical
methods for the synthesis of such compounds have been developed. Fluorination of fluoroformates
with SF4 leads to aliphatic trifluoromethyl ethers. For instance, methyl(trifluoromethoxy) acetate was
obtained by this method [11]. Nucleophilic substitution of benzylic halogen or α-halogen atoms in
acetophenones with perfluoroalcoholate anions is a suitable method for aliphatic ether preparation [12].
Oxidative desulfurization-fluorination of xanthates is now the most attractive method for primary
alkyl trifluoromethyl ether synthesis. At least 42 publications concerning this reaction are cited in
Reaxys. N-Bromo- [13] or N-iodosuccinimide [14], dibromodimethylhidantoine [15,16], and IF5 [17]
are suitable oxidants in this reaction. Complexes pyridine-HF or NEt3 -HF are commonly used as
fluorine atom sources. Bromine trifluoride [18] or p-nitrophenylsulfur chlorotetrafluoride [19] were
used as oxidants and fluorinating agents.
A number of new methods for trifluoromethyl ether synthesis were developed over the past ten
years. The progress in this field was well summarized in the [6]. It is also worth noting the recent
publication concern to asymmetric bromotrifluoromethoxylation of alkenes [8].
Molecules 2017, 22, 804; doi:10.3390/molecules22050804
www.mdpi.com/journal/molecules
Molecules
Molecules 2017,
2017, 22,
22, 804
804
22 of
of 10
10
MoleculesA
22, 804of
of 10
number
A2017,
number
of new
new methods
methods for
for trifluoromethyl
trifluoromethyl ether
ether synthesis
synthesis were
were developed
developed over
over the
the past
past 2ten
ten
years.
years. The
The progress
progress in
in this
this field
field was
was well
well summarized
summarized in
in the
the [6].
[6]. It
It is
is also
also worth
worth noting
noting the
the recent
recent
publication
publication concern
concern to
to asymmetric
asymmetric bromotrifluoromethoxylation
bromotrifluoromethoxylation of
of alkenes
alkenes [8].
[8].
Surprisingly, and to the best of our knowledge, common for aromatic and revisited for
Surprisingly,
Surprisingly, and
and to
to the
the best
best of
of our
our knowledge,
knowledge, common
common for
for aromatic
aromatic and
and revisited
revisited for
for
heterocycles
[20]
trifluoromethyl
ether
synthesis
“chlorination/fluorination”
technique
was
not
heterocycles
heterocycles [20]
[20] trifluoromethyl
trifluoromethyl ether
ether synthesis
synthesis “chlorination/fluorination”
“chlorination/fluorination” technique
technique was
was not
not
investigated
enough
forfor
aliphatic
substrates
in order
to compare
existing
methods
due to due
the necessity
investigated
aliphatic
to
investigated enough
enough for
aliphatic substrates
substrates in
in order
order to
to compare
compare existing
existing methods
methods due
to the
the
tonecessity
choose
the
most
effective
ones
leading
to
the
best
yields
and
the
lowest
percentage
of
byproducts.
of
necessity to
to choose
choose the
the most
most effective
effective ones
ones leading
leading to
to the
the best
best yields
yields and
and the
the lowest
lowest percentage
percentage
of
It byproducts.
was
reportedIt
1,1,1-trifluoro-2-(trichloromethoxy)propane
fluorination with
anhydrous
HF
was
reported
that
fluorination
with
byproducts.
Itthat
wasonly
reported
that only
only 1,1,1-trifluoro-2-(trichloromethoxy)propane
1,1,1-trifluoro-2-(trichloromethoxy)propane
fluorination
with
yielded
the corresponding
trifluoromethyl
ether
[21]. The aimether
of this
work
the was
question
anhydrous
HF
corresponding
trifluoromethyl
[21].
The
aim
this
anhydrous
HF yielded
yielded the
the
corresponding
trifluoromethyl
ether
[21].
Thewas
aimtoof
ofanswer
this work
work
was to
to
“isanswer
a
“chlorination/fluorination”
technique
suitable
for
the
aliphatic
trifluoromethoxy-containing
answer the
the question
question “is
“is aa “chlorination/fluorination”
“chlorination/fluorination” technique
technique suitable
suitable for
for the
the aliphatic
aliphatic
compound
preparation as it is for
aromatic preparation
ones” and toas
compare
of this
method
oxidative
trifluoromethoxy-containing
compound
it
aromatic
ones”
and
to
trifluoromethoxy-containing
compound
preparation
as
it is
is for
forresults
aromatic
ones”
andwith
to compare
compare
desulfurization-fluorination
at
the same
substrates.
results
desulfurization-fluorination
at
results of
of this
this method
method with
with oxidative
oxidative
desulfurization-fluorination
at the
the same
same substrates.
substrates.
2. 2.
Results
and
Results
and
Discussion
2.
Results
andDiscussion
Discussion
We
based
our
acidderivatives,
derivatives,and
and
alcohols
We
based
our
research
on
hydroxyacetic
and
β-hydroxypropionic
alcohols
We
based
ourresearch
researchon
onhydroxyacetic
hydroxyaceticand
and β-hydroxypropionic
β-hydroxypropionic acid
acid
derivatives,
and
alcohols
containing
two
and
three
carbon
atoms,
containing
two
and
three
carbon
atoms,
including
branched
structures
with
phtalimido
end
groups
containing
two
and
three
carbon
atoms,including
includingbranched
branchedstructures
structureswith
withphtalimido
phtalimidoend
endgroups
groupsas
model
objects.
as
objects.
as model
model
objects.
Xanthates
1a–g
were
prepared
in
one-pot
procedure
Xanthates
starting from
fromsodium
sodiumalcoholates
alcoholatesof
Xanthates1a–g
1a–gwere
wereprepared
prepared in
in aaa one-pot
one-pot procedure
procedure starting
starting
from
sodium
alcoholates
ofof
ω-hydroxysubstituted
aliphatic
esters,
of
carbon
ω-hydroxysubstitutedaliphatic
aliphaticesters,
esters, nitriles,
nitriles, and
N-protected
alkanolamines
by
the
action
ofof
carbon
ω-hydroxysubstituted
and N-protected
N-protectedalkanolamines
alkanolaminesby
bythe
theaction
action
carbon
disulfide
and
methyliodide.
products
yields
in
all
cases
(Scheme
1).
disulfide
andmethyliodide.
methyliodide. Target
Target products
products were
were
obtained
with
high
yields
in in
allall
cases
(Scheme
1). 1).
disulfide
and
wereobtained
obtainedwith
withhigh
high
yields
cases
(Scheme
NaH,
NaH, CS
CS22
then
then MeI
MeI
R
R OH
OH
R
R
SMe
SMe
O
O
S
S
1a-g
1a-g
O
O
Me
Me
O
O
O
O
O
O
O
O
Me
Me O
O
O
O
S
S
1a
1a
1b
1b
S
S
S
S
O
O
O
O
Me
Me
N
N
N
N
S
S
O
O
O
O
S
S
S
1c
1c S
S
S
O
O
O
O
N
N
1d
1d
S
S
S
S
O
O
O
O
1e
1e
S
S
N
N
O
O
Me
Me
O
O
1f
1f S
S
S
S
S
S
N
N
O
O
S
S
O
Me
O Me
1g
1g
Scheme
Synthesis
and
Scheme1.1.
1.Synthesis
Synthesis and
and structures
of methylxanthates.
methylxanthates.
Scheme
structures of
methylxanthates.
Chlorination
xanthates
1a–g
readily
occurred
elemental chlorine
to produce
Chlorination ofof
of xanthates
xanthates 1a–g
1a–g readily
readily occurred
occurred with
with
Chlorination
with elemental
elemental chlorine
chlorine toto produce
produce
trichloromethylethers
trichloromethylethers 2a–g,
2a–g, which
which were
were isolated
isolated with
with almost
almost quantitative
quantitative yields
yields (Scheme
(Scheme 2).
2).
trichloromethylethers 2a–g, which were isolated with almost quantitative yields (Scheme 2).
Chloroderivatives
Chloroderivatives 2a–g
2a–g can
can be
be stored
stored in
in aa fridge
fridge and
and they
they are
are extremely
extremely sensitive
sensitive to
to moisture.
moisture.
Chloroderivatives 2a–g can be stored in a fridge and they are extremely sensitive to moisture.
R
R
O
O
1a-g
1a-g
SMe
SMe
S
S
Cl
Cl22
R
R
Method
Method A:
A: SbF
SbF33 with
with SbCl
SbCl55 (cat.)
(cat.)
Method
B:
HF
with
SbCl
(cat.)
Method
B:
HF
with
SbCl
(cat.)
5
5
OCCl
OCCl33
2a-g
2a-g
R
R
OCF
OCF33
3a-g
3a-g
Method
, DBH
Method C:
C: Py
Py // HF
HF70
70 %
%, DBH
Scheme
trifluoromethoxiderivatives.
Scheme
Syntheses
of
Scheme2.2.
2.Syntheses
Syntheses of
of trifluoromethoxiderivatives.
trifluoromethoxiderivatives.
Antimony
trifluoride
and
hydrogen
fluoride
(method
B)
used
for
Antimony
(methodA)
hydrogen
fluoride
(method
were
used for
Antimony trifluoride
trifluoride (method
(method
A)A)
andand
hydrogen
fluoride
(method
B) were
were B)
used
for chlorinechlorinefluorine
because
they
the
cheapest
for
reaction.
Antimonium
pentachloride
was
fluorine exchange
exchange
becausebecause
they are
are
theare
cheapest
for this
thisfor
reaction.
Antimonium
pentachloride
was
chlorine-fluorine
exchange
they
the cheapest
this reaction.
Antimonium
pentachloride
was used as catalyst in both cases. Pyridine-HF70% and dibromodimethylhidantoine (DBH) (method
C) were used for oxidative desulfurization-fluorination. It must be added that xanthates 1a–g were
converted to trifluoromethyl ethers by the last method in the one-pot synthesis (Scheme 2).
Molecules
2017,
804
3 of
Molecules
2017,
22,22,
804
3 of
1010
Molecules
2017,
22,
804
3ofwere
of10
10
Molecules
2017,
22,
804
3were
were
used
for
oxidative
desulfurization-fluorination.
It Itmust
1a–g
were
used
for
oxidative
desulfurization-fluorination.
mustbebeadded
addedthat
thatxanthates
xanthates
1a–g
used
catalyst
in
Pyridine-HF
70%
and
(DBH)
C)
usedas
as
catalyst
inboth
bothcases.
cases.
Pyridine-HF
70%
anddibromodimethylhidantoine
dibromodimethylhidantoine
(DBH)(method
(method
C)
Molecules 2017, 22, 804
3 of 10
converted
to
trifluoromethyl
ethers
by
the
last
method
in
the
one-pot
synthesis
(Scheme
2).
converted
to
trifluoromethyl
ethers
by
the
last
method
in
the
one-pot
synthesis
(Scheme
2).
Molecules
2017,
22,
804
3
of
10
were
used
for
oxidative
desulfurization-fluorination.
It
must
be
added
that
xanthates
1a–g
were
were
used
for
oxidative
desulfurization-fluorination.
It
must
be
added
that
xanthates
1a–g
were
Molecules
2017,
22,804
804
Molecules
2017,
22,
3 3ofofC)
1010
usedasas
catalyst
bothcases.
cases.Pyridine-HF
Pyridine-HF
70%
anddibromodimethylhidantoine
dibromodimethylhidantoine(DBH)
(DBH)(method
(method
C)
used
catalyst
ininboth
70%
and
usedIn
as
catalyst
inof
both
cases.Pyridine-HF
Pyridine-HF70%
70%
and
dibromodimethylhidantoine
C)
used
as
catalyst
in
both
cases.
and
dibromodimethylhidantoine
C)
case
of
trichloromethoxyacetate
2a2a
fluorination
by
both
methods
A(DBH)
and
failed.
Inthe
the
case
trichloromethoxyacetate
fluorination
by
bothsynthesis
methods(Scheme
A(DBH)
andB(method
B(method
failed.The
The
converted
tofor
ethers
bybythe
method
in
the
one-pot
converted
totrifluoromethyl
trifluoromethyl
ethers
thelast
last
method
the
one-pot
synthesis
(Scheme
2).
wereused
used
for
oxidative
desulfurization-fluorination.
Itmust
must
beadded
added
thatxanthates
xanthates
1a–gwere
were
were
used
oxidative
desulfurization-fluorination.
ItItin
must
be
added
that
xanthates
1a–g
were
used
as
catalyst
in both cases.
Pyridine-HF
70% and dibromodimethylhidantoine
(DBH) 2).
(method
C)
were
used
for
oxidative
desulfurization-fluorination.
must
be
added
that
xanthates
1a–g
were
were
for
oxidative
desulfurization-fluorination.
It
be
that
1a–g
desired
compound
3a
was
prepared
with
yield
only
bybyoxidative
desulfurization-fluorination
of
used
catalyst
in
both
cases.
Pyridine-HF
70%
and
dibromodimethylhidantoine
(DBH)
(method
C)
desired
compound
3a
was
prepared
withlow
low
yield
only
oxidative
desulfurization-fluorination
In
the
case
of
trichloromethoxyacetate
2a
fluorination
by
both
methods
A(DBH)
and
failed.
The
used
as
catalyst
inof
both
cases.
Pyridine-HF
70%
and
dibromodimethylhidantoine
C)of
used
as
catalyst
in
both
cases.
Pyridine-HF
70%
and
dibromodimethylhidantoine
C)
Inas
the
case
trichloromethoxyacetate
2a
fluorination
by
both
methods
A(DBH)
andB(method
B(method
failed.
The
converted
to
trifluoromethyl
ethers
by
the
last
method
in
the
one-pot
synthesis
(Scheme
2).
converted
to
trifluoromethyl
ethers
by
the
last
method
in
the
one-pot
synthesis
(Scheme
2).
were
used
for
oxidative
desulfurization-fluorination.
It
must
be
added
that (Scheme
xanthates
1a–g
were
converted
to
trifluoromethyl
ethers
by
the
last
method
in
the
one-pot
synthesis
(Scheme
2).
converted
to
trifluoromethyl
ethers
by
the
last
method
in
the
one-pot
synthesis
2).
Molecules
2017,
22,
804
3
of
10
xanthate
1a
(Table
1,
Entry
1).
On
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
were
used
for
oxidative
desulfurization-fluorination.
It
must
be
added
that
xanthates
1a–g
were
xanthate
1a
(Table
1,
Entry
1). On the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
desired
compound
3a
was
prepared
with
yield
only
oxidative
desulfurization-fluorination
ofof
were
used
for
oxidative
desulfurization-fluorination.
Itby
must
be
added
thatxanthates
xanthates
1a–g
were
were
used
for
oxidative
desulfurization-fluorination.
It
must
be
added
that
1a–g
were
desired
compound
3a
was
prepared
with
low
yield
only
by
oxidative
desulfurization-fluorination
In
the
case
oftrichloromethoxyacetate
trichloromethoxyacetate
2a
fluorination
by
both
methods
Aand
andBBBB
failed.
The
In
the
case
of
trichloromethoxyacetate
2a
fluorination
by
both
methods
A
and
failed.
The
converted
to
trifluoromethyl
ethers by
thelow
last
method
in
the
one-pot
synthesis
(Scheme
2).
In
the
case
of
trichloromethoxyacetate
2a
fluorination
by
both
methods
A
and
failed.
The
In
the
case
of
2a
fluorination
by
both
methods
A
failed.
The
acids
derivatives
2b–c
and
1b–c
was
successfully
performed
by
methods
(Table
converted
to
trifluoromethyl
ethers
by
the
last
method
in
the
one-pot
synthesis
(Scheme
2).
acids
derivatives
2b–c
andxanthates
xanthates
1b–c
was
successfully
performed
byallallthree
three
methods
(Table1,1,
xanthate
1a
(Table
1,
Entry
1).
On
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
converted
tocase
trifluoromethyl
ethers
by
the
last
method
the
one-pot
synthesis
(Scheme
2).
converted
to
trifluoromethyl
ethers
by
the
last
method
ininby
the
one-pot
synthesis
(Scheme
xanthate
1a
(Table
1,
Entry
1).
Onthe
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
desired
compound
3a
was
prepared
with
low
yield
only
by
oxidative
desulfurization-fluorination
of
desired
compound
3a
was
prepared
with
low
yield
only
oxidative
desulfurization-fluorination
of
In compound
the
of3a
trichloromethoxyacetate
2a
fluorination
by
both
methods
A
and B2).
failed. The
desired
compound
3a
was
prepared
with
low
yield
only
by
oxidative
desulfurization-fluorination
ofof
desired
was
prepared
with
low
yield
only
by
oxidative
desulfurization-fluorination
of
In
the
case
of
trichloromethoxyacetate
2a
fluorination
by
both
methods
A
and
B
failed.
The
entry
2,3).
In
the
case
of
nitrile
2c
reaction
with
SbF
3 3(method
A)
lead
to
low
yield
of
entry
2,3).
In
the
case
of
nitrile
2c
reaction
with
SbF
(method
A)
lead
to
low
yield
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
1,
In
the
case
of
trichloromethoxyacetate
2a
fluorination
by
both
methods
A
and
B
failed.
The
In
the
case
of
trichloromethoxyacetate
2a
fluorination
by
both
methods
A
and
B
failed.
The
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
xanthate
1a
(Table
Entry
1).
On
the
contrary,
fluorination
trichloromethoxypropanecarboxylic
xanthate
1a
(Table
1,
Entry
1).
On
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
desired
3a
was
prepared
with
low
only byby
oxidative
desulfurization-fluorination
of1,
Incompound
the
case
of1,
trichloromethoxyacetate
2a yield
fluorination
both
methods
A and B failed. The desired
xanthate
1a
(Table
1,1,
Entry
1).
On
the
contrary,
fluorination
ofof
trichloromethoxypropanecarboxylic
xanthate
1a
(Table
Entry
1).
On
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
desired
compound
3a
was
prepared
with
low
yield
only
by
oxidative
desulfurization-fluorination
of
trifluoromethylether
3c
(Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
trifluoromethylether
3c
(Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
entry
2,3).
In
the
case
of
nitrile
2c
reaction
with
SbF
3
(method
A)
lead
to
low
yield
of
desired
compound
3a
was
prepared
with
low
yield
only
by
oxidative
desulfurization-fluorination
ofof
desired
compound
3a
was
prepared
with
low
yield
only
by
oxidative
desulfurization-fluorination
of
entry
2,3).
Inwas
the
case
of
nitrile
2c
reaction
SbF
3 (method
A)
leadmethods
to lowof
yield
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
(Table
1,
xanthate
1a (Table
1,prepared
Entry
1).
On
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
compound
3a
with
low
yield
only
by with
oxidative
desulfurization-fluorination
xanthate
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
1,1,
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
1,
xanthate
1a
(Table
1,
Entry
1).
On
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
trifluoromethylether
3c
1,
4).
Thus,
the
presence
of
carboxylic
xanthate
1a1,
(Table
Entry
1).
On
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
xanthate
1a
(Table
1,1,case
Entry
1).
On
the
contrary,
fluorination
trichloromethoxypropanecarboxylic
trifluoromethylether
3c(Table
(Table
1,Entry
Entry
4).
Thus,
the
presence
ofelectron-withdrawing
electron-withdrawing
carboxylic
entry
2,3).
the
case
of
nitrile
2c
reaction
with
SbF
3(method
(method
A)lead
leadto
tolow
low
yield
entry
2,3).
In
the
of
nitrile
2c
reaction
with
SbF
3of
A)
lead
to
low
yield
of
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
byA)
all
three
methods
(Table
1,
1a
(Table
Entry
1).
On
the
contrary,
fluorination
of
trichloromethoxypropanecarboxylic
acids
entry
2,3).
InIn
the
case
of
nitrile
2c
reaction
with
SbF
(method
A)
lead
to
low
yield
ofof
entry
2,3).
In
the
case
of
nitrile
2c
reaction
with
SbF
3 3performed
(method
yield
of
In
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
by
all
three
methods
(Table
In
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
1,1,
acids
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
1,
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
trifluoromethylether
3c
(Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
trifluoromethylether
3c
(Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
entry
2,3).
In
the
case
of
nitrile
2c
reaction
with
SbF
3 (method
A)
lead
to
low
yield
of
derivatives
2b–c
and
xanthates
1b–c
was
successfully
performed
by
all
three
methods
(Table
1,
entry
trifluoromethylether
3c
(Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
trifluoromethylether
3c
(Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
groups
(Table
1,the
Entry
4–7)
inin
higher
yields
of
products
3d–g
as
compared
with
entry2,3).
2,3).
the
case
ofnitrile
nitrile
reaction
with
SbF
3 (method
A)
lead
to
lowyield
yield
of
groups
(Table
1,
Entry
4–7)
results
higher
yields
offluorinated
fluorinated
products
3d–g
as
compared
with
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
entry
2,3).
InIn
the
case
ofresults
nitrile
2c2c
reaction
with
SbF
(method
A)
lead
low
yield
entry
In
case
of
2c
reaction
with
SbF
3 3 (method
A)
lead
toto
low
ofof3c
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
group
close
the
reaction
center
prevented
fluorination
processes.
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
trifluoromethylether
3c (Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
2,3).InIn
In
theto
case
of
nitrile
2c
reaction
with
SbF
(method
A)
lead
to
low
yield
of
trifluoromethylether
3successful
group
close
toto
the
reaction
center
prevented
successful
fluorination
processes.
group
close
the
reaction
center
prevented
successful
fluorination
processes.
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
trifluoromethylether
3c
(Table
1,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
groups
(Table
Entry
results
ininhigher
yields
of2d–g
fluorinated
products
3d–g
asas
compared
with
trifluoromethylether
3c4–7)
(Table
Entry
4).
Thus,
the
presence
ofelectron-withdrawing
electron-withdrawing
carboxylic
trifluoromethylether
3c
(Table
1,1,
Entry
4).
Thus,
the
presence
of
groups
(Table
1,
Entry
4–7)
results
higher
yields
of
fluorinated
products
3d–g
compared
with
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
In
general,
fluorination
of
trichloromethylethers
and
xanthates
1d–g
with
protected
amino
group
close
to 1,
the
reaction
center
prevented
successful
fluorination
processes.
(Table
1,general,
Entry
4).
Thus,
the
presence
of
electron-withdrawing
carboxylic
group
close
tocarboxylic
the
reaction
InIn
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
In
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
ofof
xanthate
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
xanthate
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
group
close
to
the
reaction
center
prevented
successful
fluorination
processes.
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
groups
(Table
1,
Entry
4–7)
results
higher
yields
of
fluorinated
products
3d–g
compared
with
groups
(Table
1,
Entry
4–7)
results
in
higher
yields
of
fluorinated
products
3d–g
as
compared
with
In (Table
general,
fluorination
of
trichloromethylethers
2d–g
and xanthates
1d–g
with
protected
amino
center
prevented
successful
fluorination
processes.
groups
(Table
1,result
Entry
4–7)
results
inin
higher
yields
of
fluorinated
products
3d–g
asas
compared
with
groups
1,
Entry
4–7)
results
in
higher
yields
of
fluorinated
products
3d–g
as
compared
with
In
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
1f
gave
ageneral,
than
fluorination
ofmethods.
2f
with
SbF
3 or
HF
(Table
1,
6).
An
1f
gave
abetter
better
result
than
fluorination
ofchloroderivative
chloroderivative
2f
with
SbF
3 or
HF
(Table
1,entry
entry
6).
An
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
of
xanthate
In
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
In
general,
fluorination
of
trichloromethylethers
2d–g
and
xanthates
1d–g
with
protected
amino
prepared
with
high
yields
by
all
three
Oxidative
desulfurization-fluorination
of
xanthate
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
groups
1, Entry
4–7) results
inderivatives.
higher yields
of 2d–g
fluorinated
products
3d–g
as
compared
with
In(Table
general,
fluorination
of
trichloromethylethers
and xanthates
1d–g
with
protected
amino
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
the
same
reaction
of
carboxylic
acids
Trifluoromethylethers
with
linear
chains
3d,e
were
groups
(Table
1,
Entry
4–7)
results
in
higher
yields
of
fluorinated
products
3d–g
as
compared
with
essential
difference
was
observed
in
fluorination
of
trichloromethylether
2g
and
xanthate
1g
(Table
1,
essential
difference
was
observed
in
fluorination
of
trichloromethylether
2g
and
xanthate
1g
(Table
1,
1f
gave
a(Table
better
than
fluorination
ofmethods.
2f
with
SbF
3 or
HF
(Table
1,
6).
An
groups
1,result
Entry
4–7)
results
inin
higher
yields
fluorinated
products
3d–g
asas
compared
with
groups
(Table
1,high
Entry
4–7)
results
in
higher
yields
ofofof
fluorinated
products
3d–g
as
compared
with
1f
gave
a(Table
better
result
than
fluorination
ofchloroderivative
chloroderivative
2f
with
SbF
3 or
HF
(Table
1,entry
entry
6).
An
prepared
with
high
yields
by
all
three
Oxidative
desulfurization-fluorination
of
xanthate
prepared
with
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
of
xanthate
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
groups
1,
Entry
4–7)
results
higher
yields
fluorinated
products
3d–g
compared
with
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
of
xanthate
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
of
xanthate
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
entry
7).7).Fluorination
of
compound
2g
by
oflinear
trifluoromethylether
entry
Fluorination
of
compound
2g
bymethods
methods
Aand
andB Bled
ledtotolow
lowyields
yields
of
trifluoromethylether
essential
difference
observed
in
fluorination
of
trichloromethylether
2g
and
xanthate
1g
(Table
1,
the
same
reaction
ofwas
carboxylic
acids
derivatives.
Trifluoromethylethers
with
chains
3d,e
were
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
linear
chains
3d,e
were
essential
difference
was
observed
in
fluorination
ofA
trichloromethylether
and
xanthate
1g
(Table
1,
1f
gave
abetter
better
result
than
fluorination
of
chloroderivative
with
SbF
3 2g
or
HF
(Table
1,
entry
6).
An
1f
gave
result
than
fluorination
of
chloroderivative
2f
with
SbF
3with
or
HF
(Table
1,
entry
6).
An
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
of
xanthate
the
same
reaction
of
carboxylic
acids
derivatives.
Trifluoromethylethers
with
linear
chains
3d,e
were
1f3g.
gave
better
result
than
fluorination
ofmethods.
chloroderivative
2f2f
with
SbF
or
HF
(Table
1,ether
entry
6).
An
1f
gave
aaabetter
result
than
fluorination
of
chloroderivative
2f
with
SbF
3 3or
HF
(Table
1,
entry
6).
An
3g.
Nevertheless,
oxidative
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
3g
with
prepared
with
high
yields
by
all
three
Oxidative
desulfurization-fluorination
of
xanthate
Nevertheless,
oxidative
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
ether
3g
with
entry
7).
Fluorination
of
compound
2g
by
methods
A
and
B
led
to
low
yields
of
trifluoromethylether
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
of
xanthate
prepared
with
high
yields
by
all
three
methods.
Oxidative
desulfurization-fluorination
of
xanthate
entry
7).
Fluorination
of
compound
2g
by
methods
A
and
B
led
to
low
yields
of
trifluoromethylether
essential
difference
was
observed
in
fluorination
trichloromethylether
and
xanthate
1g
(Table
1,
essential
difference
was
observed
in
fluorination
of
trichloromethylether
2g
and
xanthate
1g
(Table
1,
1f
gave adifference
better
than
fluorination
of
chloroderivative
2fdesulfurization-fluorination
with SbF32g
or2g
HF
(Table
1, 1g
entry
6). An
prepared
with result
high
yields
by allin
three
methods.
Oxidative
of
xanthate
essential
difference
was
observed
in
fluorination
ofof
trichloromethylether
2g
and
xanthate
1g
(Table
1,
essential
was
observed
fluorination
of
trichloromethylether
and
xanthate
(Table
1,
quantitative
yield.
Itoxidative
should
be
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
1f
gave
abetter
better
result
than
fluorination
of
chloroderivative
2f
with
SbF
3 or
HF
(Table
1,derivatives.
entry
6).
An
yield.
It
should
be
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
derivatives.
3g.
Nevertheless,
oxidative
desulfurization-fluorination
of
1g
allowed
obtaining
3g
with
1fquantitative
gave
result
than
fluorination
ofmethods
chloroderivative
2f
with
SbF
or
HF
(Table
entry
6).
An
1f
gave
aaFluorination
better
result
than
fluorination
of
chloroderivative
2f
with
SbF
3 3yields
or
HF
(Table
1,1,ether
entry
6).
An
3g.
Nevertheless,
desulfurization-fluorination
ofxanthate
xanthate
1g
allowed
obtaining
ether
3g
with
entry
7).
Fluorination
of
compound
2g
by
methods
A
and
B
led
to
low
of
trifluoromethylether
entry
7).
of
compound
2g
by
A
and
B
led
to
low
yields
of
trifluoromethylether
essential
difference
was
observed
in
fluorination
of
trichloromethylether
2g
and
xanthate
1g
(Table
1,
1f
gave
a
better
result
than
fluorination
of
chloroderivative
2f
with
SbF
or
HF
(Table
1,
entry
6).
3 of
entry
7).Fluorination
Fluorination
compound
2gfluorination
bymethods
methodsof
andBBled
ledtotolow
lowyields
yields
oftrifluoromethylether
trifluoromethylether
entry
7).
ofofcompound
2g
by
AAand
essential
difference
was
observed
trichloromethylether
2g
and
xanthate
1g
(Table
quantitative
yield.
Itoxidative
should
be
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
derivatives.
essential
difference
was
observed
fluorination
trichloromethylether
2g
and
xanthate
1g
(Table
essential
was
ininin
fluorination
ofof
trichloromethylether
2g
and
xanthate
1g
(Table
1,1,1,
quantitative
yield.
It
should
benoted
noted
that
both
(1g
and
2g)
are
secondary
alcohol
derivatives.
Table
1.
Structures
and
yields
ofsubstrates
chlorinated
fluorinated
products.
Table
1.
Structures
and
yields
of
chlorinated
and
fluorinated
products.
3g.
Nevertheless,
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
ether
3g
with
3g.
Nevertheless,
oxidative
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
ether
3g
with
entry
7). difference
Fluorination
ofobserved
compound
2g
methods
A
Band
led
to
low
yields
of
trifluoromethylether
An
essential
difference
was
observed
inby
fluorination
ofand
trichloromethylether
2g
and
xanthate
1g
(Table
1,
3g.
Nevertheless,
oxidative
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
ether
3g
with
3g.
Nevertheless,
oxidative
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
ether
3g
with
entry
7).
Fluorination
of
compound
2g
by
methods
A
and
B
led
to
low
yields
of
trifluoromethylether
entry
7).
Fluorination
of
compound
2g
by
methods
A
and
B
led
to
low
yields
of
trifluoromethylether
entry
7).
Fluorination
of
compound
2g
by
methods
A
and
B
led
to
low
yields
of
trifluoromethylether
quantitative
yield.
It
should
be
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
derivatives.
quantitative
yield.
ItItTable
should
be
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
derivatives.
3g.
Nevertheless,
oxidative
desulfurization-fluorination
xanthate
allowed
obtaining
3g with
entry
7). Fluorination
of
compound
2g
by
methods
A of
and
B
led
to1g
low
yields
of
trifluoromethylether
1.1.Structures
and
yields
of
and
fluorinated
products.
Structures
and
yields
ofchlorinated
chlorinated
and
fluorinated
products.
Yield
%%ether
quantitative
yield.
should
be
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
derivatives.
Yield
quantitative
yield.
ItTable
should
be
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
derivatives.
3g.
Nevertheless,
oxidative
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
ether
3g
with
3g.
Nevertheless,
oxidative
desulfurization-fluorination
xanthate
1g
allowed
obtaining
ether
3g
with
3g.
Nevertheless,
oxidative
ofof
xanthate
1g
allowed
obtaining
ether
3g
with
Yield
quantitative
yield.
Itoxidative
shoulddesulfurization-fluorination
be
noted Yield
that
both substrates
(1g
and 2g)
are
secondary
alcohol
derivatives.
3g.
Nevertheless,
desulfurization-fluorination
of
xanthate
1g
allowed
obtaining
ether
3g
with
Table
1.
Structures
and
yields
of
chlorinated
and
fluorinated
products.
Method
Method
Method
1.
Structures
and
yields
of
chlorinated
and
fluorinated
products.
Method
Method
Method
quantitative
yield.
It should
be
noted
that
both
(1g
and
2g)
are
secondary
alcohol
derivatives.
Yield
%% derivatives.
Entry
Chlorinated
Product
Fluorinated
Product
Entry yield.
Chlorinated
Product
Fluorinated
Product
Yield
Table
1.Structures
Structures
and
yields
ofsubstrates
chlorinated
and
fluorinated
products.
Table
1.
and
yields
of
chlorinated
and
fluorinated
products.
quantitative
yield.
Itshould
bebe
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
derivatives.
quantitative
ItTable
be
noted
that
both
substrates
(1g
and
2g)
are
secondary
alcohol
quantitative
yield.
Itshould
should
noted
that
%Yield
% both substrates (1g and 2g) are secondary alcohol derivatives.
Yield
Table 1. Structures and yields of chlorinated and fluorinated
A A products.
B B %%
Method
Method
Method
Method
Yield
Yield
Chlorinated
Product
Fluorinated
Product
Chlorinated
Product
Fluorinated
Product
Table
1.
Structures
and
yields
of
chlorinated
and
fluorinated
products.
Yield%%
Yield
Table
Structures
and
yields
chlorinated
and
fluorinated
products.
Table
1.1.Structures
and
yields
ofofchlorinated
and
fluorinated
products.
%Yield
%
Yield
Yield
A A products.
BB%
Yield
O OProduct
O O Product
Table
1.Product
StructuresYield
and yieldsFluorinated
of
chlorinated
and fluorinated
Method
Method
Method
Method
Me
Me
Me
Me
Entry
Chlorinated
Fluorinated
Product
Entry
Chlorinated
Method
Method
Method
Method
Yield
Entry
ChlorinatedProduct
Product
FluorinatedProduct
Product
Entry
Chlorinated
Fluorinated
traces
traces
traces
traces
Yield
Yield
Yield
%%%
%
%
O
OO
O
%
%87
1 1
Method
Method
87
Yield
A
B
A
B
Entry
Chlorinated
Fluorinated
Product
O
OOOProduct
O
Me
Me
Me
Me
Yield
Yield
CFCF
CCl
A
B
CCl
A
BMethod
O OProduct
OProduct
Method
3
3 3
Entry
Chlorinated
Fluorinated
%
traces
traces
Method
Method
Method
Method
traces
traces
Yield
%
Chlorinated
Fluorinated
Entry
Chlorinated
Product
Fluorinated
Product3
Entry
Chlorinated
Fluorinated
O
OO2a2a Product
O3a3aProduct
A
B
%
Entry
11
87
Yield%
87
O
O CCl
O
O
%
%
Me
MeProduct
Me
Me
A
B
CF
CF
O
O
Product
O
OO OO CCl
O
Me
Me
Me
Me
3 3
3 3
A
B
Atraces
Btraces
traces
traces
Method
Method
O3aO
O 2a
OOO
O
tracesA
traces B
traces
traces
3a
1 1
8787
O
MeO
MeO
O 2aO
87
11
87
CF
CCl
CF
CCl
O
O
O
O
O
O
traces
traces
Me
Me
CF333 3
CCl333 3
OO OO OO CCl
MeO OO OO CF
Me
MeO
Me
traces
traces
1
87
3a
2a
3a
2a
53
69
53
69
O3a
O2a
traces
traces
traces
traces
OOO
CF
CCl3
3a
2a
O
O
1
87
O
O
O
Me
CF
O
O
Me
3CF
O
O
89
89
87
1212
O
3 3
O
CF
87
traces
traces
CCl
O
O
Me
CCl
OCCl
MeO O 2a OO
CCl
OCCl
3
33
3a
CF
CF
O
O
3
33
33
5353
6969
O3b3b
O
OO
Me
O
MeO
CF
3a3a OOCF
3a
2a2a
22
8989
2b
O2a
O
3 3
Me
OOO 2b OOCCl
MeO
CCl
3 3
O 3b3b
5353
6969
53
69
O
53
69
O 2b2b
MeO
CF
Me
CF
OOO
O
2 2
8989
3 3
Me
CF
OOCF
Me
O
89
MeO O
CCl
O
O
22
89
Me
CCl
O
3
3
53
69
3 3
Me OO
CCl
Me
CCl
OOOCCl
CCl
CF
O
3b O
3b
Me O 3b
CF
O CF
33 33
3 33
53
69
22
89
22
66
3b
89
53
69
2b
2b
5322
6966
53
69
Me
CF3
89
NMe
92
2b O OCCl
NMe
3
NOOO3b OOO
92
N O O2b
Me
CF
Me
CF
89
23232
89
CCl
3
3
CCl
O CF3 3
Me OO 2b OOO
CCl
Me
CCl
OCCl
33 33 3
2222
6666
3b O CF
3c
3c
2c2c
3b
N N 3b
33
9292
NN 2b
2b2bO OCCl
CCl
CF
O
CF
O
3
3
3
CCl3 3
OO CCl
CF33
2222
6666
OO CF
3c3c
22
66
O2c
22
66
N N O O O CF3
3 3
9292
NNN O2c
O CCl 3
92
NN
33
N
92
22
66
3
22
66
CCl
O
CF
O
3c
3c
3
2c
CCl3 3 3
2c
OO CCl
CF
22
66
O
N
3
92
N
O
ONOO CF
ON
3c
N
N
3c
33
90
93
2c
2c
2290
6693
22
66
92
96
NNN
9296
34343
92
NNN
O OCCl
CCl
O OCFCF
3c
2c
3 3
3 3
ONON
ON2c
ONO
9090
9393
O
O
O
O3c
O
O2c
O
2d2d
3c
3c
3d3d
2c
44
96
96
CCl
O
O OCFCF
CCl
O
3 3
3 3
O
O
N
N
NO
93
9090
93
ONN
O
OO
4
96
90
93
O
3d3d
N
90
93
90
93
ON
O
O 2d2dO OCCl
ON
4 4
9696
CCl
O OCFCF
3 3
96
44
96
3 3
CCl
O
CCl
O
CF
O
CF
O
N
N
90
93
33
33
O
OOOO
O 2d2d
OO
3d3dO CF
4
96
ON N
ON
ON N
ON
2d O CCl3
2d
909090
939393
3d
3d
3
4
96
CCl
O
CF3
O
96
44
96
3
O
O
CCl
CF
CF
O
O
O
O
N
NON 2d OO CCl
O
N
3d
33
33
8888
9090
O 2d
OO 2d
OOO3d
2d
5 5
9595
3d3d
O
O
O
O OCFCF
NON
NON
O OCFCF
OO
OO
3 3
3 3
O
8888
90
O
5
95
88
9090
3e3e
2e2e
55
9595
O N
O
N
CF
N
NOO
O
O OCFCF
CF
O
O
O
O
3
3 3
3
O
8888
9090
ON 2e2e
ON
ON 3e3e
ON
88
90
88
90
5 5
9595
NO
N
95
55
95
CF
O
CF
O
O OCFCF
88
90
O
O ON
3
3
3 3
N
CF
O
CF
O
CF
O
O
CF
O
O
O
O
O
O
O
O
33
33
5
95
NN 3e3e
NN 2e2e
888888
909090
3eMe
2e
O CF3
O 3e
MeMeO CF3
Me
O 2e
55 5
959595
CF
O
CF
O
O
O
O
3e
O
3
3
N N2e OO CF
CF
OO CF
CF
OONON
OO
33
33
6060
62
3e
2e
66
82
60
6262
Me
3eMe
3e
Me
Me
2e
2e
O OCFCF
O OCFCF
Me
6
82
Me
Me
82
Me
3 3
3
3
Molecules
2017,
22,
804
O
Molecules 2017, 22, 804 ONON
ON N
O
OOO
O
OOO
6060
6262
Me
Me
Me
Me
O OCFCF
O OCFCF
2f
2f
66
8282
3f
3f
Me
Me
Me
OMe
Me
Me
Me
3 3
OMe
3 3
N
N
N
N
O Me
OON
OON
OO Me
O
6060
6262
O
O
ON
60
62
ON
60
62
O
O Me
O OCFCF
O OCFCF
2f2fMe
Me
6 6
8282
MeMe
3f3fMe
3 3
3 3
CF
CF
OO CF
N
N
MeMe
82
MeMe
Me
66
82
MeOO CF
Me
Me
3
33
3
60
62
O ON
O
O
N
ON
ON
ON
ON
60
62
Me
N
6
82
Me
N
3
3
N 2f 2fO OCFCF
N 3f 3fO OCFCF
6023
6234
60
62
23
34
Me
82
Me
2f2f OO CCl
85
23
34
3f3f O
3
3
OMe
OMe
CF
CF
CF
OO
Me
676
8285
677
82
Me
85
CCl
OCF
CF
OCF
333 3
3
3
3 3
O 2f
O 3f
OOO
MeMe
OOO
Me
Me 3f
2g2g
2f2f2f
3f3f3g3g
Entry
Entry
CC
Method
Method
CC
Method
Method
Method
Method
3636
Method
CC
C
CMethod
3636
Method
Method
C
C
C36
C36
Method
C
36
36
36
36
63
3663
36
36
6363
6363
63
63
63
63
66
66
63
63
63
6666
6666
66
66
66
66
66
96
6696
66
9696
96
9696
96
96
96
969696
9595
9595
95
9595
95
95
95
959595
8585
85
4 of
1010
4 of
8585
8585
85
85
85
85
85
85
99
99
99
Note: Method A: SbF3 with SbCl5 (cat.), method B: HF with SbCl5 (cat.), method C: Py / HF70 %, DBH.
Note:
Note:Method
MethodA:A:SbF3
SbF3with
withSbCl5
SbCl5(cat.),
(cat.),method
methodB:B:HF
HFwith
withSbCl5
SbCl5(cat.),
(cat.),method
methodC:C:PyPy/ HF70
/ HF70%,%,DBH.
DBH.
ItItmust
mustbebeadded
addedthat
thatfluorination
fluorinationwith
withpyridine-HF
pyridine-HFcomplex
complex(method
(methodC)C)requires
requiresspecial
special
polyethylene
polyethyleneororpolytetrafluoroethylene
polytetrafluoroethyleneplastic
plasticequipment,
equipment,fluorination
fluorinationwith
withanhydrous
anhydrousHF
HF(method
(methodB)B)
require
requirestainless
stainlesssteel
steelautoclave
autoclavebut
butfluorination
fluorinationwith
withantimony
antimonytrifluoride
trifluoride(method
(methodA)A)was
was
performed
in
common
glass
equipment.
All
investigated
methods
of
fluorination
(A,
B,
and
C)
can
performed in common glass equipment. All investigated methods of fluorination (A, B, and C) can
bebeapplied
appliedfor
forthe
thelarge-scale
large-scaleexperiment.
experiment.Thus,
Thus,methyl
methyl3-(trifluoromethoxy)propanoate
3-(trifluoromethoxy)propanoate3b3bwas
was
Molecules 2017, 22, 804
4 of 10
It must be added that fluorination with pyridine-HF complex (method C) requires special
polyethylene or polytetrafluoroethylene plastic equipment, fluorination with anhydrous HF (method B)
require stainless steel autoclave but fluorination with antimony trifluoride (method A) was performed
in common glass equipment. All investigated methods of fluorination (A, B, and C) can be applied for
the large-scale experiment. Thus, methyl 3-(trifluoromethoxy)propanoate 3b was prepared in quantity
above 25 g at once and protected amine 3d was obtained in ca. 50 g at once by all three methods.
The protective phthalimide group can be removed by common methods and was documented in [16].
3. Materials and Methods
1 H-NMR
spectra were recorded at 300 MHz with a Varian VXR-300 spectrometer (Varian Inc.,
Palo Alto, CA, USA), at 500 MHz with a Bruker AVANCE DRX 500 instrument (Bruker, Billerica, MA,
USA), or at 400 MHz with Varian UNITY-Plus 400 spectrometer (Varian Inc, Palo Alto, CA, USA).
13 C-NMR-spectra (proton decoupled) were recorded on a Bruker AVANCE DRX 500 instrument at
125 MHz, or at 100 MHz with Varian UNITY-Plus 400 spectrometer. 19 F-NMR spectra were recorded at
188 MHz with a Varian Geminy-200 instrument (Varian Inc, Palo Alto, CA, USA), or at 376 MHz with
Varian UNITY-Plus 400 spectrometer. Chemical shifts are given in ppm relative to Me4 Si and CCl3 F,
respectively, as internal or external standards. 1 H-, 13 C-, and 19 F-NMR spectra of the compounds can
be found in Supplementary materials. LC-MS spectra were registered on an “Agilent 1100 Series”
instrument with diode-matrix and mass-selective detector “Agilent 1100 LS/MSD SL” (ionization
method: chemical ionization at atmospheric pressure; ionization chamber operation conditions:
simultaneous scanning of positive and negative ions in the range 80–1000 m/z, Agilent Technologies,
Santa Clara, CA, USA). GC-MS spectra were registered on a Hewlett-Packard HP GC/MS 5890/5972
instrument (EI 70 eV) (Philips, Bothell, WA, USA). Melting points were determined in open capillaries
using an SMP3 instrument (Stuart Scientific Bibby Sterlin Ltd, Stone, Staffordshire, UK). Elemental
analysis was performed in the Analytical Laboratory of the Institute of Organic Chemistry, NAS of
Ukraine, Kiev.
Unless otherwise stated, commercially-available reagents were purchased from Enamine Ltd.
and were used without purification. Antimony trifluoride was sublimated immediately prior to use.
Anhydrous hydrogen fluoride was distilled in the presences of SOCl2 . HF70% /pyridine was prepared
according to the Olah method [22]. Solvents were dried before use by standard methods. All reactions
were performed in an argon atmosphere. For column chromatography, Merck Kieselgel 60 silica
gel (Merck, Darmstadt, Germany) was used. Thin-layer chromatography (TLC) was carried out on
aluminum-backed plates coated with silica gel (Merck Kieselgel 60 F254, Merck, Darmstadt, Germany).
3.1. Synthesis of Xanthates 1a–c: General Procedure
Carbon disulfide (18.1 mL, 0.3 mol) was added dropwise at −30 ◦ C to the suspension of sodium
hydride (60% in mineral oil) (4.4 g, 0.11 mol) in anhydrous dimethylformamide (DMF) (200 mL).
To this mixture the solution of corresponding hydroxyderivatives (0.1 mol) in anhydrous DMF (15
mL) was added dropwise for 3 h with mechanistic stirring at −30 ◦ C. After addition was completed,
the mixture was warmed to room temperature and stirred for 3 h. The color of the mixture gradually
changed to dark red. The reaction mixture was cooled to −10 ◦ C and methyl iodide (7.8 mL, 0.12 mol)
was added dropwise. The mixture was warmed to room temperature, stirred for 3 h until the color
changed from dark red to yellow and poured into ice (600 g), and extracted with tert-buthylmethyl
ether (MTBE) (5 × 50 mL). The extract was washed with brine (5 × 50 mL) and dried with MgSO4 .
The solvent was removed at atmospheric pressure and the residue distilled in vacuum.
3.1.1. Methyl ([(methylsulfanyl)carbonothioyl]oxy)acetate 1a
Yield 15.5 g (86%). Yellow oil: bp 129–130 ◦ C (20 Torr). 1 H-NMR (400 MHz, CDCl3 ): δ 2.60 (s, 3H,
SCH3 ), 3.77 (s, 3H, OCH3 ), 5.15 (s, 2H, CH2 ). 13 C-NMR (100 MHz, CDCl3 ): δ 19.5 (s, SCH3 ), 52.4
Molecules 2017, 22, 804
5 of 10
(s, OCH3 ), 67.6 (s, CH2 ), 167.1 (s, C=O), 215.8 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 180 (69) [M]+ .
Anal. calcd for C5 H8 O3 S2 : C, 33.32; H, 4.47; S, 35.58; found: C, 33.14; H, 4.51; S, 35.51.
3.1.2. Methyl 3-([(methylsulfanyl)carbonothioyl]oxy)propanoate 1b
Yield 17.8 g (92%). Yellow oil: bp 94–95 ◦ C (0.5 Torr). 1 H-NMR (400 MHz, CDCl3 ): δ 2.52 (s, 3H, SCH3 ),
2.80 (t, 3 J = 6.4 Hz, 2H, CH2 ), 3.70 (s, 3H, OCH3 ), 5.15 (t, 3 J = 6.4 Hz, 2H, CH2 ). 13 C-NMR (125 MHz,
CDCl3 ): δ 18.7 (s, SCH3 ), 32.9 (s, CH2 ), 51.6 (s, OCH3 ), 68.2 (s, CH2 ), 170.2 (s, C=O), 215.2 (s, C=S).
GC-MS, 70 eV, m/z (rel. int.): 194 (62) [M]+ . Anal. calcd for C6 H10 O3 S2 : C, 37.09; H, 5.19; S, 33.01;
found: C, 37.17; H, 5.29; S, 32.94.
3.1.3. O-(2-Cyanoethyl)-S-methyl-dithiocarbonate 1c
Yield 14.3 g (89%). Yellow oil: bp 94–95 ◦ C (0.3 Torr). 1 H-NMR (300 MHz, CDCl3 ): δ 2.53 (s, 3H, SCH3 ),
2.82 (t, 3 J = 6.3 Hz, 2H, CH2 ), 4.73 (t, 3 J = 6.3 Hz, 2H, CH2 ). 13 C-NMR (125 MHz, CDCl3 ): δ 17.3 (s,
CH2 ), 18.9 (s, SCH3 ), 66.2 (s, CH2 ), 116.1 (s, C≡N), 214.9 (s, C=S). GC-MS, 70 eV, m/z (rel. int.): 161 (67)
[M]+ . Anal. calcd for C5 H7 NOS2 : C, 37.24; H, 4.38; S, 39.77; found: C, 37.30; H, 5.44; S, 39.70.
3.2. Synthesis of Xanthates 1d–g: General Procedure
To the stirred solution of hydroxyderivatives (0.1 mol) in anhydrous DMF (50 mL) sodium
hydride (60% in mineral oil) (4.4 g, 0.11 mol) was added with mechanistic stirring between −5 and
0 ◦ C. After addition, stirring was continued for 2 h at room temperature. Carbon disulfide (9 mL,
0.15 mol) was added dropwise at 0 ◦ C. The reaction mixture was warmed to room temperature and
stirred for 5 h. The color of the one was gradually changed to dark red. The reaction mixture was
cooled to 0 ◦ C and methyl iodide (7.8 mL, 0.12 mol) was added dropwise. The mixture was warmed to
room temperature, stirred for 3 h until the color changed from dark red to yellow and poured into ice
(100 g), extracted with CH2 Cl2 (3 × 50 mL). The extract was washed with water (3 × 50 mL) and dried
with MgSO4 . After removal of the solvent the product was washed with hexane and dried in vacuum.
3.2.1. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl] S-Methyl Dithiocarbonate 1d
Yield 27.8 g (99%). Yellow powder: mp 105–106 ◦ C. 1 H-NMR (400 MHz, CDCl3 ): δ 2.49 (s, 3H, SCH3 ),
4.10 (t, 3 J = 5.6 Hz, 2H, CH2 ), 4.82 (t, 3 J = 5.6 Hz, 2H, CH2 ), 7.71–7.73 (m, 2H, arom H), 7.83–7.86 (m, 2H,
arom H). 13 C-NMR (125 MHz, DMSO-d6 ): δ 18.4 (s, SCH3 ), 36.3 (s, CH2 ), 70.6 (s, CH2 ), 123.2 (s, arom.
C), 131.6 (s, arom. C), 134.6 (s, arom. C), 167.7 (s, C=O), 215.2 (s, C=S). LC-MS, m/z: 282 [M + H]+ .
Anal. calcd for C12 H11 NO3 S2 : C, 51.23; H, 3.94; N, 4.98; S, 22.79; found: C, 51.30; H, 4.00; N, 4.98; S,
22.70.
3.2.2. O-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl] S-Methyl Dithiocarbonate 1e
Yield 29.5 g (100%). Yellow powder: mp 101–102 ◦ C. 1 H-NMR (300 MHz, DMSO-d6 ): δ 2.08–2.12
(m, 2H, CH2 ), 3.34 (s, 3H, SCH3 ), 3.71 (t, 3 J = 6.3 Hz, 2H, CH2 ), 4.58 (t, 3 J = 6.0 Hz, 2H, CH2 ), 7.83–7.85
(m, 4H, arom H). 13 C-NMR (100 MHz, DMSO-d6 ): δ 18.8 (s, SCH3 ), 27.3 (s, CH2 ), 35.0 (s, CH2 ), 72.4
(s, CH2 ), 123.4 (s, arom. C), 132.1 (s, arom. C), 134.7 (s, arom. C), 168.3 (s, C=O), 215.6 (s, C=S). LC-MS,
m/z: 296 [M + H]+ . Anal. calcd for C13 H13 NO3 S2 : C, 52.86; H, 4.44; N, 4.74; S, 21.71; found: C, 52.92;
H, 4.52; N, 4.68; S, 21.70.
3.2.3. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpropyl] S-Methyl Dithiocarbonate 1f
Yield 27.5 g (89%). Yellow powder: mp 85–86 ◦ C. 1 H-NMR (300 MHz, CDCl3 ): δ 1.77 (s, 6H, 2CH2 ),
2.47 (s, 3H, SCH3 ), 4.98 (s, 2H, CH2 ), 7.70–7.73 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H). 13 C-NMR
(125 MHz, CDCl3 ): δ 18.5 (s, SCH3 ), 26.2 (s, 2CH3 ), 58.7 (s, C), 77.1 (s, CH2 ), 122.5 (s, arom. C), 131.4
(s, arom. C), 133.6 (s, arom. C), 168.8 (s, C=O), 214.7 (s, C=S). LC-MS, m/z: 310 [M + H]+ . Anal. calcd
for C14 H15 NO3 S2 : C, 54.35; H, 4.89; N, 4.53; S, 20.73; found: C, 54.42; H, 4.96; N, 4.50; S, 20.75.
Molecules 2017, 22, 804
6 of 10
3.2.4. O-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-methylethyl] S-Methyl Dithiocarbonate 1g
Yield 28.9 g (98%). Yellow powder: mp 85–86 ◦ C. 1 H-NMR (300 MHz, CDCl3 ): δ 1.43 (d, 3 J = 6.4 Hz,
3H, CH3 ), 2.48 (s, 3H, SCH3 ), 3.89 (dd, 2 J = 14.4 Hz, 3 J = 3.2 Hz, 1H, CH2 ), 4.04 (dd, 2 J = 14.4 Hz,
3 J = 7.6 Hz, 1H, CH ), 6.00–7.10 (m, 1H, CH), 7.70–7.72 (m, 2H, arom H), 7.78–7.81 (m, 2H, arom H).
2
13 C-NMR (125 MHz, CDCl ): δ 17.5 (s, CH ), 18.9 (s, SCH ), 43.7 (s, CH ), 77.6 (s, C), 123.5 (s, arom. C),
3
3
3
2
132.0 (s, arom. C), 134.2 (s, arom. C), 168.1 (s, C=O), 215.3 (s, C=S). LC-MS, m/z: 296 [M + H]+ . Anal.
calcd for C13 H13 NO3 S2 : C, 52.86; H, 4.44; N, 4.74; S, 21.71; found: C, 52.88; H, 4.86; N, 4.69; S, 21.76.
3.3. Synthesis of Trichloroderivatives 2a–g: General Procedure
Chlorine was bubbled through the solution of xanthate 1a–g (50 mmol) in carbon tetrachloride
(50 mL) at 0 ◦ C for 1 h. The reaction mixture was warmed to 20 ◦ C and chlorine was bubbled for
further 1 h. Methylene chloride (10 mL) was added to the reaction mixture and chlorine was bubbled
for further 1 h. Excess of chlorine was removed with stream of nitrogen. After removal of the solvent,
product was distilled in vacuum or washed with hexane and dried in vacuum.
3.3.1. Methyl (trichloromethoxy)acetate 2a
Yield 9.0 g (87%). Colorless liquid: bp 87–88 ◦ C (10 Torr). 1 H-NMR (400 MHz, CDCl3 ): δ 3.83 (s, 3H,
OCH3 ), 4.64 (s, 2H, CH2 ). 13 C-NMR (125 MHz, CDCl3 ): δ 52.7 (s, OCH3 ), 66.7 (s, CH2 ), 112.6 (s, CCl3 ),
166.2 (s, C=O). Anal. calcd for C4 H5 Cl3 O3 : C, 23.16; H, 2.43; Cl, 51.27; found: C, 33.12; H, 2.40; Cl, 52.35.
3.3.2. Methyl 3-(trichloromethoxy)propanoate 2b
Yield 9.8 g (89%). Colorless liquid: bp 64–65 ◦ C (0.5 Torr). 1 H-NMR (300 MHz, CDCl3 ): δ 2.76
(t, 3 J = 6.4 Hz, 2H, CH2 ), 3.71 (s, 3H, OCH3 ), 5.35 (t, 3 J = 6.4 Hz, 2H, CH2 ). 13 C-NMR (125 MHz, CDCl3 ):
δ 32.9 (s, CH2 ), 51.7 (s, OCH3 ), 66.4 (s, CH2 ), 111.9 (s, CCl3 ), 169.7 (s, C=O). Anal. calcd for C5 H7 Cl3 O3 :
C, 27.12; H, 3.19; Cl, 48.02; found: C, 27.07; H, 3.12; Cl, 48.09.
3.3.3. 3-(Trichloromethoxy)propanenitrile 2c
Yield 8.7 g (92%). Colorless liquid: bp 77–78 ◦ C (0.3 Torr). 1 H-NMR (300 MHz, CDCl3 ): δ 2.83
(t, 3 J = 6.6 Hz, 2H, CH2 ), 4.29 (t, 3 J = 6.6 Hz, 2H, CH2 ). 13 C-NMR (125 MHz, CDCl3 ): δ 17.6 (s, CH2 ),
64.8 (s, CH2 ), 111.9 (s, CCl3 ), 115.5 (s, C≡N). Anal. calcd for C4 H4 Cl3 NO: C, 25.50; H, 2.14; Cl, 56.44; N,
7.43; found: C, 25.55; H, 2.14; Cl, 56.50; N, 7.40.
3.3.4. 2-[2-(Trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2d
Yield 14.8 g (96%). Colorless powder: mp 93–94 ◦ C. 1 H-NMR (300 MHz, CDCl3 ): δ 4.06 (t, 3 J = 5.3 Hz,
2H, CH2 ), 4.34 (t, 3 J = 5.3 Hz, 2H, CH2 ), 7.74–7.76 (m, 2H, arom H), 7.83–7.86 (m, 2H, arom H). 13 C-NMR
(100 MHz, CDCl3 ): δ 36.4 (s, CH2 ), 68.1 (s, CH2 ), 112.5 (s, CCl3 ), 123.5 (s, arom. C), 131.8 (s, arom. C),
134.2 (s, arom. C), 167.8 (s, C=O). Anal. calcd for C11 H8 Cl3 NO3 : C, 42.82; H, 2.61; Cl, 34.47; N, 4.54;
found: C, 42.90; H, 2.52; Cl, 34.50; N, 4.44.
3.3.5. 2-[3-(Trichloromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 2e
Yield 15.3 g (95%). Colorless powder: mp 102–103 ◦ C. 1 H-NMR (400 MHz, CDCl3 ): δ 2.12–2.19 (m,
2H, CH2 ), 3.83 (t, 3 J = 6.8 Hz, 2H, CH2 ), 4.16 (t, 3 J = 6.0 Hz, 2H, CH2 ), 7.60–7.70 (m, 2H, arom H),
7.80–7.90 (m, 2H, arom H). 13 C-NMR (125 MHz, CDCl3 ): δ 27.3 (s, CH2 ), 35.1 (s, CH2 ), 69.6 (s, CH2 ),
112.4 (s, CCl3 ), 123.3 (s, arom. C), 132.0 (s, arom. C), 134.0 (s, arom. C), 168.2 (s, C=O). Anal. calcd for
C12 H10 Cl3 NO3 : C, 44.68; H, 3.12; Cl, 32.97; N, 4.34; found: C, 44.75; H, 3.10; Cl, 33.00; N, 4.40.
3.3.6. 2-[1,1-Dimethyl-2-(trichloromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 2f
Yield 13.8 g (82%). Colorless powder: mp 93–94 ◦ C. 1 H-NMR (500 MHz, CDCl3 ): δ 1.79 (s, 6H, 2CH3 ),
4.53 (s, 2H, CH2 ), 7.68–7.71 (m, 2H, arom H), 7.75–7.80 (m, 2H, arom H). 13 C-NMR (125 MHz, CDCl3 ):
Molecules 2017, 22, 804
7 of 10
δ 24.7 (s, 2CH3 ), 58.8 (s, C), 75.6 (s, CH2 ), 112.6 (s, CCl3 ), 123.1 (s, arom. C), 131.9 (s, arom. C), 134.1
(s, arom. C), 169.4 (s, C=O). Anal. calcd for C13 H12 Cl3 NO3 : C, 46.39; H, 3.59; Cl, 31.60; N, 4.16; found:
C, 46.45; H, 3.50; Cl, 31.68; N, 4.05.
3.3.7. 2-[2-(Trichloromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 2g
Yield 13.7 g (85%). Colorless powder: mp 96–97 ◦ C. 1 H-NMR (300 MHz, CDCl3 ): δ 1.55 (d, 3 J = 6.3 Hz,
3H, CH3 ), 3.79 (dd, 2 J = 14.1 Hz, 3 J = 3.6 Hz, 1H, CH2 ), 4.06 (dd, 2 J = 14.1 Hz, 3 J = 8.1 Hz, 1H, CH2 ),
4.80–4.95 (m, 1H, CH), 7.70–7.80 (m, 2H, arom H), 7.85–7.95 (m, 2H, arom H). 13 C-NMR (125 MHz,
CDCl3 ): δ 18.4 (s, CH3 ), 42.1 (s, CH2 ), 78.2 (s, C), 123.5 (s, arom. C), 132.5 (s, arom. C), 134.2 (s, arom.
C), 167.9 (s, C=O). Anal. calcd for C12 H10 Cl3 NO3 : C, 44.68; H, 3.12; Cl, 32.97; N, 4.34; found: C, 44.75;
H, 3.20; Cl, 33.00; N, 4.35.
3.4. Fluorination of Trichloromethoxy Derivatives 2a–g with Antimony Trifluoride (Method A)
3.4.1. Fluorination of Esters 2a–b and Nitrile 2c: General Procedure
The mixture of pounded antimony trifluoride (17.9 g, 100 mmol) and antimonium pentachloride
(1.5 g, 5 mmol) was carefully heated to 30−35 ◦ C with mechanistic stirring to a homogenous pasty
mass formation. The mixture was cooled to 0 ◦ C and trichloromethoxy derivative 2a–c (50 mmol) was
added at once. The reaction mixture was heated at 90 ◦ C for 10 min. Then the mixture was heated to
120−135 ◦ C with simultaneous vacuum (150 Torr) distillation of the product in the trap cooled with
crushed ice. The pure product was obtained after redistillation.
3.4.2. Fluorination of Protected Amines 2d–g: General Procedure
The mixture of pounded antimony trifluoride (17.9 g, 100 mmol) and antimonium pentacloride
(1.5 g, 5 mmol) was carefully heated to 30−35 ◦ C with mechanistic stirring to a homogenous pasty
mass formation. The mixture was cooled to 0 ◦ C and trichloromethoxy derivative 2d–g (50 mmol) was
added at once. The reaction mixture was gradually heated firstly at 25 ◦ C for 30 min, then at 45 ◦ C
for 30 min, and finally at 95 ◦ C for 20 min. After cooling to room temperature the reaction mixture
was washed with CH2 Cl2 (5 × 50 mL), combined organic extracts were washed with 10% aqueous
HCl solution (10 × 20 mL) then with water (5 × 20 mL) and dried with MgSO4 . The solution was
filtered through SiO2 and evaporated to dryness. The pure product was obtained after crystallization
from hexane.
3.5. Fluorination of Trichloromethoxy Derivatives 2a–g with Hydrogenfluoride (Method B): General Procedure
Trichloromethoxy derivative 2a–g (50 mmol) was placed into stainless steel autoclave (100 mL
volume) and cooled to −40 ◦ C. Anhydrous HF (50 mL) and SbCl5 (0.75 g, 2.5 mmol) were added at
the same temperature. Autoclave was sealed and the reaction mixture was heated at 45 ◦ C for 0.5 h,
then at 95 ◦ C for 2.5 h, and cooled to room temperature. Excess of hydrogen fluoride and hydrogen
chloride formed in the reaction were distilled in a polyethylene trap cooled to −15 ◦ C. The residue
was dissolved in CH2 Cl2 (100 mL) washed with saturated aqueous K2 CO3 solution (4 × 20 mL), then
with water (3 × 20 mL), dried with MgSO4 , and filtered through SiO2 . After removal of the solvent,
the product was distilled in vacuum or crystallized from hexane and dried in vacuum.
3.6. Fluorination of Xanthate 1a–g with Pyridine-Hydrogenfluoride and 1,3-Dibromo-5,5-Dimethylhydantoin
(DBH) (Method C): General Procedure
Reactions were performed in a polyethylene flask (500 mL) equipped with an additional
polyethylene funnel, magnetic stirrer, and BOLA PTFE coated temperature probe.
Complex HF70% -pyridine was added dropwise at −78 ◦ C to a suspension of DBH (42.9 g, 0.15 mol)
in CH2 Cl2 (130 mL). The mixture was stirred for 10 min and the solution of corresponding xanthate
1a–g (0.05 mol) in CH2 Cl2 (70 mL) was added at the same temperature. The reaction mixture was
Molecules 2017, 22, 804
8 of 10
stirred at −78 ◦ C for 1 h, warmed to room temperature, stirred for 5 h and poured into ice (100 g).
As saturated aqueous solution of Na2 SO3 was added to the mixture until the red color of the mixture
changed to light yellow. Then the mixture was neutralized with aqueous K2 CO3 solution. The organic
layer was separated and the aqueous solution was extracted with CH2 Cl2 (3 × 50 mL). Combined
organic extracts were washed with water (3 × 500 mL) and dried with MgSO4 . After removal of the
solvent, the product was distilled or crystallized from hexane and dried in vacuum.
3.6.1. Methyl (trifluoromethoxy)acetate 3a
Yield 2.84 g (36% method C). Colorless liquid: bp 102–104 ◦ C (lit. 110 ◦ C [11]). 1 H-NMR (400 MHz,
CDCl3 ): δ 3.81 (s, 3H, OCH3 ), 4.48 (s, 2H, CH2 ). 13 C-NMR (125 MHz, CDCl3 ): δ 52.5 (s, OCH3 ), 62.9
(q, 3 JCF = 2.5 Hz, CH2 ), 121.4 (q, JCF = 256.4 Hz, CF3 ), 166.5 (s, C=O). 19 F-NMR (376.5 MHz, CDCl3 ): δ
−62.12 (s, CF3 ). GC-MS, 70 eV, m/z (rel. int.): 158 (46) [M]+ . Anal. calcd for C4 H5 F3 O3 : C, 30.39; H,
3.19; found: C, 30.12; H, 3.04.
3.6.2. Methyl 3-(trifluoromethoxy)propanoate 3b
Yield 4.55 g (53% method A). Yield 5.9 g (69% method B). Yield 5.4 g (63% method B). Colorless liquid:
bp 124–125 ◦ C. 1 H-NMR (300 MHz, CDCl3 ): δ 2.64 (t, 3 J = 5.4 Hz, 2H, CH2 ), 3.66 (s, 3H, OCH3 ),
4.17 (t, 3 J = 5.4 Hz, 2H, CH2 ). 13 C-NMR (125 MHz, CDCl3 ): δ 33.2 (s, CH2 ), 51.3 (s, OCH3 ), 62.2 (q,
3J
19
CF = 3.3 Hz, CH2 ), 121.0 (q, J CF = 253.3 Hz, CF3 ), 169.8 (s, C=O). F-NMR (188 MHz, CDCl3 ): δ
+
−61.88 (s, CF3 ). GC-MS, 70 eV, m/z (rel. int.): 172 (52) [M] . Anal. calcd for C5 H7 F3 O3 : C, 34.89; H,
4.10; found: C, 34.55; H, 4.02.
3.6.3. 3-(Trifluoromethoxy)propanenitrile 3c
Yield 1.5 g (22% method A). Yield 4.6 g (66% method B). Yield 4.6 g (66% method B). Colorless liquid: bp
100–102 ◦ C (120 Torr). 1 H-NMR (300 MHz, CDCl3 ): δ 2.70 (t, 3 J = 6.3 Hz, 2H, CH2 ), 4.11 (t, 3 J = 6.3 Hz,
2H, CH2 ). 13 C-NMR (125 MHz, CDCl3 ): δ 18.0 (s, CH2 ), 61.2 (q, 3 JCF = 3.4 Hz, CH2 ), 115.3 (s, C≡N),
120.8 (q, JCF = 255.1 Hz, CF3 ). 19 F-NMR (188 MHz, CDCl3 ): δ −62.10 (s, CF3 ). GC-MS, 70 eV, m/z (rel.
int.): 139 (66) [M]+ . Anal. calcd for C4 H4 F3 NO: C, 34.54; H, 2.90; N, 10.07; found: C, 34.40; H, 2.84;
N, 9.90.
3.6.4. 2-[2-(Trifluoromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 3d
Yield 11.65 g (90% method A). Yield 12.0 g (93% method B). Yield 12.4 g (96% method B). Colorless
powder: mp 73–74 ◦ C (lit. 77 ◦ C [16]), bp 100–102 ◦ C (0.2 Torr). 1 H-NMR (300 MHz, CDCl3 ): δ 3.93 (t,
3 J = 5.3 Hz, 2H, CH ), 4.20 (t, 3 J = 5.3 Hz, 2H, CH ), 7.70–7.77 (m, 2H, arom H), 7.80–7.90 (m, 2H, arom
2
2
H). 13 C-NMR (125 MHz, CDCl3 ): δ 36.7 (s, CH2 ), 63.9 (s, CH2 ), 121.7 (q, JCF = 255.2 Hz, CF3 ), 123.5 (s,
arom. C), 131.8 (s, arom. C), 134.2 (s, arom. C), 167.8 (s, C=O). 19 F-NMR (188 MHz, CDCl3 ): δ −61.55
(s, CF3 ). LC-MS, m/z: 260 [M + H]+ . Anal. calcd for C11 H8 F3 NO3 : C, 50.98; H, 3.11; N, 5.40; found: C,
50.90; H, 3.23; N, 5.44.
3.6.5. 2-[3-(Trifluoromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 3e
Yield 12.0 g (88% method A). Yield 12.3 g (90% method B). Yield 13.0 g (96% method B). Colorless
powder: mp 77–78 ◦ C. 1 H-NMR (400 MHz, CDCl3 ): δ 2.04–2.12 (m, 2H, CH2 ), 3.70–3.82 (m, 2H, CH2 ),
4.00–4.12 (m, 2H, CH2 ), 7.68–7.72 (m, 2H, arom H), 7.80–7.88 (m, 2H, arom H). 13 C-NMR (125 MHz,
CDCl3 ): δ 28.0 (s, CH2 ), 34.8 (s, CH2 ), 65.1 (s, CH2 ), 121.6 (q, JCF = 254.0 Hz, CF3 ), 123.4 (s, arom. C),
132.1 (s, arom. C), 134.2 (s, arom. C), 168.3 (s, C=O). 19 F-NMR (376.5 MHz, CDCl3 ): δ −61.49 (s, CF3 ).
LC-MS, m/z: 274 [M + H]+ . Anal. calcd for C12 H10 F3 NO3 : C, 52.75; H, 3.69; N, 5.13; found: C, 52.77; H,
3.70; N, 5.22.
Molecules 2017, 22, 804
9 of 10
3.6.6. 2-[1,1-Dimethyl-2-(trifluoromethoxy)ethyl]-1H-isoindole-1,3(2H)-dione 3f
Yield 8.6 g (60% method A). Yield 8.9 g (62% method B). Yield 12.2 g (85% method B). Colorless powder:
mp 73–74 ◦ C. 1 H-NMR (300 MHz, CDCl3 ): δ 1.69 (s, 6H, 2CH3 ), 4.35 (s, 2H, CH2 ), 7.60–7.67 (m, 2H,
arom H), 7.70–7.77 (m, 2H, arom H). 13 C-NMR (125 MHz, CDCl3 ): δ 24.8 (s, 2CH3 ), 58.3 (s, C), 70.7 (s,
CH2 ), 120.2 (q, JCF = 253.3 Hz, CF3 ), 122.5 (s, arom. C), 131.3 (s, arom. C), 133.6 (s, arom. C), 168.9 (s,
C=O). 19 F-NMR (376.5 MHz, CDCl3 ): δ −61.11 (s, CF3 ). LC-MS, m/z: 288 [M + H]+ . Anal. calcd for
C13 H12 F3 NO3 : C, 54.36; H, 4.21; N, 4.88; found: C, 54.47; H, 4.47; N, 4.85.
3.6.7. 2-[2-(Trifluoromethoxy)propyl]-1H-isoindole-1,3(2H)-dione 3g
Yield 3.1 g (23% method A). Yield 4.6 g (34% method B). Yield 13.5 g (99% method B). Colorless powder:
mp 71–72 ◦ C. 1 H-NMR (500 MHz, CDCl3 ): δ 1.40–1.43 (m, 3H, CH3 ), 3.79 (dd, 2 J = 14.0 Hz, 3 J = 2.0 Hz,
1H, CH2 ), 3.94–4.00 (m, 1H, CH2 ), 4.80–4.95 (m, 1H, CH), 7.74 (s, 2H, arom H), 7.87 (s, 2H, arom H).
13 C-NMR (125 MHz, CDCl ): δ 18.6 (s, CH ), 42.3 (s, CH ), 72.9 (s, C), 121.5 (q, J
3
3
2
CF = 255.1 Hz, CF3 ),
123.5 (s, arom. C), 131.7 (s, arom. C), 134.2 (s, arom. C), 168.0 (s, C=O). 19 F-NMR (376.5 MHz, CDCl3 ):
δ −59.19 (s, CF3 ). LC-MS, m/z: 274 [M + H]+ . Anal. calcd for C12 H10 F3 NO3 : C, 52.75; H, 3.69; N, 5.13;
found: C, 52.70; H, 3.44; N, 4.12.
4. Conclusions
The “chlorination/fluorination” technique for aromatic trifluoromethyl ether syntheses, since 1955,
has been a powerful driver of research in organofluorine chemistry. More than 30,000 substances [4] with
such a group were prepared in the last half century. It was shown that this method, as well as oxidative
desulfurization-fluorination, can be successfully applied for a wide range of aliphatic substrates with
various functional groups. It requires cheap reagents and it is promising in industrial applications.
Supplementary Materials:
available online.
1 H-, 13 C-,
and
19 F-NMR
spectra of products associated with this article are
Author Contributions: L.M.Y. conceived idea of the article; T.M.S., M.I.D., E.M., and Y.L.Y. conceived and
performed the experiments; and T.M.S. and Y.L.Y. wrote the paper. All authors except L.M.Y. read and approved
the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; John Wiley & Sons Ltd.: Chichester, UK, 2009.
[CrossRef]
O’Hagan, D.J. Fluorine in health care: Organofluorine containing blockbuster drugs. J. Fluor. Chem. 2010,
131, 1071–1081. [CrossRef]
Leroux, F.; Manteau, B.; Vors, J.-P.; Pazenok, S. Trifluoromethyl ethers—Synthesis and properties of
an unusual substituent. Beilstein J. Org. Chem. 2008, 4, 13. [CrossRef] [PubMed]
Leroux, F.; Jeschke, P.; Schlosser, M. α-Fluorinated Ethers, Thioethers, and Amines: Anomerically Biased
Species. Chem. Rev. 2005, 105, 827–856. [CrossRef] [PubMed]
Landelle, G.; Panossian, A.; Leroux, F.R. Trifluoromethyl Ethers and Thioethers as Tools for Medicinal
Chemistry and Drug Discovery. Curr. Top. Med. Chem. 2014, 14, 941–951. [CrossRef] [PubMed]
Besset, T.; Jubault, P.; Pannecoucke, X.; Poisson, T. New entries toward the synthesis of OCF3 -containing
molecules. Org. Chem. Front. 2016, 3, 1004–1010. [CrossRef]
Tlili, A.; Toulgoat, F.; Billard, T. Synthetic Approaches to Trifluoromethoxy-Substituted Compounds.
Angew. Chem. Int. Ed. 2016, 55, 11726–11735. [CrossRef] [PubMed]
Guo, S.; Cong, F.; Guo, R.; Wang, L.; Tang, P. Asymmetric silver-catalysed intermolecular
bromotrifluoromethoxylation of alkenes with a new trifluoromethoxylation reagent. Nat. Chem. 2017.
[CrossRef]
Yagupolskii, L.M. Synthesis of derivatives of phenyl trifluoromethyl ethers. Dokl. Acad. Nauk SSSR 1955, 105,
100–102, Chem. Abstr. 1956, 50, 11270b.
Molecules 2017, 22, 804
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
10 of 10
Yarovenko, N.N.; Vasileva, V.S. A new method of introduction of trihalomethyl group into organic
compounds. J. Gen. Chem. USSR 1958, 28, 2539.
Yagupolskii, L.M.; Alekseenko, A.N.; Ilchenko, A.Y. Perfluoroalcoxyacetic acids and they derivatives.
Sov. Prog. Chem. (Engl. Transl.), 1978, 44, 52–55.
Farnham, W.B.; Middleton, W.J. Tris(disubstituted amino)sulfonium perfluoroalkoxides and
perfluoroalkylmercaptides and process for their preparation. US Patent 4628094, 9 December 1986.
Kanie, K.; Tanaka, Y.; Shimizu, M.; Kuroboshi, M.; Hiyama, T. Oxidative desulfurization-fluorination of
alkanol xanthates. Control of the reaction pathway to fluorination or trifluoromethoxylation. Chem. Commun.
1997, 3, 309–310.
Thibaudeau, C.; Nishizono, N.; Sumita, Y.; Matsuda, A.; Chattopadhyaya, J. Determination of the Group
Electronegativity of CF3 Group in 3’-O-CF3 Thymidine by 1 H-NMR. Nucleosides Nucleotides 1999, 18,
1035–1053. [CrossRef]
Kuroboshi, M.; Suzuki, K.; Hiyama, T. Oxidative desulfurization-fluorination of xanthates. A convenient
synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers. Tetrahedron Lett. 1992, 33,
4173–4176. [CrossRef]
Blazejewski, J.-C.; Anselmi, E.; Wakselman, C. 2-Trifluoromethoxyethyl Triflate: A Versatile Trifluoromethoxyethyl
Carrier. J. Org. Chem. 2001, 66, 1061–1063. [CrossRef] [PubMed]
Inoue, T.; Fuse, C.; Hara, S. Synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers by the
reaction of dithiocarbonates with IF5 -pyridine-HF. J. Fluor. Chem. 2015, 179, 48–52. [CrossRef]
Ben-David, I.; Rechavi, D.; Mishani, E.; Rozen, S. A novel synthesis of trifluoromethyl ethers via xanthates
utilizing BrF3 . J. Fluor. Chem. 1999, 97, 75–78. [CrossRef]
Umemoto, T.; Singh, R.P. Arylsulfur chlorotetrafluorides as useful fluorinating agents: Deoxo- and
dethioxo-fluorinations. J. Fluor. Chem. 2012, 140, 17–27. [CrossRef]
Manteau, B.; Genix, P.; Brelot, L.; Vors, J.-P.; Pazenok, S.; Giornal, F.; Leuenberger, C.; Leroux, F.R. A General
Approach to (Trifluoromethoxy)pyridines: First X-ray Structure Determinations and Quantum Chemistry
Studies. Eur. J. Org. Chem. 2010, 2010, 6043–6066. [CrossRef]
Speers, L.; Szur, A.J.; Terrell, R.C.; Treadwell, J.; Ucciardi, T.U. General anesthetics. 2. Halogenated methyl
isopropyl ethers. J. Med. Chem. 1971, 14, 593–595. [CrossRef] [PubMed]
Olah, G.A.; Nojima, M.; Kerekes, I. Synthetic Methods and Reactions II. Hydrofluorination of Alkenes,
Cyclopropane and Alkynes with Poly-Hydrogen Fluoride/Pyridine (Trialkylamine)Reagents. Synthesis 1973,
1973, 779–780. [CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).