Oxidative Desulfurization-Fluorination: A Facile Entry to a Wide Variety of Organofluorine Compounds Leading to Novel Liquid-Crystalline Materials

Article abstract of DOI:10.1002/1615-4169(20010330)343:3<235::AID-ADSC235>3.0.CO;2-0

The oxidative desulfurization-fluorination reaction of organosulfur compounds using an N-haloimide and a fluoride source is demonstrated to be an effective and mild fluorination method that allows us to synthesize in high yields with high chemoselectivity

Full text of DOI:10.1002/1615-4169(20010330)343:3<235::AID-ADSC235>3.0.CO;2-0

REVIEWS
Oxidative Desulfurization-Fluorination:
A Facile Entry to a Wide Variety of
Organofluorine Compounds Leading to
Novel Liquid-Crystalline Materials
a
b
c,
Manabu Kuroboshi, Kiyoshi Kanie, Tamejiro Hiyama *
a
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushima-naka, Okayama 700±8530, Japan
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo,
b
Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Yoshida, Sakyo-ku,
c
Kyoto 606-8501, Japan
Tel.: (+81) 75-754-5555, Fax: (+81) 75-754-5555, E-mail: thiyama@NPC05.kuic.kyoto-u.ac.jp
Received September 9, 2000; Accepted January 19, 2001
1
2
2
.
.
Introduction
Fluorination Reactions
Abstract: The oxidative desulfurization-fluorination
reaction of organosulfur compounds using an N-ha-
loimide and a fluoride source is demonstrated to be
.1 Fluorination of Sulfides and Thiols
an effective and mild fluorination method that 2.2 Fluorination of Dithioacetals
allows us to synthesize in high yields with high 2.3 Oxidative Desulfurization-Fluorination of Di-
chemoselectivity various types of gem-difluoro
compounds, trifluoromethyl-substituted (hetero)-
aromatics, trifluoromethyl ethers, and N-trifluoro-
methylanilines. Herein briefly summarized are the
synthetic procedures as well as the scope and limita-
tions of the reaction. The applicability of the reac-
tion is demonstrated by the synthesis of a difluori-
thioester and Orthothioester
.4 Synthesis of Trifluoromethyl Ethers from Dithio-
carbonates
.5 Oxidative Desulfurization-Fluorination of Thi-
onesters and Thioncarbonates
.6 Synthesis of Trifluoromethylamines from
Dithiocarbamates
2
2
2
nated glutamic acid and novel liquid-crystalline 3. Synthesis and Electro-Optical Properties of No-
vel Fluorine-Containing Liquid Crystals
.1 Synthesis and Electro-Optical Properties of N-Tri-
fluoromethylamino-Substituted Liquid Crystals
.2 Syntheses and Electro-Optical Properties of Li-
quid Crystals having Trifluoromethoxy Polar
Functional Group
materials having an N-trifluoromethylamino, tri-
fluoromethoxy, or 1,2-difluoroethylene group. The
fluorine-containing liquid-crystalline materials are
compared with the corresponding non-fluorinated
materials in respect to phase transition behaviors
and electro-optical properties and shown to be suita-
3
3
ble for not only super twisted nematic (STN) but also 3.3 Synthesis and Properties of 3-Substituted Phenyl
for thin film transistor (TFT)-addressed liquid crys-
tals displays.
Trifluoromethyl Ethers
.4 Synthesis and Electro-Optical Properties of Liquid
Crystals with a vic-Difluoro-Olefinic Moiety
3
1. Introduction
properties can be understood in terms of the isoelec-
tronic structures of fluorine and oxygen, mimicking
Recent rapid progress in or- and blocking effects in the inhibition of enzymatic
.
. .
Keywords: desulfuri-
zation-fluorination;
fluorine; fluorination;
sulfur; synthetic meth-
ods; liquid crystals
ganofluorine chemistry has process, hydrogen-bond formation of the H F type,
[
2]
made it possible to produce and the large energy of a carbon-fluorine bond. Ac-
many organofluorine com- cordingly, a diversity of novel materials, pharmaceu-
pounds possessing unique ticals, and agrochemicals have been designed and
and superb physical proper- synthesized.
ties and biological activ-
Fluorine is rich in nature with the Clarke number of
ities. Theoretical and ex- 625 ppm, existing mostly as CaF and Na AlF . In con-
perimental studies have demonstrated that these trast, naturally occurring organofluorine compounds
[
1]
2
3
6
Adv. Synth. Catal. 2001, 343, No. 3
Ó WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2001
1615-4150/01/34301-235±250 $ 17.50-.50/0
235

M. Kuroboshi, K. Kanie, T. Hiyama
REVIEWS
returned to Kyoto University and studied there un-
til 1981, when he moved to Sagami Chemical Re-
search Center as Research Fellow and Group Lead-
er. There he was promoted to Senior Research
Fellow in 1983 and then to Executive Research Fel-
low in 1988. In 1992, he joined the Research Lab-
oratory of Resources Utilization, Tokyo Institute of
Technology, as Professor of the Division of Newer
Metal Resources. In April 1, 1997, he moved to the
present position as Professor of Organic Material
Chemistry. He is a recipient of Young Chemist
Award of the Chemical Society of Japan, April,
Manabu Kuroboshi, born in
Kobe, Japan, in 1961, graduated
(1984) and received his Dr.
Eng. degree (1990) from Kyoto
University, Professor Kiitiro
Utimoto and Dr. Takashi Ishi-
hara being the thesis supervisor
and adviser, respectively. He
joined the group of Professor
Tamejiro Hiyama at Sagami
Chemical Research Center as
researcher in 1989. In 1992, he was appointed as
Instructor in the Research Laboratory of Resources
Utilization, Tokyo Institute of Technology (Super-
visor: Prof. Tamejiro Hiyama). In 1995, he moved
to the present position as Lecturer (Supervisor:
Prof. Sigeru Torii). His current research interests
extend to electro-organic synthesis using multi-re-
dox systems and asymmetric electro-organic
synthesis.
1
980. His current research interest include the de-
velopment of new organometallic reagents for se-
lective organic synthesis, organofluorine and or-
ganosilicon chemistry, synthesis of biologically
active substances, design and synthesis of new
functionality molecules and materials. He has pub-
lished more than 300 original papers, 30 review
articles and one book.
Kiyoshi Kanie, born in 1971, re-
ceived his bachelor's degree in
chemistry from Nagoya Insti-
tute of Technology in 1994 and
master's degree from the Inter-
disciplinary Graduate School of
Science and Engineering, To-
kyo Institute of Technology, in
are very rare except for fluoroacetic acid, w-fluori-
nated fatty acids, fluorocitrate, fluorothreonine, and
[3]
fluorinated nucleoside. Therefore, organofluorine
compounds are available solely by organic synthesis.
There are two synthetic methods for organofluor-
ine compounds: the building block method and the
fluorination method.
1996. Then he was appointed to
be Instructor at the Graduate
School of Engineering, Univer-
The building block method uses fluorinated small
organic molecules which are incorporated into target
molecules by appropriate chemical transformations.
Various kinds of building blocks have been developed
sity of Tokyo, June, 1998. In 2000, he received his
Ph.D. degree from Kyoto University; his doctoral
study dealt with synthetic fluorine chemistry and
liquid-crystal materials science. His current re-
search topics at the University of Tokyo relate to
the exploration of materials with novel organic
functionality through self-organization.
[4]
and now commercially available.
The fluorination method is concerned with intro-
duction of fluorine into organic molecules using F ,
2
[5]
HF, SF , or reagents derived from these. Because
4
these fluorination reagents are usually extremely re-
active and toxic, the reaction conditions should be
carefully controlled by special skill using an appropri-
ate apparatus.
Tamejiro Hiyama, born in Osa-
ka, Japan, in 1946, received his
B. Eng. and M. Eng. degrees
both from Kyoto University,
Professor Hitosi Nozaki being
the thesis advisor. After another
year of graduate research, he
was appointed Instructor in De-
partment of Industrial Chemis-
For the synthesis of the requisite fluorinated target
molecules, fluorination reaction should be 1) regio-,
stereo-, and chemoselective enough to be applicable
to complex organic molecules, 2) easy to manipulate,
and 3) fast enough to complete quickly under mild
conditions. Very often, the selectivity and reactivity
contradict each other.
try, Kyoto University, and con-
tinued to work with Professor
Nozaki. Immediately after receiving the Doctor of
Engineering degree in 1975 from Kyoto University,
he joined the group of Professor Yoshito Kishi at
Harvard University. After the postdoctoral year, he
When a specific functional group in a substrate is
activated electrophilically, selective fluorination can
be achieved using a relatively mild nucleophilic fluor-
inating agent. For example, when a substrate is acti-
vated by a mild oxidant, fluoride ion can react with
the substrate to form a C±F bond. According to this re-
action design, oxidative fluorination, halo- (and thio-,
236
Adv. Synth. Catal. 2001, 343, 235±250

Oxidative Desulfurization-Fluorination
REVIEWS
[
6]
[13]
seleno-) fluorination of olefins,
tion,
deazo-fluorina- CF OF and/or HF/F ,
reagents that need special
3
2
[
7]
[8]
and fluorination of alkynes
have been care upon use. The combined use of 70% HF/pyridine
achieved. Fine tuning of the reactivities of a fluoride (py) (Olah's reagent) and N-bromosuccinimide (NBS)
source and an oxidant depending on a substrate gives or dialkylaminosulfur trifluoride (DAST) and NBS is
[
9]
rise to the fluorinated target product in high yields.
conveniently used for fluorosugar synthesis starting
Recently, the authors have studied the oxidative from phenylthiosugars (Equation 1 and Equa-
[
14]
fluorination of organosulfur compounds and found tion 2).
The fluorosugars are versatile intermedi-
that a variety of organofluorine compounds can be ates for O-glucosidation reaction.
readily prepared. The reaction is called oxidative de-
sulfurization-fluorination and is reviewed herein with
the emphasis on principle, scope, limitations, and ap-
plications. The synthetic potential of this methodol-
ogy is demonstrated by the synthesis of fluorinated li-
quid crystalline materials whose properties also will
be described. The basic concept is summarized in
Scheme 1
The third reagent for oxidative fluorination is ArIF2,
whose fluorination is considered to proceed in an S i
N
[
15]
fashion with inversion of configuration.
+
±
Reagents consisting of NO [BF ] and 60% HF/py
4
[
16]
[17]
(
Equation 3)
or CsF and FSO Me
are also em-
3
ployed for the fluorination of sulfides.
Scheme 1. Oxidative desulfurization-fluorination of orga-
nosulfur compounds.
When alkyl aryl sulfides, Ar±S±R, are treated with
these reagents, the arylthio group ArS is substituted
+
The positive halogen species X attacks the sulfur by F to give rise to fluoroalkanes F±R.
atom to activate the C-S bond. Nucleophilic substitu-
The authors have developed the oxidative desulfu-
tion with the fluoride species occurs to form the C-F rization-fluorination reaction using a combination of
bond. In the case of a substrate having a C=S double tetrabutylammonium
bond, double desulfurization-fluorination occurs to (TBAH F ) and 1,3-dibromo-5,5-dimethylhydantoin
dihydrogen
trifluoride
2
3
[
18]
give difluoromethylene compounds. An advantage of (DBH). A fluoro-Pummerer rearrangement
this methodology is that the starting organosulfur ma- found to take place to give the corresponding 1-
is
[
19]
terials are easily accessible.
fluoroalkyl sulfides selectively (Figure 1).
Fluoro-
The research described in this article was carried methyl sulfides are obtained from aryl methyl sulfides
out at the Sagami Chemical Research Center and To- bearing an electron-donating or electron-withdraw-
kyo Institute of Technology.
ing group in the aryl moiety. The corresponding
fluoro(methylthio)acetate results from the reaction
with ethyl (methylthio)acetate.
The fluoride reagent TBAH F can be easily pre-
2
3
2
. Fluorination Reactions
pared from aqueous HF, KHF , and tetrabutylammo-
2
[
20]
nium fluoride (TBAF)
and is currently available
2
.1 Fluorination of Sulfides and Thiols
from Acros Organics as a dichloromethane solution.
[
21]
TBAH F is more stable than the HF/py complex:
2
3
Monofluorination results in the formation of fluoro-
methylene group ±CHF± that is particularly essential
in enzyme inhibitors and liquid-crystalline materials.
This particular functional group has been introduced
so far by 1) halogen-exchange,
fluorination of alcohols,
no trace of HF elimination or loss of fluorination
[
10]
2) deoxygenation-
or 3) addition of HF to ole-
For this purpose, the oxidative desulfuriza-
[
11]
[
12]
fins.
tion-fluorination of sulfides and thiols is also effec-
tive. For example, fluorinated amino acids are
prepared from the corresponding thiols with HF/
Figure 1. Fluoro-Pummerer rearrangement of sulfides.
Adv. Synth. Catal. 2001, 343, 235±250
237

M. Kuroboshi, K. Kanie, T. Hiyama
REVIEWS
power is observed during storage at room tempera-
ture. The fluoride reagent is easy to manipulate. For
example, all the reactions can be carried out in ordin-
ary glassware.
Electrochemical oxidation can replace the use of an
oxidant. Thus, electrochemical oxidative fluorination
[
18a]
of alkyl aryl sulfides
induces the fluoro-Pum-
merer rearrangement smoothly, particularly when
an electron-withdrawing group is substituted at the
a-position in an alkyl group. Diastereoselective fluor-
[
18b,18c]
ination also is feasible.
2.2 Fluorination of Dithioacetals
There are many biologically active synthetic agents
[
22]
Scheme 2. Synthesis of difluoroglutamic acid from aspartic
acid.
that contain a difluoromethylene (±CF ±) group.
2
Such gem-difluoro compounds are prepared by treat-
ment of aldehydes or ketones with SF , DAST, or a
4
similar reagent. The gem-difluorination can be more
easily performed starting with dithioacetals, for which
a reagent system consisting of HF/py and an oxidant
The same transformation is achievable with p-(di-
fluoroiodo)toluene (Equation 5). Dithioacetals de-
rived from aliphatic ketones are less efficiently con-
verted into the corresponding gem-difluorination
[
24]
[25]
+
± [16]
such as DBH, NBS,
SO ClF,
or NO [BF ]
2
4
is preferable to the HF/CF OF combination (Equa-
[27]
3
products.
[23]
tion 4).
The gem-difluorination is sometimes accompanied
by a side reaction: aromatic ring halogenation takes
place especially when DBH is used as an oxidant,
and an acid-sensitive functional group does not toler-
ate these reaction conditions.
The electrochemical oxidation of p-iodoanisole pro-
ceeds in the presence of a fluoride ion and gives p-(di-
fluoro)iodoanisole, which can mediate the difluorina-
[
28]
tion of dithioacetals (Scheme 3).
The authors have found that such gem-difluorina-
tion can be conveniently carried out with TBAH2F3
under milder conditions. Functional groups like oxi-
rane, OH, and a C=C double bond are compatible
[26]
(Figure 2).
The strategy is applied to the synthesis of difluoro-
[
26b]
glutamic acid (Scheme 2).
Scheme 3. Electrochemical fluorination of dithioacetals.
Using 70% HF/py or 80% HF/melamine (HF/mel),
gem-difluorination of dithioacetals derived from per-
fluoroalkyl ketones is also possible and gives rise to
perfluoroalkyl-substituted aromatic compounds (Fig-
[
29]
ure 3).
Since the starting ketones are available
from perfluoroalkanoic acids by reaction with aryl-
magnesium reagents, the net transformation allows
the perfluoroalkylation of aromatic compounds.
Figure 2. gem-Difluorination.
238
Adv. Synth. Catal. 2001, 343, 235±250

Oxidative Desulfurization-Fluorination
REVIEWS
TBAH2F3 in lesser amounts, difluoro(methylthio)-
[
35a]
methylated (hetero)arenes 3 are produced.
The
difluorination products 3 are intermediates of the tri-
fluoromethylation. In fact, the trifluoromethylated
compounds 2 are obtained by treatment of 3 with
[
35a]
TBAH F /DBH (Equation 6).
2
3
The substrates, methyl (hetero)arenedithiocarboxy-
lates 1, are readily accessible by sequential treatment
of the corresponding (hetero)arenemagnesium ha-
Figure 3. Synthesis of perfluoroalkyl-substituted aromatic
compounds.
[
35a]
lides with CS and MeI.
Because a CS Me group
2
.3 Oxidative Desulfurization-Fluorination of
Dithioester and Orthothioester
2
2
is in this way introduced electrophilically, the net
transformation is regarded as electrophilic trifluoro-
methylation.
Fluorination methods known for trifluoromethylar-
enes are the reaction of arenecarboxylic acids with
In a similar way, a,b-unsaturated dithiocarboxy-
lates are conveniently converted into the correspond-
ing 3,3,3-trifluoropropenes. The starting materials
are conveniently prepared by the cross-aldol reaction
of aromatic aldehydes and lithium enolates derived
from dithiocarboxylates followed by dehydration
[
30]
SF4,
halogen exchange of trichloromethylar-
Friedel-Crafts alkylation/halogen exchange
[
31]
enes,
[
32]
of aromatics with CCl /HF, and oxidative desulfu-
rization-fluorination of arenedithiocarboxylic acid
with XeF .
able.
4
[33]
The building block method is also avail-
2
[
34]
[
35a]
(Scheme 4).
The oxidative desulfurization-fluorination reaction
also gives trifluoromethylarenes. The starting materi-
als are (hetero)arenedithiocarboxylates 1, which
upon treatment with TBAH2F3 and DBH, give tri-
fluoromethyl-substituted aromatic compounds 2 as
[35]
Scheme 4. Synthesis of a,b-unsaturated carbodithioates.
shown in Table 1.
For this transformation, 70% HF/py is also effec-
tive; however, extreme care should be taken during
handling, reaction, and work-up. It is worthy of note
that when NBS or NIS is employed along with
The trifluorination of a,b-unsaturated dithiocarboxy-
lates is smoothly carried out with TBAH F (6 mol)
2
3
and NIS (12 mol), and various kinds of 3,3,3-trifluoro-
propenes substituted by an aryl group are readily pre-
pared, except for NO -substituted ones, which afford
2
[
35a]
difluorination products (Figure 4).
Table 1. Oxidative desulfurization-fluorination of methyl
arenecarbodithioates 1.
When the amounts of NIS and TBAH2F3 are re-
duced, the yield of 5 decreases, giving the thiocarbox-
ylate RCH=CHC(O)SR as a by-product. DBH or NBS in
lieu of NIS and HF/py in lieu of TBAH F result in the
2
3
formation of a complex mixture of unidentified prod-
[
35a]
ucts.
Figure 4. Trifluorination or difluorination of a,b-unsatu-
rated dithiocarboxylates.
Adv. Synth. Catal. 2001, 343, 235±250
239

M. Kuroboshi, K. Kanie, T. Hiyama
REVIEWS
Since the building block method has limitations in Products of type 7a are transformed to olefins 8 by
the preparation of 3,3,3-trifluoropropene deriva- the oxidation-thermolysis sequence (Scheme 6). Sub-
[
33]
tives,
this method is considered to be a potent al- sequent metalation of 8 followed by reaction with an
[
33]
ternative.
electrophile affords various 1,1-difluoroalkenes.
In contrast, methyl dithiocarboxylates RCS Me,
2
upon treatment with 70% HF/py, HgF and KF, give
2
the difluorination products RCF SMe, which are con-
2
verted into gem-difluoro olefins via oxidation and
[
36]
thermolysis (Scheme 5).
Scheme 6. Synthesis of 2-bromo-1,1-difluoro-1-alkenes.
When tris(methylthio)ethanol derivatives 9 are treat-
ed with TBAH F and DBH, difluorination and oxida-
2
3
tion takes place to give difluoro(methylthio)methyl
Scheme 5. gem-Difluoroolefin synthesis from
carboxylate.
a dithio-
[
38]
ketones 10 (Figure 7).
Substrates 9 are easily pre-
pared from aldehydes RCHO and LiC(SMe) . When
3
Aromatic orthothioesters show a reactivity similar to NIS and/or HF/py were used as the component of the
that of dithioesters. For example, trifluoromethylar- reagent, no trifluoromethylation occurred even un-
enes are obtained by treatment with 70% HF/py and der forcing conditions. The hydroxy group in a sub-
[
37]
DBH (Figure 5).
nying reaction when the substrate has an electron- Treatment of 9 with DAST causes fluorination and re-
Ring bromination is an accompa- strate containing a pyridine ring remains unchanged.
donating alkoxy group.
arrangement of a methylthio group to afford difluori-
nation products 11 (Figure 8).
[
19]
In summary, the oxidative desulfurization-fluorina-
tion of arenedithioester or areneorthothioesters af-
Figure 5. Oxidative desulfurization-fluorination of ortho-
thioesters.
Upon treatment of aliphatic orthothioesters 6 with
TBAH F and DBH, difluorination followed by b-bro-
2
3
mination occurs to give RCXBrCF SMe 7a (X = H) or
2
Figure 7. Oxidative desulfurization-fluorination of 2,2,2-
tris(methylthio)ethanols.
[
38]
7b (X = Br) depending on the kind of R (Figure 6).
Figure 8. Fluorination of 2,2,2-tris(methylthio)ethanols with
Figure 6. Brominative fluorination of orthothioesters.
DAST.
240
Adv. Synth. Catal. 2001, 343, 235±250

Oxidative Desulfurization-Fluorination
REVIEWS
fords trifluoromethylarenes with all C±S bonds being containing a trifluoromethoxy group, though com-
converted into C±F bonds, whereas the same reaction mercially available, are in general expensive and in-
with aliphatic orthothioesters results in brominative convenient.
difluorination.
The oxidative desulfurization-fluorination of di-
thiocarbonates using 70% HF/py and DBH gives tri-
fluoromethyl aryl and alkyl ethers in good yields after
2
.4 Synthesis of Trifluoromethyl Ethers from
Dithiocarbonates
purification by silica-gel column chromatography
[47]
(
Table 2) . The starting dithiocarbonates are easily
Trifluoromethyl ethers are a very important class of prepared by treatment of phenols or alcohols with
compounds particularly in materials, agrochemical, CS and MeI. Ring bromination frequently occurs
2
and pharmaceutical sciences owing to their high when the substrates lack an electron-withdrawing
chemical and thermal stabilities as well as their lipo- group in the phenolic moiety. This side reaction is
[
1]
philicity and gas solubility.
ethers are prepared usually by 1) halogen exchange When TBAH
reaction of aryl trichloromethyl ethers with SbF / of compounds, difluoro(methylthio)methyl ethers 14,
Aryl trifluoromethyl suppressed by using a smaller amount of HF/py.
and NBS are employed, a novel class
F
2 3
3
[39]
[40]
SbCl5
or HF,
2) trichloromethylation/halogen are isolated as the sole products.
exchange of phenols with CCl /HF,
[
41]
or 3) oxidative
The isolated difluorinated products can be con-
4
fluorination of fluorodithioformates or chlorodithio- verted into trifluoromethyl ethers 13. Thus, 14 are
[
42]
[43]
[47]
formates with SF4
or MoF6.
Alkyl trifluoro- considered to be precursors of 13 (Equation 7).
methyl ethers are available by 1) addition of CF OF
3
[
44]
to alkenes,
2) trifluoromethylation of alcohols with
[
45]
O-trifluoromethylbenzofuranium salts,
ination of alkyl fluoroformates.
or 3) fluor-
These reactions
[
46]
are, however, often hard to control and require toxic
reagents thus being disfavored. Some building blocks
When dithiocarbonates derived from secondary and
tertiary alkanols or benzylic alcohols are treated with
70% HF/py and NBS, fluorination instead of the for-
mation of trifluoromethyl ethers takes place to give
Table 2. Oxidative desulfurization-fluorination of dithiocar-
bonates 12.
[
47]
alkyl or benzylic fluorides 15.
NIS also promotes
the fluorination efficiently without ring halogenation.
Table 3. Synthesis of alkyl fluorides 15 from xanthates of
secondary or benzylic alcohols.
Adv. Synth. Catal. 2001, 343, 235±250
241

M. Kuroboshi, K. Kanie, T. Hiyama
REVIEWS
The group R' in R'SC(S)OR has little effect on the reac-
tivity: all of dithiocarbonates (R' = Me, i-Pr, and Ph)
give the R±F 15. DBH is shown to be the best oxidant
for the fluorination of dithiocarbonates R'SC(S)OR
(R = benzylic) (Table 3).
Depending on the structure of the starting com-
pounds 12, trifluoromethyl ethers 13 or fluorides 15
are produced selectively. The reaction is assumed to
proceed through carbocationic intermediates in con-
Figure 9. Synthesis of a,a-difluoro ethers by oxidative de-
sulfurization-fluorination.
[48]
trast to the similar reaction with p-TolIF2.
Hereby
fluorides 15 are produced irrespective of the starting
material, the reaction is possibly proceeding through
an S i mechanism.
N
In contrast, use of 50% HF/py or 70% HF/py/KHF2
affords trifluoromethyl ethers 13 from the dithiocar-
[
47a,49]
bonates derived from secondary alcohols.
Thus, either trifluoromethyl ethers 13 or fluorides 15
can selectively be prepared by acidity control of the
fluoride reagent (Scheme 7). The oxidative desulfuri-
zation-fluorination is an exclusive method for the
synthesis of secondary alkyl trifluoromethyl ethers
from the corresponding secondary alcohols, though
yields remain yet to be improved.
Figure 10. Synthesis of carbonyl fluoride acetals by oxida-
tive desulfurization-fluorination.
erations. The direct fluorination of esters leading to
[56]
1
7 is achieved under harsh conditions.
In a similar way, fluorocarbonyl acetals 19 are
[
53]
available from thionocarbonates 18 (Figure 10).
This approach is useful for the preparation of 2,2-di-
fluoro-1,3-benzodioxolanes, a characteristic structur-
al moiety found in some potent pharmaceuticals and
agrochemicals.
2
.6 Synthesis of Trifluoromethylamines from
Dithiocarbamates
Scheme 7. Synthesis of secondary alkyl fluorides or triflu-
oromethyl ethers from dithiocarbonates.
Recorded synthetic methods for N-trifluoromethyl-
amines are 1) fluorination of N-formamides or N-tri-
chloromethylamines with SF , SbF , DAST, or anhy-
Recently, BrF3 was shown to be applicable to the
synthesis of primary alkyl trifluoromethyl ethers
4
3
[57±61]
drous HF,
2) fluoromethylation of secondary
[
50]
through the oxidative desulfurization-fluorination.
Although the mechanism still remains to be clarified,
amines with CF Br and tetrakis(dimethylami-
2
2
[62]
no)ethylene,
kylamines,
3) electrochemical fluorination of al-
and 4) trifluoromethylation of amines
[51]
BrF or BrF
is suggested for the active species in
this transformation. Since a haloimide reagent can
be replaced by PhI(OCOCF ) for the trifluoromethy-
[63]
3
[64]
with an O-(trifluoromethyl)dibenzofuranium salt.
However, very often these reactions are avoided be-
cause 1) the reagents are relatively toxic, corrosive,
and/or explosive, 2) special apparatus is sometimes
needed, and 3) scope and limitations of each reaction
are not well-studied.
3
2
lation, cooperation of both an oxidant and a fluoride
reagent appears to be essential.
2.5 Oxidative Desulfurization-Fluorination of
The authors have found that N-trifluoromethyl-
amines 21 are readily prepared by oxidative desulfur-
Thionoesters and Thionocarbonates
Thionoesters 16, that are easily prepared from the ization-fluorination of dithiocarbamates 20 (Ta-
[
65]
corresponding esters with the Lawesson reagent ble 4).
[
52]
(
[4-MeOC H P(=S)S] ),
upon treatment with
The starting dithiocarbamates 20 are a well-known
6
4
2
TBAH F and NBS, give a,a-difluoroalkyl ethers 17 class of compounds and are prepared in high yields
2
3
[53]
(
Figure 9).
Although ethers 17 appear to be sensi- by sequential treatment of amines with a base, CS2,
tive to moisture, the purification can be easily per- and MeI. The oxidative desulfurization-fluorination
formed by flash silica-gel chromatography. The same of 20 using TBAH2F3 and NBS affords N-trifluoro-
[
54]
[55]
transformation is achieved with BrF3
or DAST,
methylamines 21 in high yields. Among the various
which sometimes cause troubles in experimental op- fluoride sources (TBAH F , 70% HF/py, and 3 HF/
2
3
242
Adv. Synth. Catal. 2001, 343, 235±250

Oxidative Desulfurization-Fluorination
REVIEWS
Table 4. Synthesis of N-trifluoromethylamines.
When DBH is used in lieu of NBS for the fluorination
of (heteroaryl)dithiocarbamates, trifluoromethyla-
tion is attained at room temperature, whereas ring-
bromination at the p-position is an accompanying re-
action at the reflux temperature of CH Cl2
2
[
65]
(Scheme 8).
This side reaction is suppressed by
use of NBS.
The presence of a bromo functionality allows for
the introduction of a variety of functional groups
[
65]
(Equation 8 and Equation 9).
The applicability of the oxidative desulfurization-
fluorination is demonstrated by a facile synthesis of a
trifluoromethyl-substituted nucleoside base from the
[
65]
corresponding dithiocarbamate (Equation 10).
NEt ), TBAH F is the reagent of choice because it al-
3
2 3
lows the use of ordinary glassware. No difluorination
products are isolable. Use of a smaller amount of Diphenyl(trifluoromethyl)amine is disclosed to have
either of the two reagents gives a mixture of N-tri- a redox potential similar to that of diphenyl ether,
fluoromethylamine 21 and substrate 20.
manifesting that a CF group endows an amino group
3
The trifluoromethylation reaction is applicable to a with resistance against oxidation.
wide range of substrates: aromatic, heteroaromatic,
A perfluoroalkyl group can also be introduced to
and aliphatic amines can be converted into the corre- secondary amines, taking advantage of the oxidative
sponding N-trifluoromethylamines. Aryl(trifluoro- desulfurization-fluorination. Although perfluoro-
methyl)amines are stable to moisture, whereas di- alkylamines, components of artificial blood, are avail-
alkyl(trifluoromethyl)amines are highly susceptible able by electrochemical fluorination, tertiary amines
to hydrolysis. Thus, work-up and isolation of dialkyl- with a single perfluoroalkyl group are hardly accessi-
[
2]
(
trifluoromethyl)amines are effected by filtration, ble. Tertiary mono(perfluoroalkyl)amines can be
concentration, and distillation under reduced pres- synthesized by treatment of perfluoroalkanethio-
sure.
Scheme 8. Synthesis of trifluoromethylamines.
Adv. Synth. Catal. 2001, 343, 235±250
Figure 11. Preparation of perfluoroalkylamines 23.
243

M. Kuroboshi, K. Kanie, T. Hiyama
REVIEWS
[
66]
amides 22 with TBAH F and NBS (Figure 11).
Sub- 3.1 Synthesis and Electro-Optical Properties of N-
2
3
strates 22 are prepared from perfluoroalkanamides
Trifluoromethylamino-Substituted Liquid
Crystals
and P S , or alternatively, the Lawesson reagent. Per-
2
5
fluoroalkyl(aryl)amines having an electron-donating
group on the aryl group are susceptible to hydrolysis
but are isolable provided that special care is taken
during the isolation.
LC materials with an amino group show smectic C
[
71]
(SC) phases in a wide range of temperatures.
Due
to their strong basicity and low resistance to oxida-
tion, however, amines are not appropriate materials.
In contrast, the trifluoromethyl group on an amine ni-
trogen enhances resistance to oxidation and reduces
basicity and nucleophilicity. As described in Section
3
. Synthesis and Electro-Optical
Properties of Novel Fluorine-
Containing Liquid Crystals
2
.6, (p-bromoaryl)trifluoromethylamines are pro-
duced in high yields under forcing conditions. The
bromine functionality can advantageously be utilized
for the synthesis of N-trifluoromethylamino-substi-
Recently, STN (supertwisted nematic for passive ma- tuted LCs 24 through the palladium-catalyzed cross-
[
72]
trix) and TFT (thin film transistor for active matrix) coupling reaction using arylzinc reagents.
The
mode displays have been rapidly becoming important yields isolated as well the as phase transition behav-
[
67]
in flat panel displays.
Owing to the new technology, iors of 24 as observed with a polarizing microscope
large size portable color displays with low-voltage and differential scanning calorimeter (DSC) are sum-
and high-speed addressing are now commercialzed. marized in Table 5.
More recently, twisted nematic (TN) TFT-mode, in-
[Methyl(trifluoromethyl)amino]pyridines exhibited
plane switching TFT-mode, and vertical alignment smectic A (S ) phases, whereas the corresponding 2-
A
TFT-mode are evolving, and thus a great demand is (dimethylamino)pyridines lost the LC phases. Thus, a
[
68]
growing for new types of LC materials.
4-Cyano- trifluoromethylamino group appears to induce liquid
4
'-pentylbiphenyl and its analogues, which are uti- crystallinity. The corresponding pyrimidines showed
[
72a]
lized widely for passive matrix LC displays (LCDs), only simple melting points.
are not applicable to the TFT-mode LCD due to low
voltage holding ratio of the materials.
A cross-coupling reaction with organosilane re-
[
73]
agents
was also effective for the preparation of tri-
In general, fluorine-substituted LCs are gifted with fluoromethylamino-substituted heterobiaryls (Equa-
a high voltage holding ratio and a low threshold vol- tion 11).
tage as well as high chemical and thermal stabilities.
The trifluoromethylamino-substituted LCs serve as
Accordingly, novel fluorine-containing LC materials versatile additives for ferroelectric LCs (FLCs). For
have attracted much attention in the recent develop- example, 2-[methyl(trifluoromethyl)amino]-5-(4-oc-
[
1,69]
ment of LC materials,
and various types of fluor- tyloxyphenyl)pyridine when added to an FLC host
ine-containing LCs with high positive or negative di- mixture improved both the range of the chiral SC
electric anisotropy have been designed and
synthesized.
Table 5. Synthesis of trifluoromethylamino-substituted
heterobiaryls.
Syntheses of fluorine-containing LCs are carried
out starting with commercially available fluorinated
building blocks. This synthetic strategy is very often
hampered by the inaccessibility of the requisite
fluorinated building blocks. In addition, the fluorine
functionality induces unusual reactivity and prevents
[
1]
conventional synthetic transformations. An alterna-
tive method is fluorination using very reactive and/or
toxic reagents and thus is rarely employed.
As discussed in Section 2, oxidative desulfurization-
fluorination is a convenient approach for the syn-
thesis of organofluorine compounds. We have applied
the reaction to the syntheses of novel LC materials
having a fluorine functional group such as an N-tri-
fluoromethylamino, trifluoromethoxy, or 1,2-di-
fluoroethylene group. In this section, we briefly sum-
marize the synthesis and electro-optical properties of
[67,70]
such LCs.
244
Adv. Synth. Catal. 2001, 343, 235±250

Oxidative Desulfurization-Fluorination
REVIEWS
(
S *) phase and the rate of response to an electric sulfurization-fluorination of the corresponding
C
[
72a]
[47,49]
field.
dithiocarbonates.
In view of the facts that LCs
with a 4-(trifluoromethoxy)phenyl mesogen exhibit
low viscosity and high voltage holding ratio and thus
are widely used as a switching element of TFT-
[
74]
LCDs
and also that LCs with a cyclohexane meso-
gen show smaller birefringence than those with a
[
75]
benzene mesogen,
we considered that LCs with a
(trifluoromethoxy)cyclohexane mesogen would ex-
hibit much better physical and electro-optical proper-
ties and synthesized trifluoromethoxy-substituted cy-
clohexane-type LCs according to the route shown in
[
76]
Scheme 9.
We have also prepared compounds 25, all having a cy-
clohexyl(cyclohexyl)benzene mesogen, and sum-
marize their phase transition temperatures in Ta-
[
72a]
ble 6.
Compounds 25 mainly exhibit smectic B
(
SB) phases in a wide range of temperatures and are
effective additives for STN-LC materials in reducing
threshold voltage (V ). In addtion, compounds 25
th
were shown to be thermally and chemically stable
and miscible with nematic host LCs for STN-mode
displays. Accordingly, the trifluoromethylamino-sub-
stituted LCs are suitable additives for both STN and
FLC materials
Scheme 9. Synthesis of trifluoromethoxycyclohexane-type
liquid crystals.
Table 6. Phase transition temperatures of trifluoromethyl-
amino-substituted liquid crystals.
An example is compound 26 which showed an N
phase from 147 to 189 °C on heating, whereas meth-
oxycyclohexane 27 exhibited only an S phase in a
B
[
76b]
narrow range of temperature.
Furthermore, com-
pound 26 had a high nematic-to-isotropic transition
temperature as compared with trifluoromethoxyben-
zene 28. These results indicate that a trifluoro-
methoxycyclohexane mesogen appears to stabilize
the N phase.
We next compared 26, 27, and 28 as an additive for
[
76b]
nematic LC materials.
Each was added at 20 wt %
to a host nematic mixture, and nematic-isotropic
temperature (T ), dielectric anisotropy (De), V , bi-
NI
th
refringence (Dn), and response time (t) of the result-
ing mixture were measured in a TN cell. Rising
switching time (t ) and decay switching time (t )
r
d
were measured as the electro-optical response from
00% to 10% and from 0% to 90%, respectively, to es-
1
timate t. The values t were obtained when t became
r
equal to t at a properly applied voltage. The results
Trifluoromethylamines are shown to have much bet-
ter liquid crystallinity and electro-optical properties
d
are summarized in Table 7. Trifluoromethoxycyclo-
hexane 26 induced a larger De value than methoxycy-
clohexane 27. In general, when Vth becomes smaller,
De becomes larger. However, both Vth and De were re-
duced with 26 as compared with 28. Thus, a trifluoro-
methoxycyclohexane mesogen contributes to the re-
duction of Vth of the host mixture. Furthermore, 26
improved the TNI and Dn of the host. Thus, 26 is ob-
viously a better additive than 28 that is currently uti-
[
72a]
than the corresponding methylamines.
Thus, the
trifluoromethylamino-substituted LCs will find wide
applications as a stable component of LCD materials.
3
.2 Syntheses and Electro-Optical Properties of
Liquid Crystals having a Trifluoromethoxy
Polar Functional Group
As we described in Section 2.4, trifluoromethyl ethers lized for TN-displays.
derived from primary and secondary alcohols in addi-
We next studied the possibility of 26 as an additive
tion to phenols are readily obtained by oxidative de- for TFT-addressed LCDs, adding 26 to a TFT mixture
Adv. Synth. Catal. 2001, 343, 235±250
245

M. Kuroboshi, K. Kanie, T. Hiyama
REVIEWS
to observe that the nematic phase range expanded
and response time was improved without decrease of
[
76b]
voltage holding ratio as summarized in Figure 12.
The TNI of the resulting 26/TFT mixture was not low-
Table 7. Electro-optical properties of trifluoromethyl ethers
Figure 13. Chiral dopants for TN- and TFT-TN-LC displays.
(
added at 20 wt % to the host liquid crystal).
ered at all upon heating at 80 °C for 10 h or under UV
irradiation. Accordingly, LCs with the trifluoro-
methoxycyclohexane mesogen are shown to be very
stable against heat and light.
We further studied the possibility of a trifluoro-
methoxy-substituted LCs as a chiral dopant for TN-
[
76b]
LCDs (Figure 13).
Cholesteryl nonanoate (29) is
currently used as a chiral dopant for STN-LCDs. We
prepared 3b-trifluoromethoxycholestane (30) and 3b-
methoxycholestane (31), mixed each at 1 wt % with a
TN-host mixture consisting of 4-alkoxyphenyl 4-alkyl-
cyclohexane-1-carboxylates, and measured helical
pitches of each mixture at 25 °C. The pitch of the mix-
ture including 29, 30, or 31 was 15.9, 15.9, or 39.2 mm,
respectively. Thus, a trifluoromethoxy group in a chi-
ral dopant acts as a polar functionality clearly better
than a methoxy group. Because LCs containing a cya-
no or alkyloxycarbonyl group bring a striking decrease
in voltage holding ratio, ester 29 is seemingly inap-
propriate for TFT-LCDs. To confirm this hypothesis,
we mixed 29 or 30 (2 wt %) to an LC mixture for TFT-
LCDs and measured the voltage holding ratios of the
resulting mixture: 29 reduced the value from 97.5% to
9
7.0% at 80 °C; 30 held at 97.4%. The helical pitch of
both the mixtures was 8.0 mm at 25 °C. Therefore,
compound 30 is concluded to be an excellent chiral do-
pant for not only STN-LCDs but also TFT-TN-LCDs.
Because LCs containing an w-methoxyalkyl moiety
show high De, broad nematic phases, and low viscos-
[
77]
ity as well as high voltage holding ratios,
we envi-
saged that replacement of the methoxy group by a tri-
fluoromethoxy group would improve the properties.
Thus, we prepared w-trifluoromethoxyalkyl-substi-
Figure 14. Structures of w-trifluoromethoxycyclohexane-
type LCs.
Figure 15. Dielectric anisotropy of trifluoromethyl ether-
Figure 12. Materials for TFT-addressed twisted nematic LC
type LCs.
displays.
246
Adv. Synth. Catal. 2001, 343, 235±250

Oxidative Desulfurization-Fluorination
REVIEWS
tuted LCs 32 and 33 and examined their phase transi- method for the synthesis of LC materials having a
[
76b]
tion behaviors (Figure 14).
were observed depending mainly on the structure of terminal olefins.
the mesogen: 32 and 33 showed N and S phases, re- which involves 1) thio-fluorination
Different mesophases vic-difluoro-olefinic moiety from the corresponding
[
82]
The route is shown in Scheme 10
[
5b]
of 34 (or, alter-
followed by sulfide sub-
stitution), 2) fluoro-Pummerer rearrangement to give
B
[
5a]
spectively. Those with a longer alkyl chain had higher natively, halo-fluorination
mesomorphic-isotropic transition temperatures.
The electro-optical properties of the LCs were a,b-difluoroalkyl phenyl sulfides,
[
76b]
[
19]
4) oxidation of
found to be independent of the length of the alkyl the sulfides to sulfoxides, and 5) thermolysis of the re-
chain except for the De values. As readily seen in Fig- sulting sulfoxides. The isomers cis-35 and trans-35
ure 15, a trifluoromethoxy group connected directly thus synthesized were easily separated by flash col-
to a cyclohexane mesogen induces a positive De.
umn chromatography on silica gel.
The phase transition behaviors of those compounds
were compared with those of the parent olefins 34.
The fluorine-introduction effect was obvious. For ex-
ample, cis-35a showed nematic phase at higher tem-
peratures than 34a, whereas the temperature range
of the nematic phase in trans-35 was reduced, and
the TNI was lowered (Figure 16).
[
82]
3
.3 Synthesis and Properties of 3-Substituted
Phenyl Trifluoromethyl Ethers
It is also possible to introduce a trifluoromethoxy
[
78]
group into a lateral position of a mesogen.
Use of
[79]
8
0% HF/mel
for oxidative desulfurization-fluorina-
tion of the corresponding dithiocarbonate was essen-
tial: 70% HF/py gave complex mixtures. Under these
reaction conditions, trifluoromethylation as well as
bromination of the phenyl ring took place. Debromi-
nation was easily performed by treatment with n-
BuLi followed by protonation (Equation 12).
Scheme 10. Synthesis of vic-difluoro-olefins from terminal
olefins.
Although the 3-trifluoromethoxy-substituted benzenes
did not exhibit a mesophase, they did prove to be versa-
tile additives for reducing Vth and Dn of LC materials.
To examine the electro-optical properties of com-
pounds cis-35a, trans-35a, and 34a, each of those
compounds was mixed at 20 wt % with the host (cf.
3
.4 Synthesis and Electro-Optical Properties of
Liquid Crystals with a vic-Difluoro-Olefinic
Moiety
In order to evaluate the fluorine effect, fluorinated
functional materials need to be well-compared with
non-fluorinated functional materials. For this pur-
pose, the direct transformation of a C±H bond in the
parent materials to a C±F bond should be straightfor-
ward. In view of the observations that LCs containing
an w-alkenyl side chain are known to show low vis-
Figure 16. Phase transition behavior of vic-difluoro-olefins.
Table 8. Electro-optical properties of vic-difluoro-olefins.
[
80]
cosity and Vth and high voltage holding ratio
and
that LCs with a vic-difluoro-olefinic functionality in a
connecting part of mesogens exhibit low viscosity and
[
81]
high polarity,
we envisaged that LCs having an w-
vic-difluoroalkenyl group might exhibit properties fa-
vorable for LCDs. We thus developed a convenient
Adv. Synth. Catal. 2001, 343, 235±250
247

M. Kuroboshi, K. Kanie, T. Hiyama
REVIEWS
Table 7), and the properties of the resulting mixtures
were measured and are summarized in Table 8.
[4] (a) T. Kitazume, T. Yamazaki, Experimental Methods
in Organic Fluorine Chemistry, Kodansha, Tokyo,
[82]
1
998; (b) Chemistry of Organic Fluorine Compounds
Compound trans-35a exhibited a De similar to that of
the parent olefin 34a, probably because the dipole
moments of the two C±F bonds compensate each
other. In contrast, cis-35a showed a De higher than that
of 34a. Whereas the mixing of 34a at 20 wt % raised
the Vth of the host mixture, addition of both cis-35a
II, A Critical Review, (Eds.: M. Hudlicky, A. E. Pavlath),
ACS Monograph 187, Washington, DC, 1995; (c) L. M.
Yagupolskii in Houben-Weyl, Methods of Organic
Chemistry, Vol. E10 a, (Eds.: B. Baasner, H. Hagemann,
J. C. Tatlow), Thieme, Stuttgart, 1999, pp. 245±249.
5] (a) T. Kitazume, T. Ishihara, T. Taguchi, Chemistry of
Fluorine, Kodansha Scientific, Tokyo, 1993; (b) Syn-
thetic Fluorine Chemistry (Eds.: G. A. Olah, R. D.
Chambers, G. K. S. Prakash), John Wiley & Sons, New
York, 1992; (c) Houben-Weyl, Methods of Organic
Chemistry, Volumes E10 (Eds.: B. Baasner, H. Hage-
mann, J. C. Tatlow), Thieme, Stuttgart, 1999±2000.
[
[
and trans-35a reduced the V . Since all the com-
th
pounds reduced equally Dns, the fluorine effect on Dn
was not obvious. Both cis-35a and trans-35a were
thermally stable, as no decomposition was detected
upon heating their xylene solutions at 170 °C for 24 h.
As we have described above, activation of a leaving
group in a substrate by an electrophilic oxidant facil-
itates the nucleophilic substitution by a weakly nu-
cleophile fluoride ion. This reaction design suggests
that not only organosulfur compounds but also nitro-
gen compounds can be employed as the substrates for
fluorination. According to this synthetic methodology,
a variety of organofluorine compounds will be avail-
able for testing the biological and/or electro-optical
profiles required for spcecific drugs and/or materials
in the 21st century.
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6] (a) Ref.
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3
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C. Saluzzo, J. Org. Chem. 1992, 57, 714; (f) H. Pole-
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