An Electrophilic Trifluoromethylthiolation of Silylenol Ethers and β-Naphthols with Diethylaminosulfur Trifluoride and (Trifluoromethyl)trimethylsilane

Article abstract of DOI:10.1002/adsc.201800366

An efficient and general trifluoromethylthiolation of silylenol ethers and β-naphthols have been accomplished employing the combination of diethylaminosulfur trifluoride (DAST) and (trifluoromethyl)trimethylsilane (CF₃TMS) as source of electrophilic trifluoromethylthio moiety for the synthesis of α-trifluoromethylthiolated carbonyl compounds and β-naphthols in good yields. Important features of this method include wide functional group tolerance and use of readily available DAST/CF₃TMS. Potential of the methodology was demonstrated via the synthesis of α-trifluoromethylthiolated (+)-4-cholesten-3-one and naphthoquinone. (Figure presented.).

Full text of DOI:10.1002/adsc.201800366

Title: An Electrophilic Trifluoromethylthiolation of Silylenol Ethers
and β-Naphthols with Diethylaminosulfur Trifluoride and
(Trifluoromethyl)trimethylsilane
Authors: Perumal Saravanan and Pazhamalai Anbarasan
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800366
Link to VoR: http://dx.doi.org/10.1002/adsc.201800366

10.1002/adsc.201800366
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Electrophilic Trifluoromethylthiolation of Silylenol Ethers
and β-Naphthols with Diethylaminosulfur Trifluoride and
(Trifluoromethyl)trimethylsilane
Perumal Saravanan and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai – 600036. Email: anbarasansp@iitm.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. An efficient and general trifluoromethylthiolation readily available DAST/CF3TMS. Potential of the
of silylenol ethers and β-naphthols have been accomplished methodology was demonstrated via the synthesis of α-
employing the combination of diethylaminosulfur trifluoride trifluoromethylthiolated
(DAST) and (trifluoromethyl)trimethylsilane (CF3TMS) as naphthoquinone.
source of electrophilic trifluoromethylthio moiety for the
(+)-4-cholesten-3-one
and
synthesis of α-trifluoromethyl-thiolated carbonyl compounds
and β-naphthols in good yields. Important features of this
method include wide functional group tolerance and use of
Keywords: trifluoromethylthiolation; Diethylaminosulfur
Trifluoride; (Trifluoromethyl)trimethylsilane; enol ether;
naphthol
diethylaminosulfur
trifluoride
(DAST)
and
Introduction
(trifluoromethyl)trimethylsilane (CF3TMS), where
DAST and CF3TMS offer sulfur and trifluoromethyl
moiety of ‘SCF3’.[6d]
Over the decades, significant attention has been
devoted to the development of efficient methods for
the selective introduction of fluoro and fluorinated
moieties in the molecules of high importance.
Because, the presence of fluorinated moieties in
target
molecules
dramatically
alters
the
physiochemical properties, such as solubility,
lipophilicity, metabolic
stability,
and
bioavailability.[1] Among the various established
fluoroalkyl groups, trifluoromethylthio group (SCF3)
is of current interest in agrochemicals and
pharmaceuticals due to its remarkable properties.
Particularly, ‘ SCF3 ’
group has highest
lipophilicity value (πx = 1.44) that helps permeation
across biological membranes, high stability, and
electronegativity.[2] In addition, properties of the
molecules could be altered through simple oxidation
of ‘SCF3’, which is highly useful in the rational
design of drug candidates.
Scheme 1. DAST
trifluoromethylthiolating reagent with ‘C’-nucleophile.
&
CF3TMS as electrophilic
Recently, various methodologies have been
developed for the trifluoromethylthiolation of organic
molecules through nucleophilic,[3] electrophilic or
radical strategies.[4] Among them, electrophilic
strategy gained significant attention, especially in the
Interestingly, employing trifluoromethyl analog of
DAST (DAST-CF3) as an electrophilic reagent, very
recently Shibata and co-workers demonstrated the
successive C–C bond cleavage followed by
fluorination and trifluoromethylthiolation of β-
ketoesters.[10] Employing the same reagent, they have
development
of
new
electrophilic
trifluoromethylthiolating reagent. The known
reagents include Munavalli,[5] Billard,[6] Shen,[7]
Shibata[8] and other.[9] Most of these reagents were
synthesized from AgSCF3 and corresponding
electrophilic partner. But the Billard’s reagent is
unique in this respect and are achieved from aniline,
also
established
the
electrophilic
trifluoromethylthiolation of β-ketoesters.[11] Inspired
1
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10.1002/adsc.201800366
Advanced Synthesis & Catalysis
by these studies and our interest in the development
of a method for the introduction of the fluorinated
moiety,[12] we herein disclose a general and direct
electrophilic trifluoromethylthiolation of carbon-
based nucleophiles employing the combination of
DAST and CF3TMS, avoiding the synthesis of
trifluoromethylthiolating reagent.
the reaction was performed in the presence of aniline,
expecting an in-situ generation of Billard’s reagent
and subsequent trapping, afforded the product 1a in
54% yield (Table 1, entry 7). Finally, it was realized
that the concentration of DCM solution of 1a, as well
as the mode of addition, have an important role in the
present reaction. Thus, the faster addition of 1.0 M
solution of 1a in DCM furnished the product 2a in
86% 19F NMR yield and 80% isolated yield (Table 1,
entry 8).
Results and Discussion
To begin with, trifluoromethylthiolation of various
carbon-based nucleophiles have been tested using
DAST and CF3TMS in the presence of
diisopropylethylamine (DIPEA) in dichloromethane
(DCM) at –60 °C. Among them, tetralone derived
trimethylsilylenol ether (TMSEE) 1a showed the
promising result with the formation of α-
trifluoromethylthiolated tetralone 2a in 35% yield,
based on 19F NMR (see supporting information and
Table 1). Subsequently, various structurally different
silylenol ether (1b-1e) were synthesized and treated
with DAST and CF3TMS. Unfortunately, all of them
failed to provide the expected product, which
suggested that the stability, reactivity, and
conformation of silylenol ether is highly important
for the successful trifluoromethylthiolation (Table 1,
entry 2). Next, increasing the equivalents of 1a
afforded only the comparable yield (Table 1, entry 3).
On the other hand, increasing the equivalents of
either DAST, CF3TMS or DIPEA decreased the yield
of 2a (Table 1, entries 4-6).
OTMS
O
DAST (1.1 equiv)
CF3TMS (1.0 equiv)
DIPEA (1.0 equiv)
DCM, -60 °C - rt, 4 h
SCF3
R
R
1 (1.5 equiv)
2
O
R = H; 2a: 80%
R = Me; 2b: 79%
R = OMe; 2c: 64%
R = Cl; 2d: 65%
R = Br; 2e: 61%
O
O
SCF3
SCF3
R
SCF3
O
2f: 43%
O
O
O
SCF3
SCF3
2i: 62%
2g: 76%
2h: 67%
O
O
O
BnO
SCF3
SCF3
SCF3
SCF3
HO
TfO
2j: 50%
2k: 80%†
2l: 60%
O
O
O
SCF3
SCF3
F
Cl
2n: 60%
2m: 60%
O
2o: 46%
F
Table 1. Trifluoromethylthiolation of silylenol ethers with
O
SCF3
R = H; 2p: 56%
R = Me; 2q: 68%
R = OMe; 2r: 64%
R = Cl; 2s: 60%
DAST and CF3TMS: Optimization.a)
SCF3
2t: 70%
R
O
O
O
SCF3
SCF3
SCF3
MeO
Entry
Conditions
Yield(%)b)
S
2v: 47%
2u: 74%
2w: 65%
1
2
3
4
5
6
7
Standard conditions with 1a
1b-e instead of 1a
With 2 equiv. of 1a
With 2.2 equiv. of DAST
With 2 equiv. of CF3TMS
With 2 equiv. of DIPEA
Addition of 0.5 equiv. of aniline
Rapid addition of 1.5 equiv. of 1a
35
-
40
20
28
28
Robustness screening‡
O
O
H
CN
N
H
OH
O
Me
MeO
81% (- [50%]*)
Br
80% (96%)
90% (98%)
Ph
86% (95%)
O
50
8
84 (80)c)
Ph
a)
Me
Reaction conditions: 1 (0.69 mmol, 1 equiv.), DAST
(0.76 mmol, 1.1 equiv.), CF3TMS (0.69 mmol, 1 equiv.)
DIPEA (0.69 mmol, 1 equiv.), DCM (0.23 M), –60 °C to rt.
85% (89%)
O
82% (92%)
OEt
84% (87%)
80% (95%)
OH
O
O
O
b)
Yield based on 19F NMR (hexafluorobenzene used as
OEt
reference). c) Isolated yield. TMS = trimethylsilyl. TBDMS
tBu
= (tert-butyl)dimethylsilyl. DPMS = diphenylmethylsilyl.
80% (94%)
94% (92%)
60% (56%)
Scheme 2. Trifluoromethylthiolation of silylenol ethers 1
with DAST and CF3TMS: Scope and limitations. All are
†
isolated yields. Corresponding TMS ether was used as
‡
starting material.
Reactions were performed with 1a
under the optimized conditions with the equimolar amount
of additives. All are yield of 2a and yield in parenthesis are
Similar results were observed when the initial
reaction temperature was raised above –60 °C. When
2
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10.1002/adsc.201800366
Advanced Synthesis & Catalysis
the recovered functionalized compounds. * Yield of N,N-
diethylbenzamide.
directed us to investigate the trifluoromethylthiolation
of reactive phenol, such as β-naphthol, with DAST
and CF3TMS. Thus, the treatment of β-naphthol 3a
under the optimized conditions afforded the α-
trifluoromethylthiolated β-naphthol 4a in 20% yield
(Table 2). Mimicking the TMSEE substrate,
trimethylsilyl-protected β-naphthol 3b was subjected
under the optimized conditions, which also gave 4a in
22%, even at prolonged reaction time (18 h).
Subsequently, increasing the amount of 3b to 5
equivalents afforded the corresponding product 4a in
70% yield in 4 h. Interestingly, use of 5 equivalents
of β-naphthol 3a also furnished the product 4a in
67% yield, but after 18 h. On the other hand, β-
naphthol methyl ether did not afford the expected
With the best-optimized conditions in hand, the
generality of the trifluoromethylthiolation of TMSEE
was investigated. As can be seen in Scheme 2,
structurally and functionally different TMSEE
derived from tetralone were tested under the
optimized conditions. For instance, alkyl substitution
at the various position of tetralone TMSEE gave the
product 2b, 2g, and 2h in good yield. The racemic 4-
methyl tetralone TMSEE provided the α-
trifluoromethylthiolated product 2i in 62% as a
mixture of diastereomer in 1:1 ratio. Similarly,
electron-donating
alkoxy
substituted
α-
product.
Since
trifluoromethylthiolation
of
trifluoromethylthiolated tetralone 2c, 2f and 2j were
trimethylsilyl-protected
β-naphthol derivative
achieved in good yield. Interestingly, electron
withdrawing
requires an addition step for its synthesis, the scope
and generality of the method were investigated with
unprotected β-naphthol derivatives.
trifluoromethylsulfonyloxy
and
functionalizable halo substituted tetralone TMSEE
also furnished the corresponding products 2l and 2d,
2e, 2m, 2n, respectively. Subsequently, to extent the
present scope, simple cyclohexenone derived TMSEE
were subjected under the present optimized
conditions. Gratifyingly, TMSEE derived from 4,4-
dimethylcyclohexenone afforded the product 2o in
46% yield. Having seen the promising result, various
3-aryl substituted cyclohexeone derived TMSEE
were examined. All of them furnished the
corresponding α-trifluoromethylthiolated product 2p-
2v in 56-74% yield. Furthermore, 3-thiophen-2-yl
substituted cyclohexeone also gave the product 2w in
65% yield.
Table 2. Trifluoromethylthiolation of β-naphthols with
DAST and CF3TMS: Optimization.a)
SCF3
OR
DAST + CF3TMS
DIPEA, DCM
OH
4a
–60 °C-rt, time
3
R (3, equiv.) Time Yield R (3, equiv.) Time Yield
(h)
(%)b)
(h)
TMS (3b, 5) 4
H (3a, 5) 18
(%)b)
H (3a, 1)
4
20
22
70
TMS (3b, 1) 18
Reaction conditions: 3 (equiv.), DAST (0.76 mmol, 1.1
67 (30)c)
a)
equiv.), CF3TMS (0.69 mmol, 1 equiv.) DIPEA (0.69
b)
After successful demonstration of generality and
scope, we directed our attention to validate the
robustness of the present trifluoromethylthiolation
with respect to various reactive functional groups
employing the ingenious method developed by
mmol, 1 equiv.), DCM (0.23 M), –60 °C to rt. Yield
based on 19F NMR (hexafluorobenzene used as reference).
c) 4 h.
Glorius
and
co-workers.[13]
Thus,
the
SCF3
OH
DAST + CF3TMS
DIPEA, DCM
OH
trifluoromethylthiolation of 1a with DAST and
CF3TMS was carried out in the presence of an
equimolar amount of a number of potentially
competing nucleophiles as additives under the
optimized conditions (Scheme 2). Interestingly, no
competing side reaction was observed with any of
these nucleophiles, most importantly, the reactive β-
keto esters showed high compatibility under the
reaction conditions. In all the cases, expected product
2a was also observed in comparable yield and most
of the additives were recovered in high yield, except
the carboxylic acid that reactivity with byproduct and
converted to the corresponding amide. However, the
presence of tert-butylphenol significantly affected the
reaction and let to the trifluoromethylthiolation of 1a
R
R
-60 °C-rt, 18 h
4
3
SCF3
SCF3
OH
SCF3
OH
OH
OMe
OR
Br
R = Me; 4d: 82%
R = OBn; 4e: 64%†
SCF3
4b: 67%
O
4c: 48%
SCF3
SCF3
OH
OH
OH
4h: 52%
4g: 50%
4f: 66%
CO2Et
Cl
SCF3
OH
SCF3
SCF3
OH
OH
in 60% yield and
a
detectable amount of
MeO
MeO
trifluoromethylthiolation of phenol was observed.
These studies demonstrated the robustness of the
developed trifluoromethylthiolation towards various
functional groups and possible application to
complex silylenolether.
EtO2C
NC
4k: 60%
4j: 62%
4i: 61%
SCF3
OH
SCF3
SCF3
OH
OH
O
BnO
The involvement of phenol in robustness screening
and our initial studies with different nucleophiles
4m: 55%†
4n: 84%
4l: 65%
O
3
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10.1002/adsc.201800366
Advanced Synthesis & Catalysis
Scheme 3. Trifluoromethylthiolation of β-naphthols 3 with
DAST and CF3TMS: Scope and limitations. All are
isolated yields. † Yield based on 1H NMR.
Simple bromo and phenyl at the 6th position of β-
naphthol gave the products 4b and 4f in 67 and 66%
yield (Scheme 3). Similarly, 3-chloro, 3-
ethoxycarbonyl, 3,4-dimethoxy substituted phenyl
containing β-naphthol also furnished the product 4g-
4i in good yield. Both electron-withdrawing
methoxycarbonyl and electron donating alkoxy
substitution at 3rd position of β-naphthols were well
tolerated and afforded the corresponding product 4c,
4d and 4e in 48, 82 and 64% yield. Electron-deficient,
6-cyano, 6-ethoxycarbonyl, and 6-benzyloxycarbonyl
substituted β-naphthols also underwent smooth
reaction to furnish the corresponding product 4j-4l in
good yield. Interestingly, active methylene containing
cyclohexenyl-substituted β-naphthols gave the
product 4m in 55% yield. In addition to β-naphthols,
polycyclic phenol like phenanthren-9-ol also afforded
10-(trifluoromethylthio)-phenanthren-9-ol 4n in 84%
yield.
Scheme 5. Synthesis of α-trifluoromethylthiolated
naphthoquinone 7.
Thus, oxidation of 2a with periodic acid (H5IO6) in
the presence of catalytic amount of CrO3 in
acetonitrile at room temperature gave the
naphthoquinone derivative 7a in 89% yield and no
oxidation of sulfur was observed.[16] This selective
oxidation was subsequently applied for the synthesis
of
substituted
α-trifluoromethylthiolated
naphthoquinones 7b-7d in excellent yield.
Based on the above observation and literature
precedent, we postulate the following mechanism for
the trifluoromethylation of nucleophiles with DAST
and CF3TMS. DAST is known to exist in equilibrium
with the isomeric form A, which on reaction with
CF3TMS would afford the intermediate B (Scheme 6).
Reaction of formed B with reactive TMSEE 1 might
furnish the intermediate D via the possible transition
state C. Finally, base promoted reductive
fragmentation of D would give the expected product
2. Similar pathway could be anticipated for
trifluoromethylthiolation of β-naphthols 3.
Having
successfully
demonstrated
the
trifluoromethyl-thiolation of TMSEE and β-naphthol,
the potential of the methodology was studied
employing biologically important molecule like (+)-
4-cholesten-3-one.
Thus,
the
reaction
of
trimethylsilylenol ether of (+)-4-cholesten-3-one 5
with DAST and CF3TMS in the presence of DIPEA
in DCM at –60 °C afforded the corresponding
product 6 in 55% yield as a diastereomeric mixture in
9:1 ratio, demonstrating the potency of the developed
transformation (Scheme 4).
H
H3C
H
H
H3C
H
CF3
R
F
Si
R
F
F
H3C
S
H3C
DAST + CF3TMS
DIPEA, DCM
-60 °C-rt, 4 h
55% (dr 9:1)
F
N
F
F
N
N
CF3
F3CS
O
S
F
S
F
H
H
H
H
(DAST)
B
TMSO
5
A
6
1
a-SCF3 (+)-4-Cholesten-3-one
CH3
CH3
+ HF
N
R =
CH3
Si
O
O
F
S
F
CF3
S
F
CF3
N
H
Scheme 4. Trifluoromethylthiolation of 5.
2
R
N
R
DIPEA
Me3SiF
D
C
Subsequently,
trifluoromethylthiolated tetralones
trifluoromethylthiolated naphthoquinones
conversion
of
α-
α-
was
2
to
7
Scheme 6. Plausible mechanism.
envisioned, since quinones play a major role in
various biological processes, as well as in drug
discovery.[14] For instance, 2-trifluoromethyl-1,4-
naphthoquinones have exhibited an antimalarial
activity.[15]
Conclusion
In conclusion, we have successfully developed an
efficient and general trifluoromethylthiolation of
silylenol ethers derived from tetralones and
cyclohexenone as well as β-naphthols employing a
combination of DAST and CF3TMS as a source of
the electrophilic trifluoromethylthio group. These
reactions work well with various highly
functionalized molecules and allow the synthesis of
α-trifluoromethylthiolated carbonyls and naphthols in
good yields. Additionally, robustness screening also
4
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10.1002/adsc.201800366
Advanced Synthesis & Catalysis
We acknowledge Indian Institute of Technology Madras (Project
No. CHY/16-17/840/RFIR/ANBA) for financial support. P.S.
thanks CSIR, New Delhi for a fellowship.
demonstrated excellent tolerance of the present
reaction to various nucleophiles. Potential of the
developed methodology was further demonstrated
through the synthesis of biologically important α-
trifluoromethylthoilated (+)-4-cholesten-3-one and
naphthoquinone.
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Experimental Section
General
procedure
for
the
synthesis
of
trimethylsilylenol ether 1: To the solution of carbonyl
compound (3 mmol, 1 equiv.) in dry DCM (0.25 M) at
0 °C, triethylamine (6 mmol, 2 equiv.) was added drop-
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General procedure for the trifluoromethylthiolation of
1 to 2: A flame-dried Schlenk tube was successively
charged with DIPEA (0.69 mmol) and anhydrous
dichloromethane (2 mL) under the nitrogen atmosphere.
The resulting mixture was cooled to –60 °C and DAST
(0.76 mmol) was added followed by CF3TMS (0.69 mmol)
was introduced in 10 min intervals. After 1 hour at –60 °C,
the solution of 1 (0.69 mmol) in DCM (1 M) was added in
one shot at –60 °C. The reaction mixture was then warmed
to room temperature over 4 h and diluted with 50 mL of
DCM, followed by washing with 6% aq. NaHCO3 and
water. The combined organic phase was dried over Na2SO4
and evaporated under reduced pressure. The crude mixture
was purified by column chromatography over Silica gel
using ethylacetate/hexane mixture as eluent to afford the
corresponding α-trifluoromethylthiolated product 2.
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General procedure for the trifluoromethylthiolation of
3 to 4: A flame-dried Schlenk tube was successively
charged with DIPEA (0.69 mmol) and anhydrous
dichloromethane (2 mL) under nitrogen atmosphere. The
resulting mixture was cooled to –60 °C and DAST (0.76
mmol) was added followed by CF3TMS (0.69 mmol) was
introduced in 10 min intervals. After 1 hour at –60 °C, the
solution of β-naphthols 3 (3.45 mmol) in DCM (3.4 M)
was added in one shot at –60 °C. The reaction mixture was
then warmed to room temperature over 18 h and diluted
with 50 mL of DCM, washed with 6% aq. NaHCO3
followed by water. The combined organic phase was dried
over Na2SO4 and evaporated under reduced pressure. The
crude product was purified by column chromatography
over Silica gel using ethylacetate /hexane mixture as eluent
to afford the corresponding α-trifluoromethylthiolated β-
naphthol 4.
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General procedure for the synthesis of 7: To the mixture
of compound 2 (3.0 mmol) and H5IO6 (13.5 mmol), the
solution of CrO3 (0.3 mmol, 10 mol%) in acetonitrile was
added under argon atmosphere over 20 min. The resultant
reaction mixture was stirred for 4 h at room temperature.
The mixture was diluted with water followed by extracted
with diethyl ether. The combined organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The
obtained crude product was purified by column
chromatography over Silica gel using ethylacetate/hexane
as eluent to furnish the compound 7.
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10.1002/adsc.201800366
Advanced Synthesis & Catalysis
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10.1002/adsc.201800366
Advanced Synthesis & Catalysis
FULL PAPER
An Electrophilic Trifluoromethylthiolation of
Silylenol Ethers and β-Naphthols with
Diethylaminosulfur Trifluoride and
(Trifluoromethyl)trimethylsilane
OTMS
OH
Et
N
SCF3
OH
O
R
R
F
F
SCF3
S
F
Et
R
R
+
Adv. Synth. Catal. Year, Volume, Page – Page
Si
14 examples
up to 84% yield
high FG tolerance
24 examples
up to 80% yield
high FG tolerance
Robustness screening
F3C
Ready mix!
Perumal Saravanan and Pazhamalai Anbarasan*
7
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