Pd-Catalyzed Difluoromethylthiolation of Aryl Chlorides, Bromides and Triflates

Article abstract of DOI:10.1002/cjoc.201800306

A highly efficient Pd-catalyzed difluoromethylthiolation of aryl chlorides, bromides and triflates is described. A variety of aryl halides with common functional groups were difluoromethylthiolated in moderate to excellent yields. Furthermore, several nat

Full text of DOI:10.1002/cjoc.201800306

Pd-Catalyzed Difluoromethylthiolation of Aryl Chlorides, Bromides
and Triflates
Jiang Wu,a Changhui Lu,a Long Lua and Qilong Shen*,a
a Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. China
A highly efficient Pd-catalyzed difluoromethylthiolation of aryl chlorides, bromides and triflates is described. A va-
riety of aryl halides with common functional groups were difluoromethylthiolated in moderate to excellent yields.
Furthermore, several natural, drug and material molecules containing an aryl chloride, bromide, and phenol unit
were successfully difluoromethylthiolated, thus providing medicinal chemists a general method for late-stage
difluoromethylthiolation of leading compounds.
Keywords Pd-catalyzed, difluoromethylthiolation, late-stage modification
Introduction
PhS(O)(NTs)CF2H etc.[5] Alternatively, difluoromethyl-
thiolated arenes may be synthesized by reaction of ar-
ylthiolate with an electrophilic[6] or a radical[7] difluo-
romethylating reagent. In addition, difluoromethylthio-
lated arenes can also be synthesized by difluoromethyl-
ation of disulfides via a single-electron-transfer (SET)
process.[8] Nevertheless, these methods typically require
the preformation of a thiol or its derivative, that may be
challenging for structurally complicated molecules,
which limits to its widespread applications. Very re-
cently, Goossen discovered that difluoromethylthiolated
arenes could be accessed by initial generation of ArSCN
from aryl diazonium salts, followed by replacing the
cyano group with in situ formed [CuCF2H], thus open-
ing a door to new horizon for the preparation of difluo-
romethylthiolated compounds.[9]
An alternative yet equally attractive approach for the
preparation of difluoromethylthiolated arenes is to use a
difluoromethylthiolative reagent that can react with
various substrates. In this respect, Billard and Besset
independently developed two masked electrophilic
difluoromethylthiolation reagents.[10] Once the masked
difluoromethylthiolated group was introduced, the mask
group was removed to generated the desired difluoro-
methylthiolated compounds. More recently, we have
pushed the frontier of this sub-filed one step further by
successively inventing the first nucleophilic,[11] the first
electrophilic,[12] and the first radical difluoromethylthi-
olting reagent[13] that allow to direct difluoroemethyl-
thiolate a wide range of substrates under mild condi-
tions.
It has been well-established that introduction of a
fluorine atom or a fluoroalkyl group may significantly
improve the drug molecule’s pharmacologic properties
such as lipophilicity and metabolic stability.[1] As a re-
sult, “fluorine scan” has become a routine practice in the
optimize the structure of the lead compound.[2] Among
many fluoroalkyl groups, difluoromethylthio group
(-SCF2H), represents an under-developed structural mo-
tif with great potential. First, the difluoromethylthio
group which bears a slightly acidic proton, is generally
considered as a lipophilic hydrogen-bonding donor that
may improve the molecule’s binding selectivity with its
hosting enzyme.[3] Secondary, the difluoromethylthio
group is less lipophilic, less electron-withdrawing and
less stable to strong acid than the analogous trifluoro-
methylthio group (-SCF3), thus providing medicinal
chemists an opportunity to regulate the drug molecule’s
metabolic stability.[4] Consequently, there is a urgent
recent need for development of efficient methods for the
introduction of the difluoromethylthio group into small
molecules under mild conditions.
Toward this end, several strategies have been devel-
oped to get access to the difluoromethylthiolated com-
pounds. Traditional methods for the preparation of
difluoromethylthiolated arenes were typically based on
the insertion of an in situ generated difluorocarbene into
the ArS-H bond, as initially described by Porter et al. in
1957, in which HCF2Cl (F-22) was served as a
difluorocarbene precursor.[5a] Since then, a variety of
other easily accessible difluorocarbene precursors have
More specifically, in 2015, we reported that in the of
presence of a palladium catalyst generated from a com-
bination Pd(dba)2/Xantphos, nucleophilic difluoro-
been
disclosed,
such
as
FSO2CF2CO2TMS,
ClCF2CO2Na, TMSCF3, TMSCF2Br, HCF2OTf,
BrCF2P(O)(OEt)2,
Ph3P+CF2CO2
and
-
*
E-mail: shenql@sioc.ac.cn; Tel.: 0086-21-54925197.
Received ((will be filled in by the editorial staff)); accepted ((will be filled in by the editorial staff)); published online XXXX, 2018.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.2013xxxxx or from the author.
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800306
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meththiolating reagent [(SIPr)Ag(SCF2H)] (SIPr =
1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene)
was able to couple with (hetero)aryl iodides, activated
bromides and triflates under mild conditions.[14-15] While
activated heteroaryl bromides such as 2-bromopyridine
or its derivatives reacted to give the corresponding
difluoromethylthiolated pyridine derivatives in accepta-
ble yields, aryl bromides and chlorides using the same
catalyst did not react at all.
It is well-known that carbon-bromine bond in aryl
bromide is much stronger than carbon-bromine bond in
2-bromopyridine, and the carbon-chloride bond in aryl
chloride is more stronger. To activate the strong aryl
bromide or chloride bond, a palladium catalyst bearing
an electron-rich, sterically bulky alkylphosphine is re-
quired.[16] Inspired by these previous observations, we
seek to achieve the difluoromethylthiolation of aryl
bromides and chlorides by employing a palladium cata-
lyst containing an electron-rich, sterically bulky al-
kylphosphine ligand. Herein, we report that in the pres-
ence of a catalyst generating from a combination of
Buchwald’ precatalyst with Brettphos, a variety of aryl
bromides, chlorides and triflates reacted with
(SIPr)Ag(SCF2H) efficiently to give the corresponding
difluoromethylthiolated arenes in high yields. [17]
Scheme 1. Optimization of the conditions for Pd-catalyzed
difluoromethylthiolation of aryl bromide. a,b
SCF2H
Br
+
conds
(SIPr)Ag(SCF2H)
ligand
Ph
Ph
entry
2a
1a
[Pd]
temp
50 o
yield (%)b
solvent
toluene
-
1
2
Cat-1
Cat-2
Cat-3
Cat-4
Cat-5
Cat-6
Cat-1
Cat-1
Cat-1
Cat-1
Cat-1
Cat-1
Cat-1
Cat-1
C
79
-
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DME
50 o
50 o
50 o
50 o
50 o
50 o
50 o
50 o
50 o
50 o
rt
C
C
C
C
C
C
C
C
C
C
71
-
3
10
-
4
<2
-
5
10
-
6
<2
-
7
68 c,d
54 c,d
47 c,d
73 c,d
-
8
-
9
-
10
11
12
13
14
THF
c,d,e
Brettphos
Brettphos
Brettphos
Brettphos
THF
97
c,d,e
THF
70
THF
50 o
50 o
C
C
67 c,d,f
23 c,g
THF
Ligand
L1: BrettPhos
L2: XPhos
L3: RuPhos
L4: DPPF
NH2
Pd
Cat-n:
L
(n = 1-6)
L5: Xantphos
L6: DPEphos
OMs
aReaction condition: 1a (11.6 mg, 0.0500 mmol),
(SIPr)Ag(SCF2H) (29 mg, 0.050 mmol), [Pd] (10.0 mol%) and
ligand (20.0 mol%) in toluene (1.0 mL) for 2 h under an argon
atmosphere; bYields were determined by 19F NMR analysis of the
crude reaction mixture with trifluorotoluene as an internal stand-
Results and Discussion
Initially, we chose the reaction of 4-bromobiphenyl
1a with [(SIPr)Ag(SCF2H)] in the presence of a palla-
dium catalyst as a model reaction to optimize the reac-
tion conditions. Our initial efforts in search of a suitable
palladium catalyst by employing a combination of 10
mol% of Pd(dba)2 with 10 mol% of common monoden-
tate phosphine ligands such as XPhos, SPhos and
BrettPhos or bidendate ligands such as DPPE, Xantphos
and DPEphos, were less successful, giving the corre-
sponding product 2a in less than 15% yield. Interest-
ingly, when Buchwald’s precatalyst Cat-1 or Cat-2 that
was generated from a palladacycle and BrettPhos or
XPhos ligand was used as the catalyst, the yield in-
creased significantly to 79% and 71% yield, respective-
ly, while reaction using Buchwald’s precatalyst Cat-3
bearing RuPhos occurred in much lower yield (Scheme
1, entries 1-3). Likewise, the same type of catalyst con-
taining other bidentate ligands such as DPPF, Xantphos
or DPEphos were not efficient at all (Scheme 1, entries
4-6). The yield decreased slightly to 68% when 5.0 mol%
of Cat-1 was used when 1.2 equivalents of
[(SIPr)Ag(SCF2H)] was used (Scheme 1, entry 7). To
probe the effect of the solvent, we studied the reaction
in different solvents. It turned out that reactions in sol-
vents such as dioxane or DME gave lower yields, while
the yield was improved to 73% when THF
c
d
ard; 1.2 equiv of (SIPr)Ag(SCF2H) was used; [Pd] (5.0 mol%)
was used; eBrettphos (5.0 mol%) was added; Brettphos (3.0
mol%) was added; [Pd] (3.0 mol%) and Brettphos (3.0 mol%)
f
g
was added.
was used as the solvent (Scheme 1, entries 8-10). Nota-
ble, the yield was further increased to 97% when addi-
tional 5.0 mol % of BrettPhos was added (Scheme 1,
entry 11). The same reaction conducted at room tem-
perature occurred in lower yield (70%) (Scheme 1, entry
12). When the amount of the additional BrettPhos was
decreased to 3.0 mol%, the yield of the product 2a also
decreased (Scheme 1, entry 13). Likewise, the yield de-
creased dramactically to 23% when 3.0 mol% of Cat-1
and 3.0 mol% BrettPhos was used (Scheme 1, entry 14).
Under the conditions of entry 11 in Scheme 1, we
next studied the generality of the reactions toward other
aryl bromides. As shown in Scheme 2, the optimized
conditions were quite effective for a variety of aryl
bromide with different substituted groups. In general,
reactions of aryl bromides with electron-donating sub-
stituents occurred faster and more efficiently than those
with electron-withdrawing groups. For example, reac-
tions of aryl bromides with para-ketone, ester or me-
ta-cyano group required to increase the catalyst to 7.0
mol% to occur in full conversions (Scheme 2, 2i-l).
Polycyclic aromatic bromides, and aryl bromides with
carbazole or thiophene moiety as well, can also be
difluoromethylthiolated in good to excellent yields.
(Scheme 2, 2m-2v). It is
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Scheme 2. Scope of Pd-catalyzed difluoromethylthiolation of
aryl bromide. a
Scheme 4. Scope of Pd-catalyzed difluoromethylthiolation of
aryl chlorides.a
Cat-1 (5.0 mol%)
Brettphos (5.0 mol%)
Br
SCF2H
NH2
R
Cat-1 (10.0 mol%)
Brettphos (10.0 mol%)
+
(SIPr)Ag(SCF2H)
R
Cl
NH2
Pd Brettphos
OMs
SCF2H
THF, 50 oC, 2 h
R
+
(SIPr)Ag(SCF2H)
Pd Brettphos
OMs
R
THF, 80 oC, 2 h
1
2a-v
Cat-1
5
6a-l
Cat-1
SCF2H
SCF2H MeO
SCF2H
SCF2H
SCF2H
SCF2H
SCF2H
Ph
SCF2H
Ph
N
N
MeO
Ph
O
Ph
OMe
2c, 53%
MeO2C
NC
O
O
2a, 94%
2b, 41%
2d, 98%
6a, 71%
SCF2H
6b, 58%
6c, 65%
6d, 89%
SCF2H
O
O
SCF2H
Ph
SCF2H
SCF2H
SCF2H
SCF2H
N
MeO
NC
Ph
Cl
2e, 63%b
2i, 70%b
2g, 64%
2h, 65%
2l, 62%b
2f, 81%
SCF2H
O
N
SCF2H
SCF2H
SCF2H
6e, 23%b
6f, 68%
6h, 51%
6g, 72%
SCF2H
O
S
Me
SCF2H
MeO2C
Ph
O
CN
2k, 58%b
SCF2H
Me
N
SCF2H
2j, 63%b
SCF2H
OMe
O
6i, 57%
6j, 64%
SCF2H
SCF2H
R
aReaction conditions: aryl chloride
5
(0.5 mmol),
R = H, 2m, 78%
F, 2n, 84%b
2p, 99%
2o, 91%
2q, 99%
(SIPr)Ag(SCF2H) (0.6 mmol), Cat-1 (10.0 mol %), BrettPhos
SCF2H
2-naphthyl
o
SCF2H
(10.0 mol %) in THF (10.0 mL) at 80 C for 2 h; b Yields were
SCF2H
determined by 19F NMR analysis of the crude reaction mixture
with trifluorotoluene as an internal standard.
N
SCF2H
2s, 85%
S
2-naphthyl
2r, 45%
2t, 41%
2u, 85%
conditions, it was found that aryl triflates can also be
difluoromethylthiolated in moderate to good yields
when 2.0 equivalent KBr was added and the reaction
aReaction conditions: aryl bromides (0.5 mmol), (SIPr)Ag(SCF2H)
(0.6 mmol), Cat-1 (5.0 mol %), BrettPhos (5.0 mol %) in THF
o
b
(10.0 mL) at 50 C for 2 h; isolated yields; Cat-1 (7.0 mol %),
o
temperature was increased to 80 C. As summarized in
BrettPhos (7.0 mol %) was used.
Scheme 3, a variety of aryl triflates were difluorome-
thylthiolated. Again, common functional groups such as
thioether (4d), ketone (4f), ester (4g), nitro (4h), and
cyano group (4i) were tolerant.
Scheme 3. Scope of Pd-catalyzed difluoromethylthiolation of
aryl triflates.a
Aryl chlorides are the most cheap, abundant and eas-
ily available coupling partners.[19] Because of C-Cl bond
of aryl chloride is stronger than C-Br bond of aryl bro-
mide, it was found that we need increased the amount of
Cat-1 and additional BrettPhos to 10.0 mol% to enable
the reaction to full conversion. Under these conditions,
aryl chlorides bearing with electron-withdrawing groups
such as ester (6a), ketone (6b, 6d, 6g, 6l), cyano (6c) or
electron-poor heteroaryl chloride (6h and 6j) could be
difluoromethylthiolated in moderate to good yields, as
summarized in Scheme 4. Nevertheless, the reactions of
aryl chlorides with electron-donating groups occurred in
low yield and will be the subject of future study
(Scheme 4, 6e).
Cat-1 (7.0 mol%)
Brettphos (7.0 mol%)
OTf
SCF2H
NH2
R
+
(SIPr)Ag(SCF2H)
R
Pd Brettphos
OMs
KBr (2.0 equiv)
THF, 80 oC, 2 h
3
4a-l
Cat-1
MeO
SCF2H
SCF2H
SCF2H
SCF2H
OMe
MeO
Me
MeS
Ph
Et
OMe
Me
4a, 84%
SCF2H
4b, 58%
4c, 87%
4d, 66%
SCF2H
SCF2H
SCF2H
BnO2C
NO2
O
4e, 71%
SCF2H
4f, 52%
SCF2H
4g, 56%
4h, 56%
SCF2H
CO2Me
SCF2H
CN
4i, 51%
4j, 79%
4k, 65%
4l, 54%
To demonstrate the applicability of this difluorome-
thylthiolating protocol, we studied the difluoromethyl-
thiolation of some natural, medicinally important com-
pounds and material molecules. Fluoranthene, a fluo-
rescer for metal defect detection, can been difluorome-
thylthiolated in 73% yield (Scheme 5, Eq. 1). Likewise,
a difluoromethylthiolated natural product oestrone and
tocopherol was generated in moderate yield *Scheme 5,
Eqs 2-3. Furthermore, a difluoromethylthiolated Feno-
fibrate, a medication that treats with hyperlipemia, was
formed in an 88% yield under standard reaction condi-
tions (Scheme 5, Eq. 4).
aReaction conditions: aryl triflates
(SIPr)Ag(SCF2H) (0.6 mmol), Cat-1 (7.0 mol %), BrettPhos
(7.0 mol %) and KBr (2.0 equiv) in THF (10.0 mL) at 80 oC for 2
h; isolated yields.
3
(0.5 mmol),
noteworthy that common functional groups such as
chloride (2e), alkene (2g), enolizable ketone (2i), ester
(2j), and cyano group (2h and 2k) were compatible.
Phenol is a common structure in natural products or
drugs, and the corresponding triflates are valuable cou-
pling partners for transition metal-catalyzed cross cou-
pling reactions.[18] After a quick screen of the reaction
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[4] Langlois, B. R. J. Fluorine Chem. 1988, 41, 247.
Scheme 5. Preparation of the difluoromethylthiolated natural,
medicinally important compounds and material molecule.
[5] Selected examples for the difluoromethylation of thiolates via
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Br
SCF2H
(SIPr)Ag(SCF2H) (1.2 equiv)
(1)
Cat-1 (5.0 mol%)
Brettphos (5.0 mol%)
THF, 50 oC, 2 h
Fluoranthene 2A
7, 73%
O
O
H
H
(SIPr)Ag(SCF2H) (1.2 equiv)
(2)
Cat-1 (7.0 mol%)
Brettphos (7.0 mol%)
KBr (2.0 equiv)
H
H
H
H
TfO
HF2CS
THF, 80 oC, 2 h
1,3,5(10)-Estratrien-3-ol-17-one 2B
8, 85%
TfO
HF2CS
(SIPr)Ag(SCF2H) (1.2 equiv)
(3)
O
R
O
R
Cat-1 (10.0 mol%)
Brettphos (10.0 mol%)
KBr (2.0 equiv)
Me
Me
D-delta-Tocopherol 2C
THF, 80 oC, 2 h
9, 55%
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R:
O
O
O
O
O
O
O
(SIPr)Ag(SCF2H) (1.2 equiv)
(4)
Cat-1 (10.0 mol%)
Brettphos (10.0 mol%)
THF, 80 oC, 2 h
HF2CS
O
Cl
Fenofibrate 2D
10, 88%
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In summary, we developed a palladium-catalyzed
direct difluoromethylthiolation of aryl bromides, chlo-
rides and triflates with (SIPr)Ag(SCF2H) by employing
a combination of Buchwald’s precatalyst Cat-1 and
BrettPhos as the catalyst. The mild conditions, good
functional group compatiblility, and the ease in applica-
tions in the difluoromethylthioation of a few natural,
pharmaceutical and material molecules make the current
a powerful tool for the medicinal chemists in the late
stage modification of drug compounds. Efforts to eluci-
dation of the reaction mechanism and expand the scope
of the reaction toward aryl chlorides with electron-rich
is currently undergoing in our lab.
Acknowledgement
The authors gratefully acknowledge the financial
support from National Natural Science Foundation of
China (21625206, 21632009, 21572258, 21572259,
21421002) and the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB20000000)
and the Syngenta Ph.D. Fellowship (C. Lu).
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Entry for the Table of Contents
Page No.
Pd-Catalyzed Difluoromethylthiola-
tion of Aryl Chlorides, Bromides and
Triflates
Cat-1 (5.0-10.0 mol%)
Brettphos (5.0-10.0 mol%)
X
SCF2H
NH2
R
+ (SIPr)Ag(SCF2H)
R
Pd Brettphos
OMs
THF, 50-80 oC, 2 h
X = Cl, Br, OTf
Cat-1
A highly efficient Pd-catalyzed difluoromethylthiolation of aryl chlorides, bromides and
triflates is described. A variety of aryl halides with common functional groups were
difluoromethylthiolated in moderate to excellent yields. Furthermore, several natural,
drug and material molecules containing an aryl chloride, bromide, and phenol unit were
successfully difluoromethylthiolated, thus providing medicinal chemists a general
method for late-stage difluoromethylthiolation of leading compounds.
Jiang Wu, Changhui Lu, and Qilong Shen
This article is protected by copyright. All rights reserved.