Synthesis of Difluoromethylthioesters from Aldehydes

Article abstract of DOI:10.1002/anie.201710731

Difluoromethylthioester compounds are yet another important kind of organofluorine compound and are reported here for the first time. They can be efficiently synthesized from various aldehydes. The synthetic method features mild reaction conditions, good

Full text of DOI:10.1002/anie.201710731

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Accepted Article
Title: Synthesis of Difluoromethylthioesters from Aldehydes
Authors: Shi-Huan Guo, Xing-Long Zhang, Gao-Fei Pan, Xue-Qing
Zhu, Ya-Ru Gao, and Yong-Qiang Wang
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Synthesis of Difluoromethylthioesters from Aldehydes
Shi-Huan Guo, Xing-Long Zhang, Gao-Fei Pan, Xue-Qing Zhu, Ya-Ru Gao, and Yong-Qiang Wang*
Abstract: Difluoromethylthioester compounds as another important
kind of organofluorine compounds are reported for the first time.
They can be facilely and efficiently synthesized from various
aldehydes. The synthetic method is featured by mild reaction
conditions, good tolerance of functional groups, broad substrate
scope, and especially no metal involving in the reaction. The
approach has the potential to become an important tool for the late-
stage functionalization of advanced synthetic intermediates, and
should have many applications in medical chemistry.
About 25% of pharmaceuticals and 40% of agrochemicals on
[1]
the market contain fluorine atoms.
Accordingly, the
incorporation of fluorine atoms into molecules has become
standard procedure in the discovery of such new active
[2]
substances. Recently, difluoromethylthiol (-SCF
2
H) group has
drawn exceptional attention because its acidic proton as a
[3]
hydrogen bonding donor could enhance the drug molecule’s
[4]
binding selectivity, and its electron-withdrawing nature could
increase the drug molecule’s metabolic stability, and its
[5]
distinctive Hansch parameter (π
R
= 0.68) would provide
medicinal chemists the opportunity to fine tune the drug
molecule’s lipophilicity. To date, there are numerous reports on
difluoromethylthiolated compounds about their synthesis and
[
6,7]
bioactivity,
which should permit the effective design of novel
[8]
drug candidates.
Indeed, several difluoromethylthioethers
Figure 1. Difluoromethylthiolether, Monofluoromethylthioester Compounds
residues have been demonstrated to be uniquely efficient, such
and the First Synthesis of Difluoromethylthioesters from Aldehydes.
as the β-lactamase-resistant oxcephalosporin antibiotic
[
9]
[10]
Flomoxef sodium and insecticide Pyriprole (Figure 1a).
However, to the best of our knowledge, the present reports
were limited in the difluoromethylthioether compounds (Figure
Aldehydes are cheap and abundant chemical materials, and
they can serve as versatile acyl radical precursors in the
[12a]
reactions.
difluoromethylthioesters could be produced by incorporation
difluoromethylthiol radical (·SCF H) with acyl radicals that come
Therefore, we envisaged if the desired
[6,7]
1b),
and there is no case of difluoromethylthioester
compounds reported (Figure 1c) though they are another
important kind of difluoromethylthiol compounds. Due to different
chemical property of difluoromethylthioester from that of
difluoromethylthioether,
would predictably derive new bioactive molecules which have
been indirectly demonstrated by anti-inflammatory
monofluoromethylthioester drug Fluticasone and its derivative
2
from aldehydes. In order to examine this idea, we initially chose
p-tolualdehyde (1a) as acyl radical precursor, and three
[7k,3v]
difluoromethylthioester
compounds
difluoromethylthiolation reagents (2a, 2b, and 2c)
respectively as difluoromethylthiol radical source, employing di-
tert-butyl peroxide (DTBP) as radical initiator, 1,2-dichloroethane
as solvent at reflux temperature (Table 1, entries 1-3).
Gratifyingly, the desired difluoromethylthioester 3a was obtained
in 35% yield after 24 h with difluoromethylthiolation reagent 2b
which was developed by Lu and Shen and could be readily
[11]
Fluticasone propionate (Figure 1d). Herein, we firstly disclose
a facile and efficient synthesis of difluoromethylthioesters from
aldehydes and
a difluoromethylthiol reagent through an
[7v]
intermolecular radical process (Figure 1e).
prepared from 2a by two steps (entry 2). Encouraged by these
meaningful results, with 1a and 2b as the substrates, other
radical initiators, such as tert- butyl hydroperoxide (TBHP, 70
wt. % in H
were then tested. TBHP (70 wt. % in H
superior to the others with a slightly higher yield (38%) (entries 4
2
O), K
2
S
2
O
8
, (NH
4
)
2
S
2
O
8
, and H
2
O
2
(30 wt. % in H
2
O)
[a]
Shi-Huan Guo, Xing-Long Zhang, Gao-Fei Pan, Xue-Qing Zhu, Ya-
Ru Gao, Prof. Yong-Qiang Wang
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Department of Chemistry &
Materials Science
2
O) was found to be
– 7). The influence of the solvent was next studied (entries 8 –
4). To our delight, CH CN afforded corresponding
1
3
Northwest University
Xi’an 710069, P. R. China
E-mail: wangyq@nwu.edu.cn.
difluoromethylthioester 3a in 53% isolated yield (entry 11). When
the amount of TBHP was increased to 2.0 equiv, the yield was
improved to 87% (entry 15). Interestingly, a similar result was
obtained when the reaction was performed under an Ar
atmosphere (entry 16). The control experiment showed that the
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Table
1.
Optimization
of
the
Reaction
Conditions
O
for
[
a]
Difluoromethylthiolation
O
H
initiator
solvent
reflux, 24 h
+
[SCF2H]
2
SCF H
2
Me
1a
SCF H
Me
3a
O
O
SO2SCF2H
2
N
SCF2H
2a
2b
2c
entry
2
initiator
x equiv)
solvent
conv.
(%)
yield
(%)
[
b]
[c]
(
1
2
3
4
5
6
7
8
9
2a
DTBP (1.0)
DTBP (1.0)
DTBP (1.0)
TBHP (1.0)
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
0
-
2b
2c
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
43
0
35
-
45
25
23
15
31
18
15
60
19
12
25
38
17
15
8
2 2 8
K S O (1.0)
2
(NH4) S
O
2 8
(1.0)
2 2
H O
(1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (2.0)
TBHP (2.0)
-
CHCl
3
21
-
DMSO
DMF
Scheme 1. Scope of Difluoromethylthiolation of (Hetero)aromatic Aldehydes.
Reaction conditions: 1 (0.75 mmol), 2b (0.5 mmol), TBHP (1.0 mmol, 70 wt.%
10
11
12
13
14
15
16
17
-
2 3
in H O), and CH CN (2.5 mL) at 82 °C. All yields given are isolated yields.
CH
3
CN
53
11
-
3e – 3h), ether (3i, 3s, and 3t), ester (3l), nitro (3j), and cyano
toluene
THF
groups (3k) were compatible with this process, which offered
valuable synthetic handles for further transformations.
Particularly
noticeable
is
the
performance
of
4-
iodobenzaldehyde (1h) in the reaction. On the basis of Shen’s
H
2
O
17
87
86
6
[5c]
study, I also was possible difluoromethylthiolation site, so 1h
contains two possible reaction sites. Surprisingly, it provided
difluoromethylthioester 3h as the sole difluoromethylthiolation
product in 87% yield. The position of substitution groups on the
phenyl ring has no effect on this reaction (3a, 3n, and 3q). The
reaction with naphthyl aldehydes also proceeded smoothly (3u
and 3v). Heteroarenes are prevalent in many biologically
relevant molecules. Therefore, aldehydes containing thiophene,
indole, and pyrole motifs were subjected to the reaction
conditions. Pleasingly, they provided the desired products in
good yields (3w – 3y) with no by-products resulting from radical
addition to the heterocyclic rings observed. The structure of
difluoromethylthioesters 3k and 3w were unambiguously
confirmed by single-crystal X-ray diffraction analysis.
CH
CH
CH
3
CN
3
CN
3
CN
100
100
12
[
d]
[
a] Reaction conditions: 1a (0.75 mmol), 2 (0.5 mmol), initiator, solvent (2.5
mL), at reflux tempreture under air. [b] Based on 2. [c] Isolated yields of 3a.
d] Under Ar. DTBP = di-tert-butyl peroxide. TBHP = tert-butyl hydroperoxide
70 wt. % in H O). conv. = conversion.
[
(
2
difluoromethylthioester 3a was obtained in only 6% yield when
the reaction was carried out in the absence of TBHP (entry 17);
the small amount of the product might result from thermal-
[12a,13]
induced radical reaction.
Thus, the optimized reaction
conditions for the synthesis of difluoromethylthioesters 3a were
identified as the following: 1a (0.75 mmol), 2b (0.5 mmol), TBHP
Encouraged by the success of (hetero)aromatic aldehydes,
aliphatic aldehydes and α, β-unsaturated aldehydes were then
[14]
(
1.0 mmol), and CH
3
CN (2.5 mL) at 82 °C.
investigated. As summarized in Scheme 2, the reactions of a
variety of aliphatic aldehydes with 2b proceeded smoothly under
above standard conditions to give the corresponding
difluoromethylthioesters (3aa – 3aj) in good yields. It is worth
mentioning that not only primary aliphatic aldehydes (1aa – 1af)
and secondary aliphatic aldehydes (1ag) but also tertiary
aliphatic aldehydes (1ah) were suitable substrates. The efficacy
of the methodology was further verified by the compatibility of α,
With optimized reaction conditions in hand, substrate scope of
the transformation was investigated (Scheme 1). In general, the
reactions of a variety of aryl aldehydes bearing either electron-
donating groups or electron-withdrawing groups occurred with
moderate to high yields (3a – 3t). A broad range of common
functional groups such as alkyls (3a – 3d), halides (F, Cl, Br, I,
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β-unsaturated aldehyde. (-)-Myrtenal (1ai) and (E)-non-2-enal
(
1aj) could be successfully converted into the corresponding
difluoromethylthioesters 3ai and 3aj in good yields. All
difluoromethylthioesters above are not air and moisture sensitive.
No detectable decomposition was observed after more than a
month of storage at ambient temperature. Considering some
aldehydes are expensive, two experiments of materials ratio
were carried out. 1a and 2b with the ratio of 1:1 or 1:1.2, both
reacted smoothly using TBHP (2.0 equiv) as radical initiator,
3
CH CN as solvent at reflux temperature to afford 3a in 81% and
90% yields, respectively.
(
12 h) to give 3a in 56% and 16% yields, respectively [Eq. (6)].
The photoreactions again supported the radical process of the
transformation.
Scheme 2. Scope of Difluoromethylthiolation of Aliphatic Aldehydes and α, β-
Unsaturated Aldehydes. Reaction conditions: 1 (0.75 mmol), 2b (0.5 mmol),
[7v]
In literature, 2b was demonstrated to be an efficient reagent
for radical difluoromethylthiolation. Based on these results and
TBHP (1.0 mmol, 70 wt.% in H
given are isolated yields.
2 3
O), and CH CN (2.5 mL) at 82 °C. All yields
[
7v,12,16]
the related literatures,
the synthesis of difluoromethylthioesters was proposed in Figure
. The reaction begins with abstraction of H from aldehyde (1)
by TBHP to generate acyl radical A. Then acyl radical A reacts
with 2b affording desired product (3) and PhSO radical which
a tentative reaction mechanism for
To understand the mechanism of this reaction, we carried out
series of radical-trapping experiments. First, under the
2
a
standard reaction conditions, TEMPO (2.0 equiv) was introduced
into the reaction system of 1a with 2b. After 24 h at reflux, 68%
of 1a was recovered while 2b was completely consumed, and a
main product, namely the adduct (4a) of 1a with TEMPO, was
isolated in 25% yield [Eq. (1)], indicating acyl radical existed in
reaction system. Then two control experiments were
implemented under the standard conditions. Without
difluoromethylthiol reagent 2b, aldehydes 1a and 1v reacted
with TEMPO, affording 4a and 4v in 89% and 83% yields,
respectively [Eq. (2) and (3)]. The two control experiments
further demonstrated that acyl radical was very likely involved in
the difluoromethylthiolation reaction. Without aldehyde, 2b with
TEMPO presented mess reaction. Next, under the standard
reaction conditions, another classical radical-trapping reagent 1,
2
[16]
has been reported by the literatures and is also supported by
product 5b isolated. Further investigations on more detailed
mechanism are ongoing.
PhSO SCF H
PhSO2
2
2
2b
O
O
O
TBHP
R
H
R
R
SCF H
2
1
A
3
Figure 2. Plausible Mechanism.
In summary, difluoromethylthioester compounds as another
important kind of organofluorine compounds are reported for the
first time. Difluoromethylthioester compounds have been
efficiently synthesized from cheap and abundant aldehydes
including (hetero)aromatic aldehydes, aliphatic aldehydes, and α,
β-unsaturated aldehydes. Featured by mild reaction conditions,
good tolerance of functional groups, broad substrate scope, and
especially no metal involving in the reaction, the approach has
the potential to become an important tool for the late-stage
functionalization of advanced synthetic intermediates, and
should have many applications in medical chemistry. Preliminary
mechanistic studies suggest that the protocol proceeds via a
1-diphenylethylene was introduced into the reaction system of
1a with 2b. After 24 h at reflux, most of 1a and 2b were
recovered, while adducts 5a and 5b were isolated in 13% and
5% yields, respectively [Eq. (4)], showing SCF H radical and
PhSO radical likely existed in reaction system. Without
1
2
2
aldehyde 1a, 1, 1-diphenylethylene reacted with 2b under above
standard conditions also affording 5a in 13% [Eq. (5), 85% 2b
[15]
recovered].
Finally, visible light-promoted experiments were
investigated. Reactions carried out by irradiation with natural
sunlight (5 h) or a commercially available 23 W white LED bulb
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COMMUNICATION
Shi-Huan Guo, Xing-Long Zhang, Gao-
Fei Pan, Xue-Qing Zhu, Ya-Ru Gao,
Yong-Qiang Wang*
Page No. – Page No.
Synthesis of Difluoromethylthioesters
from Aldehydes
Text for Table of Contents
Difluoromethylthioester compounds have been efficiently synthesized from aldehydes for the first time. The synthetic method was
featured by mild reaction conditions, good tolerance of functional groups, and broad substrate scope including (hetero)aromatic
aldehydes, aliphatic aldehydes, and α, β-unsaturated aldehydes.
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