Nucleophilic (Phenylsulfonyl/arylthio)difluoromethylation of Aldehydes with TMSCF2Br: A Three-Component Strategy

Article abstract of DOI:10.1021/acs.orglett.9b03520

An efficient method for nucleophilic (phenylsulfonyl/arylthio)difluoromethylation of aldehydes with TMSCF₂Br was developed. The reaction proceeds through in situ generation of difluorocarbene, which is captured by PhSO₂Na or ArSNa to

Full text of DOI:10.1021/acs.orglett.9b03520

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nucleophilic (Phenylsulfonyl/arylthio)difluoromethylation of
Aldehydes with TMSCF2Br: A Three-Component Strategy
Qiqiang Xie, Ziyue Zhu, Chuanfa Ni, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Ling-Ling Road, Shanghai 200032,
China
S
* Supporting Information
ABSTRACT: An efficient method for nucleophilic (phenyl-
sulfonyl/arylthio)difluoromethylation of aldehydes with
TMSCF2Br was developed. The reaction proceeds through
in situ generation of difluorocarbene, which is captured by
PhSO2Na or ArSNa to form the corresponding PhSO2CF2− or
−
PhSCF2 anions, followed by nucleophilic addition to
aldehydes to give the desired difluoromethylated products.
ecause of the unique physicochemical and biological
properties of lightly fluorinated organic compounds, the
the structure of two ends of the −SCF2− group is highly
desired.
B
selective incorporation of fluorine atom(s) or fluorine-
containing groups into organic molecules have attracted great
attention in life science- and material science-related realms.1
Among various fluorinated moieties, difluoromethylene (CF2)
group is of particular interest, because it is known to be
isosteric to ethereal oxygen atom.2 On the other hand, sulfur-
containing fluoroalkyl groups have attracted much attention in
recent years, because the introduction of sulfur-containing
functionalities can further change the properties of the
molecules;3 therefore, many bioactive compounds contain
fluoroalkylthio or fluoroalkylsulfonyl moieties. For example,
compound A is a PDE4 (phosphodiesterase-4) inhibitor,4 and
compound (−)-B shows potent antifungal activity against
Candida albicans in vivo for both oral and intravenous
administrations5 (see Figure 1).
Difluorocarbene is an ideal reaction intermediate to
incorporate CF2 into organic molecules. Although many
difluorocarbene reagents have been developed thus far, most
of these reagents were focused on (1) the [2 + 1]
cycloaddition reactions with alkenes and alkynes, (2)
difluorocarbene insertion into Y−H (Y = heteroatoms)
bonds to achieve the introduction of CF2H functionality, and
(3) transformation of carbonyls into difluoromethylidene
(=CF2).7 However, using difluorocarbene to achieve CF2
incorporation in multicomponent cascade reaction has not
attracted much attention; only some examples have been
reported by the Dilman group with limited nucleophiles.8
Therefore, it is highly desirable to use difluorocarbene as an
efficient synthetic intermediate for CF2 incorporation into
various types of molecules.
Our group has been focusing on sulfur-based fluoroalkyla-
tion chemistry and difluorocarbene chemistry.6c,d,7e,9 In the
past decade, tremendous efforts have been made in the
development of new (phenylsulfonyl/phenylthio)-
difluoromethylation reagents and reactions.6 Among these
−
−
reactions, nucleophilic addition of PhSO2CF2 or PhSCF2
anion to carbonyl compounds (such as aldehydes) is an
important way to synthesize α-difluorocarbinols (see Scheme
1a). To achieve the valuable −SCF2− group introduction with
two tunable ends, we envisioned that difluorocarbene could be
used to accomplish the (arylsulfonyl/arylthio)-
difluoromethylation reaction if a proper S-nucleophile is used
to capture the in situ formed difluorocarbene to form the
corresponding difluorocarbanion, which could then attack an
electrophile. Herein, we report our new strategy to achieve
Figure 1. Bioactive compounds containing −SCF2− fragments.
Because of the importance of −SCF2− fragments, many
methods have been developed to incorporate them into
organic molecules,6 but these methods are mainly dependent
on the use of PhSO2CF2X or PhSCF2X (X = H, TMS, Br, I)
reagents. As a result, one end of the S atom is fixed to phenyl
group, which is difficult to change to other groups. To meet
the demand of pharmaceutical development, an efficient
method to introduce the −SCF2− group that can easily tune
Received: October 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Different Strategies for (Phenylsulfonyl/
phenylthio)difluoromethylation of Aldehydes: (a) Previous
Work and (b) This Work
Table 1. Optimization of Reaction Conditions
Lewis
entry acid, LA
temperature,
T (°C)
reaction
5
b
time, t (h) 2a (%) 4 (%) (%)
cd
,
1
2
−
−
−
100
100
100
100
rt
rt
rt
0
0
0
0
0
0
0
0
2
2
2
2
2
2
2
2
4
8
8
8
8
2
2
trace
trace
trace
13
49
59
trace
trace
trace
6
28
21
14
19
15
13
21
17
9
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
20
17
8
13
3
ce
,
c
3
f
f
4
5
6
7
8
9
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiCl
LiI
g
35
(phenylsulfonyl/arylthio)difluoro- methylation of aldehydes
using difluorocarbene as the CF2 source (see Scheme 1b).
Our work started with using 2-naphthaldehyde 1a as the
model substrate, PhSO2Na as the nucleophile, and TMSCF2Br,
a versatile difluorocarbene reagent developed by us that can
generate difluorocarbene under various mild condi-
tions,8k,p,9k,10 as the CF2 source. In the initial studies, we
tried to use a catalytic amount of n-Bu4NBr to initiate the
generation of difluorocarbene at 100 °C. Although TMSCF2Br
was completely consumed, only a trace amount of the desired
product 2a was detected (see Table 1, entries 1−3). We
reasoned that the aldehyde might be not sufficiently electro-
philic, and adding a metal salt as a Lewis acid to activate the
carbonyl group might be helpful to the reaction. Gratifyingly,
when LiBr was used instead of n-Bu4NBr, 2a was formed in
13% yield (Table 1, entry 4). When the reaction proceeded at
room temperature, a significant improvement of reaction
efficiency was observed, with 2a being formed in 49% yield,
together with 28% yield of protonation product 4 (Table 1,
entry 5). The higher efficiency might attribute to the higher
50 (90)
73 (92)
83
83
87
19
84
96
10
11
12
13
14
15
MgCl2
LiI
LiI
n.d.
22
6
h
i
6
5
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), TMSCF2Br (2.0
equiv), LA (0.7 equiv), THF (1 mL). Yields were determined by 19F
NMR spectroscopy, using PhOCF3 as an internal standard. n.d.= not
detected. The conversion of TMSCF2Br is given in the parentheses;
if not, the conversion is >99%. 0.1 equiv of n-Bu4NBr was used
instead of LiBr. PhCH3 was used as the solvent. CH3CN was used
b
c
d
e
f
g
as the solvent. LiBr (1.0 equiv) was used. LiBr (0.5 equiv) was used.
h
After reacted at 0 °C for 2 h, the mixture was slowly warmed to
i
room temperature (rt) and stirred for 2 h. After reacted at 0 °C for 2
h, the mixture was slowly warmed to rt and stirred for 6 h.
electron-donating groups, as well as halogens, are all well
compatible under the reaction conditions, giving good yields of
the corresponding products (3a−3l). When cinnamaldehyde
was used as the substrate, the desired product 3m was formed
in 70% yield, and no difluorocyclopropane byproduct was
observed by 19F NMR spectroscopy. Heteroaromatic aldehydes
are also suitable substrates; for example, 5-bromo-2-furalde-
hyde and 4-bromothiophene-2-carboxaldehyde reacted under
the standard reaction conditions could give the corresponding
products 3n and 3o in 74% and 91% yields, respectively. It is
noteworthy that both nonenolizable and enolizable aldehydes
exhibited good reactivity, and good to excellent yields of
products were obtained (3p−3t). Unfortunately, under the
standard reaction conditions, when 4-bromoacetophenone (a
simple ketone) was used as a substrate, no desired
(phenylsulfonyl)difluoromethylated carbinol product was
formed.
Encouraged by the successful (phenylsulfonyl)-
difluoromethylation of aldehydes using TMSCF2Br as the
CF2 source, we turned our attention to arylthio)-
difluoromethylation, which might be achieved by using the
same strategy with ArS− as the nucleophile. After a quick
modification of reaction parameters (for details, see the
Supporting Information), the best conditions were obtained:
1 equiv of aldehyde 1, 2 equiv of ArSH, NaH used as the base,
LiI as the Lewis acid, and DMF as the solvent; the reaction
proceeded at 0 °C for 3 h. A series of aromatic thiols and
−
stability of the in-situ-formed PhSO2CF2 anion at room
temperature than that observed at 100 °C. Screening of the
equivalent of LiBr showed that a substoichiometric amount of
the LiBr was sufficient to promote the reaction, with 0.7 equiv
of LiBr giving the best results (Table 1, entries 5−7). When
the reaction proceeded at 0 °C for 2 h, moderate yield was
obtained, but the conversion of TMSCF2Br was only 90%, and
a new byproduct PhSO2CF2TMS was observed in 20% yield
(Table 1, entry 8). Prolonged reaction time could achieve
complete conversion of TMSCF2Br, and the yield of 2a was
increased to 83% (Table 1, entries 9 and 10). Using other
Lewis acids showed that LiI could increase the yield to some
extent, while MgCl2 was inferior to that of LiBr (Table 1,
entries 11−13). Because of the fact that the byproduct
PhSO2CF2TMS was observed when the reaction was
conducted at 0 °C, while this byproduct was not observed at
or above room temperature, we envisioned that if we could
transform this byproduct to the desired product, the reaction
efficiency could be further improved. When we performed the
reaction at 0 °C for 2 h and then raised the temperature to
room temperature to react for additional 6 h, the yield was
finally increased to 96% (see Table 1, entries 14 and 15).
With the optimal conditions (Table 1, entry 15) in hand, the
substrates scope of this difluorocarbene-involved cascade
reaction was explored. The results are shown in Scheme 2.
Aromatic aldehydes bearing electron-withdrawing groups and
B
DOI: 10.1021/acs.orglett.9b03520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
aromatic rings (7d and 7e). The reaction with 6e was also
performed on a 1 mmol scale, and an excellent yield (92%) of
7e was still obtained. When PhS− was used as a nucleophile,
different aromatic aldehydes all showed high reactivity (7g−
7i). When nonenolizable aliphatic aldehyde (trimethylacetal-
dehyde) was used as a substrate, the desired product could be
formed in 71% yield (7j). Note that, although NaH was used
as the base to generate ArS−, enolizable aldehyde was also
compatible to the reaction conditions, and the desired product
(7k) was formed in 94% yield.
Scheme 2. (Phenylsulfonyl)difluoromethylation of
Aldehydes with TMSCF2Br
a
A plausible reaction mechanism is shown in Scheme 4. The
activation of TMSCF2Br by a Lewis base activator (LB−
=
Scheme 4. Proposed Mechanism for (Phenylsulfonyl/
Arylthio)difluoromethylation of Aldehydes with TMSCF2Br
a
Reaction conditions: 1 (0.4 mmol, 1.0 equiv), TMSCF2Br (2.0
equiv), PhSO2Na (3.0 equiv), THF (2 mL), TBAF (2.5 equiv). Yields
were isolated yields.
aldehydes could be used to accomplish the desired trans-
formation (see Scheme 3). For aromatic thiols, whether
electron-donating or electron-withdrawing groups on the
aromatic rings, the desired products could be formed in
excellent yields (7a−7f). The reaction efficiency was also not
sensitive to the positions where substituents located on the
−
PhSO2 , PhS−, or 8) generates CF2, which is trapped by a
nucleophile (Nu− = PhSO2 or PhS−) to give a difluorinated
carbanion, NuCF2 . This carbanion undergoes nucleophilic
−
−
addition to the LiI-activated aldehyde, giving the alkoxide 8
(cheme 4, path A). Alternatively, the reaction between
NuCF2− and TMSCF2Br gives TMSCF2Nu, which then reacts
with aldehydes (under the activation of a Lewis base activator)
to yield 8 (Scheme 4, path B). The reaction of 8 with
TMSCF2Br affords 9, together with the generation of
difluorocarbene. Desilylation of 9 by using TBAF gives the
final products 3 or 7. Path B cannot be ruled out, as
TMSCF2Nu can be observed as a byproduct during the
reaction.
Scheme 3. (Arylthio)difluoromethylation of Aldehydes with
TMSCF2Br
a
In conclusion, we have developed a new strategy to
accomplish the (phenylsulfonyl/arylthio)difluoromethylation
of aldehydes. This three-component protocol allows the rapid
introduction of (phenylsulfonyl/arylthio)difluoromethyl
groups into aldehydes using commercially available TMSCF2Br
as the CF2 source, and PhSO2 or ArS− as the nucleophiles,
−
which avoids multistep preparation of PhSO2CF2X or
PhSCF2X (X = H, Br, TMS) reagents in advance. Moreover,
different arylthio groups could be introduced by simply using
different aromatic thiols. The ability of simultaneous change of
two ends of the −SCF2− group shows great potential of this
method for rapid construction of various substituted SCF2-
containing analogues, which is beneficial for drug development
and late-stage modification of bioactive molecules. Further
efforts to explore the synthetic utility of this new strategy are
currently ongoing in our laboratory.
a
Reaction conditions: 1 (0.4 mmol, 1.0 equiv), TMSCF2Br (2.0
equiv), 6 (2.0 equiv), NaH (2.5 equiv), DMF (4 mL), TBAF (2.5
equiv). Yields were isolated yields. Performed on 1 mmol scale of 1.
b
C
DOI: 10.1021/acs.orglett.9b03520
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03520.
■
S
Experimental procedures and characterization data for
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jinbohu@sioc.ac.cn.
ORCID
Jinbo Hu: 0000-0003-3537-0207
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Basic Research
Program of China (Nos. 2015CB931900 and
2016YFB0101200), the National Natural Science Foundation
of China (Nos. 21632009 and 21421002), the Key Programs
of the Chinese Academy of Sciences (No. KGZD-EW-T08),
the Key Research Program of Frontier Sciences of CAS (No.
QYZDJ-SSW-SLH049), and Shanghai Science and Technol-
ogy Program (No. 18JC1410601). We thank Mr. Shitao Pan
for reproducing some of the experimental results (3a in
Scheme 2; 7b in Scheme 3).
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Org. Lett. XXXX, XXX, XXX−XXX