Preparation of difluoromethylthioethers through difluoromethylation of disulfides using TMS-CF2H

Article abstract of DOI:10.1039/c6cc02693a

We report an operationally simple, metal-free approach for the late-stage introduction of the important lipophilic hydrogen-bond donor motif, SCF₂H. This reaction converts diaryl- and dialkyl-disulfides into the corresponding aryl/alkyl-SCF₂H through the nucleophilic transfer of a difluoromethyl group with good functional group tolerance. This method is notable for its use of commercially available TMSCF₂H, and does not rely on the need for handling of sensitive metal complexes.

Full text of DOI:10.1039/c6cc02693a

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Preparation of difluoromethylthioethers through
difluoromethylation of disulfides using TMS-CF2H
Received 00th January 20xx,
Accepted 00th January 20xx
Joseph L. Howard, Christiane Schotten, Stephen T. Alston, and Duncan L. Browne*
DOI: 10.1039/x0xx00000x
We report an operationally simple, metal-free approach for the late-stage introduction of the important lipophilic
hydrogen-bond donor motif, SCF2H. This reaction converts diaryl- and dialkyl-disulfides into the corresponding aryl/alkyl-
SCF2H through the nucleophilic transfer of a difluoromethyl group with good functional group tolerance. This method is
notable for its use of commercially available TMSCF2H, and does not rely on the need for handling of sensitive metal
complexes.
www.rsc.org/
sulfur by cytochromes (such as P450). The resultant
The fluorination of organic molecules continues to lead to
materials with improved properties with which to fuel our
modern society. As testament to the dramatic improvements
available by the fluorination of organic materials, recent years
have seen a growth, at the discovery phase, of a late-stage
fluorine scanning approach.1 Such an approach looks to fine-
tune physicochemical properties by the inclusion of fluorine
atoms.2 Whilst some effects of fluorination can be rationally
predicted and thus provide a toolbox to guide fine-tuning,
several key observations have not been predictable, but have
lead to exciting new observations for organo-fluorine
chemistry.3 It is perhaps owing to this rich-seam of
unchartered beneficial effects that the synthesis community
are increasingly interested in organo-fluorine methods. In
contrast to this late-stage approach however, there is now
increasing pressure to reduce the amount of fluorinated waste
materials making it into waste streams and eventually in to the
ecosystem. Especially given that degradation of fluorous
compounds through standard biological processes is greatly
retarded by natures poor ability to process fluorinated
materials.4 As a fine balance between this dichotomy we are
interested in developing rationally designed methods for late
stage fluorination approaches to under-represented fluorous
motifs. Herein our particular focus has been on the series
consisting of fluorinated methylthioethers R-SCFxH(3-x) (Figure
1). Initially we considered the x = 0 state; methylthioethers.
This motif is rarely present in biologically active materials,
owing to a poor metabolic profile characterised by oxidation at
sulfoxides/sulfones are then more easily cleared before the
target is reached. Notably, stable sulfoxides and sulfones are
not uncommonly found in biologically active materials.5
Assessment of the fully fluorinated variant; x = 3 state,
highlights several examples of this motif present in successful-
to-market biologically active materials.6 From an electronics
perspective the sulfur atom in this case is more electron
deficient (than in the x = 0 case) so the rate of oxidation
through a nucleophilic at sulfur mechanism is greatly reduced
(comparatively), resulting in reduced metabolism and reduced
clearance levels. This leads to an ability for these molecules to
reach the intended target before being metabolically cleared.
This is however an over simplified view as the cLogP or
liphophilicity of SCF3 is also different (greater) from that of
SCH3.7 Increased lipophilicity manifests in to a number of
phenomena, not the least of which include less specific binding
to enzymes and better transport across the blood:brain
barrier. Regarding the x = 2 state, the SCF2H motif maintains
many of the properties displayed by SCF3, but, in addition,
gains hydrogen-bond donor capabilities. Thus SCF2H essentially
serves as a lipophilic hydrogen-bond donor motif for drug
discovery, however the range of methods for the preparation
of this motif are relatively narrow (compared to SCF3).
properties of thioethers and fluorous congeners - R-SCFxH(3-x)
oxidation potential at sulfur reduced
R
SCH3
1
2
3
4
liphophilicity increased
R SCFH2
R SCF2H
R SCF3
prevalence in effective biologically active
materials increases
methods for preparation of 1 and 4 well
known, 2 and 3 lesser known
Figure 1 Effect of fluorine addition on thioethers
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carbene approaches
carbenes generated from
S
S
TMSCF2H (2.0 equiv)
SCF2H
HCF2Cl
activating agent (equiv)
solvent
SH
R
SCF2H
R
BrCF2P(O)(OEt)2
ClCF2CO2Na
etc.
rt, 16 h
1
thiols
Entry
activating agent (equiv)
yielda
solvent
electrophilic approach (transition metal free)
O
1
2
3
4
5
6
7
8
TBAF (2.0)
CsF (2.0)
KF (2.0)
t-BuOK (2.0)
CuI/t-BuOK (2.0)
CuI/CsF (2.0)
KF (2.0)
14%
1%
0%
5%
4%
0%
0%
10%
3%
16%
5%
39%
63%
36%
76%
73%
52%
82%
THF
THF
THF
THF
THF
B(OH)2
R
or
R
SCF2H
N
SCF2H
H
R
O
boronic acids or
C-H bonds
THF
MeCN
MeCN
DMA
DMA
DMF
DMSO
NMP
NMP
NMP
NMP
NMP
NMP
nucleophilic approach (metal mediated)
CsF (2.0)
KF (2.0)
CuSCN
9
SCN
TMSCF2H
R
10
11
12
13
14b
15c
16c
17
18c
CsF (2.0)
CsF (2.0)
CsF (2.0)
CsF (2.0)
CsF (2.0)
CsF (2.0)
CsF (4.0)
CsF (4.0)
CsF (8.0)
R
R
SCF2H
SCF2H
thiocyanate
[Cu(MeCN)4PF6]/bpy
[(SIPr)Ag(SCF2H)]
N2
X
Ar
diazonium salts
nucleophilic approach (metal free - this work)
TMSCF2H
S
R
spectroscopy with internal standard (b) reaction conducted at 60 oC, (c) 4 equiv
of TMSCF2H used
R
SCF2H
R
S
Scheme 1 Synthetic routes to difluoromethylthioethers
An alternative copper mediated approach was reported for the
conversion of thiocyanates or aryl diazonium salts using
TMSCF2H.11 Our approach was to develop an operationally
simple method, whereby transfer of the required fluorinated
carbon unit from a silicate complex to a disulfide electrophile
would result in formation of the difluoromethylthioether.
Indeed, during the course of our studies, very recently Zhang,
Zhu and co-workers published on an identical strategy12
Notably an analogous approach exists for trifluoromethylation
of disulfides as reported by Langlois.13 In this instance the
Ruppert-Prakash reagent, activated by fluoride from TBAF was
shown to transfer to the corresponding benzylic disulfides in
good yield. It was noted that aromatic disulfides offer poor
conversion under these conditions with a single example
reported (Scheme 2). For the difluoromethylthioether we
initially commenced by simply repeating this approach with
TMSCF2H. Under these conditions, a poor conversion of 14%
was found and a control experiment in our hands highlighted
that the work of Langlois was perfectly reproducible. This
observation suggested that the lower conversion for -CF2H
variants is inherent in the reactivity of these species. Indeed a
report from Fuchikami describes the stability of both the
TMSCF3 and the TMSCF2H fluoro-silicate complexes.14 Notably
the authors calculate that the bond order (a reflection on the
ion formation potential) for TMSCF3 was approximately half
that of TMSCF2H, at 0.220, implying that the
difluoromethylsilicate complex was less prone to generating
the required difluoromethyl anion species. We hypothesised
that appropriate choice of activating agent and solvent could
help to destabilise the silicate complex and/or stabilise the
desired ion formation, which would lead to improved
nucleophile transfer. Our studies commenced by treating a
solution of dibenzyldisulfide and TMSCF2H in THF with a range
of activating agents (Table 1). Notably a range of
The most commonly explored approch to the SCF2H motif
features the in situ generation of difluorocarbene followed by
nucleophilic attack from a thiol or thiolate and protonation of
the resulting difluoromethide (Scheme 1).8 With increasing
attention in this moiety there have been recent examples of
methods developed for its late stage introduction. For example
an electrophilic strategy was reported, whereby N-
difluoromethylthiophthalimide was demonstrated for the
direct difluoromethylthiolation of a range of nucleophilic
substrates such as boronic acids and aromatic C-H bonds.9
Shen has also developed a metal mediated nucleophilic
protocol for the conversion of aromatic diazonium salts in to
the
corresponding
aryl-SCF2H
compounds
using
[(SIPr)Ag(SCF2H)] as the SCF2H source.10
Table 1 Optimisation of reaction conditions (a) Yields calculated using 19F NMR
Experimental Observations
trifluoromethylation of disulphides using TMSCF3
S
TMSCF3
S
SCF3
TBAF (1M in THF)
70%
16 h, rt
difluoromethylation of disulphides using TMSCF2H
S
TMSCF2H
S
SCF2H
14%
TBAF (1M in THF)
16 h, rt
Justification
calculated bond orders of silicate complexes
calc. as 0.220
TMS
F
CF3
F
F
TMS CF3
TMS CF3
F
calc. as 0.436
TMS
F
CF2H
TMS CF2H
TMS CF2H
F
Hypothesis
destabilise silicate and/or stabilise anion through optimisation
of activating agent and solvent choice
2 | J. Name., 2012, 00, 1-3
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fluoride sources, t-BuOK (previously shown to effectively testament to this compounds 10 and 18 have been found to be
activate TMSCF2H),15 and a combination of either of these with isolable.17
TMSCF2H (4.0 equiv)
(Het)Aryl
(Het)Aryl
S
TMSCF2H (4.0 equiv)
alkyl
SCF2H
alkyl
S
S
(Het)Aryl
SCF2H
CsF (8.0 equiv)
NMP, 0 oC - rt, 16 h
S
alkyl
CsF (8.0 equiv)
NMP, 0 oC - rt, 16 h
SCF2H
SCF2H
SCF2H
SCF2H
SCF2H
SCF2H
SCF2H
8, 72%
9, 59%
1, 82%
2, 70%
Br
Br
Cl
SCF2H
3, 73%
4, 53%
10, 99%
11, 49%
13, 88%
(67%)a
Cl
F
Br
SCF2H
SCF2H
F3C
SCF2H
SCF2H
HO
SCF2H
12, 99%
SCF2H
8
SCF2H
5, 34%
Scheme 3 Reaction scope for dialkyldisulfides
6, 49%
7, 69%
MeO
14, 81%
16, 56%
15, 97%
17, 49%
MeO
copper (I) salts failed to provide much conversion to the
desired product. Upon switching to different solvents, it was
found that simple fluoride sources could perform the required
activation with CsF out-performing KF in both acetonitrile and
N,N-dimethylacetamide (cf entries 7 & 8 and entries 9 & 10,
Table 1). Indeed, further solvent probing with CsF highlighted
N-methylpyrrolidine as optimal, affording the desired product
in 63% conversion. An increase in reaction temperature
resulted in a poorer reaction yield, (Table 1, entry 14, 36 %).
Optimal conditions were reached by increasing the equivalents
of TMSCF2H and CsF further (entry 18, 82% yield). With
optimal conditions in hand for the metal-free nucleophilic
difluoromethylation of dibenzyldisulfide we then turned
attention to the generality of the scope of this method with
respect to dialkyldisulfides. We evaluated several methods for
the reliable and rapid synthesis of disulfide starting materials
and found treatment of thiols with inexpensive
dibromodimethylhydantoin to be the most effective.16
SCF2H
Br
SCF2H
N
SCF2H
18, 72%
(62%)a
Scheme 4 Reaction scope for diaryldisulfides (a) isolated yield.17
Conclusions
In summary, we report conditions for the preparation of a
range of difluoromethylthioethers from their corresponding
disulfide starting materials. The reported method is
operationally simple, metal-free and uses commercially
available fluorinating agents. The method is applicable to a
range of dialkyldisulfides and diaryldisulfides and is tolerant to
a range of functionalities, including free alcohols and pyridine
nitrogens.
Pleasingly,
difluoromethylation reaction to provide the products in good
yield (Scheme 3), including the ortho-bromo derivative (73%
a range of dibenzyldisulfides underwent the
3
yield). Non-benzylic substrates also participated in the
reaction, including secondary alkyl disulfides, with the
Acknowledgements
cyclopentyl variant
are also amenable under the present methodology, with the
difluoromethylthioether undergoing reaction in 49% yield.
5 proceeding in 34 % yield. Free alcohols
We thank the School of Chemistry, Cardiff University for
generous support, Fluorochem for kind donations of TMSCF2H
and the EPSRC UK National Mass Spectrometry Facility at
Swansea University for mass spec data.
6
However, in stark contrast to the trifluoromethylation
approach reported by Langlois, the present method of
difluoromethylation was highly effective on diaryldisulfides. As
shown in Scheme 4, diaryldisulfides convert to the desired
fluorinated products with good to excellent conversion. Both
electron rich and electron poor examples proceed well, as do
ortho-substituted systems and heteroaromatics, with a 2-
pyridyl example converting to the SCF2H product (17) in 49%
yield. Notably, whilst we have proven that isolation and
accurate depiction of isolated yields is somewhat hampered by
compound volatility, we believe that the late stage fluorination
of more advanced drug-like scaffolds (higher molecular
weight) would permit ready isolation of the SCF2H material as
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