An Electrophilic Reagent for the Direct Introduction of the SCF2PO(OEt)2Group to Molecules

Article abstract of DOI:10.1002/anie.201607231

An unprecedented electrophilic difluoromethylthiolating reagent (MesNHSCF₂PO(OEt)₂) was designed. Under mild and metal-free conditions, this new reagent reacted with various nucleophiles, thus offering an efficient and operationally

Full text of DOI:10.1002/anie.201607231

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Communications
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International Edition: DOI: 10.1002/anie.201607231
German Edition: DOI: 10.1002/ange.201607231
Synthetic Methods
An Electrophilic Reagent for the Direct Introduction of the
SCF2PO(OEt)2 Group to Molecules
Heng-Ying Xiong, Alexandre Bayle, Xavier Pannecoucke, and Tatiana Besset*
Abstract: An unprecedented electrophilic difluoromethylthio-
To date, only a handful of reports have dealt with the
lating reagent (MesNHSCF2PO(OEt)2) was designed. Under synthesis of SCF2PO(OR)2-containing molecules. They relied
mild and metal-free conditions, this new reagent reacted with on the difluorination of PhSCH2PO(OEt)2 by either an
various nucleophiles, thus offering an efficient and operation- electrochemical pathway (Scheme 1a)[11a] or by means of
À
À
ally simple tool for the construction of C SCF2PO(OR)2, N
a halogen-exchange using 3HF·NEt3 and ZnBr2 starting from
SCF2PO(OR)2, and S SCF2PO(OR)2 bonds. Finally, thanks the corresponding chlorinated analogue (Scheme 1b).[11b,c]
À
to this new methodology, the synthesis of the non-stereoidal Alternatively, either the nucleophilic addition of LiCF2PO-
anti-inflammatory diflumidone was achieved.
[11d]
(OR)2
to diphenyl disulfide (Scheme 1c)[11b,d] or the
addition of a fluorinated radical, generated from ICF2PO-
ecause of the importance of the fluorine-containing (OiPr)2, to the Barton carbonate were reported by Lequeux
B
molecules in pharmaceuticals and agrochemicals,[1] the orga- (Scheme 1d).[11e] It is worth mentioning that to date, there is
nofluorine chemistry research field is continually and rapidly no general and efficient access to SCF2PO(OEt)2-containing
evolving.[2] Indeed, the presence of either a fluorine atom or molecules and only a couple of products are available
a fluorinated group in molecules has a strong impact on their (MeSCF2PO(OR)2 and PhSCF2PO(OR)2).
biological and physical properties.[3] Consequently, the design
of new fluorinated groups is still a compelling challenge in this
blooming field. Recently, SRf-containing groups have
appeared as key motifs and, among them, the SCF3 and
SCF2H residues have attracted a strong interest from the
scientific community thanks to their great features. Therefore,
and the SCF2H[5]
[2a,4]
transformations to introduce the SCF3
groups to molecules have been developed. Inspired by these
recent advances, a promising approach relying on the design
of original SCF2-containing residues bearing an additional
functional group (FG) has emerged. Indeed, by modulating
Scheme 1. State of the art.
Thus, the design of a bench-stable reagent to directly
the nature of the FG, the properties of the fluorinated residue introduce an SCF2PO(OEt)2 residue will enlarge the current
could be fine-tuned at will. Taking into consideration the toolbox of fluorinated groups and open new routes for
myriad of available fluorinated groups (CF3, CF2H, CF2PO- functionalizing complex molecules. Herein, we disclosed
(OR)2, CF2SO2Ph, CnF2n+1…), the synthesis of their sulfur- a simple and straightforward synthesis of the first electro-
containing analogues would provide a new generation of philic SCF2PO(OEt)2 source and its broad application in
fluorinated residues. This strategy has been recently illus- various transformations. Inspired by the recent studies from
trated by the contributions of the groups of Hu,[6] Gooßen,[7] Gooßen and co-workers,[5a,b,12] and taking advantage of our
Billard,[8] and others.[9] Indeed, various SCF2FG-containing own expertise for the preparation of N-(cyanosulfanyl)aniline
molecules (FG = SO2Ph, Rf, SAr and COAr) were success- derivatives,[13] we hypothesized that the synthesis of the
fully synthesized using two main synthetic pathways: 1) the electrophilic SCF2PO(OEt)2 reagent might be realized in two
À
construction of a S CF2FG bond by reaction of a CF2FG steps from the corresponding and readily available aniline
reagent with either thiols or disulfides, and 2) the direct and TMSCF2PO(OEt)2. Indeed, the N-(cyanosulfanyl)aniline
introduction of a SCF2FG group to molecules thanks to newly derivative 1, prepared in 66% yield (on 10 mmol scale) from
designed reagents. With these considerations in mind, we 2,4,6-trimethylaniline and NaSCN,[13,14] was engaged in
turned our attention to the SCF2PO(OR)2 group. We
a nucleophilic cyanide–CF2PO(OEt)2 substitution with
imagined that the original combination of a thioether with in situ generated CuCF2PO(OEt)2.[15] With this approach,
the CF2PO(OR)2 residue will be highly beneficial considering the electrophilic SCF2PO(OEt)2 source 2 was prepared in
the intrinsic properties of both functional groups.[10]
71% yield on 0.25 mmol scale (Scheme 2). Its synthesis was
conveniently scalable and the bench-stable reagent[16] 2 was
obtained in 60% yield on 4.4 mmol scale.
Then, to showcase the potential of this reagent, we first
studied the electrophilic (diethyl phosphono)difluoro-
methylthiolation reaction of electron-rich (hetero)arenes
(Scheme 3). With exposure to air, a large variety of indole
derivatives were functionalized, in the presence of TsOH, to
[*] H.-Y. Xiong, Dr. A. Bayle, Prof. X. Pannecoucke, Dr. T. Besset
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR
6014), 76000 Rouen (France)
E-mail: tatiana.besset@insa-rouen.fr
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607231.
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Scheme 2. Synthesis of the electrophilic SCF2PO(OEt)2 reagent 2.
[a] Reaction performed on 0.25 mmol scale. [b] Reaction performed on
4.4 mmol scale. TMS=trimethylsilyl.
Scheme 4. (Diethyl phosphono)difluoromethylthiolation of ketones
and b-ketoester. Reaction performed on 0.2 mmol scale. Yields of
isolated products are given. [a] 1.5 equiv of 2 were used. [b] 3 equiv of
2 were used, 20 h. [c] 16 h. NMP=N-methylmorpholine-N-oxide.
all cases, the expected a-substituted ketones were synthesized
in good yields. Ketones substituted by a heteroaromatic
substituent such as thienyl and pyridyl groups afforded the
products 6e and 6 f in 44% and 25% yields, respectively. The
functionalization on a methylene at the a-position of a car-
bonyl group was also evaluated, thus furnishing 6g in 48%
yield. Interestingly, the reaction proved to be selective for the
Scheme 3. Electrophilic substitution of electron-rich arenes and hetero-
renes. Reaction performed on 0.15 mmol scale. Yields of isolated
products are given. [a] 4 h. [b] Reaction performed on 2 mmol scale.
[c] 8 h. [d] 1 h. [e] 12 h. TsOH=p-toluenesulfonic acid.
À
secondary C H bond as demonstrated with 6h, which was
isolated in 61% yield. The scope of this reaction was further
extended to the cyclic ketone and b-ketoester (5i and 5j).
Worth mentioning is that in all these cases, only the selective
monofunctionalization was observed, and it is highly desir-
able for late-stage functionalization.
the corresponding products 4 in high yields at room temper-
ature. Pleasingly, when the reaction of 3a with 2 was carried
out, the (diethyl phosphono)difluoromethylthiolated indole
4a was obtained in 91% yield. Several indoles substituted
with electron-donating groups (4b and 4c) and a halogen (4d)
were selectively functionalized at C3.[14] A reaction was
performed on a 2 mmol scale and 4d was obtained in 83%
yield showcasing the synthetic utility of 2. Note that 2- and 3-
methyl-substituted indoles (3e and 3 f) were suitable sub-
strates, thus affording 4e and 4 f, respectively, in good yields
and the structure of 4 f was further confirmed by X-ray
analysis.[17] Even the N-methyl indole 3g and the pyrrole 3h
were efficiently converted into the (diethyl phosphono)di-
fluoromethylthiolated products 4g (82%) and 4h (83%),
respectively. Anisole and phenol derivatives (3i and 3j) were
also compatible and the corresponding products (4i and 4j)
were obtained in somewhat lower yields (56% and 70%,
respectively).
Encouraged by these results, we turned our attention to
the synthesis of (diethyl phosphono)difluoromethanesulfena-
mides, as sulfenamide-containing molecules are important
compounds in various fields of chemistry.[19] Pleasingly, the
transfer of the SCF2PO(OEt)2 from the sterically hindered 2
to various anilines was successfully achieved in a metal-free
process (Scheme 5). A panel of difluoromethylthiolated
Aimed at demonstrating further the synthetic utility of 2,
we explored the functionalization of cyclic and acyclic
ketones (Scheme 4). With the assistance of acetyl chloride
as recently developed by the group of Cao,[18] the (diethyl
phosphono)difluoromethylthiolation reaction of acetophe-
none (5a) was successfully achieved at room temperature,
thus leading to 6a in 72% yield. The methodology was
extended to acetophenone derivatives bearing electron-
donating (6b) and electron-withdrawing groups (6c, 6d). In
Scheme 5. Reaction of the aniline derivatives 7 with 2 to produce the
sulfenamides 8. Reaction performed on 0.2 mmol scale. Yields of
isolated products are given. [a] 258C, 0.15 mmol scale. [b] 18 h.
[c] 42 h. [d] 72 h, 508C. TFA=trifluoroacetic acid.
2
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sulfenamides (8) was synthesized in good to high yields (56–
91% yields) in the presence of trifluoroacetic acid. We were
delighted to find that the transformation demonstrated a good
functional-group tolerance as anilines bearing an electron-
donating substituent such as methoxy (8b) or electron-
withdrawing groups (halogen, CF3 and ketone, 8c–f) were
functionalized in high yields (up to 91% yield). The versatility
of the method was further illustrated through the synthesis of
SCF2PO(OEt)2-containing analogues of biorelevant mole-
cules such as triflumidate and the diflumidone (8e) as well as
the coumarin 120 (8g). Interestingly, the secondary amine 7h
was functionalized in 56% yield, albeit a longer reaction time
and an increase of the temperature to 508C were needed.[20]
We next found that thiol derivatives were also suitable
nucleophiles (Scheme 6), thus offering an efficient access to
the otherwise difficult-to-synthesize unsymmetrical fluori-
nated disulfides. The reaction proceeded smoothly at room
Scheme 7. Post-functionalization reactions. m-CPBA=meta-chloro-
perbenzoic acid, THF=tetrahydrofuran.
Scheme 6. Synthesis of unsymmetrical fluorinated disulfides 8. Reac-
tion performed on 0.2 mmol scale of 2. Yields of isolated products are
given based on 2. [a] 1.7 equiv of 9e was used, 18 h. MsOH=
methanesulfonic acid.
Scheme 8. Synthesis of Diflumidone.
sequence from the commercially available 3-aminobenzophe-
none (7e) in 74% overall yield (Scheme 8). Worth mention-
ing is that the previous approach provided 15 from 7e in a low
yield (28%)[23] by employing the rather expensive difluoro-
methanesulfonyl chloride,[24] and it required a two-step syn-
thesis using the ozone-depleting HCF2Cl.
temperature with thiophenol derivatives bearing either an
electron-donating substituent (10b) or an electron-withdraw-
ing group (10c and 10d). Finally, the functionalizations of
heteroaromatic (9e) and benzyl (9 f) thiols was efficiently
achieved, thus affording the corresponding products 10e and
10 f in high yields (72% and 86%, respectively).
Further exploration of the potential of the SCF2PO(OEt)2
group led to its conversion into the corresponding sulfoxide
11 and sulfone 12 in good yields, thus affording straightfor-
ward access to other high-value added fluorinated groups
(Scheme 7a). As the SCF2H group is considered as an
emergent fluorinated group,[5] we investigated the possibility
of converting the S(O)nCF2PO(OEt)2 residue (n = 0 or 2) into
the corresponding S(O)nCF2H group.[21] After intensive
investigations, it turned out that under basic conditions
In conclusion, the electrophilic reagent 2 was successfully
synthesized as a unique bench-stable and easy-to-handle
SCF2PO(OEt)2 source. It was efficiently applied to the
functionalization of C(sp2) and C(sp3) centers. In addition,
nucleophiles such as primary and secondary amines as well as
aromatic and aliphatic thiols were efficiently functionalized.
Furthermore, access to sulfoxide and sulfone derivatives was
achieved after a simple oxidation step, and is particularly
interesting from a synthetic point of view. The conversion of
the SCF2PO(OEt)2 residue into SCF2H and SO2CF2H groups
illustrated the versatility of this fluorinated group. Moreover,
the synthesis of a biorelevant molecule, Diflumidone, was
achieved in high yield. The selective introduction of the
SCF2PO(OEt)2 group to a panel of molecules considerably
extended the scope of the SCF2PO(OEt)2-containing deriv-
atives and we believe that the design of this electrophilic
reagent will open new avenues towards further investigations
regarding the potential of the SCF2PO(OEt)2 residue.
À
(NaOH) and using water as an additive, the CF2 P bond
cleavage occurred, thus leading to 13 and 14 in 32 and 83%
yield, respectively (Scheme 7b).
With all these synthetic tools in hand, we applied them to
the synthesis of Diflumidone (15), a non-stereoidal anti-
inflammatory compound.[22] Indeed, we succeeded in
a straightforward access to 15 in a three-step/two-purification
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This work was partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-
0029), and Rꢀgion Haute-Normandie (Crunch Network). H.-
Y.X. thanks the CSC (China Scholarship Council) for
a doctoral fellowship.
Keywords: electrophilic reagents · fluorine · sulfur ·
synthetic methods · difluoromethylthiolation
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Received: July 26, 2016
Published online: && &&, &&&&
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Communications
Synthetic Methods
Tool up: A new electrophilic difluoro-
methylthiolating reagent
H.-Y. Xiong, A. Bayle, X. Pannecoucke,
(MesNHSCF2PO(OEt)2) was reacted with
various nucleophiles under mild and
metal-free conditions, thus offering an
efficient and operationally simple tool for
T. Besset*
&&&& — &&&&
An Electrophilic Reagent for the Direct
Introduction of the SCF2PO(OEt)2 Group
to Molecules
À
À
the construction of C SCF2PO(OR)2, N
À
SCF2PO(OR)2, and S SCF2PO(OR)2
bonds. The versatility of this method was
illustrated through the synthesis of the
non-stereoidal anti-inflammatory com-
pound diflumidone.
6
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!