An electrophilic reagent for the synthesis of OCHFMe-containing molecules

Article abstract of DOI:10.1039/c8cc00921j

Herein the synthesis of a novel and bench stable electrophilic reagent to construct the OCFHMe motif from O-nucleophiles has been described. This sulfonium salt, readily obtained in 5 steps, reacted with various phenols and alcohols. The resulting products, including complex molecules, were obtained in good yields. This reagent was also used for the functionalization of thiol derivatives.

Full text of DOI:10.1039/c8cc00921j

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: E. Carbonnel, X.
Pannecoucke, T. BESSET, P. Jubault and T. Poisson, Chem. Commun., 2018, DOI: 10.1039/C8CC00921J.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C8CC00921J
Journal Name
COMMUNICATION
An Electrophilic Reagent for the Synthesis of OCHFMe-Containing
Molecules.
Elodie Carbonnel,a Xavier Pannecoucke,a Tatiana Besset,*a Philippe Jubault,*a and Thomas
Poisson*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
O
F
Herein the synthesis of a novel and bench stable electrophilic
reagent to construct the OCFHMe motif from O-nucleophiles was
described. This sulfonium salt, readily obtained in 5 steps, reacted
with various phenols and alcohols. The resulting products,
including complex molecules, were obtained in good yields. This
reagent was also used for the functionalization of thiol
derivatives.
N
O
N
GPR119 Modulator
Glucose control agent
O
N
F
SO2Me
N
O
Figure 1 A bioactive molecule bearing a OCHFMe residue.
The search for new bioactive molecules is a strategic research
field and the contribution of organic chemists is of prime
importance for the quest of new pharmaceuticals and
agrochemicals.1 In that context, organofluorine chemistry
plays an indisputable role, mainly due to the intrinsic
properties of the fluorine atom.2,3 Hence, a plethora of drugs
or agrochemicals, currently on the market, are fluorinated
molecules.4 Thus, the demand for this class of compounds, and
particularly original molecules, is steadily increasing and the
search for new fluorinated groups to discover bioactive
molecules is an appealing and stimulating task. For instance,
various promising motifs have recently attracted the attention
developments are still required to extend the current portfolio
of electrophilic reagents to other fluorinated groups.
In that context, we designed a new electrophilic reagent to
build up the OCHFMe group from phenols or alcohols.
Although this motif is present in bioactive molecule (Figure
1),14 only a handful of reports described preparative methods
for the construction of this underexplored fluorinated residue.
Indeed, the existing methods rely on 1)
a bromo-
fluorination/reduction sequence starting from enol ethers,15 2)
the use of fluorine gas to oxidize ether functional group,16 3)
the anodic oxidation of ethers or carbonates17 and 4) the Mn-
catalyzed decarboxylative fluorination.18
6
of the scientific community such as the CF2H,5 the SCF3 and
the OCF37 groups.
Known approaches:
An efficient strategy to introduce or build up fluorinated
motifs relies on the design of new reagents and particularly
electrophilic ones as demonstrated by Togni’s reagents8 and
various sulphur-based electrophilic reagents,9 which have
been used in a broad range of transformations. Among the
latter, are the contributions from Umemoto,10 Shibata,11
Prakash12 and Shen13 for the introduction of the CF3, CF2H and
CH2F motifs by means of the design of sulfonium salts and
ylide-based reagents. Despite these considerable advances
further
O
R
O
2 examples
CO2H
F
R
R
O
O
4 examples
R
O
4 examples
Our approach: a new electrophilic reagent
OMe
F
R
H
MeO
OMe
F
R
O
O
S
BF4
+ gram scale synthesis
+ bench stable
+ air and moisture tolerant
Scheme 1 State of the art and present work.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
View Article Online
DOI: 10.1039/C8CC00921J
COMMUNICATION
Journal Name
S
F
F
OH
1
, Cs2CO3
OCHFMe
a, b
thiophenol
R
R
MeCN, rt, 16 h
3
6a-l
7a-l
OMe
OCHFMe
c, d
OCHFMe
OCHFMe
MeO
OMe
F
O
S
Cl
NC
O
e
S
7a, 83%
OCHFMe
7b, 85%
OCHFMe
7c, 85%
BF4
OCHFMe
1
5
EtO
O2N
CN
Scheme 2 Synthesis of the reagent 1. a) (CH2O)n, toluene/HCl, 50 °C to rt, 95%. b)
O
KF, 18-crown-6, MeCN, 90°C, 98%. c) mCPBA, DCM, 0 °C, 63%. d) LiHMDS, MeI,
THF/HMPA, - 98 °C, 79%. e) Tf2O, TMB, Et2O, 0 °C, 67%, d.r. = 3:1. TMB = 1,3,5-
trimethoxybenzene.
7d, 68%
OCHFMe
7e, 81%
7f, 94%
OCHFMe
O
O
OCHFMe
N
These methods either proceed under harsh conditions or use
toxic reagents. Moreover, these approaches suffer from poor
functional groups tolerance and limited substrates scope
(Scheme 1).
O
7i, 69%
7h, 79%
7g, 86%
Boc
NH
OCHFMe
OCHFMe
S
N
MeO
H2N
Thus, the design of a sulfonium salt as an electrophilic reagent
enabling the formation of a O-CHFMe bond appeared as a
straightforward approach. Herein, the efficient synthesis of the
first electrophilic CHFMe-source and its application with O-
nucleophiles were depicted.
O
7j, 52%
7k, 31% (1:1.4)
OCHFMe
H
H
H
The sulfonium
1 was readily synthesized from thiophenol in
O
7l, 70% (1:1.5)
five steps (Scheme 2). First, the chloromethylation of
thiophenol, followed by the halogen exchange furnished the
Reluctant substrates:
3
in an excellent yield,19 without
N
OH
OH
OH
OH
fluoromethylsulfane
purification. Then, the oxidation of the sulfane and
a
N
MeO
B(OH)2 H2N
subsequent alkylation reaction gave the sulfoxide
yield over two steps. Finally,
sulfonium salt
diastereoisomers on a gram scale.20 The reagent
stable solid and is air and moisture tolerant.
5
in 50%
5
was converted into the
in 67% yield, as 3:1 mixture of
is a bench
Scheme 3 Scope of the reaction between 1 and phenols. Reaction conditions: 1
(0.2 mmol), 6 (0.24 mmol), Cs2CO3 (0.24 mmol), MeCN, rt, 16 h. Isolated yields
are given. Diastereoisomeric ratios are reported into parenthesis.
1
a
1
obtained as a mixture of diastereoisomers. Unfortunately,
some phenol derivatives were reluctant under our reaction
conditions, like the 2-hydroxyquinoxaline, the para-guaiacol,
the 2-hydroxyphenylboronic acid and the 4-hydroxyaniline.
Having this reagent in hands, we first explored its reactivity
toward phenol derivatives (Scheme 3). The reaction of para-
chlorophenol with
1 in the presence of Cs2CO3 in MeCN at
room temperature gave the desired product 7a in a good 83%
yield. The transformation was tolerant to several functional
groups since phenols bearing a cyano, ketone, ester and nitro
group, furnished the corresponding OCFHMe-containing
derivatives 7b-f in good to excellent yields (68%-94%). Note
that the substitution pattern did not have any impact on the
outcome of the transformation since the ortho-cyanophenol
afforded 7f in 94% yield. To our delight, 3-hydroxyquinoline 6g
reacted smoothly to deliver 7g in a decent 86% yield. This
example demonstrated the possible functionalization of
heterocyclic derivatives, which are of high importance in
pharmaceutical and agrochemical research. Then, the reagent
Then, we sought to explore the reactivity of
1 with alcohols
(Scheme 4). Under the same reaction conditions, para-
methoxybenzylic alcohol 8a and homobenzylic alcohol 8b were
converted into the OCFHMe derivatives 9a and 9b in 30% and
59% yields. Pleasingly, complex secondary alcohols, namely
the (–)-menthol 8c and the trans-androsterone 8d, were
1, Cs2CO3
R
OH
R
OCHFMe
9a-d
MeCN, rt, 16 h
8a-d
OCHFMe
OCHFMe
MeO
1
was used to functionalize relevant molecules as the
9a, 36%
9b, 59%
coumarin 6h and the raspberry ketone 6i. The corresponding
OCFHMe derivatives 7h and 7i were isolated in 79% and 69%,
respectively. Then, the Riluzole analogue 7j was obtained in
H
OCHFMe
H
H
H
OCHFMe
52% yield, starting from 2-amino-6-hydroxybenzothiazole 6j
.
Finally, N-Boc-tyrosine methyl ester 6k and estrone 6l were
converted into the corresponding compounds 7k and 7l in 31%
and 70% yields, respectively. Note that both compounds were
O
9c, 47% (1:1.5)
9d, 33% (1:1)
Scheme 4 Scope of the reaction between
(0.2 mmol),
are given. Diastereoisomeric ratios are reported into parenthesis.
1
and alcohols. Reaction conditions: 1
8
(0.24 mmol), Cs2CO3 (0.24 mmol), MeCN, rt, 16 h. Isolated yields
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
View Article Online
DOI: 10.1039/C8CC00921J
Journal Name
COMMUNICATION
conditons A or B
4
5
(a) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem.
Rev., 2014, 114, 2432–2506. (b) E. A. Ilardi, E. Vitaku and J. T.
Njardarson, J. Chem. Educ., 2013, 90, 1403–1405. (c) E. A.
or
R
SO2CHFMe
R
SH
R
S
CHFMe
11
10a-c
12a-b
SCHFMe
SO2CHFMe
SO2CHFMe
Ilardi, E. Vitaku and J. T. Njardarson, J. Med. Chem., 2014, 57
2832–2842.
,
EtO2C
Cl
(a) Y. Zafrani, D. Yeffet, G. Sod-Moriah, A. Berliner, D. Amir,
D. Marciano, E. Gershonov and S. Saphier, J. Med. Chem.,
2017, 60, 797–804. (b) C. D. Sessler, M. Rahm, S. Becker, J.
M. Goldberg, F. Wang and S. J. Lippard, J. Am. Chem. Soc.,
2017, 139, 9325–9332. (c) M.-C. Belhomme, T. Poisson and
X. Pannecoucke, J. Org. Chem., 2014, 79, 7205–7211.
(a) F. Toulgoat, S. Alazet and T. Billard, Eur. J. Org. Chem.,
2014, 2415–2428. (b) X.-H. Xu, K. Matsuzaki and N. Shibata,
Chem. Rev., 2015, 115, 731–764. (c) S. Barata-Vallejo, S.
Bonesi and A. Postigo, Org. Biomol. Chem., 2016, 14, 7150–
7182.
12a, 92% (B)
11, 90% (A)
12b, 72% (B)
(0.2 mmol),
Scheme 5 Functionalization of thiols with 1. Reaction conditions A:
10 (0.24 mmol), Cs2CO3 (0.24 mmol), MeCN, rt, 16 h. Reaction conditions B: i.
1
1
(0.2 mmol), 10 (0.24 mmol), Cs2CO3 (0.24mmol), DCM, rt, 16 h. ii. mCPBA (71%,
1.2 mmol), DCM, rt, 2 h. Isolated yields are given.
6
7
suitable substrates giving the corresponding products 9c and
9d as a mixture of diastereoisomers in moderate yields (47%
and 33%). Finally, as sulfur-containing fluorinated motifs are
important in drug discovery,4c,6,21 we took advantage of the
(a) T. Besset, P. Jubault, X. Pannecoucke and T. Poisson, Org.
Chem. Front., 2016, 3, 1004–1010. (b) A. Tlili, F. Toulgoat and
reactivity of
1 to extend the reaction to thiol derivatives to
T. Billard, Angew. Chem. Int. Ed., 2016, 55, 11726–11735.
J. Charpentier, N. Früh and A. Togni, Chem. Rev., 2015, 115
650–682.
construct the SCHFMe motif (Scheme 5).22 First, the ethyl para-
mercaptobenzoate 10a was converted into 11 in an excellent
90% isolated yield. Regarding the reaction of the para-
8
9
,
C. Ni, M. Hu and J. Hu, Chem. Rev., 2015, 115, 765–825.
10 (a) T. Umemoto, Chem. Rev., 1996, 96, 1757–1778. (b) T.
,
chlorothiophenol 10b and the benzylmercaptan 10c
, an
Umemoto and S. Ishihara, J. Am. Chem. Soc., 1993, 115
2156–2164.
additional oxidation step of the sulfane intermediate was
required to isolate the corresponding sulfones 12a and 12b in
excellent yields over two steps, 92% and 72% yields,
respectively.23
11 (a) A. Matsnev, S. Noritake, Y. Nomura, E. Tokunaga, S.
Nakamura and N. Shibata, Angew. Chem. Int. Ed., 2010, 49
,
572–576. (b) H. Kawai, T. Furukawa, Y. Nomura, E. Tokunaga
and N. Shibata, Org. Lett., 2011, 13, 3596–3599. (c) G. Liu, X.
Wang, X.-H. Xu, X. Lu, E. Tokunaga, S. Tsuzuki and N. Shibata,
Org. Lett., 2013, 15, 1044–1047. (d) X. Wang, G. Liu, X.-H. Xu,
N. Shibata, E. Tokunaga and N. Shibata, Angew. Chem. Int.
Ed., 2014, 53, 1827–1831. (e) S. Arimori and N. Shibata, Org.
Lett., 2015, 17, 1632–1635. (f) Y. Nomura, E. Tokunaga and
N. Shibata, Angew. Chem. Int. Ed., 2011, 50, 1885–1889.
12 (a) G. K. S. Prakash, S. Krishnamoorthy, S. K. Ganesh, A.
Kulkarni, R. Haiges and G. A. Olah, Org. Lett., 2014, 16, 54–
57. (b) G. K. S. Prakash, I. Ledneczki, S. Chacko and G. A.
Olah, Org. Lett., 2008, 10, 557–560. (c) G. K. S. Prakash, C.
In summary, we reported the straightforward synthesis of a
new electrophilic reagent for the synthesis of OCHFMe
derivatives. This sulfonium salt broadens the current toolbox
of electrophilic reagents and was applied to the
functionalization of a broad range of substrates including
phenols, alcohols and thiols. The resulting products were
obtained in moderate to excellent yields under simple and
practical reaction conditions. This new methodology allows an
easy access to the underdeveloped OCHFMe motif. Thus, we
believe that this reagent will be useful to the discovery of new
bioactive molecules bearing the OCHFMe motif.
Wéber, S. Chacko and G. A. Olah, Org. Lett., 2007,
1866. (d) E. Carbonnel, T. Besset, T. Poisson, D. Labar, X.
Pannecoucke and P. Jubault, Chem. Commun., 2017, 53
9, 1863–
,
5706–5709. (e) P. Ivashkin, G. Lemonnier, J. Cousin, V.
Grégoire, D. Labar, P. Jubault and X. Pannecoucke, Chem.
Eur. J., 2014, 20, 9514–9518.
This work was partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, LabexSynOrg (ANR-11-LABX-0029),
Région Normandie (Crunch Network) and the IUF (Institut
Universitaire de France). E.C. thanks the LabexSynOrg (ANR-11-
LABX-0029) for a doctoral fellowship.
13 (a) Y. Liu, X. Shao, P. Zhang, L. Lu and Q. Shen, Org. Lett.,
2015, 17, 2752–2755. (b) J. Zhu, Y. Liu and Q. Shen, Angew.
Chem. Int. Ed., 2016, 55, 9050–9054. (c) Y. Liu, L. Lu and Q.
Shen, Angew. Chem. Int. Ed., 2017, 56, 9930–9934.
14 D. J. Buzard, S. H. Kim, J. Lehmann, S. Han, I. Calderon, A.
Wong, A. Kawasaki, S. Narayanan, R. Bhat, T. Gharbaoui, L.
Lopez, D. Yue, K. Whelan, H. Al-Shamma, D. J. Unett, H.-H.
Shu, S.-F. Tung, S. Chang, C.-F. Chuang, M. Morgan, A.
Sadeque, Z.-L. Chu, J. N. Leonard and R. M. Jones, Bioorg.
Med. Chem. Lett., 2014, 24, 4332–4335
Conflicts of interest
There are no conflicts to declare.
15 D. Limat, G. Guggisberg and M. Schlosser, Liebigs Ann. 1995,
849-853.
16 H.-D. Quan, M. Tamura, J. Murata, R.-X. Gao and A. Sekiya, J.
Fluorine Chem. 2000, 106, 121-125.
17 M. Hasegawa, H. Ishii, Y. Cao and T. Fuchigami, J.
Electrochem. Soc., 2006, 153, D162.
18 X. Huang, W. Liu, J. M. Hooker and J. T. Groves, Angew.
Chem. Int. Ed., 2015, 54, 5241–5245.
19 Note that 3 can be prepared in one step from the
Notes and references
1
2
3
K. C. Nicolaou, Angew. Chem. Int. Ed., 2014, 53, 9128–9140.
D. O'Hagan, Chem. Soc. Rev., 2008, 37, 308–319.
(a) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur,
Chem. Soc. Rev., 2008, 37, 320–330. (b) E. P. Gillis, K. J.
Eastman, M. D. Hill, D. J. Donnelly and N. A. Meanwell, J.
Med. Chem., 2015, 58, 8315–8359. (c) H.-J. Böhm, D. Banner,
S. Bendels, M. Kansy, B. Kuhn, K. Müller, U. Obst-Sander and
commercially available thioanisole, see: T. Umemoto and G.
Tomizawa, Bull. Chem. Soc. Jpn., 1986, 59, 3625-3629.
M. Stahl, ChemBioChem, 2004, 5, 637–643.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
View Article Online
DOI: 10.1039/C8CC00921J
COMMUNICATION
Journal Name
20 Compound 1 is bench-stable and can be stored at -20 °C for
months without traces of decomposition.
21 H.-Y. Xiong, X. Pannecoucke and T. Besset, Chem. Eur. J.,
2016, 22, 16734–16749.
22 For selected examples, see: (a) M. Fujita, M. Suzuki, K. Ogata
and K. Ogura, Tetrahedron Lett. 1991, 32, 1463-1466. (b) T.
Fuchigami, A. Konno, K. Nakagawa and M. Shimojo, J. Org.
Chem. 1994, 59, 5937-5941. (c) A. Konno, K. Nakagawa and
T. Fuchigami, J. Chem. Soc., Chem. Commun., 1991, 1027.
23 Note that, in these cases, the SCFHMe derivatives
decomposed upon purification.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins