Monofluoromethyl-Substituted Sulfonium Ylides: Electrophilic Monofluoromethylating Reagents with Broad Substrate Scopes

Article abstract of DOI:10.1002/anie.201704175

Two electrophilic monofluoromethylating reagents, monofluoromethyl(phenyl)sulfonium bis(carbomethoxy)methylide (3 a) and monofluoromethyl(4-nitrophenyl)sulfonium bis(carbomethoxy)methylide (3 b), and their reactions under mild conditions with a variety of nucleophiles, such as alcohols and malonate derivatives, sulfonic and carboxylic acids, phenols, amides, and N heteroarenes, are described. Mechanistic studies with deuterated reagents [D₂]3 a/[D₂]3 b suggest that these monofluoromethylation reactions proceed through an electrophilic substitution pathway.

Full text of DOI:10.1002/anie.201704175

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Monofluoromethyl-Substituted Sulfonium Ylides: Electrophilic
Monofluoromethylating Reagents with Broad Substrate Scopes
Authors: Yafei Liu, Long Lu, and Qilong Shen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704175
Angew. Chem. 10.1002/ange.201704175
Link to VoR: http://dx.doi.org/10.1002/anie.201704175
http://dx.doi.org/10.1002/ange.201704175

10.1002/anie.201704175
Angewandte Chemie International Edition
COMMUNICATION
Monofluoromethyl-Substituted Sulfonium Ylides: Electrophilic
Monofluoromethylating Reagents with Broad Substrate Scopes
Yafei Liu,[a] Long Lu*[a] and Qilong Shen*[a]
Abstract: Two electrophilic monofluoromethylating reagents S-
monofluoromethyl-S-phenyl-bis(carbomethoxy) methylide sulfonium
monofluoromethylating reagents mentioned above, Prakash and
coworkers reported, in 2008, the first shelf-stable yet highly
reactive electrophilic monofluoromethylating reagent S-
monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium
tetrafluoroborate 1,[12] which allowed to efficiently transfer the
monofluoromethyl group to various substrates such as amines,
phosphines, sulfonic and carboxylic acids and phenols. The
reactions of reagent 1 with alcohols or carbon nucleophiles,
however, were less successful. Only the trifluoromethyl-
substituted alcohols with low basicity and carbon-nucleophiles
with three electron-withdrawing groups were able to react with
reagent 1 to give the corresponding monofluoromethylated
products in high yields. Shortly after, Shibata and coworkers
ylide 3a
and S-monofluoromethyl-S-(4-nitrophenyl)-bis(carbo -
methoxy) methylide sulfonium ylide 3b and their reactions with a
variety of nucleophiles such as alcohols and malonate derivatives,
sulfonic and carboxylic acids, phenols, amides, and nitrogen of
heteroarenes under mild conditions were described. Mechanistic
studies by employing deuterated reagents 3a-D2/3b-D2 suggest that
these monofluoromethylating reactions proceed via an electrophilic
substitution pathway.
Over the past 20 years, fluorine and its magic “fluorine effect”,
which was coined as “a small atom with a big ego”,[1] have been
well recognized in the fields of pharmaceutical and agrochemical
industry.[2] Nowadays, strategic incorporation of a fluorine atom
or a fluoroalkyl group at different stage of drug development has
become a routine practice for new drug discovery.[2a-b,f] Thus, the
high demands in these fields have urged organic chemists to
develop general, efficient reagents and methods for the
preparation of fluorinated compounds.[3] Consequently, in recent
discovered that
a new electrophilic monofluoromethylating
reagent N,N-dimethyl-S-monofluoromethyl-S-phenyl-sulfoximin-
ium hexafluorophosphate 2[13] was able to react with a variety of
1,3-dicarbonyl
compounds,
although
O-selective
monofluoromethyl enol ethers were obtained. Reagent 2 was
also capable of monofluoromethylation of other oxygen-
containing nucleophiles such as sulfonic and carboxylic acids
and phenols. However, again, conventional alcohols did not
react with reagent 2 under the same reaction conditions. Thus,
clearly, new, readily accessible and easy-to-handle electrophilic
monofluoromethylating reagents that are effective with a broad
substrate scope under mild conditions are highly desirable.[14]
years,
elegant
methods
for
trifluoromethylation
or
difluoromethylation have emerged, which now allows for the
effective late-stage installation of a trifluoromethyl (CF3)[4] or a
difluoromethyl (CF2H)[5] on the target molecules. In contrast,
methods that are capable of direct introduction of their
analogous monofluoromethyl group (CH2F) are far less
developed.[6-7]
Direct
electrophilic
monofluoromethylation
through
nucleophilic attack of an appropriate nucleophile with an
electrophilic monofluoromethylating reagent represents one of
potentially applicable strategies for the introduction of the
monofluoromethyl group. Early studies on direct electrophilic
Figure 1. Electrophilic monofluoromethylating reagents.
monofluoromethylation
typically involved the use of
fluoromethanol[8] and its derivative fluoromethyl triflate[9] or
fluoromethyl halides (ClCH2F[10] or ICH2F[11]). However,
preparation of fluoromethanol and fluoromethyl triflate typically
required special equipments or harsh conditions and the scope
for their reactions was rather limited. On the other hand, even
Recently,
difluoromethyl-substituted sulfonium ylides can be served as
electrophilic trifluoromethylating or difluoromethylating
reagents,[15] we thus
questioned ourselves whether
we
discovered
that
trifluoromethyl-
or
monofluoromethyl-substituted sulfonium ylide is an electrophilic
monofluoromethylating reagent. We now disclose herein the
invention of two monofluoromethyl-substituted sulfonium ylides
3a-b[16] that were able to electrophilically monofluoromethylate a
variety of alcohols and malonate derivatives, for the first time. In
addition, the superior reactivity of reagent 3a-b was further
demonstrated by electrophilic monofluoromethylating a variety of
nucleophiles such as sulfonic and carboxylic acids, phenols,
amides, and nitrogen of heteroarenes under mild conditions.
Mechanistic studies by employing deuterated reagents 3a-
D2/3b-D2 suggest that these monofluoromethylating reactions
proceed via an electrophilic substitution pathway.
though chlorofluoromethane reacted with
a
variety of
nucleophiles, it is an ozone depleting gas, and its future use is
thus questionable, while iodofluoromethane was mainly used to
synthesize 18[F]-labeled radiopharmaceuticals.[11]
To overcome the drawbacks of the electrophilic
[a]
Y. Liu, Prof. Dr. L. Lu, Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032
lulong@sioc.ac.cn; shenql@sioc.ac.cn
S-monofluoromethyl-S-phenyl-bis(carbomethoxy) methylide
sulfonium ylide 3a could be easily synthesized as crystalline
white solids in 69% yield on a 7.5 g scale by initial treatment of
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
This article is protected by copyright. All rights reserved.

10.1002/anie.201704175
Angewandte Chemie International Edition
COMMUNICATION
commercially available chloromethyl phenylthioether with CsF in
Scheme 1. Scope for the reaction of reagent 3a with alcohols.a,b
a
mixed PEG-200/CH3CN (1:2) for 2.0 h to generate
fluoromethyl phenylthioether,[17] followed by reaction of the crude
fluoromethyl phenylthioether with dimethyl diazomalonate in the
presence of 0.1 mol% Rh2(esp)2 (esp = α,α,α',α'-tetramethyl-1,3-
benzenedipropionic acid) in dichloromethane after 24 h at 40 oC
(Eq.1).
Likewise,
S-monofluoromethyl-S-(4-nitrophenyl)-
bis(carbomethoxy)methylide sulfonium ylide 3b was synthesized
by reaction of dimethyl diazomalonate with fluoromethyl 4-
nitrophenylthioether in 72% yield. Compounds 3a-b were
characterized by 1H, 13C, and 19F NMR spectroscopies and both
structures were unambiguously confirmed by X-ray analysis of
their single crystals (See supporting information for details). No
detectable decomposition was observed after one-month
storage on shelf at ambient temperature.
With these new reagents in hand, we first explored the
reactivity of reagents 3a-b with aliphatic alcohols. After
extensive survey of the bases and the solvents, it was
discovered that reactions of a variety of alcohols with reagent 3a
in DMF occurred to full conversion after 12 h at room
temperature when NaH was used as the base, as summarized
in Scheme 1. In general, not only primary and secondary
alcohols but also tertiary alcohols reacted to give the
corresponding monofluoromethyl ethers in good to excellent
yields. Allylic or propargyl alcohols reacted smoothly to form the
desired products in high yields (Scheme 1, 4n, 4p-q, 4z, 4aa).
Likewise, alcohols with heteroaryl moiety such as quinoline,
benzothiophene or benzofuran also reacted efficiently to give the
corresponding monofluoromethyl ethers in high yields (Scheme,
1, 4i, 4l-k). Substrates with functional groups such as chloride,
bromide, iodide, cyano or cyclopropyl group were compatible
with the reaction conditions (Scheme 1, 4b-d, 4h, 4l, 4y, 4aa).
[a] Reaction conditions: Alcohol (0.5 mmol), reagent 3a (0.5 mmol), NaH (60%
purity, 2.1 equiv.) in DMF (3.0 mL) at room temperature for 12 h; [b] Isolated
yields; [c] 2.0 equiv of reagent was used; [d] 1.2 equiv of tBuONa was used; [e]
2.0 equiv of alcohol was used.
Having established that compound 3a is a good electrophilic
monofluoromethylating reagent, we next tried to address another
challenging
reaction-monofluoromethylation
of
carbon
nucleophiles. Reaction of diethyl 2-phenylmalonate with reagent
3a was initially chosen as a model reaction to optimize the
reaction conditions. However, the yields for the formation of the
desired monofluoromethyl-substituted product were less than
13% as determined by 19F NMR spectroscopy whatever the
reaction was conducted in the presence of common inorganic
bases such as Li2CO3, Na2CO3, Cs2CO3, K2CO3, K3PO4, KOH,
tBuOK or organic bases such as DMAP, DBU, DABCO in
different solvents such as toluene, CH2Cl2, THF, diglyme, DMF,
CH3CN, acetone or NMP. Interestingly, the yield for the
formation of the desired diethyl 2-phenyl-2-monofluoromethyl
malonate was significantly improved to 87% yield when reagent
3b was allowed to react with diethyl 2-phenylmalonate in NMP
for 4 h at room temperature in the presence of 2.0 equivalents of
Cs2CO3 (see Supporting Information for details). Under the
optimized conditions, we then explored the applicability of these
conditions to other malonate derivatives. As summarized in
Mechanistically, monofluoromethylation of alcohols with
reagent 3a may process via a monofluorocarbene pathway or a
pathway involving direct nucleophilic attack of the alkoxide to the
electrophilic monofluoromethyl-substituted sulfonium ylide 3a.
To distinguish these two pathways, we synthesized a deuterated
monofluoromethyl-substituted sulfonium ylide 3a-D2 and
subjected it to the optimized reaction conditions. Experimentally,
partial loss of deuterium in the products was observed (Eq. 2).
Further studies indicated that the partial loss of deuterium is due
to H/D exchange in compound 3a-D2 under the basic conditions
(see supporting information for details). Thus, these results
suggest that the monofluoromethylether formation reaction
Scheme 2,
a
variety of malonate derivatives were
monofluoromethylated in moderate to high yields. In general,
both 2-aryl or 2-alkyl-substituted malonates reacted with reagent
3b to generate the corresponding monofluoromethylated
malonates in high yields. For example, reaction of diethyl 2-(4-
proceeds highly likely through
a nucleophilic substitution
pathway instead of a monofluorocarbene pathway.
This article is protected by copyright. All rights reserved.

10.1002/anie.201704175
Angewandte Chemie International Edition
COMMUNICATION
Scheme 2. Scope for the reaction of reagent 3b with diethyl 2-
Scheme 3. Scope for the reaction of reagent 3a/3b with other
nucleophiles.a,b
substituted malonates.a,b
[a] Reaction conditions: diethyl 2-substituted malonate (0.5 mmol), reagent 3b
(0.6 mmol), Cs2CO3 (1.0 mmol) in NMP (3.0 mL) at room temperature for 4 h;
[b] Isolated yields.
methylphenyl)malonate with reagent 3b generated compound
5b in 97% yield, while reaction of diethyl 2-allylmalonate with
reagent 3b occurred to full conversion to give 5m in 87% yield
(Scheme 2, 5b and 5m). Electron-donating or electron
withdrawing substituted groups on the arene moiety of diethyl 2-
arylmalonates have negligible effect on the yields of the
reactions (Scheme 2, 5a-i). Due to the mild conditions, common
functional groups such as chloro, fluoro, cyano, nitro group or
ester, enolizable ketone were compatible. Again, no H/D
exchange was observed for the reaction of deuterated reagent
3b-D2 with diethyl 2-phenylmalonate under the optimized
conditions, which indicates a nucleophilic substitution pathway
(Eq. 3).
Encouraged by the excellent electrophilicity of reagents 3a/3b,
we next studied their reactions with a variety of oxygen-or
nitrogen-nucleophiles. As summarized in Scheme 3, a variety of
phenols with electron-donating or withdrawing groups reacted
with reagent 3a in good to excellent yields (Scheme 3, 6a-n).
Likewise, both aryl- or alkyl-substituted carboxylic acids also
reacted with reagent 3a to give the corresponding
monofluoromethyl carboxylic esters in high yields when the
reactions were conducted in NMP in the presence of 1.2
equivalents of DBU (Scheme 3, 7a-e, 7i-m). Benzoic acids with
strong electron-withdrawing groups such as cyano, ketone or
nitro group reacted with reagent 3a much slower and in lower
yields than other carboxylic acids. In these cases, switching the
reagent from 3a to 3b greatly improved the conversion and the
[a] Reaction conditions as indicated in the table; [b] Isolated yields; [c]
Reagent 3b was use and the reaction was conducted at room temperature for
2 h.
yields of the corresponding esters (Scheme 3, 7f-h), which again
suggests the higher electrophilicity of reagent 3b than that of 3a.
Interestingly, reactions of sulfonic acids with reagent 3a
occurred smoothly in full conversion without the need of any
additive or base. Mixing the sulfonic acid with reagent 3a in
This article is protected by copyright. All rights reserved.

10.1002/anie.201704175
Angewandte Chemie International Edition
COMMUNICATION
acetone at 40 oC for 5 min generated the corresponding
monofluoromethyl sulfonate in good yields (Scheme 3, 8a-h).
Finally, nitrogen nucleophiles including amides or heteroarenes
such as indazole, pyrazole, imidazole, pyrrolo[2,3-d]pyrimidine
or benzotrizole can also be efficiently monofluoromethylated in
good yields (Scheme 3, 9a-i). Again, no H/D exchange was
observed when 3a-D2 was used in these reactions, which
indicates the nucleophilic substitution pathway (See Supporting
Information for details).
methods for difluoromethylation, see: c) Y. Fujiwara, J. A. Dixon, R. A.
Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins, D. G. Blackmond,
P. S. Baran, J. Am. Chem. Soc. 2012, 134, 1494; d) P. S. Fier, J. F.
Hartiwg, J. Am. Chem. Soc. 2012, 134, 5524; e) G. K. S. Prakash, S. K.
Ganesh, J.-P. Jones, A. l. Kulkarni, K. Masood, J. K. Swabeck, G. A.
Olah, Angew. Chem. Int. Ed. 2012, 51, 12090; f) J.-B. Xia, C. Zhu, C.
Chen, J. Am. Chem. Soc. 2013, 135, 17494; g) P. Xu, S. Guo, L.-Y.
Wang, P.-P. Tang, Angew. Chem. Int. Ed. 2014, 53, 5955; h) X.-L.
Jiang, Z.-H. Chen, X.-H. Xu, F.-L. Qing, Org. Chem. Front. 2014, 1, 774;
i) Y. Gu, X.-B. Leng, Q. Shen, Nat. Commun. 2014, 5, 6405, DOI:
10.1038/ncomms6405; j) X.-Y. Deng, J.-H. Lin, J.-C. Xiao, Org. Lett.
2016, 18, 4384; k) K. Aikawa, H. Serizawa, K. Mikami, Org. Lett. 2016,
18, 3690; l) L. Xu, Vicic, D. A. J. Am. Chem. Soc. 2016, 138, 2536; m)
Z. Feng, Q.-Q. Min, X.-P. Fu, L. An, X.-G. Zhang, Nat. Chem. 2017, doi:
10.1038/nchem.2746.
In summary, we have successfully developed two electrophilic
monofluoromethylating reagents S-monofluoromethyl-S-phenyl-
bis(carbomethoxy) methylide sulfonium ylide 3a
and S-
monofluoromethyl-S-(4-nitrophenyl)-bis(carbomethoxy)methylide
sulfonium ylide 3b that can be easily synthesized from easily
available starting materials. Both reagents showed much higher
electrophilicity than the reagents previously reported. A variety
of nucleophiles such as alcohols and malonate derivatives,
sulfonic and carboxylic acids, phenols, amides, and nitrogen of
heteroarenes reacted with either reagent 3a or 3b to give the
corresponding monofluoromethylated products in high yields
under mild conditions. Mechanistic studies by employing
deuterated reagents 3a-D2/3b-D2 suggest that these
monofluoromethylating reactions proceed via an electrophilic
substitution pathway. Further expand the scope of these
reagents are undergoing currently in our laboratory.
[6]
[7]
For transition metal-catalyzed monofluoromethylation, see: a) J.-Y. Hu,
B. Gao, L.-C. Li, C.-F. Nie, J.-B. Hu, Org. Lett. 2015, 17, 3086; b) Y.-M.
Su, G.-S. Feng, Z.-Y. Wang, Q. Lan, X.-S. Wang, Angew. Chem., Int.
Ed. 2015, 54, 6003; c) L. An, Y.-L. Xiao, Q.-Q. Min, X.-G. Zhang,
Angew. Chem. Int. Ed. 2015, 54,9079.
A few nucleophilic monofluoromethylation methods using synthetic
equivalent of fluoromethide species have also been reported. For
selected examples, see: a) Y. Li, J. Hu, Angew. Chem. Int. Ed. 2005,
44, 5882; b) T. Fukuzumi, N. Shibata, M. Sugiura, H. Yasui, S.
Nakamura, T. Toru, Angew. Chem. Int. Ed. 2006, 45, 4973; c) G. K. S.
Prakash, S. Chacko, S. Alconcel, T. Stewart, T. Mathew, G. A. Olah,
Angew. Chem. Int. Ed. 2007, 46, 4933.
[8]
[9]
G. A. Olah, A. Pavlath, Acta Chim. Acad. Sci. Hung. 1953, 3 (203), 425.
R. Iwataa, C. Pascalic, A. Bognic, S. Furumotob, K. Terasakid, K. Yanai,
Appl. Radiat. Isot. 2002, 57, 347.
[10] a) I. I. Gerusa, A. A. Kolomeitsevb, M. I. Kolychevaa, V. P. Kukhar, J.
Fluorine Chem. 2000, 105, 31; b) W. Zhang, L.-G. Zhu, J.-B. Hu,
Tetrahedron 2007, 63, 10569.
Acknowledgements
[11] a) L. Zheng, M. S. Berridge, Appl. Radiat. Isot. 2000, 52, 55; b) M.-R.
Zhanga, M. Ogawaa, K. Furutsukaa, Y. Yoshidaa, K. Suzuki. J.
Fluorine Chem. 2004, 125, 1879.
The authors gratefully acknowledge the financial support
from National Natural Science Foundation of China
(21625206, 21632009, 21372247, 21572258, 21572259,
21421002) and the Strategic Priority Research Program of the
[12] G. K. S. Prakash, I. Ledneczki, S. Chacko, G. A. Olah, Org. Lett. 2008,
10, 557.
Chinese Academy of Sciences (XDB20000000)
.
[13] Y. Nomura, E. Tokunaga, N. Shibata, Angew. Chem. Int. Ed. 2011, 50,
1885.
[14] Hu and co-workers reported the monofluoromethylation of a variety of
nucleophiles such as phenols, thiols, nitrogen of heteroarenes,
phosphines and carboxylic acids with PhSO(NTs)CH2F. The reactions
were proposed to occur via a radical mechanism involving an SET
process: X. Shen, M. Zhou, C.-F. Ni, W. Zhang, J.-B. Hu, Chem. Sci.
2014, 5, 117.
Keywords: fluorine • monofluoromethyl • electrophilic • ylide •
sulfonium ylide
[1]
[2]
a) H. Amii, K. Uneyama, Chem. Rev. 2009, 109, 2119; b) C.-F. Ni, J.-B.
Hu, Synlett 2011, 6, 770.
a) D. T. Wong, K. W. Perry, F. P. Bymaster, Nat. Rev. Drug Discovery
2005, 4, 764; b) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305; c) W.
K. Hagmann, J. Med. Chem. 2008, 51, 4359; d) S. Purser, P. R. Moore,
S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; e) N. A.
Meanwell, J. Med. Chem. 2011, 54, 2529; f) J. Wang, M. Sꢀnchez-
Rosellꢁ, J. Aceꢂa, C. Pozo, A. E. Sorochinsky, S. Fustero, V. A.
Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432.
[15] a) Y.-F. Liu, X.-X. Shao, L. Lu, Q. Shen, Org. Lett. 2015, 17, 2752; b)
J.-S. Zhu, Y.-F. Liu, Q. Shen, Angew. Chem. Int. Ed. 2016, 55, 9050.
[16] For reviews on preparation and applications of sulphur ylides: a) B. M.
Trost, L. S. Melvin, Sulfur Ylide: Emerging Synthetic Intermediates,
Academic Press, New York, 1975; b) V. K. Aggrawal, C. L. Winn, Acc.
Chem. Res. 2004, 37, 611; c) Y. Tang, S. Ye, X-L. Sun, Synlett 2005,
18, 2720; d) A. C. B. Burtoloso, R. M. P. Dias, I. A. Leonarczyk, Eur. J.
Org. Chem. 2013, 5005.
[3]
[4]
Selected reviews for fluoroalkylations: a) T. Liang, C. N. Neumann, T.
Ritter, Angew. Chem. Int. Ed. 2013, 52, 8214; b) X.-H. Xu, K. Matsuzaki,
N. Shibata, Chem. Rev. 2015, 115, 731; c) C.-F. Ni, M.-Y. Hu, J.-B. Hu,
Chem. Rev. 2015, 115, 765; d) X. Yang, T. Wu, R. J. Phipps, F. D.
Toste, Chem. Rev. 2015, 115, 826; e) C. Alonso, E. M. de Marigorta, G.
Rubiales, F. Palacios, Chem. Rev. 2015, 115, 1847.
[17] D. P. Matthews, R. A. Persichetti, J. R. McCarthy, Org. Prep. Proc. Int.
1994, 26, 605.
[18] CCDC 1544317/1544316 contains the supplementary crystallographic
data for the compound 3a/b reported in this communication. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif or pm
application to CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK [fax:
+44-1223/336-033; email: deposit@ccdc.cam.ac.uk].
For selected recent reviews on trifluoromethylation methods, see: a) T.
Umemoto, Chem. Rev. 1996, 96, 1757; b) J.-A. Ma, D. Cahard, Chem.
Rev. 2008, 108, PR1; c) S. Roy, B. T. Gregg, G.W. Gribble, V.-D. Le, S.
Roy, Tetrahedron 2011, 67, 2161; d) O. A. Tomashenko, V. V. Grushin,
Chem. Rev. 2011, 111, 4475; e) T. Furuya, A. S. Kamlet, T. Ritter,
Nature 2011, 473, 470; f) T. Besset, C. Schneider, D. Cahard, Angew.
Chem. Int. Ed. 2012, 51, 5048; g) F.-L. Qing, Chin. J. Org. Chem. 2012,
32, 815; h) T. Liu, Q. Shen, Eur. J. Org. Chem. 2012, 6679; h) J.
Charpentier, N. Früh, A. Togni Chem. Rev. 2015, 105, 650.
[5]
For recent reviews on difluoromethylation methods, see: a) J.-B. Hu, W.
Zhang, F. Wang, Chem. Commun. 2009, 7465; b) A. Koperniku, H.-Q.
Liu, P. B. Hurley, Eur. J. Org. Chem. 2016, 5, 871; For selected
This article is protected by copyright. All rights reserved.

10.1002/anie.201704175
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Two sulfonium ylide-based
electrophilic
Yafei Liu, Long Lu* and Qilong
Shen*
monofluoromethyl-ating
reagents 3a and 3b were
invented. These reagents
Page No. – Page No.
Monofluoromethyl-
Substituted Sulfonium Ylides:
Electrophilic
Monofluoromethylating
Reagents with Broad
Substrate Scopes
were
capable
of
a
monofluoromethylating
variety of nucleophiles such
as alcohols and malonate
derivatives,
sulfonic
and
carboxylic acids, phenols,
amides, and nitrogen of
heteroarenes under mild
conditions.
This article is protected by copyright. All rights reserved.