An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18F-Labeled α-SCF3 Carbonyl Compounds

Article abstract of DOI:10.1002/anie.201611761

Trifluoromethylthiolation by sulfuration of difluorocarbene with elemental sulfur is described for the first time, which overrides long-standing trifluoromethyl anion-based theory. Mechanistic elucidation reveals an unprecedented chemical process for the

Full text of DOI:10.1002/anie.201611761

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201611761
German Edition: DOI: 10.1002/ange.201611761
Organofluorine Chemistry
An Unconventional Mechanistic Insight into SCF3 Formation from
18
Difluorocarbene: Preparation of F-Labeled a-SCF3 Carbonyl
Compounds
Jian Zheng+, Ran Cheng+, Jin-Hong Lin, Dong-Hai Yu, Longle Ma, Lina Jia, Lan Zhang,
Lu Wang, Ji-Chang Xiao,* and Steven H. Liang*
Abstract: Trifluoromethylthiolation by sulfuration of di-
fluorocarbene with elemental sulfur is described for the first
time, which overrides long-standing trifluoromethyl anion-
based theory. Mechanistic elucidation reveals an unprece-
dented chemical process for the formation of thiocarbonyl
fluoride and also enables transition-metal-mediated tri-
fluoromethylthiolation and [18F]trifluoromethylthiolation of
a-bromo carbonyl compounds with broad substrate scope and
compatibility.
demonstrated the novelty and utility of difluorocarbene in
[18F]trifluoromethylthiolation, the characteristics of these
radiofluorination reactions—including the underlying mech-
anism and interaction with transition metals—remain elusive
and present a major roadblock to further advancement of
these reactions in radiolabeling of SCF3-containing pharma-
ceuticals such as Cefazaflur.
Herein, we report an unprecedented mechanistic obser-
vation of trifluoromethylthio formation from difluoro-
carbene, sulfur, and fluoride, and the subsequent interactions
between the generated SCF3 anions and transition metals.
Supported by experimental and theoretical studies, this work
overrides our putative and long-standing interpretation of
trifluoromethylthio group formation from difluorocarbene
and has lead us to discover a new class of trifluoromethyl-
thiolation for a-bromo carbonyl compounds in the presence
of a copper complex. As a proof of concept, we demonstrate
a general and practical copper-mediated radiosynthesis of
18F-labeled SCF3 carbonyl compounds with broad substrate
scope and functional group compatibility, which is otherwise
O
ver the past several decades, there have been significant
advances in the chemistry of difluorocarbene, which is
a valuable and versatile intermediate for organic synthesis
and particularly for fluorine incorporation.[1] As a singlet
carbene,[2] and the most stable dihalocarbene,[1d] difluoro-
carbene shows moderate electrophilicity because of a strong
inductive effect and an electron-donating resonance effect
induced by fluorine. Understanding of difluorocarbene
reactivity has led to development of a variety of novel organic
transformations,[1] including difluoromethylation,[3] tri-
fluoromethylation,[4] and [2+1] cycloaddition.[3a] We recently
hardly achievable by traditional methods.
difluorocarbene-derived one-step [18F]-
Difluoromethylene
phosphobetaine
Ph3P+CF2CO2
ꢀ
discovered
a
trifluoromethylthiolation method,[5] which is one of the first
examples[5,6] of its type despite significant progress with the
non-radioactive version of the transformation. While we have
(PDFA), first developed by us[4i,j,5,7] and utilized by other
groups,[4k,8] was found to be an efficient difluorocarbene agent
for one-step trifluoromethylthiolation.[5] On the basis of
several known reports showing that trifluoromethyl anion is
formed from difluorocarbene[9] and reacts with elemental
sulfur to give trifluoromethylthio anion,[10] we originally
postulated that difluorocarbene generated in situ from
PDFA might be readily trapped by fluoride to produce
trifluoromethyl anion A, which reacts with elemental sulfur to
give trifluoromethylthio anion B and eventually yields SCF3
products (Scheme 1).[5]
[*] Dr. J. Zheng,[+] Dr. J.-H. Lin, D.-H. Yu, Prof. Dr. J.-C. Xiao
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 (China)
E-mail: jchxiao@sioc.ac.cn
R. Cheng[+]
However, further studies on the process indicated an
unconventional mechanistic pathway for trifluoromethyl-
thiolation. Specifically, difluorocarbene may undergo
sulfuration with elemental sulfur to afford thiocarbonyl
School of Pharmaceutical Science and Technology, Tianjin University
92 Weijin Road, Nankai District, Tianjin 300072 (China)
R. Cheng,[+] Dr. L. Ma, Dr. L. Wang, Prof. Dr. S. H. Liang
Division of Nuclear Medicine and Molecular Imaging and Gordon
Center for Medical Imaging
Massachusetts General Hospital & Department of Radiology
Harvard Medical School
55 Fruit St., White 427, Boston, MA (USA)
E-mail: liang.steven@mgh.harvard.edu
=
fluoride (S CF2) instead of being trapped by fluoride to
ꢀ
give CF3 anion A. If anion A were generated during the
reactions, the presence of water in the reaction system would
lead to a rapid and irreversible formation of trifluoromethane
Dr. L. Jia, Dr. L. Zhang
Shanghai Institute of Applied Physics, Chinese Academy of Sciences
2019 Jialuo Road, Shanghai 201800 (China)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201611761.
Scheme 1. Originally proposed mechanism for trifluoromethyl-
thiolation.
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by protonation of CF3ꢀ anion A.[11] However, despite the fact
that a decreased yield of SCF3 products was noted, addition of
water did not change the amount of trifluoromethane
generated during the reaction (Scheme 2). These observa-
tions questioned our initially proposed mechanism and
prompted us to conduct further investigations on the mode
tetrafluoroethylene) and/or harsh reaction conditions (pyrol-
ysis at 5008C for example).[16] Safety precaution must also be
taken during storage and transfer of thiocarbonyl fluoride
obtained by previous approaches[16] because of the chemicalꢀs
toxicity and low boiling point (ꢀ548C).[16b] In sharp contrast,
synthesis of thiocarbonyl fluoride by our method is conven-
ient and attractive because the reactive material is generated
in situ and is rapidly converted in one pot under mild
conditions.
DFT calculations at the M06/6-311 + G* level also
provided insight into the mechanism for sulfuration of
difluorocarbene with elemental sulfur (Figure 1). A weak
Scheme 2. The effect of water on trifluoromethylthiolation. [a] Yields
were determined by 19F NMR spectroscopy; R=4-PhC6H4CH2.
of formation of the trifluoromethylthio anion B from
difluorocarbene—a process which was believed to occur by
generation of a trifluoromethyl anion.[12]
We speculated that difluorocarbene could react with
sulfur directly, on the basis of heterocycle carbenes[13] and
metal carbenes[14] that can undergo sulfuration with elemental
=
sulfur to form a C S bond. We found that elemental sulfur
Figure 1. Relative free energies for sulfuration of difluorocarbene
calculated at the M06/6-311+G* level.
alone can significantly speed up the dissociation of PDFA,
suggesting difluorocarbene generated from PDFA may ini-
tially react with elemental sulfur instead of fluoride ion.
Indeed, the reactive intermediate thiocarbonyl fluoride
interaction exists between these two species, meaning that
complex In1 may be formed upon generation of difluoro-
carbene. A low activation barrier energy (34.21 kJmolꢀ1) is
=
(S CF2) was observed by heating a mixture of PDFA and
elemental sulfur, and detected by GC-MS (electron impact)
with ethyl acetate (EtOAc) or MeNO2 as the solvent
(Scheme 3, Eq. (1); Supporting Information, Section 2).
Furthermore, the addition of sodium phenoxide (PhONa)
into the PDFA/S8 system produced isolable O,O-diphenyl
carbonothioate (Scheme 3, compound I) via intermediates
C/D, confirming the formation of thiocarbonyl fluoride during
the process (Scheme 3, Eq. (2)).
Notably, although difluorocarbene can be trapped by
elemental substances (for example I2 and Cl2)[15] sulfuration of
difluorocarbene with elemental sulfur has never been realized
in the past. All reported preparative methods for thiocarbonyl
fluoride, an important fluorinated material,[15,16] necessitate
the use of hazardous agents (such as thiophosgene or
ꢀ
required to weaken one of the S S(CF2) bonds and for :CF2 to
approach the sulfur atom further (TS1). The redistribution of
ꢀ
electron density in TS1 leads to the formation of a S CF2
bond and a charge separation with a partially positive charge
and a partially negative charge on the sulfur atoms of the
(CF2)S and (CF2S)S groups, respectively (In2). A bridged
structure (TS2) is the transition state for the conversion of
intermediates In2 into In3. Intermediate In3 can be consid-
ered as a complex between S7 and thiocarbonyl fluoride.
Dissociation of In3 affords thiocarbonyl fluoride and S7,
which may undergo iterative reactions with difluorocarbene
to provide additional thiocarbonyl fluoride. Successful iden-
tification of transition state TS2 allowed us to calculate the
overall activation energy (In1!TS2) as 66.09 kJmolꢀ1, which
is in agreement with the experimental observation that
elemental sulfur can apparently accelerate the dissociation
of PDFA. The formation of thiocarbonyl fluoride is thermo-
dynamically favored, as revealed by a relatively low free
energy (ꢀ207.13 kJmolꢀ1).
Based on the mechanistic investigation, it is evident that
thiocarbonyl fluoride is a key intermediate for the generation
of trifluoromethylthio anion. A revised mechanism is shown
in Scheme 4. Decarboxylation of PDFA and the subsequent
ꢀ
dissociation of the P CF2 bond produce difluorocarbene and
triphenylphosphine.[7b] While triphenylphosphine is con-
verted by elemental sulfur into triphenylphosphine sulfide,
difluorocarbene readily undergoes sulfuration to give thio-
carbonyl fluoride E. As a highly electrophilic intermediate,
Scheme 3. The formation of thiocarbonyl fluoride. [a] Yield of isolated
product.
2
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Table 1: The substrate scope for trifluoromethylthiolation of a-bromo-
ketones.
Scheme 4. The revised mechanism for the formation of trifluoro-
methylthio anion.
thiocarbonyl fluoride E is readily trapped by fluoride to
generate trifluoromethylthio anion B.
Successful elucidation of the mechanism by which tri-
fluoromethylthio anion is formed allowed us to extend the
method to trifluoromethylthiolation of a-bromoketone com-
pounds. However, prior reaction conditions[5] for trifluoro-
methylthiolation of aliphatic electrophiles were not efficient
for the conversion of a-bromoketones, with < 1% yield
attained in dimethylformamide (DMF) and 2% in nitro-
methane (MeNO2). To our delight, we found the addition of
a copper source substantially increased the yields by 15–20-
fold (Supporting Information, Table S1). A quick survey of
reaction parameters revealed that efficient transformation of
our test substrate, 2-bromoacetophenone with PDFA/S8/CsF,
was achieved in 74% yield by the addition of CuBr2. We have
proposed that copper-promoted trifluoromethylthiolation
ꢀ
reactions occur by ligand exchange of SCF3 with a copper
source to generate a [CuSCF3] complex,[17,18] followed by
addition and reductive elimination to furnish the final SCF3
products. Indeed, we have observed the [CuSCF3] complex by
19F NMR spectroscopy in the trifluoromethylthiolation reac-
tion systems (Supporting Information, Section 5), further
supporting this proposed reaction pathway.
Under optimized reaction conditions (Supporting Infor-
mation, Section 3), we investigated substrate scope for
trifluoromethylthiolation of a-bromoketones and esters by
sulfuration of difluorocarbene (Table 1). The examination of
electronic effects on substituents (2a–2k) in aryl ketones
suggested that electron-donating (2a–2h) and moderately
electron-withdrawing (2i–2j) substituents were favorable for
this type of conversion, while a strong electron-withdrawing
substituent suppressed the desired reaction (2k). The trans-
formation is also compatible with heterocycles (2l and 2m),
sterically hindered substrate (2n), alkyl ketone (2o), and
a-bromo esters (2p–2s).
Yields of isolated products. [a] The yield was determined by 19F NMR
spectroscopy.
[18F]fluoride) was used to replace CsF to react with PDFA and
S8, realizing [18F]trifluoromethylthiolation of 1a with 36%
radiochemical conversion (RCC) within 2 min (Table 2,
entry 1). Consistent with non-radioactive trifluoromethylth-
iolation of a-bromo carbonyl compounds, addition of copper
catalyst could significantly increase RCC to 64% (Table 2,
entry 2). Solvent screening revealed that acetonitrile (MeCN;
72%) provided superior results compared to dimethyl
sulfoxide (DMSO; 32%) and DMF (23%; Supporting
Information, Table S2). Finally, we found that optimal results
were achieved when the reaction was carried out using PDFA
(30 mmol) and S8 (90 mmol) at 408C, which produced
18F-labeled 3a in 72% RCC (Table 2, entry 5). Additionally,
It is worth mentioning that addition of water into the
copper-promoted trifluoromethylthiolation reaction system
did not lead to formation of trifluoromethane (Supporting
Information). Furthermore, in all these copper-promoted
trifluoromethylthiolation reactions, no trifluoromethylated
product was observed. Since the substrates are able to
undergo copper-promoted trifluoromethylation with tri-
fluoromethyl anion,[9,17] these results (no trifluoromethane
and no trifluoromethylation product) further confirmed that
trifluoromethyl anion was not the intermediate involved in
generation of trifluoromethylthio anion.
Using a-bromoketone (1a) as a model compound,
[18F]trifluoromethylthiolation of a-bromoketones was per-
formed and optimized under a comprehensive array of
labeling conditions (Supporting Information, Section 6.2).
Briefly, azeotropically dried [18F]TEAF (generated in situ
from tetraethylammonium bicarbonate (TEAB) and aqueous
Table 2: Radiofluorination conditions.[a]
Entry
PDFA [mmol]
S8 [mmol]
Copper
T [8C]
Yield [%][b]
1
2
3
4
20
20
20
20
30
30
60
60
60
60
90
90
none
CuI
CuI
CuI
CuI
CuI
70
70
40
RT
40
40
36ꢁ6
64ꢁ6
65ꢁ6
3ꢁ2
5
72ꢁ6
8ꢁ4
6[c]
[a] Reaction conditions: precursor (10 mmol), PDFA, S8, and CuI
(10 mmol) in MeCN (400 mL). [b] Radiochemical conversion yields and
product identity were determined by radioTLC and radioHPLC, respec-
tively; n=3. [c] Water (1%) was added to the reaction.
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[18F]trifluoromethylthiolation showed little tolerance of aque-
ous conditions with only 8% RCC (Table 2, entry 6).
difluorocarbene with elemental sulfur. This process is the
most convenient synthetic approach to produce thiocarbonyl
fluoride, which is an important fluorinated material previ-
ously prepared by hazardous agents and/or harsh conditions.
This sulfuration method has been developed into a versatile
synthetic tool to realize transition-metal-based trifluoro-
methylthiolation and [18F]trifluoromethylthiolation of
a-bromo carbonyl compounds. We envisage that this opera-
tionally simple and highly efficient method for generation and
transformation of thiocarbonyl fluoride will advance multi-
fluorination research.
Reactions with a-bromoketones bearing a phenyl ring
with either electron-withdrawing or -donating groups
occurred smoothly to afford the corresponding products
(Table 3, 3a–3j) >) in 56–73% RCCs. The results of
[18F]trifluoromethylthiolation of benzothiophene 3l (63%)
and pyrazole a-bromoketone 3m (64%) demonstrated the
compatibility of this method with heterocyclic substituents.
The scope of this method was also extended to aliphatic
a-bromoketone 3o (64%), a-bromo esters 3p (44%), 3q
(30%), 3r (20%), and allylic a-bromo ester 3s (53%). As
a proof of concept, [18F]trifluoromethylthiolation products
(3a, 3 f, 3l, 3m, 3p, and 3s) were isolated and purified in
30–42% radiochemical yields by semi-preparative HPLC.
The specific activity of [18F]3a was determined to be
2.02 mCimmolꢀ1 at the end of synthesis (Supporting Informa-
tion, Section 6.4), which is comparable with reported aryl
[18F]-CF3[4g] and aryl-/alkyl-[18F]SCF3 labeling.[5,6]
Acknowledgements
We would like to thank Dr. Shubin Liu (University of North
Carolina) for helpful discussion. This work was financially
supported by the National Basic Research Program of China
(2015CB931900, 2012CBA01200), the National Natural Sci-
ence Foundation (21421002, 21472222, 21502214, 21672242),
the Chinese Academy of Sciences (XDA02020105,
XDA02020106), and the Science and Technology Commission
of Shanghai Municipality (15DZ1200102, 14ZR1448800).
R.C. is supported by China Scholarship Council
(201506250036). S.H.L. is a recipient of an NIH career
development award (DA038000).
In summary, our putative understanding of SCF3 forma-
tion from difluorocarbene, sulfur, and fluoride ion has been
challenged and revised to an unprecedented pathway.
Supported by experimental and theoretical studies, we have
discovered a new mechanism that operates by sulfuration of
Table 3: [18F]Trifluoromethylthiolation of a-bromo carbonyl precursors.[a]
Conflict of interest
The authors declare that there is no conflict of interest
regarding the publication of this paper.
Keywords: 18F-labeling · difluorocarbene · fluorine · sulfuration ·
trifluoromethylthiolation
[1] For reviews, see: a) D. L. S. Brahms, W. P. Dailey, Chem. Rev.
1996, 96, 1585 – 1632; b) D. Burton, Z.-Y. Yang, W. Qiu, Chem.
Rev. 1996, 96, 1641 – 1716; c) W. R. Dolbier, M. A. Battiste,
Chem. Rev. 2003, 103, 1071 – 1098; d) C. Ni, J. Hu, Synthesis
2014, 46, 842 – 863; for recent examples, see: e) K. Fuchibe, T.
Aono, J. Hu, J. Ichikawa, Org. Lett. 2016, 18, 4502 – 4505; f) Y.
Zafrani, D. Amir, L. Yehezkel, M. Madmon, S. Saphier, N.
Karton-Lifshin, E. Gershonov, J. Org. Chem. 2016, 81, 9180 –
9187; g) P. Rulliꢁre, P. Cyr, A. B. Charette, Org. Lett. 2016, 18,
1988 – 1991; h) H. Baars, J. Engel, L. Mertens, D. Meister, C.
Bolm, Adv. Synth. Catal. 2016, 358, 2293 – 2299.
[2] A. M. Trozzolo, E. Wasserman, W. A. Yager, J. Am. Chem. Soc.
1965, 87, 129 – 130.
[3] a) J. Hu, C. Ni, Synthesis 2014, 46, 842 – 863; b) J. Hu, W. Zhang,
F. Wang, Chem. Commun. 2009, 7465 – 7478; c) X.-Y. Deng, J.-H.
Lin, J.-C. Xiao, Org. Lett. 2016, 18, 4384 – 4387.
[4] a) D. J. Burton, D. M. Wiemers, J. Am. Chem. Soc. 1985, 107,
5014 – 5015; b) D. M. Wiemers, D. J. Burton, J. Am. Chem. Soc.
1986, 108, 832 – 834; c) J. H. Clark, M. A. McClinton, R. J. Blade,
J. Chem. Soc. Chem. Commun. 1988, 638 – 639; d) Q.-Y. Chen,
S.-W. Wu, J. Chem. Soc. Chem. Commun. 1989, 705 – 706; e) Q.-
Y. Chen, J.-X. Duan, Tetrahedron Lett. 1993, 34, 4241 – 4244;
f) J.-X. Duan, D.-B. Su, Q.-Y. Chen, J. Fluorine Chem. 1993, 61,
[a] All radiochemical reactions were carried out at least three times.
Radiochemical conversions and product identity were determined and
confirmed by radioTLC and radioHPLC, respectively. [b] Reaction carried
out at 808C. [c] Yield of isolated products determined by HPLC.
4
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
279 – 284; g) M. Huiban, M. Tredwell, S. Mizuta, Z. Wan, X.
[11] G. K. S. Prakash, F. Wang, Z. Zhang, R. Haiges, M. Rahm, K. O.
Zhang, T. L. Collier, V. Gouverneur, J. Passchier, Nat. Chem.
2013, 5, 941 – 944; h) B. R. Ambler, R. A. Altman, Org. Lett.
2013, 15, 5578 – 5581; i) X. Deng, J. Lin, J. Zheng, J. Xiao, Chin. J.
Chem. 2014, 32, 689 – 693; j) J. Zheng, J. H. Lin, X. Y. Deng, J. C.
Xiao, Org. Lett. 2015, 17, 532 – 535; k) Y. Liu, K. Zhang, Y.
Huang, S. Pan, X.-Q. Liu, Y. Yang, Y. Jiang, X.-H. Xu, Chem.
Commun. 2016, 52, 5969 – 5972.
Christe, T. Mathew, G. A. Olah, Angew. Chem. Int. Ed. 2014, 53,
11575 – 11578; Angew. Chem. 2014, 126, 11759 – 11762.
[12] Q.-Y. Chen, J.-X. Duan, J. Chem. Soc. Chem. Commun. 1993,
918 – 919.
[13] a) H. Finch, L. M. Harwood, G. M. Robertson, R. C. Sewell,
Tetrahedron Lett. 1989, 30, 2585 – 2588; b) J. Huang, H.-J.
Schanz, E. D. Stevens, S. P. Nolan, K. B. Capps, A. Bauer, C. D.
Hoff, Inorg. Chem. 2000, 39, 1042 – 1045.
[14] a) J. U. Kçhler, J. Lewis, P. R. Raithby, Angew. Chem. Int. Ed.
Engl. 1996, 35, 993 – 995; Angew. Chem. 1996, 108, 1071 – 1073;
b) Z. Y. Zheng, J. Z. Chen, N. Luo, Z. K. Yu, X. W. Han,
Organometallics 2006, 25, 5301 – 5310.
[5] J. Zheng, L. Wang, J. H. Lin, J. C. Xiao, S. H. Liang, Angew.
Chem. Int. Ed. 2015, 54, 13236 – 13240; Angew. Chem. 2015, 127,
13434 – 13438.
[6] T. Khotavivattana, S. Verhoog, M. Tredwell, L. Pfeifer, S.
Calderwood, K. Wheelhouse, T. L. Collier, V. Gouverneur,
Angew. Chem. Int. Ed. 2015, 54, 9991 – 9995; Angew. Chem.
2015, 127, 10129 – 10133.
[15] W. Mahler, Inorg. Chem. 1963, 2, 230.
[16] a) W. J. Middleton, E. G. Howard, W. H. Sharkey, J. Am. Chem.
Soc. 1961, 83, 2589 – 2590; b) W. J. Middleton, E. G. Howard,
W. H. Sharkey, J. Org. Chem. 1965, 30, 1375 – 1384; c) M.
Eschwey, W. Sundermeyer, D. S. Stephenson, Chem. Ber. 1983,
116, 1623 – 1630; d) A. Waterfeld, Chem. Ber. 1990, 123, 1635 –
1640.
[17] a) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470 – 477;
b) Y. Ye, M. S. Sanford, Synlett 2012, 23, 2005 – 2013; c) P. Chen,
G. Liu, Synthesis 2013, 45, 2919 – 2939; d) H. Egami, M.
Sodeoka, Angew. Chem. Int. Ed. 2014, 53, 8294 – 8308; Angew.
Chem. 2014, 126, 8434 – 8449; e) C. Alonso, E. M. de Marigorta,
G. Rubiales, F. Palacios, Chem. Rev. 2015, 115, 1847 – 1935.
[18] a) Z. Weng, W. He, C. Chen, R. Lee, D. Tan, Z. Lai, D. Kong, Y.
Yuan, K. W. Huang, Angew. Chem. Int. Ed. 2013, 52, 1548 – 1552;
Angew. Chem. 2013, 125, 1588 – 1592; b) Z. Y. Wang, Q. Q. Tu,
Z. Q. Weng, J. Organomet. Chem. 2014, 751, 830 – 834; c) Y.
Zhang, K. Gan, Z. Weng, Org. Process Res. Dev. 2016, 20, 799 –
802; d) H. Zheng, Y. Huang, Z. Weng, Tetrahedron Lett. 2016, 57,
1397 – 1409.
[7] a) J. Zheng, J. Cai, J.-H. Lin, Y. Guo, J.-C. Xiao, Chem. Commun.
2013, 49, 7513 – 7515; b) J. Zheng, J.-H. Lin, J. Cai, J.-C. Xiao,
Chem. Eur. J. 2013, 19, 15261 – 15266; c) Q. Li, J.-H. Lin, Z.-Y.
Deng, J. Zheng, J. Cai, J.-C. Xiao, J. Fluorine Chem. 2014, 163,
38 – 41; d) X.-Y. Deng, J.-H. Lin, J. Zheng, J.-C. Xiao, Chem.
Commun. 2015, 51, 8805 – 8808; e) J. Zheng, J.-H. Lin, L.-Y. Yu,
Y. Wei, X. Zheng, J.-C. Xiao, Org. Lett. 2015, 17, 6150 – 6153;
f) X.-Y. Deng, J.-H. Lin, J.-C. Xiao, J. Fluorine Chem. 2015, 179,
116 – 120; g) X.-Y. Deng, J.-H. Lin, J.-C. Xiao, Org. Lett. 2016, 18,
4384 – 4387.
[8] a) V. V. Levin, A. L. Trifonov, A. A. Zemtsov, M. I. Struchkova,
D. E. Arkhipov, A. D. Dilman, Org. Lett. 2014, 16, 6256 – 6259;
b) Y. Qiao, T. Si, M.-H. Yang, R. A. Altman, J. Org. Chem. 2014,
79, 7122 – 7131; c) L. I. Panferova, A. V. Tsymbal, V. V. Levin,
M. I. Struchkova, A. D. Dilman, Org. Lett. 2016, 18, 996 – 999;
d) M.-Q. Hua, W. Wang, W.-H. Liu, T. Wang, Q. Zhang, Y.
Huang, W.-H. Zhu, J. Fluorine Chem. 2016, 181, 22 – 29.
[9] O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475 –
4521.
[10] C. Chen, L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012, 134, 12454 –
12457.
Manuscript received: December 3, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Organofluorine Chemistry
J. Zheng, R. Cheng, J.-H. Lin, D.-H. Yu,
L. Ma, L. Jia, L. Zhang, L. Wang,
J.-C. Xiao,* S. H. Liang*
&&&& — &&&&
An Unconventional Mechanistic Insight
into SCF3 Formation from
Difluorocarbene: Preparation of 18F-
Labeled a-SCF3 Carbonyl Compounds
A trifluoromethylthio anion generated
from a S8/:CF2/Fꢀ system occurs by
sulfuration of difluorocarbene rather than
capture of difluorocarbene by fluoride.
This process translates well to rapid
trifluoromethylthiolation and
[18F]trifluoromethylthiolation of a-bromo
carbonyl compounds.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!