Synthesis of difluoromethyl thioethers from difluoromethyl trimethylsilane and organothiocyanates generated in situ

Article abstract of DOI:10.1002/anie.201500899

A copper-CF₂H complex generated in situ from copper thiocyanate and TMS-CF₂H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one-pot protocols, allowing late-stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts. This strategy enables the introduction of difluoromethylthio groups - a largely unexplored substituent with highly promising properties - into drug-like molecules. A copper-CF₂H complex generated in situ from copper thiocyanate and TMS-CF₂H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one-pot protocols, allowing late-stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts.

Full text of DOI:10.1002/anie.201500899

Angewandte
Chemie
DOI: 10.1002/anie.201500899
Synthetic Methods
Synthesis of Difluoromethyl Thioethers from Difluoromethyl
Trimethylsilane and Organothiocyanates Generated In Situ**
Bilguun Bayarmagnai, Christian Matheis, Kꢀvin Jouvin, and Lukas J. Goossen*
Abstract: A copper-CF2H complex generated in situ from
and only few methods reach the efficiency of the correspond-
ing trifluoromethylations.[17]
À
copper thiocyanate and TMS CF2H smoothly converts orga-
nothiocyanates into valuable difluoromethyl thioethers. This
reaction step can be combined with several thiocyanation
methods to one-pot protocols, allowing late-stage difluorome-
thylthiolations of widely available alkyl halides and arenedi-
azonium salts. This strategy enables the introduction of
difluoromethylthio groups—a largely unexplored substituent
with highly promising properties—into drug-like molecules.
With SCF3 receiving increasing attention as an enhanced
version of CF3 in bioactive molecules, one might expect
a similar shift in interest from CF2H to SCF2H. Indeed,
difluoromethylthio residues were shown to be uniquely
effective in the b-lactamase-resistant oxcephalosporin anti-
biotic Flomoxef sodium (Figure 1). In 2-(difluoro[(4-methyl-
pyrimidin-2-yl)thio]methyl)benzoxazole, the SCF2 bridge is
crucial for its activity against HIV-1, whereas the OCF2-
substituted analogue is inactive.[18]
Close to 40% of marketed agrochemicals and 25% of
pharmaceuticals contain fluorine atoms. Fluorine-containing
residues are central functionalities in such active substances,[1]
because they modulate their metabolic stability, lipophilicity,
and bioavailability. So-called “fluorine scans”, i.e., systematic
derivatizations through the introduction of groups such as
CF3,[2] C2F5,[3] SCF3,[4] and OCF3,[5] have become standard
procedure in drug discovery. New fluorine-containing resi-
dues and efficient methods for their introduction into
functionalized molecules are, thus, constantly sought.
Trifluoromethyl groups are incorporated into bioactive
molecules to enhance their membrane permeability.[1d,6]
Recent years have witnessed a tremendous development in
trifluoromethylation technology. Efficient benzotrifluoride
syntheses that can be employed even at late stages within
a synthetic sequence have been disclosed for example, by the
groups of Prakash,[7] Grushin,[8] Buchwald,[9] and others.[10]
Lately, there is a shift in focus toward trifluoromethylthio
groups, because these are even more effective in inducing
lipophilicity and membrane permeability (Hansch constants
1.44 vs. 0.88 for CF3).[11] Contemporary late-stage trifluoro-
methylthiolations of arenes employ Pd,[12] Cu,[13] Ni,[14] and
Ag[12] catalysts.
Figure 1. Biologically active a-difluoromethyl thioethers.
The proton in SCF2H groups is even more acidic than that
in CF2H groups.[19] This underlines the potential of SCF2H
groups as lipophilic OH or NH surrogates. It would be highly
desirable to routinely examine SCF2H substituents during
drug discovery. However, no presently available synthetic
method is mild and selective enough for their late-stage
introduction into drug-like molecules.
Traditional syntheses of SCF2H moieties are based on the
À
insertion of difluorocarbene into the S H bond of thiophe-
nols, as first described by Porter et al. in 1957.[20] Originally,
the difluorocarbenes were generated from the ozone-deplet-
ing chlorodifluoromethane (Scheme 1).[21] The groups of
Difluoromethyl groups, in contrast, are potent hydrogen
donors.[15] They serve as lipophilic and membrane perme-
ability-enhancing isosteric and isopolar analogues to OH and
SH groups.[1b,16] Difluoromethylations still face challenges,
Scheme 1. Strategies to access difluoromethyl thioethers.
[*] B. Bayarmagnai, C. Matheis, Dr. K. Jouvin, Prof. Dr. L. J. Goossen
FB Chemie-Organische Chemie
Hu[22] and Dolbier[23] recently utilized TMS CF2Br or CF3H
À
Technische Universitꢀt Kaiserslautern
Erwin-Schrçdinger-Strasse Geb. 54
67663 Kaiserslautern (Germany)
E-mail: goossen@chemie.uni-kl.de
as more environmentally benign CF2 sources. Thiols and
thiophenols can also be difluoromethylated using electro-
philic reagents.[24] However, these approaches suffer from the
limited availability of thiol substrates, the incompatibility of
the strongly basic reaction conditions with sensitive function-
alities, and the low selectivity of the CF2 insertion step.
A method to introduce SCF2H groups in a single step,
using an inexpensive reagent, and substituting a widely
available leaving group such as a halide, mesylate, or
Homepage: http://www.chemie.uni-kl.de/goossen
[**] We thank Bholanath Maity for DFT calculations as well as the
Heinrich-Bçll-Stiftung e.V. (scholarship to B.B.) and Nanokat for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500899.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
diazotized amino group would be highly desirable. Preformed
SCF3 reagents are laborious to prepare and rather expen-
sive,[12,13,25] and the same limitations must be expected for
their presently unknown SCF2H counterparts. Therefore, we
decided to base our difluoromethylthiolation process on
a stepwise assembly first of S, introduced by way of an SCN
group, then of CF2H by the in situ conversion of SCN to
SCF2H using a nucleophilic CF2H source, preferentially
À
TMS CF2H, which is easily accessible from the inexpensive
Ruppert–Prakash reagent.
Langlois et al.[26] found that SCF3 groups can be generated
from thiocyanates by nucleophilic displacement of the CN
Scheme 2. Cu-mediated difluoromethylation of organothiocyanates.
Reaction conditions: 1.0 mmol of organothiocyanate, 1.0 mmol of
À
group using TMS CF3. However, the corresponding reaction
À
between organothiocyanates with TMS CF2H has not yet
À
CuSCN, 4.0 mmol of CsF, 2.0 mmol of TMS CF2H in 2 mL of DMF,
been achieved. Since such a transformation would constitute
the pivotal step in our desired synthesis of organodifluoro-
methyl thioethers, we focused our initial research efforts on
this step in isolation. Using the model reaction of benzyl
12 h, RT. Yields are of isolated products. [a] Yields determined by
19F NMR spectroscopy using trifluoroethanol as an internal standard.
thiocyanate (1) with TMS CF2H, we investigated a range of
to the above-mentioned anti-HIV-1 agents,[18] and a 2-
(difluoromethylthio)pyridine related to the 2-(difluorome-
thyl)pyridine herbicide thiazopyr.
The discovery of this mild, copper-mediated difluorome-
thylation of organothiocyanates should be combinable with
syntheses of organothiocyanates from various carbon electro-
philes, overall leading to one-step synthesis of difluoromethyl
thioethers from widely available starting materials. Indeed,
upon briefly heating alkyl bromides with sodium thiocyanate
in DMF and then adding the difluoromethylation reagent
À
reaction conditions, starting with those reported for the
analogous trifluoromethylation (TBAF, THF, 08C). None of
the fluoride sources tested in various solvents promoted the
formation of benzyl difluoromethyl sulfide (2, Table 1,
entries 1–4) in more than trace amounts, confirming that
a noncatalyzed introduction of the sensitive CF2H moiety is
not feasible.
Table 1: Optimization of the reaction conditions.[a]
À
mixture composed of TMS CF2H, CsF, and CuSCN, the
corresponding alkyl difluoromethyl thioethers were cleanly
obtained in high yields and purities.
The scope of this one-pot difluoromethylthiolation is
shown in Table 2. Primary and secondary alkyl bromides, as
well as mesylates conveniently accessible from ubiquitous
Entry
Additive
Mediator
Solvent
2 [%][b]
1[c]
2
3
TBAF
CsF
TBAF
KF
CsF
CsF
CsF
–
–
–
–
THF
THF
trace
0
trace
trace
51
DMF
DMF
DMF
DMF
DMF
4
5
Table 2: One-pot difluoromethylthiolation of alkyl bromides and mesy-
–
lates.[a]
6[d]
7[e]
CuSCN
CuSCN
85
98
[a] Reaction conditions: 0.5 mmol of benzyl thiocyanate, 1.0 mmol of
À
additive, 1 mL solvent, 1.0 mmol of TMS CF2H, RT. [b] Yields were
determined by 19F NMR spectroscopy using trifluoroethanol as an
À
internal standard. [c] TMS CF2H was added at 08C, then the mixture was
slowly warmed up to RT. [d] 0.5 mmol of CuSCN. [e] 0.5 mmol of CuSCN
and 2.0 mmol of CsF were used.
Systematic investigations of potential mediators identified
copper salts, particularly copper thiocyanate, as strong
promoters of the desired reaction. NMR investigations
showed that Cu–CF2H is intermediately formed and acts as
the actual difluoromethylation reagent (entries 6 and 7).[27]
Under optimal conditions, that is, in the presence of CsF and
CuSCN in DMF, 1 is converted into benzyl difluoromethyl
sulfide (2) in quantitative yields within 12 h at room temper-
ature (entry 7).
As illustrated in Scheme 2, the new difluoromethylation
protocol extends to aliphatic, aromatic, and heteroaromatic
thiocyanates. They include substructures of particular inter-
est, namely a 2-[(difluoromethyl)thio]pyrimidine analogous
[a] 1.0 mmol of alkyl bromide and 1.2 mmol of NaSCN in 4 mL DMF
were heated for 2 h (see SI for detailed conditions). After cooling to RT,
À
1.0 mmol of CuSCN, 4.0 mmol of CsF, and 2.0 mmol of TMS CF2H were
added, and stirring continued for 12 h at RT. Yields are of isolated
products. [b] Yields determined by 19F NMR spectroscopy using tri-
fluoroethanol as an internal standard. [c] Starting from mesylate.
2
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
alcohols, were converted in high yields, and a range of
common functionalities was tolerated.
The synthesis of aromatic derivatives by this strategy is
limited to strongly activated aryl halides capable of under-
going nucleophilic aromatic thiocyanation. Therefore, we
cesium fluoride to the reaction mixture. The carbonate base is
required for the Sandmeyer step, and CsF promotes the
transfer of CF2HÀ from silicon to copper.[17a,b] The ratio
between the two cesium bases has a crucial influence on the
yield. Both cesium carbonate and sodium thiocyanate inter-
fere with the difluoromethylation step, so that an excess of
these reagents must be avoided. Under optimized conditions,
the only remaining byproduct is anisole, which results from
competing protodediazotization. Further control experiments
showed that the Sandmeyer thiocyanation and the formation
of Cu–CF2H species each require one equivalent of
CuSCN.[29]
À
sought another protocol for the C S bond-forming step
capable of converting the entire range of aromatic and
heteroaromatic substrates. A Sandmeyer-type approach as
recently implemented in several fluoroalkylations of diazo-
nium salts[17b,28] appeared to be promising for a generally
applicable synthesis of difluoromethylthio arenes.
To probe the viability of this approach, we treated 4-
methoxybenzenediazonium tetrafluoroborate (21) with
DMF was found to be the most effective solvent for the
difluoromethylation step,[17a,b] but the Sandmeyer reaction
proceeds best in acetonitrile.[30] Near-quantitative yields were
achieved only when performing the reaction steps in different
solvents. Thus, 21 in MeCN is first added to a mixture of
NaSCN, Cs2CO3, and CuSCN in MeCN. After stirring for 1 h,
the solvent is evaporated, and a solution of CsF, CuSCN, and
À
sodium thiocyanate and TMS CF2H in the presence of
copper thiocyanate (Table 3). The optimal literature condi-
Table 3: Difluoromethylthiolation of arenediazonium salts.[a]
À
TMS CF2H in DMF is added to the residue. This way, the
desired product 22 can be isolated in 95% yield.
Having thus identified a highly efficient protocol, we next
investigated its scope. The examples in Table 3 illustrate that
diversely substituted arenediazonium tetrafluoroborates are
smoothly converted into the corresponding aryl difluoro-
methyl thioethers in high yields. Electron-rich and electron-
deficient substrates give similarly high yields, and various
heterocycles such as quinolines and carbazoles are smoothly
converted. Common functionalities including ester, ether,
keto, amino, cyano, and bromo groups are tolerated.
Remarkably, in compound 33, the acetyl substituent in the
para-position is left intact whereas the same group in the
meta-position is converted into the corresponding difluoro-
methyl alcohol (product 34). The successful synthesis of 22 in
89% yield on a 10 mmol scale demonstrates the scalability of
the process.
Control experiments suggest that the reaction indeed
proceeds through a Sandmeyer-type mechanism, as proposed
also for related fluoroalkyl(thiol)ations. This copper-medi-
ated radical dediazotative thiocyanation step is followed by
nucleophilic displacement of a cyanide group by CF2H via
a CuCF2H species.
In conclusion, a copper-mediated difluoromethylation of
organothiocyanates has opened up new opportunities for the
synthesis of difluoromethyl thioethers from widely available
substrates such as alkyl halides or (hetero)aryl amines via
their diazonium salts. The mild and efficient synthetic
approach is suitable for the late-stage functionalization of
complex molecules and thus meets the requirements of
pharmaceutical and agrochemical research. Many difluoro-
methyl thioethers have thus become accessible for the first
time and may now be screened for biological activity.
[a] 1.0 mmol of arenediazonium tetrafluoroborate in 2 mL of MeCN was
slowly added to a mixture of 1.0 mmol of CuSCN, 0.75 mmol of Cs2CO3,
and 1.5 mmol of NaSCN in 2 mL of MeCN, and stirred for 1 h at RT. Then
MeCN was evaporated, 1.0 mmol of CuSCN, 4.0 mmol of CsF, and
À
2.0 mmol of TMS CF2H in 4 mL DMF were added, stirring was
continued for 12 h at RT. Yields are of isolated products.
tions for the trifluoromethylthiolation of diazonium salts
(Cs2CO3, MeCN)[28a] did not yield any of the desired
difluoromethylthiolated product (see the Supporting Infor-
mation, SI). However, upon switching to DMF as the solvent,
the arenethiocyanate was fully consumed, and the desired
product was detected in modest yield along with anisole,
diaryl disulfide, and biaryl byproducts. By careful optimiza-
tion of the conditions, the yield could be increased to
a satisfactory 83% by adding both cesium carbonate and
Received: January 30, 2015
Published online: && &&, &&&&
Keywords: copper · difluoromethylthiolation · fluorine ·
.
Sandmeyer reaction · synthetic methods
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Xie, L. Chu, R.-W. Wang, X. Zhang, F.-L. Qing, Angew. Chem.
Int. Ed. 2012, 51, 2492 – 2495; Angew. Chem. 2012, 124, 2542 –
2545; d) L. D. Tran, I. Popov, O. Daugulis, J. Am. Chem. Soc.
2012, 134, 18237 – 18240.
[1] a) Fluorine-containing Amino Acids (Eds.: V. P. Kukhar, V. A.
Soloshonok), Wiley, Hoboken, 1995; b) Fluorine in Medicinal
Chemistry and Chemical Biology (Eds.: I. Ojima), Wiley, Chi-
chester, 2009; c) Bioorganic and Medicinal Chemistry of Fluo-
rine (Eds.: J.-P. Bꢀguꢀ, D. Bonnet-Delpon), Wiley, Hoboken,
2008; d) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359 – 4369;
e) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reac-
tivity, Applications, 2nd ed., Wiley-VCH, Weinheim, 2013; f) J.
Wang, M. Sꢁnchez-Rosellꢂ, J. L. AceÇa, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem. Rev.
2014, 114, 2432 – 2506.
[2] a) O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111,
4475 – 4521; b) T. Furuya, A. S. Kamlet, T. Ritter, Nature 2011,
473, 470 – 477; c) X.-F. Wu, H. Neumann, M. Beller, Chem. Asian
J. 2012, 7, 1744 – 1754; d) X. Liu, C. Xu, M. Wang, Q. Liu, Chem.
Rev. 2015, 115, 683 – 730; e) T. Liu, Q. Shen, Eur. J. Org. Chem.
2012, 6679 – 6687; f) T. Liang, C. N. Neumann, T. Ritter, Angew.
Chem. Int. Ed. 2013, 52, 8214 – 8264; Angew. Chem. 2013, 125,
8372 – 8423.
[14] C.-P. Zhang, D. A. Vicic, J. Am. Chem. Soc. 2012, 134, 183 – 185.
[15] a) Y. Li, J. Hu, Angew. Chem. Int. Ed. 2005, 44, 5882 – 5886;
Angew. Chem. 2005, 117, 6032 – 6036; b) J. A. Erickson, J. I.
McLoughlin, J. Org. Chem. 1995, 60, 1626 – 1631; c) G. K. S.
Prakash, C. Weber, S. Chacko, G. A. Olah, Org. Lett. 2007, 9,
1863 – 1866.
[16] a) F. Narjes, K. F. Koehler, U. Koch, B. Gerlach, S. Colarusso, C.
Steinkꢄhler, M. Brunetti, S. Altamura, R. De Francesco, V. G.
Matassa, Bioorg. Med. Chem. Lett. 2002, 12, 701 – 704;
b) G. K. S. Prakash, M. Mandal, S. Schweizer, N. A. Petasis,
G. A. Olah, J. Org. Chem. 2002, 67, 3718 – 3723.
[17] a) P. S. Fier, J. F. Hartwig, J. Am. Chem. Soc. 2012, 134, 5524 –
5527; b) C. Matheis, K. Jouvin, L. J. Goossen, Org. Lett. 2014, 16,
5984 – 5987; c) Y. Gu, X. Leng, Q. Shen, Nat. Commun. 2014, 5,
5405; d) G. K. S. Prakash, S. K. Ganesh, J.-P. Jones, A. Kulkarni,
K. Masood, J. K. Swabeck, G. A. Olah, Angew. Chem. Int. Ed.
2012, 51, 12090 – 12094; Angew. Chem. 2012, 124, 12256 – 12260;
e) X.-L. Jiang, Z.-H. Chen, X.-H. Xu, F.-L. Qing, Org. Chem.
Front. 2014, 1, 774.
[18] C. R. Burkholder, W. R. Dolbier, M. Mꢀdebielle, J. Fluorine
Chem. 2000, 102, 369 – 376.
[19] For DFT calculations, see the SI. SCF2H groups can be
deprotonated with KOH: J. Hu, J. Fluorine Chem. 2009, 130,
1130 – 1139.
[20] J. Hine, J. J. Porter, J. Am. Chem. Soc. 1957, 79, 5493 – 5496.
[21] a) R. Van Poucke, R. Pollet, A. De Cat, Tetrahedron Lett. 1965,
6, 403 – 406; b) B. R. Langlois, J. Fluorine Chem. 1988, 41, 247 –
261.
[22] L. Li, F. Wang, C. Ni, J. Hu, Angew. Chem. Int. Ed. 2013, 52,
12390 – 12394; Angew. Chem. 2013, 125, 12616 – 12620.
[23] C. S. Thomoson, W. R. Dolbier, J. Org. Chem. 2013, 78, 8904 –
8908.
[24] a) W. Zhang, F. Wang, J. Hu, Org. Lett. 2009, 11, 2109 – 2112;
b) Q.-Y. Chen, S.-W. Wu, J. Fluorine Chem. 1989, 44, 433 – 440;
c) Y. Zafrani, G. Sod-Moriah, Y. Segall, Tetrahedron 2009, 65,
5278 – 5283.
[25] a) R. Pluta, P. Nikolaienko, M. Rueping, Angew. Chem. Int. Ed.
2014, 53, 1650 – 1653; Angew. Chem. 2014, 126, 1676 – 1679; b) C.
Xu, B. Ma, Q. Shen, Angew. Chem. Int. Ed. 2014, 53, 9316 – 9320;
Angew. Chem. 2014, 126, 9470 – 9474.
[26] T. Billard, S. Large, B. R. Langlois, Tetrahedron Lett. 1997, 38,
65 – 68.
[27] R. Eujen, B. Hoge, D. J. Brauer, J. Organomet. Chem. 1996, 519,
7 – 20.
[28] a) G. Danoun, B. Bayarmagnai, M. F. Gruenberg, L. J. Goossen,
Chem. Sci. 2014, 5, 1312 – 1316; b) B. Bayarmagnai, C. Matheis,
E. Risto, L. J. Goossen, Adv. Synth. Catal. 2014, 356, 2343 – 2348;
c) J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X. Lu, L. Liu,
Y. Fu, J. Am. Chem. Soc. 2013, 135, 8436 – 8439; d) X. Wang, Y.
Xu, F. Mo, G. Ji, D. Qiu, J. Feng, Y. Ye, S. Zhang, Y. Zhang, J.
Wang, J. Am. Chem. Soc. 2013, 135, 10330 – 10333; e) A.
Lishchynskyi, G. Berthon, V. V. Grushin, Chem. Commun.
2014, 50, 10237; f) G. Danoun, B. Bayarmagnai, M. F. Grꢄnberg,
L. J. Gooßen, Angew. Chem. Int. Ed. 2013, 52, 7972 – 7975;
Angew. Chem. 2013, 125, 8130 – 8133; g) G. Danoun, B. Bayar-
magnai, M. Grꢄnberg, C. Matheis, E. Risto, L. J. Gooßen,
Synthesis 2014, 2283 – 2286.
[3] A. Lishchynskyi, V. V. Grushin, J. Am. Chem. Soc. 2013, 135,
12584 – 12587.
[4] F. Toulgoat, S. Alazet, T. Billard, Eur. J. Org. Chem. 2014, 2415 –
2428.
[5] a) G. L. Trainor, J. Carbohydr. Chem. 1985, 4, 545 – 563; b) K. N.
Hojczyk, P. Feng, C. Zhan, M.-Y. Ngai, Angew. Chem. Int. Ed.
2014, 53, 14559 – 14563; Angew. Chem. 2014, 126, 14787 – 14791.
[6] L. M. Yagupolꢃskii, A. Y. Ilꢃchenko, N. V. Kondratenko, Russ.
Chem. Rev. 1974, 43, 32 – 47.
[7] a) G. K. S. Prakash, P. V. Jog, P. T. D. Batamack, G. A. Olah,
Science 2012, 338, 1324 – 1327; b) G. K. S. Prakash, R. Krishna-
murti, G. A. Olah, J. Am. Chem. Soc. 1989, 111, 393 – 395;
c) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757 – 786.
[8] a) P. Novꢁk, A. Lishchynskyi, V. V. Grushin, Angew. Chem. Int.
Ed. 2012, 51, 7767 – 7770; Angew. Chem. 2012, 124, 7887 – 7890;
b) S. Takemoto, V. V. Grushin, J. Am. Chem. Soc. 2013, 135,
16837 – 16840; c) A. Lishchynskyi, M. A. Novikov, E. Martin,
E. C. Escudero-Adꢁn, P. Novꢁk, V. V. Grushin, J. Org. Chem.
2013, 78, 11126 – 11146.
[9] a) A. T. Parsons, S. L. Buchwald, Angew. Chem. Int. Ed. 2011, 50,
9120 – 9123; Angew. Chem. 2011, 123, 9286 – 9289; b) T. D.
Senecal, A. T. Parsons, S. L. Buchwald, J. Org. Chem. 2011, 76,
1174 – 1176; c) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang,
D. A. Watson, S. L. Buchwald, Science 2010, 328, 1679 – 1681.
[10] a) H. Morimoto, T. Tsubogo, N. D. Litvinas, J. F. Hartwig,
Angew. Chem. Int. Ed. 2011, 50, 3793 – 3798; Angew. Chem.
2011, 123, 3877 – 3882; b) N. D. Litvinas, P. S. Fier, J. F. Hartwig,
Angew. Chem. Int. Ed. 2012, 51, 536 – 539; Angew. Chem. 2012,
124, 551 – 554; c) G. G. Dubinina, H. Furutachi, D. A. Vicic, J.
Am. Chem. Soc. 2008, 130, 8600 – 8601; d) T. Liu, X. Shao, Y. Wu,
Q. Shen, Angew. Chem. Int. Ed. 2012, 51, 540 – 543; Angew.
Chem. 2012, 124, 555 – 558; e) L. Chu, F.-L. Qing, Org. Lett.
2010, 12, 5060 – 5063; f) T. Knauber, F. Arikan, G.-V.
Rçschenthaler, L. J. Gooßen, Chem. Eur. J. 2011, 17, 2689 –
2697; g) B. A. Khan, A. E. Buba, L. J. Gooßen, Chem. Eur. J.
2012, 18, 1577 – 1581.
[11] C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani, E. J.
Lien, J. Med. Chem. 1973, 16, 1207 – 1216.
[12] G. Teverovskiy, D. S. Surry, S. L. Buchwald, Angew. Chem. Int.
Ed. 2011, 50, 7312 – 7314; Angew. Chem. 2011, 123, 7450 – 7452.
[13] 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) X. Shao, X.
Wang, T. Yang, L. Lu, Q. Shen, Angew. Chem. Int. Ed. 2013, 52,
3457 – 3460; Angew. Chem. 2013, 125, 3541 – 3544; c) C. Chen, Y.
[29] See SI. Additional NaSCN or Cs2CO3 hinders the difluorome-
thylation of preformed p-methoxyphenyl thiocyanate.
[30] A. Roglans, A. Pla-Quintana, M. Moreno-MaÇas, Chem. Rev.
2006, 106, 4622 – 4643.
4
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
B. Bayarmagnai, C. Matheis, K. Jouvin,
L. J. Goossen*
&&&& — &&&&
Synthesis of Difluoromethyl Thioethers
from Difluoromethyl Trimethylsilane and
Organothiocyanates Generated In Situ
A copper–CF2H complex generated
in situ from copper thiocyanate and
combined with several thiocyanation
methods to one-pot protocols, allowing
late-stage difluoromethylthiolations of
widely available alkyl halides and arene-
diazonium salts.
À
TMS CF2H smoothly converts organo-
thiocyanates into valuable difluoromethyl
thioethers. This reaction step can be
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!