Bis(difluoromethyl)trimethylsilicate Anion: A Key Intermediate in Nucleophilic Difluoromethylation of Enolizable Ketones with Me3SiCF2H

Article abstract of DOI:10.1002/anie.201605280

A pentacoordinate bis(difluoromethyl)silicate anion, [Me₃Si(CF₂H)₂]^?, is observed for the first time by the activation of Me₃SiCF₂H with a nucleophilic alkali-metal salt and 18-crown-6. Further study on its reactivity by tuning the countercation effect led to the discovery and development of an efficient, catalytic nucleophilic difluoromethylation of enolizable ketones with Me₃SiCF₂H by using a combination of CsF and 18-crown-6 as the initiation system. Mechanistic investigations demonstrate that [(18-crown-6)Cs]⁺[Me₃Si(CF₂H)₂]^?is a key intermediate in this catalytic reaction.

Full text of DOI:10.1002/anie.201605280

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605280
German Edition: DOI: 10.1002/ange.201605280
Reactive Intermediates
Bis(difluoromethyl)trimethylsilicate Anion: A Key Intermediate in
Nucleophilic Difluoromethylation of Enolizable Ketones with
Me3SiCF2H
Dingben Chen, Chuanfa Ni, Yanchuan Zhao, Xian Cai, Xinjin Li, Pan Xiao, and Jinbo Hu*
Dedicated to Professor K. Barry Sharpless on the occasion of his 75th birthday
Abstract:
A
pentacoordinate bis(difluoromethyl)silicate
Me3SiCF2H, as an analogue of Me3SiCF3, has recently
emerged as a potentially useful difluoromethanide anion
(HCF2 ) source for the nucleophilic introduction of a difluor-
anion, [Me3Si(CF2H)2]À, is observed for the first time by the
activation of Me3SiCF2H with a nucleophilic alkali-metal salt
and 18-crown-6. Further study on its reactivity by tuning the
countercation effect led to the discovery and development of an
efficient, catalytic nucleophilic difluoromethylation of enoliz-
able ketones with Me3SiCF2H by using a combination of CsF
and 18-crown-6 as the initiation system. Mechanistic inves-
tigations demonstrate that [(18-crown-6)Cs]+[Me3Si(CF2H)2]À
is a key intermediate in this catalytic reaction.
À
omethyl group.[7–9] However, because of the weaker electron-
withdrawing ability of the CF2H group (compared with CF3
group),[10] the reactivity of Me3SiCF2H is distinct from the
well-developed Me3SiCF3 in nucleophilic fluoroalkylation
reactions. The trifluoromethylation with Me3SiCF3 readily
takes place under the activation of a wide range of Lewis
bases,[11] whereas the similar difluoromethylation normally
requires harsher reaction conditions, thus limiting the sub-
strate scope.[7–9] To address these challenges in difluorome-
thylation with Me3SiCF2H, it is essential to investigate the
hypervalent silicon intermediate in the nucleophilic activation
of Me3SiCF2H and to probe its difluoromethyl-transfer
reactivity. Herein, we describe the discovery and character-
ization of a unique pentacoordinate bis(difluoromethyl)sili-
cate anion [Me3Si(CF2H)2]À derived from Me3SiCF2H and the
tuning of its reactivity with the countercation [(18-crown-
6)Cs]+, as well as its application in the efficient difluorome-
thylation of enolizable ketones, a reaction which was pre-
viously difficult to achieve.[7–9]
H
ypercoordinate silicates are key intermediates in nucleo-
philic substitution on silicon and activation of organosilicon
compounds.[1] Many pentacoordinate silicates containing at
least one electronegative heteroatom ligand such as F, Cl, O,
and N have been prepared to study their structures and
reactivities.[2] However, pentaorganosilicate species contain-
À
ing five Si C bonds are rare, and little is known about their
carbon–ligand transfer reactivity.[3–5] In 1999, the groups of
Naumann[5a] and Rçschenthaler[5b] independently reported
the preparation and characterization of the pentaorganosili-
cate anion [Me3Si(CF3)2]À, which is derived from the inter-
action of a pentacoordinate [Me3SiF(CF3)]À with the Rup-
pert–Prakash reagent (Me3SiCF3). The formation of such an
acyclic pentaorganosilicate is attributed to the pronounced
group electronegativity of the trifluoromethyl unit, which
renders Me3SiCF3 of sufficient Lewis acidity to accept an
We began our study with an investigation on the
interaction between Me3SiCF2H and various nucleophilic
activators in THF without adding the carbonyl substrate
(Scheme 1a). Based on our previous report on the difluoro-
methylation of various aldehydes, diaryl ketones, and imines
incoming trifluoromethanide anion (CF3 ).[6] In 2014, Prakash
À
and co-workers[5c] elegantly demonstrated that the penta-
coordinate [Me3Si(CF3)2]À prepared from a bulky tert-butoxy
anion with a [K(18-crown-6)]+ countercation and Me3SiCF3
can dissociate to give a CF3À. They observed the CF3À species
by NMR spectroscopy and ascertained its reactivity in
nucleophilic trifluoromethylations.[5c]
[*] Dr. D. Chen, Dr. C. Ni, Dr. Y. Zhao, X. Cai, X. Li, P. Xiao, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai 200032 (China)
E-mail: jinbohu@sioc.ac.cn
Dr. D. Chen
College of Pharmaceutical and Chemical Engineering
Taizhou University, Taizhou, Zhejiang 318000 (China)
Scheme 1. Activation of Me3SiCF2H with various nucleophiles and
observation of the pentacoordinate difluoromethylsilicate. THF=tetra-
hydrofuran.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605280.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

Angewandte
Communications
Chemie
with Me3SiCF2H,[7b] stoichiometric amounts of CsF and
tBuOK were initially tested as the activators. However, only
the signals of CF2H2 and unreacted Me3SiCF2H were detected
by 19F NMR spectroscopy at a wide range of temperatures
(À708C to room temperature). The failure to observe any
pentacoordinate difluoromethyl silicate species probably
À112.1 ppm) versus Me3SiCF3 (d = 5.4 ppm).[5a] In the
1H NMR spectrum, both the signals of the CF2H (d =
5.00 ppm) and Me (d = À0.24 ppm) groups are also detected
to be upfield compared with those of Me3SiCF2H [d(CF2H) =
1
5.85 ppm; d(Me) = 0.14 ppm]. The JH-F coupling constant is
in good agreement with the corresponding coupling observed
in 19F NMR [d = À130.0 ppm (d, 1JH-F = 47.3 Hz)]. According
to the ratio (2:9) of integrated area of the 1H NMR signals of
CF2H and Me, we inferred that the above silicon species is
À
arises from the strong affinity of the HCF2 to the alkali-
metal cations, and thus leads to a spontaneous decomposition
of the difluoromethyl silicates into HCF2À, with subsequent
protonation by either adventitious water or the solvent THF.
Considering that the countercation effect can significantly
influence the stability of hypercoordinate silicate anions,[3f,5b]
we turned our attention to the employment of a crown
ether[12] as an additive to stabilize the silicate intermediate by
À
a pentacoordinated bis(difluoromethyl)slicate with five Si C
bonds, that is, [(18-crown-6)M]+[Me3Si(CF2H)2]À (M = Na, K,
Cs).[16] The observed quintet peak in 29Si{1H} NMR spectrum
supports a trigonal-bipyramidal structure with two axial CF2H
groups and three equatorial methyl groups, and it is similar to
the structure of [Me3Si(CF3)2]À.[5a] Moreover, the 13C NMR
À
minimizing the interaction between HCF2 and the alkali
1
metal cations (Scheme 1b). To our delight, a weak signal at
around d = À130.0 ppm was observed by 19F NMR spectros-
copy at room temperature using the combination of CsF/18-
crown-6 as the activator (see Figure S1 in the Supporting
Information). Much stronger signals with the similar chemical
shifts were observed at temperatures ranging from À788C to
room temperature when the combinations of more soluble
tBuOK/18-crown-6, tBuOCs/18-crown-6, and even tBuONa/
18-crown-6 were used. Compared with the 19F NMR chemical
shift of Me3SiCF2H (d = À140.7 ppm), the downfield shift of
the observed signal is likely to correspond to an anionic
species.[13] To determine the structure of the observed species,
we further carried out 29Si{1H} NMR, 13C{1H} NMR,
1H NMR, and heteronuclear multiple quantum coherence
(HMQC) experiments of the reaction between Me3SiCF2H
and tBuOCs/18-crown-6 in [D8]THF (Figure 1; see Figur-
signals of CF2H [d = 140.3 ppm (t, JC-F = 285 Hz)] and Me
(d = À3.2 ppm), which were assigned by 1H-13C HMQC
analysis, appear downfield from those of Me3SiCF2H
[d(CF2H) = 123.7 ppm
(t,
1JC-F = 253 Hz);
d(Me) =
À6.5 ppm]. An increase in 1JC-F coupling as well as a decrease
2
in JSi-F coupling, which have been observed in the trans-
formation of Me3SiCF3 into [Me3Si(CF3)2]À,[5a] are probably
characters of bipyramidal [R3Si(Rf)2]À species with two Rf
groups at the axial positions.
It is noteworthy that these pentacoordinate silicates were
relatively stable below À308C and decomposed gradually to
CF2H2 when slowly raising the temperature from À308C to
208C [for variable-temperature (VT) NMR study, see Figur-
es S7 and S17]. Moreover, [Me3Si(CF2H)2]À was the only
detectable difluoromethylated hypercoordinate silicon spe-
cies regardless the ratio of Me3SiCF2H/tBuOM (either > 1:1
or not). We also attempted to observe CF2HÀ at a wide range
of temperatures (from À788C to 208C), but no evidence
supported the persistence of this species in our system, which
À
is significantly different from the CF3 anion derived from
Me3SiCF3.[5c] The generation of CF2HD and CF2H2 as side
products when using [D8]THF as the solvent indicates that
CF2HÀ is kinetically unstable and has a high tendency to
abstract a proton from both THF and 18-crown-6 (see
Figures S3 and S13).
Having identified the relatively stable intermediate
[Me3Si(CF2H)2]À, we next sought to probe its reactivity in
nucleophilic difluoromethylation reactions. The experiment
was conducted by adding the electrophilic substrate to a THF
solution of [Me3Si(CF2H)2]À pre-generated from stoichiomet-
ric amounts of tBuOM (M = Na, K, Cs), 18-crown-6, and
Me3SiCF2H in a molar ratio of 1:1:2. To our surprise,
enolizable ketones, which are challenging substrates under
previously reported difluoromethylation conditions,[7a,b,d] can
be readily difluoromethylated. Thus, the reaction between 1-
(2-methoxyphenyl) ethanone (1i) and [Me3Si(CF2H)2]À, gen-
erated from tBuOCs/18-crown-6/Me3SiCF2H, gave the corre-
sponding difluoromethylated alcohol in good yield (Sche-
me 2a; for details see Figure S8). However, when tBuONa
was used instead of tBuOCs, the pre-generated [Me3Si-
(CF2H)2]À failed to undergo addition to 1i, only affording
CF2H2 as the detectable side product. Based on these results,
we concluded that the countercation effect not only influen-
ces the stabilization of [Me3Si(CF2H)2]À, but it also dramat-
Figure 1. 29Si{1H} NMR (a) and 1H NMR (b) spectra of [Me3Si-
(CF2H)2]À, generated from tBuOCs/18-crown-6 and Me3SiCF2H in
[D8]THF at À308C. In (a), the signals (*) at d=7.5–7.0 ppm are
assigned to Me3SiOtBu as well as side-products arising from the
silylation of [D8]THF and 18-crown-6.
es S2–S6 and Table S1).[14] In the 29Si{1H} NMR spectrum, the
2
signal is shifted upfield [d = À118.4 ppm (quint, JSi-F
=
10.3 Hz)] compared with that of Me3SiCF2H [d = À0.04 ppm
2
(t, JSi-F = 28.8 Hz)], and is in accordance with the formation
of a pentacoordinated silicate species.[15] This chemical shift
change is similar to that of the reported [Me3Si(CF3)2]À (d =
2
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
results, we conclude that the cesium ion played an important
role in (tBuOÀ/18-crown-6)-initiated difluoromethylation of
enolizable ketones.
Since [Me3Si(CF2H)2]À can also be generated from the
combination of CsF/18-crown-6, albeit in a low yield, we
explored the difluoromethylation by employing the more
readily available CsF instead of tBuOCs (Scheme 2c; for
details see Table S1). We were pleased to find that reaction
employing 10 mol% of CsF/18-crown-6 also provided a high
yield of the difluoromethyl addition product. A screening of
the solvent showed that the ether solvent dimethoxyethane
(DME) is slightly superior to THF in improving the yield.
Therefore, the combination of CsF/18-crown-6 was chosen as
the optimal initiation system and DME was chosen as the
optimal solvent for the reaction between Me3SiCF2H and
enolizable ketones.
With the optimized reaction conditions in hand, we
subsequently investigated the substrate scope. As shown in
Scheme 3, most of the enolizable ketones examined provided
good to excellent yields. In general, substituted aromatic
ketones bearing electron-donating groups (such as Ph, iPr,
OMe, and NMe2) showed higher reactivity (2b–f) than those
Scheme 2. Nucleophilic difluoromethylation of enolizable ketones.
[a] Yield was determined by 19F NMR spectroscopy. TBAF=tert-n-
butylammonium fluoride.
ically alters the reactivity of [Me3Si(CF2H)2]À towards enoliz-
able ketones.
Inspired by the observed excellent reactivity of [(18-
crown-6)Cs]+[Me3Si(CF2H)2]À towards the ketone 1i, we
decided to develop a catalytic difluoromethylation method
for synthesizing tertiary carbinols from Me3SiCF2H and the
challenging enolizable ketones by employing the impressive
countercation effect.[17] Thus, substoichiometric amounts of
tBuOM (M = Na, K, Cs)/18-crown-6 were used as an initiator
to investigate the reaction between 1i and Me3SiCF2H. As
shown in Scheme 2b, a remarkable metal-ion effect was also
found in this catalytic reaction and [(18-crown-6)Cs]+ again
proved to be the most effective countercation.
To determine the role of [Me3Si(CF2H)2]À in the catalytic
cycle, we investigated the progress of the (tBuOCs/18-crown-
6)-initiated reaction by VT 19F NMR experiments. The
experiment was carried out by adding a mixture of 1i
(1 equiv) and Me3SiCF2H (2 equiv) to a THF solution of
tBuOCs (20 mol%) and 18-crown-6 (20 mol%) at À708C. As
the reaction temperature gradually rose, the intermediate
[Me3Si(CF2H)2]À was observed first (À708C to À208C),
followed by the observation of the difluoromethylation
product (> À208C). Interestingly, the silicate intermediate
maintained a certain concentration even when the reaction
temperature was elevated to 58C (see Figures S10 and S11),
thus indicating a continuous consumption and regeneration of
[Me3Si(CF2H)2]À during the reaction. In contrast, when
tBuONa was used instead of tBuOCs, although the formation
of [Me3Si(CF2H)2]À was observed first, it could not difluoro-
methylate 1i to initiate the reaction. According to these
Scheme 3. Direct nucleophilic difluoromethylation of various carbonyl
compounds with Me3SiCF2H. Reaction conditions (unless otherwise
noted): Me3SiCF2H (1.2 mmol), 1 (0.6 mmol), CsF (10 mol%),
18-crown-6 (10 mol%), DME (3 mL). Yields of isolated products are
reported. [a] CsF (100 mol%), 18-crown-6 (100 mol%). [b] CsF
(20 mol%), 18-crown-6 (20 mol%). [c] Yield was determined by
19F NMR spectroscopy.
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

Angewandte
Communications
Chemie
with electron-withdrawing groups (such as Br, Cl, COOMe,
and NO2; 2g–k). 1-Phenylalkyl-1-ones containing alkyl
groups of different chain lengths gave difluoromethylated
products in good yields (2o,p). The CsF/18-crown-6/DME
system was also suitable for difluoromethylation of aliphatic
ketones (2s–v). Particularly, the readily enolizable 1,3-diphe-
nylpropan-2-one and steroid could also react with Me3SiCF2H
to afford the products 2t and 2v in 65 and 53% yields,
respectively. When conjugated methyl ketone (E)-4-phenyl-
but-3-en-2-one was subjected to the reaction, the alcohol 2r
resulting from the carbonyl addition was obtained as the sole
product. To demonstrate both the potential pharmaceutical
relevance and the functional-group tolerance of the present
direct difluoromethylation protocol, we applied it in the
synthesis of the compound (Æ)-2w, a potential antagonist of
the orexin receptor. It was previously prepared using a two-
step method: nucleophilic (phosphoryl) difluoromethylation
of the corresponding ketone followed by removal of the
phosphonate group.[18] In addition to enolizable ketones,
other carbonyl compounds including diaryl ketones, aromatic
aldehyde, enolizable aliphatic aldehyde, phthalimide, and
phthalide could also be difluoromethylated by Me3SiCF2H
under the similar reaction conditions, thus affording the
products 2x–ab in 37–90% yields.
formation of the alcoholate B, which continues to attack the
silicon atom of Me3SiCF2H to produce a new pentacoordinate
silicate C. This step is followed by the transfer of a difluoro-
methanide anion to Me3SiCF2H to release the target product
and to regenerate A. A will be constantly generated until all
of the carbonyl substrate is consumed. In view of the fact that
A is formed much faster than the carbonyl addition product,
another pathway involving the difluoromethanide anion
addition to the carbonyl group at the initiation stage
(Scheme 4, dashed arrow), which is similar to the commonly
assumed trifluoromethylation of carbonyl compounds with
Me3SiCF3,[11] is less likely to occur as a major pathway under
our conditions.
In summary, [Me3Si(CF2H)2]À,
a
pentacoordinate
À
difluoromethylsilicate anion with five Si C bonds, was
observed for the first time through the activation of
Me3SiCF2H with a nucleophilic alkali-metal salt and 18-
crown-6. It is found that the countercation effect plays
important roles in both stabilizing the [Me3Si(CF2H)2]À
intermediate and improving its nucleophilic difluoromethy-
lation potency. By employing the combination of a cesium salt
and 18-crown-6 as the initiator, catalytic difluoromethylation
of enolizable ketones was achieved in high yields because of
the avoidance of the competitive enolization, which is usually
encountered when using other initiators. During the whole
reaction, [Me3Si(CF2H)2]À is not only the difluoromethanide
anion source, but also acts as a difluoromethanide reservoir.
The formation of the bis(difluoromethyl)trimethylsilicate
intermediate with [(18-crown-6)Cs]+ as countercation alle-
viates the strong basicity of a difluoromethanide, which is of
great significance for the catalyzed difluoromethylation of
enolizable ketones.
Finally, based on our investigation, a mechanism involving
[(18-crown-6)Cs]+[Me3Si(CF2H)2]À (A) as a key intermediate
was proposed. As is shown in Scheme 4, the process
Acknowledgments
This work was supported by the National Basic Research
Program of China (2015CB931900, 2012CB821600), the
National Natural Science Foundation of China (21421002,
21472221, 21372246, 21302135), Shanghai Science and Tech-
nology program (15XD1504400 and 16QA1404600), Youth
Innovation Promotion Association CAS (2014231), and the
Chinese Academy of Sciences. Professor Aiguo Zhong (TU)
and Dr. Haoyang Wang (SIOC) are thanked for helpful
discussions.
Keywords: fluorine · ketones · reactive intermediates ·
reaction mechanisms · silicates
Scheme 4. Possible mechanism of the difluoromethylation between
Me3SiCF2H and enolizable ketones.
commences with the initial generation of [Me3Si(CF2H)2]À
from a catalytic amount CsF (or tBuOCs)/18-crown-6 and
Me3SiCF2H. The complexation of 18-crown-6 with Cs+
inhibits the formation of the strongly basic, free difluorome-
thanide, thus stabilizing [Me3Si(CF2H)2]À and favoring the
carbonyl addition rather than the enolization. The subsequent
reaction between A and carbonyl substrate leads to the
[1] Selected reviews: a) H. Sakurai, Synlett 1989, 1; b) C. Chuit,
R. J. P. Corriu, C. Reye, J. C. Young, Chem. Rev. 1993, 93, 1371;
c) R. R. Holmes, Chem. Rev. 1996, 96, 927; d) J. Hermanns, B.
Schmidt, J. Chem. Soc. Perkin Trans. 1 1999, 81; e) K. Uneyama,
J. Fluorine Chem. 2007, 128, 1087.
[2] a) E. P. A. Couzijn, D. W. F. van den Engel, J. C. Slootweg, F. J. J.
de Kanter, A. W. Ehlers, M. Schakel, K. Lammertsma, J. Am.
Chem. Soc. 2009, 131, 3741, and references therein; b) E. P. A.
4
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!

Angewandte
Communications
Chemie
Couzijn, J. C. Slootweg, A. W. Ehlers, K. Lammertsma, Z.
[8] Difluoromethylation of (hetero)arenes: a) P. S. Fier, J. F. Hart-
Anorg. Allg. Chem. 2009, 635, 1273, and references therein.
[3] a) S. A. Sullivan, C. H. DePuy, R. Damrauer, J. Am. Chem. Soc.
1981, 103, 480; b) D. A. Dixon, W. R. Hertler, D. B. Chase, W. B.
Farnham, F. Davidson, Inorg. Chem. 1988, 27, 4012;
c) I. A. H. J. F. de Keijzer, F. J. J. de Kanter, M. Schakel, R. F.
Schmitz, G. W. Klumpp, Angew. Chem. Int. Ed. Engl. 1996, 35,
1127; Angew. Chem. 1996, 108, 1183; d) A. H. J. F. de Keijzer,
F. J. J. de Kanter, M. Schakel, V. P. Osinga, G. W. Klumpp, J.
Organomet. Chem. 1997, 548, 29; e) D. Ballweg, Y. Liu, I. A.
Guzei, R. West, Silicon Chem. 2002, 1, 55; f) S. Deerenberg, M.
Schakel, A. H. J. F. de Keijzer, M. Kranenburg, M. Lutz, A. L.
Spek, K. Lammertsma, Chem. Commun. 2002, 348; g) E. P. A.
Couzijn, M. Schakel, F. J. J. de Kanter, A. W. Ehlers, M. Lutz,
A. L. Spek, K. Lammertsma, Angew. Chem. Int. Ed. 2004, 43,
3440; Angew. Chem. 2004, 116, 3522; h) E. P. A. Couzijn, A. W.
Ehlers, M. Schakel, K. Lammertsma, J. Am. Chem. Soc. 2006,
128, 13634.
wig, J. Am. Chem. Soc. 2012, 134, 5524; b) Y. Gu, X. Leng, Q.
Shen, Nat. Commun. 2014, 5, 5405; c) X.-L. Jiang, Z.-H. Chen,
X.-H. Xu, F.-L. Qing, Org. Chem. Front. 2014, 1, 774; d) C.
Matheis, K. Jouvin, L. J. Goossen, Org. Lett. 2014, 16, 5984;
e) D. E. Stephens, G. Chavez, M. Valdes, M. Dovalina, H. D.
Arman, O. V. Larionov, Org. Biomol. Chem. 2014, 12, 6190;
f) M. Nagase, Y. Kuninobu, M. Kanai, J. Am. Chem. Soc. 2016,
138, 6103; g) X. Wang, E. Tokunaga, N. Shibata, ScienceOpen
Research 2014, DOI: 10.14293/S2199-1006.1.SOR-CHEM.-
AD1QVW.v2.
[9] Difluoromethylation of heteroatoms: a) B. Bayarmagnai, C.
Matheis, K. Jouvin, L. J. Goossen, Angew. Chem. Int. Ed. 2015,
54, 5753; Angew. Chem. 2015, 127, 5845; b) K. Jouvin, C.
Matheis, L. J. Goossen, Chem. Eur. J. 2015, 21, 14324; c) J.-B.
Han, H.-L. Qin, S.-H. Ye, L. Zhu, C.-P. Zhang, J. Org. Chem.
2016, 81, 2506; d) J. L. Howard, C. Schotten, S. T. Alston, D. L.
Browne, Chem. Commun. 2016, 52, 8448.
[10] K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford,
2006.
[11] a) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757; b) X.
Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 2015, 115, 683.
[12] G. W. Gokel, W. M. Leevy, M. E. Weber, Chem. Rev. 2004, 104,
2723.
[4] a) M. Ishikawa, K. Nishimura, H. Sugisawa, M. Kumada, J.
Organomet. Chem. 1981, 218, C21; b) N. Tokitoh, T. Matsumoto,
H. Suzuki, R. Okazaki, Tetrahedron Lett. 1991, 32, 2049; c) Z.
Wang, H. Fang, Z. Xi, Tetrahedron Lett. 2005, 46, 499; d) L.
Bonnafoux, R. Scopelliti, F. R. Leroux, F. Colobert, Tetrahedron
Lett. 2007, 48, 8768; e) P. Zheng, Z. Cai, A. Garimallaprabha-
karan, P. Rooshenas, P. R. Schreiner, M. Harmata, Eur. J. Org.
Chem. 2011, 5255; f) M. Onoe, T. Morioka, M. Tobisu, N.
Chatani, Chem. Lett. 2013, 42, 238, and references therein.
[5] a) N. Maggiarosa, W. Tyrra, D. Naumann, N. V. Kirij, Y. L.
Yagupolskii, Angew. Chem. Int. Ed. 1999, 38, 2252; Angew.
Chem. 1999, 111, 2392; b) A. Kolomeitsev, V. Movchun, E.
Rusanov, G. Bissky, E. Lork, G.-V. Roschenthaler, P. Kirsch,
Chem. Commun. 1999, 1107; c) G. K. S. Prakash, F. Wang, Z.
Zhang, R. Haiges, M. Rahm, K. O. Christe, T. Mathew, G. A.
Olah, Angew. Chem. Int. Ed. 2014, 53, 11575; Angew. Chem.
2014, 126, 11759.
[6] a) S. Steinhauer, J. Bader, H.-G. Stammler, N. Ignatꢀev, B. Hoge,
Angew. Chem. Int. Ed. 2014, 53, 5206; Angew. Chem. 2014, 126,
5307; b) W. Tyrra, D. Naumann, N. V. Kirij, A. A. Kolomeitsev,
Y. L. Yagupolskii, J. Chem. Soc. Dalton Trans. 1999, 657.
[7] Difluoromethylation of carbonyl compounds and imines: a) T.
Hagiwara, T. Fuchikami, Synlett 1995, 717; b) Y. Zhao, W.
Huang, J. Zheng, J. Hu, Org. Lett. 2011, 13, 5342; c) A. A.
Tyutyunov, V. E. Boyko, S. M. Igoumnov, Fluorine Notes 2011,
[13] W. R. Dolbier, Jr., Guide to Fluorine NMR for Organic Chem-
ists, Wiley, Hoboken, 2009, pp. 118 – 119.
[14] For the NMR data of [Me3Si(CF2H)2]À generated from
Me3SiCF2H and tBuONa/18-crown-6, see the Supporting Infor-
mation.
[15] For example, the 29Si NMR signal of lithium 2,2’-biphenyldiyl-
trimethylsilicate appears at d = À116.9 ppm. See Ref. [3c].
[16] For examples on the complexation of Na+, K+, and Cs+ with 18-
crown-6, see: a) M. D. Brown, J. M. Dyke, F. Ferrante, W.
Levason, J. S. Ogden, M. Webster, Chem. Eur. J. 2006, 12, 2620;
b) T. Arliguie, M. Fourmiguꢁ, M. Ephritikhine, Organometallics
2001, 20, 282.
[17] During our preparation of this manuscript, a direct nucleophilic
difluoromethylation of enolizable ketones with Me3SiCF2H/CsF/
HMPA was developed by Radchenko and co-workers. However,
the yields are only moderate (see Ref. [7f]). In addition, both our
group and that of Radchenko (see Ref. [7f]) were not able to
reproduce Tyutyunovꢀs results of efficient difluoromethylation
of enolizable ketones with Me3SiCF2H (see Ref. [7c]).
[18] S. D. Kuduk, N. J. Liverton, J. W. Skudlarek, WO Patent Appl.
176142, 2014.
5(78),
http://notes.fluorine1.ru/public/2011/5 2011/letters/
letter4.html; d) G. Du, Y. Wang, C. Gu, B. Dai, L. He, RSC
Adv. 2015, 5, 35421; e) E. Obijalska, G. Utecht, M. K. Kowalski,
´
G. Mloston, M. Rachwalski, Tetrahedron Lett. 2015, 56, 4701;
Received: May 30, 2016
f) O. M. Michurin, D. S. Radchenko, I. V. Komarov, Tetrahedron
2016, 72, 1351.
Revised: July 19, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Reactive Intermediates
D. Chen, C. Ni, Y. Zhao, X. Cai, X. Li,
P. Xiao, J. Hu*
&&&& — &&&&
Bis(difluoromethyl)trimethylsilicate
Anion: A Key Intermediate in
Nucleophilic Difluoromethylation of
Enolizable Ketones with Me3SiCF2H
Hail to the crown: A pentacoordinate
bis(difluoromethyl)silicate anion [Me3Si-
(CF2H)2]À is observed for the first time
through the activation of Me3SiCF2H with
CsF (or tBuOCs) and 18-crown-6. Study
on its reactivity leads to the discovery and
development of an efficient, catalytic
nucleophilic difluoromethylation of eno-
lizable ketones by tuning the counter-
cation effect.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!