Carbon-Selective Difluoromethylation of Soft Carbon Nucleophiles with Difluoromethylated Sulfonium Ylide

Article abstract of DOI:10.1002/cjoc.201800383

A highly carbon-selective difluoromethylation of soft carbon nucleophiles including β-ketoesters, malonates, oxindoles, benzofuranones and ketene silyl acetals with a difluoromethylated sulfonium ylide under mild conditions was described. Mechanistic studies suggest that these difluoromethylating reactions proceed via a difluorocarbene pathway.

Full text of DOI:10.1002/cjoc.201800383

Carbon-Selective Difluoromethylation of Soft Carbon Nucleophiles with
Difluoromethylated Sulfonium Ylide
Jiansheng Zhu,a Hanliang Zheng,b Xiao-Song Xue,*, b Yisa Xiao,a Yafei Liua and Qilong Shen*,a
ABSTRACT A highly carbon-selective difluoromethylation of soft carbon nucleophiles including β-ketoesters, malonates, oxindoles, benzofuranones and
ketene silyl acetals with a difluoromethylated sulfonium ylide under mild conditions was described. Mechanistic studies suggest that these
difluoromethylating reactions proceed via a difluorocarbene pathway.
KEYWORDS fluorine, electrophilic substitution, ylides, regioselectivity
which was difficult to separate was also generated.[13] Likewise,
Introduction
when
N,N-dimethyl-S-difluoromethyl-S-phenylsulfonximinium
Difluoromethyl group (-CF2H), an analog of
well-recognized trifluoromethyl group (-CF3), has attracted
considerable recent attention from both academia and the
pharmaceutical industry.[1] The difluoromethyl group has
well-known common beneficial properties of the fluoroalkyl
moiety such as high lipophilicity that may improve the
molecule’s cell membrane permeability, and strong
electron-withdrawing ability that may increase the drug’s
metabolic stability.[2] In addition, because the C-H bond in
the difluoromethyl groups is slightly acidic, the
difluoromethyl group is generally considered as a surrogate
of a hydroxyl or a thiol group,[3] that may improve the drug
molecule’s enzyme binging selectivity. Thus, incorporation of
the difluoromethyl group into leading drug candidates has
become an indispensable strategy for new drug discovery.
Consequently, over the past decade, significant progress has
been achieved in the development of efficient method for
the introduction of the difluoromethyl group into small
molecules.[4]
tetrafluoroborate 2 was used under the similar conditions, the C-
and O-difluoromethylated products were formed with a ratio of
<2:1.[14] Magnier and coworkers also reported that -ketoester
derivated
from
indanone
reacted
with
or
N-tosyl-S-difluoro-methyl-S-phenylsulfoximine
3
N-triflyl-S-difluoro-methyl-S-phenylsulfoximine 4 using DBU as a
base to give, again, a mixture of C- and O-difluoromethylated
products with a ratio of 1.3:1 in moderate yields (Figure 1).[15] In
these reactions, a mechanism involved a nucleophilic attack of
the enolate on the in situ formed difluorocarene was proposed.
Nevertheless, the low regioselectivity of the reactions makes
them less applicable. Thus, clearly, development of an efficient
method for the highly carbon-selective difluoromethylation of
soft carbon nucleophiles such as -ketoesters is highly desirable.
Previous work
O
O
OCF2H
CO2R
CF2H
CO2R
1 - 4
CO2R
+
DBU
One straightforward and attractive route for the preparation
of difluoromethylated compounds is the direct nucleophilic attack
of a nucleophile with an in situ generated difluorocarbene species
under mild conditions.[5] In this respect, a variety of different
difluorocarbene precursors[6] have been invented and their
reactions with different nucleophiles have been extensively
C/O = 1.3:1 - 7.3:1
Me CF2Br
MeO2C
CO2Me
O
S
NMe2
O
NR
Me
Me
S
S
Ph
S
Ph
CF2H Ph
CF2H
CF2H
OTf
BF4
R = Ts, 3
Tf, 4
O2N
Me
1
2
5
This work
studied. For example, reaction of difluorocarbene with
a
heteroatom-centered nucleophile such as phenol,[7] alcohol,[8]
thiol[6d,7i-j,8b,9] or amine[10] occurred quite efficiently to afford the
corresponding difluoromethyl ether, thioether or amine in good
yields. Alternatively, difluorocarbene may react with an alkene or
O
O
OCF2H
EWG
EWG
5
EWG
+
Li2CO3
or LiOtBu
CF2H
n
n
n
EWG = electron-withdrawing group
C/O = 6:1 - 100:0
alkyne
to
give
gem-
difluorocyclopropane
or
Figure 1 Reactions of -ketoesters with different difluorocarbene reagents.
gem-difluorocyclopropene.[6e-f,8b,11] Furthermore, hard carbon
nucleophiles such as alkyl zinc reagents also reacted efficiently
with difluorocarbene, as reported by Dilman and coworkers.[12] In
these reactions, the in situ generated difluorocarbene reacted
with nucleophile to form an alkyl-substituted difluoromethyl
anion, which was then trapped by different electrophiles to give
difluoromethylene compounds in high yields.
Herein, we reported that when Li2CO3 or LiOtBu was used as a
base, reactions of a variety of soft carbon nucleophiles including
-ketoesters, malonates, oxindoles, benzofuranones, and ketene
silyl acetals with a difluoromethylated sulfonium ylide 5, which
was developed previously in our group as an electrophilic
difluoromethylating reagent that can react with alcohols in the
presence of a Lewis acid or BrØnsted acid,[16] occurred to give the
difluoromethylated products with excellent C/O regioselectivity in
high yields (Figure 1). Mechanistic studies suggest that these
Despite of the tremendous success in the reactions of
difluorocarbene with different nucleophiles, the reactions of
difluorocarbene with soft carbon nucleophiles such as
-ketoesters were problematic. For example, Shibata and
coworkers reported that reactions of several -ketoesters with
S-(bromodifluoromethyl)diarylsulfonium salts 1 in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave a mixture of C-
and O-difluoromethylated products with a ratio of 2.3:1-7.3:1 in
moderate yields. In addition, a carbon brominated side product
difluoromethylating reactions proceed via
pathway.
a difluorocarbene
Results and Discussion
Initially, we chose the reaction of -ketoester methyl
a Key Laboratory of Organofluorine Chemistry, Center for Excellence in
Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032.
b State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineer, Nankai University, Tianjin 300071
E-mail: shenql@sioc.ac.cn; xuexs@nankai.edu.cn
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article as doi: 10.1002/cjoc.201800383

6-methul-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
with
the reactions (Scheme 1, 6e-j). Reaction of -ketoesters derived
from tetralone was also found to be good substrate for
difluoromethylation and furnished the product 6k in 56% yields
and excellent C/O regioselectivity, while the regioselectivity (87:13)
was decreased for the reaction of β-ketoester derived from
1-benzosuberone with reagent 5 under the standard conditions
(Scheme 1, 6k-l). Interestingly, linear -ketoesters also reacted
with reagent 5 to give the corresponding difluoromethylated
products 6m-o in high yields with high C/O regioselectivities
(Scheme 1, 6m-o).
reagent 5 as a model reaction to optimize the reaction conditions.
To our surprise, when an organic base such as DBU, Et3N or
4-dimethylaminopyridine (DMAP) was used as the base,[17] the
formation of the difluoromethylated compounds were observed
in less than 10% yields (Table 1, entries 1-3). Instead, the
N-difluoromethylated side product of the base was generated in
high yields. In contrast, when an inorganic base such as Na2CO3,
K2CO3, Cs2CO3, KOAc, NaOAc, NaHCO3, K3PO4, NaOH, the reactions
occurred smoothly to give the C-difluoromethylated product 6a in
moderate 20-44% yields (Table 1, entries 4-11). To our delight, the
yield of 6a was improved significantly to 76% when Li2CO3 was use
as the base (Table 1, entry 12). Interestingly, in these cases, the
O-difluoromethylated product 6a’ was generated in less than 2%,
as determined by 19F NMR spectroscopy of the reaction mixture.
Next, we studied the effect of the solvents on the yields and the
regioselectivity of the reaction. It was found that the polarity of
the solvent plays a decisive role for the high yielding formation of
compound 6. Reactions using Li2CO3 as the base in less polar
solvents such as toluene, CH2Cl2 did not take place at all and the
same reaction in THF or CH3CN occurred in less than 10% yields,
while reactions in polar aprotic solvents such as
dimethylacetamide (DMAc) or N-methyl-2-pyrrolidone (NMP)
occurred in high yields (Table 1, entries 13-18). We then further
investigated the effect of other lithium bases. As shown in entries
19-22, the yields were slightly lower when LiOHH2O, LiOH, LiOAc
or LiOMe was used as the base than that using Li2CO3 as the base.
Finally, the amount of reagent 5 could be further decrease to 1.3
equivalents without erosion of the yield (Table 1, entries 23-24).
Again, the formation of the O-difluoromethylated side product 6a’
in these cases was less than 2%.
Scheme 1 Scope for the reactions of reagent 5 with -ketoesters.a,b
Table 1 Optimization of the conditions for the reaction of -ketoester with
reagent 5 in the presence of different bases.a
[a] Reaction conditions: -ketoester (0.5 mmol), reagent 5 (0.65 mmol),
Li2CO3 (1.0 mmol) in DMF (2.5 mL) at room temperature for 12 h; [b]
Isolated yields. The C/O ratio was shown in parenthesis as determined by
19F NMR spectroscopy of the reaction crude with 1-fluoronaphthalene as
the internal standard; [c] LiOH was used instead of Li2CO3; [d] LiOtBu was
used as the base at -40 oC for 1.0 h.
Encouraged by excellent C/O difluoromethylation selectivity
for the reactions of -ketoesters with reagent 5, we next tried to
extend this difluoromethylation protocol to other soft carbon
nucleophiles such as malonates, oxindoles and benzofuranones.
As summaried in Scheme 2, a variety of malonate derivatives were
difluoromethylated in moderate to high yields when LiOtBu was
used as the base. In general, only the C-difluoromethylated
products were observed, while the O-difluoromethylated
products were not detected by 19F NMR spectroscopy of the
reaction mixture. Both 2-aryl or 2-alkyl-substituted malonates
[a] Reaction conditions: -ketoester (0.1 mmol), reagent 5 (0.15 mmol),
base (0.2 mmol) in solvent (0.5 mL) at room temperature for 12 h; [b]
Yields were determined by 19F NMR spectroscopy with
1-fluoronaphthalene as the internal standard; [c] 0.1 mmol of reagent 5
was used; [d] 0.13 mmol of reagent 5 was used.
reacted with reagent
difluoromethylated malonates in high yields. For example,
reactions of diethyl 2-(3,4-dichlorophenyl)malonate and triethyl
5 to generate the corresponding
Having the suitable conditions for the highly carbon-selective
difluoromethylation of -ketoesters identified, we next explored
the generality of the difluoromethylation protocol. As summarized
in Scheme 1, a variety of -ketoesters were difluoromethylated in
moderate to high yields with high C/O regioselectivity. In general,
the substituents on the ester group have negligible effect on the
yields and the C/O selectivity of the reactions. For example,
reaction of ethyl, isopropyl or adamantyl ester of -ketoester
derived from indanone with reagent 5 occurred to full conversion
to give 6b-d in 65%, 67% and 70%, respectively, with excellent C/O
selectivity (Scheme 1, 6b-d). Likewise, -ketoesters with both
electron-donating or electron-withdrawing substituted groups on
the arene moiety did not affect the yields or the selectivtivity of
ethane-1,1,2-tricarboxylate with reagent
5 occurred to full
conversion to give compounds 7i and 7r in quantitative yield,
respectively (Scheme 2, 7i and 7r). In addition, electron-donating
or electron withdrawing substituted groups on the arene moiety
of diethyl 2-arylmalonates did not affect the yields of the
reactions (Scheme 2, 7a-j). Likewise, the substituted group of the
ester moiety of the malonate did not affect the yields of the
reaction as well. For example, di-tert-butyl-2-phenylmalonate
reacted with regent 5 to give the corresponding product 7l in 83%
yields. Furthermore, ethyl cyanozcylate also reacted efficiently
(Scheme 2, 7v-w). Besides, reactions of oxindoles and
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benzofuranones with reagent 5 occurred in good yields with good
to excellent C/O regioselectivities (85:15-99:1) (Scheme 2, 8a-d,
9a-d). Because of the mild conditions, common functional groups
such as chloride (7h-i, 9a), fluoride (7j, 8c, 9b), nitro (7f), cyano
(7s, 9c), enolizable ketone (7d), protected aldehyde (7t), and
amide (7k) were compatible. Importantly, the reaction conducted
at gram-scale worked equally well (Scheme 2, 7a and 7l-m).
Scheme 2 Scope for the reactions of reagent 5 with malonates, oxindoles
and benzofuranones.a,b
MeO2C
CO2Me
CF2H
S
conditions
Nu
+
Nu CF2H
O2N
7-9
malonate, reagent 5, LiOtBu, CH3CN, rt, 20 min; E = CO2Et
[a] Reaction conditions: ketene silyl acetal (1.0 mmol), reagent 5 (1.5
mmol), LiOtBu (2.0 mmol) in CH3CN (5.0 mL) at -40 oC for 10 min; [b]
Isolated yields. The yields determined by 19F NMR spectroscopy of the
reaction mixture with 1-fluoronaphthalene as the internal standard were
shown in the parenthesis.
R = CF3, 90%, 7e
NO2, 88%, 7f
CO2Me, 97%, 7g
E
E
R = H, 99%, 7a (1.4 g)
Me, 82%, 7b
E
E
R
CF2H
CF2H
OMe, 87%, 7c
COCH3, 91%, 7d
R
E
E
E
E
E
E
O
E
E
Cl
CF2H
Cl
CF2H
CF2H
Ph
N
CF2H
H
Mechanistically, the carbon-selective α-difluoromethylation of
-ketoester might proceed via three different pathways, as shown
in Figure 2. 1) A single-electron transfer (SET) process may take
place between the enolate and reagent 5, followed by the
cleavage of S-CF2H bond to generate a difluoromethyl radical,
which may add to the enolate radical cation to give the product
(Pathway I). 2) The enolate may directly nucleophilic attack of the
difluoromethyl group of reagent 5 (Pathway II). 3) In the presence
of a base, reagent 5 may undergo deprotonation to generate
difluorocarbene, which is then attacked by the enolate of
-ketoester (Pathway III).
Cl
Cl
99%, 7i
F
99%, 7h
99%, 7j
92%, 7k
tBuO2C CO2tBu
CF2H
R = H, 83%, 7l
EtO2C CF2H R = Me, 62%, 7n
Et, 82%, 7o
(1.4 g)
isobutyl, 70%, 7m
Bn, 90%, 7pc
allyl, 78%, 7q
EtO2C
R
(0.8 g)
R
NC CO2Et
CF2H
NC CO2Et
CF2H
EtO2C
EtO2C
R
EtO2C CF2H
EtO2C CF2H
R = CO2Et, 99%, 7r
CH2CN, 85%, 7s
84%, 7u
84%, 7v
55%, 7w
CH2CH(OMe)2, 80%, 7t
oxindole, reagent 5, Li2CO3, DMF, rt, 12 h
tBu
F
CF2H
O
CF2H
CF2H
CF2H
O
MeO
O
O
N
N
N
N
Boc
Boc
Boc
Boc
57% (86:14), 8a
44% (89:11), 8b
56% (89:11), 8c 40% (85:15), 8d
benzofurabne, reagent 5, LiOMe, DMF, rt, 12 h
Cl NC
F
MeO2C
Figure 2 Reactions of -ketoesters with different difluorocarbene reagents.
CF2H
O
CF2H
O
CF2H
CF2H
O
To probe whether the reaction proceeds via a SET process, we
studied the reaction in the presence of 1.0 equivalent of SET
inhibitor 1,4-dinitrobenzene or 2,6-di-tert-butyl-4-methylphenol
O
O
O
O
O
65% (91:9), 9a
54% (91:9), 9bd
71% (99:1), 9c
63% (97:3), 9d
(BHT)
and
a
free
radical
trap
[a] Reaction conditions as indicated in the table; [b] Isolated yields. The
C/O ratio was shown in parenthesis as determined by 19F NMR
spectroscopy of the reaction crude with 1-fluoronaphthalene as the
internal standard; [c] DMF was used as the solvent; [d] LiOtBu was used as
the base.
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). It was found that
the yields in the presence of these reagents were slightly lower.
Likewise, the yields of the C-difluoromethylated products for
reactions of other nucleophile with reagent 5 in the presence of
these SET inhibitors decreased slightly. Yet, the reactions were
not completely inhibited (Eq. 1). These results clearly exclude the
SET pathway I.
To distinguish pathways II and III, we synthesized a deuterated
difluoromethyl-substituted sulfonium ylide 5-D and subjected it to
the difluoromethylating reactions. Theoretically, if the reaction
proceeds via a difluorocarbene pathway, the product derived from
significant H/D exchange would be expected. Otherwise, low H/D
exchange would be observed for the direct nucleophilic
substitution pathway. Experimentally, reactions of -ketoester
with reagent 5-D generated compound 6a-H/D in 66% yield with
27% deuteration (Eq. 2). Since both reagent 5-D and the
difluomethylated product did not undergo H/D exchange under
the reaction conditions, these observations are inconsistent with
a direct nucleophile subsitition pathway. Likewise, reactions of
other nucleophiles such as malonates, oxindoles and
benzofuranones with reagent 5-D generated the corresponding
products with deuterated-scrambling (see SI for details). These
Finally, it was found that ketene silyl acetals reacted efficiently
with reagent 5 to give the C-difluoromethylated products in good
yields when the reactions were coducted in MeCN at -40 oC for 10
min using LiOtBu as the base (see Supporting Information for
details).[18-20] The formation of the O-difluoromethylated products
were not detected. As shown in Scheme 3, reactions of ketene
silyl acetals bearing C-C double bond, four and five-membered
rings with reagent 5 occurred smoothly gave the corresponding
difluoromethylated products in moderate yields.
Scheme 3 Scope for the reactions of reagent 5 with ketene silyl acetals.a,b
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results
clearly
support
that
the
carbon-selective
the percentage of deuteration of reagent 5 increased during the
reaction. As shown in Eq. 3, reaction of -ketoester with 1.3
difluoromethylating reaction proceeds highly likely via
difluorocarbene pathway.
a
equivalents of 43% deuterated reagent
5 under standard
conditions occurred to full conversion to give the desired product
in 56% yield with 8% deuteration, while the percentage of
deuteration of the remaining reagent 5 increased to 60%. These
results indicate
a significant kinetic isotope effect for the
difluoromethylation of -ketoester with reagent 5, which is
consistent with the theoretical studies that the formation of
difluorocarbene is the rate limiting step.
To gain more support for the difluorocarbene pathway, we
studied the reaction of -ketoester with reagent 5 by DFT
calculation.[21] As shown in Figure 3, these studies showed that
the formation of difluorocarbene by treatment of reagent 5 with
Li2CO3 is an exothermic process (G = -1.3 kcal/mol) with a barrier
of 15.6 kcal/mol. In addition, the relative free energy of the
transition structure TS-C-1 for the nucleophilic attack of the
carbon is energetically lower by 1.6 kcal/mol than that of the
transition structure TS-O-1 for the nucleophilic attack of the
oxygen (Fig. 4), which corresponds to
a
ratio of
C/O-difluoromethylated product of 94:6 in favor of the
C-difluoromethylated product. These results are consistent with
the C/O regioselectivity observed experimentally. Furthermore,
these studies also showed that the barrier (15.6 kcal/mol) for the
formation of difluorocarbene is much higher than that of
nucleophilic attack of enolate to difluorocarbene (5.7 kcal/mol),
which suggests that the rate limiting step of the reaction is the
formation of difluorocarbene. Experimentally, it was found that
Figure
3
Energy profile (G in kcal/mol) computed at the
MD-M06-2X/6-311+G(2d, p)//SMD-M06-2X/6-31G(d, p) level of theory for
difluorocarbene formation from reagent 5.
Figure 4 Energy profile (G in kcal/mol) computed at the SMD-M06-2X/6-311+G(2d, p)//SMD-M06-2X/6-31G(d, p) level of theory for the formation of C-
and O- difluoromethylated products proceeding via difluorocarbene mechanism.
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room temperature for 12 h. Then 20 mL of distilled water and 20
mL of Et2O was added and the organic phase was separated. The
aqueous phase was extracted with Et2O (2 x 20 mL) and the
combined organic layer was washed with brine (2 x 20 mL). The
separated organic phase was dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. The product was purified by
flash chromatography on silica gel.
Supporting Information
Finally, as an example of the applicability of the current
difluoromethylation protocol, we tried to synthesize the
difluoromethylated analog Ibuprofen, an anti-inflammatory and
analgesic drug. As shown in Figure 5, treatment of compound 7m,
which was obtained in gram scale from the reaction of
di-tert-butyl 2-(4-isobutylphenyl)malonate with reagent 5, with
CF3COOH in CH2Cl2 at room temperature for 3.0 h to give the
corresponding acid. Without further purification, the acid
underwent decarboxylation after 12 h in acetone at room
temperature to give compound 11 in 76% yield. To the best of our
knowledge, it represents the first efficient method for the
preparation of difluoromethylated analog of ibuprofen.
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
The authors gratefully acknowledge the financial support from
National Natural Science Foundation of China (21625206,
21632009, 21572258, 21572259, 21421002, 21772098) and the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDB20000000) for financial support.
References
tBuO2C CO2tBu
CF2H
CF2H
CO2H
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2) acetone, rt, 12 h
(3)
7m (0.8 g)
11 (76%, 0.34 g)
Figure 5 Synthesis of the analog of Ibuprofen.
Conclusions
In conclusion, we have developed
a new protocol for
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carbon-selective difluoromethylation of soft carbonyl compounds
including β-ketoesters, malonates, oxindoles, benzofuranones
and ketene silyl acetals under mild conditions. For most of the
substrates, excellent C/O regioselectivities were achieved.
Mechanistic studies suggest that these difluoromethylating
reactions proceed via a difluorocarbene pathway. In addition, the
method can be applied in the preparation of the
difluoromethylated analog of Ibuprofen. Development of the
asymmetric difluoromethylation of these soft carbon nucleophiles
is undergoing currently in our laboratory.
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Experimental
General information.
All solvents were purified by standard method. 1H NMR
spectra were recorded on a 500 MHz, 400 MHz or 300 MHz
spectrometer. 19F NMR spectra were recorded on a 376 MHz or
282 MHz spectrometer. 13C NMR spectra were recorded on a 125
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Zhang, C.-P. ; Chen, Q.-Y.; Guo, Y.; Xiao, J.-C.; Gu, Y.-C. Coord. Chem.
Rev. 2014, 261, 28; (e) Zhang, C. Adv. Syn. Catal. 2017, 359, 372.
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1
or 100 MHz spectrometer. H NMR and 13C NMR chemical shifts
were determined relative to internal standard TMS at δ 0.0 and
19F NMR chemical shifts were determined relative to CFCl3 as inter
standard. Chemical shifts (δ) are reported in ppm, and coupling
constants (J) are in Hertz (Hz). The following abbreviations were
used to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad. Flash column
chromatograph was carried out using 300-400 mesh silica gel at
medium pressure.
General Procedure for Difluoromethylation of β-Ketoester
β-ketoester (0.50 mmol), Li2CO3 (74 mg, 1.0 mmol), and
reagent 5 (218 mg, 0.65 mmol) were placed into an oven-dried
Schlenk tube that was equipped with a stirring bar. The tube was
quickly sealed with a rubber stopper and 2.5 mL of freshly
distilled DMF was added. The reaction mixture was stirred at
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developed by reactions of the enolates with CF3H. A mechanism
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reacted with in situ generated difluorocarbene to from
difluorocyclopropane, which underwent ring opening to give
halogenative difluorohomologation product upon addition of
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Revision D.01; Gaussian Inc.: Wallingford, CT, 2013. For details, see
the SI.
[22] During the preparation of the manuscript, Shibata and coworkers
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-ketoesters: Wang, J.-D; Tokunaga, E.; Shibata, N. Chem. Commun.
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97.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2017
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
[13] Liu, G.-K.; Wang, X.; Lu, X.; Xu, X.-H.; Tokunaga, E.; Shibata, N.
ChemistryOpen 2012, 1, 227.
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Entry for the Table of Contents
O
Page No.
EtO2C CF2H
CF2H
Carbon-Selective Difluoromethylation of
EtO2C
R
CO2Me
Soft
Carbon
Nucleophiles
with
MeO2C
CO2Me
Ar
Ar
CF2H
Difluoromethylated Sulfonium Ylide
CO2Et
NC
S
O
CF2
CF2H
CF2H
N
O
O2N
Boc
CF2H
CF2H
CO2R
O
A highly carbon-selective difluoromethylation of soft carbon nucleophiles including β-ketoesters,
malonates, oxindoles, benzofuranones and ketene silyl acetals with difluoromethylated
a
sulfonium ylide under mild conditions was described. Mechanistic studies suggest that these
difluoromethylating reactions proceed via a difluorocarbene pathway.
Jiansheng Zhu, Hanliang Zheng, Xiaosong
Xue,* Yisa Xiao, Yafei Liu and Qilong Shen*
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