A General Protocol for C?H Difluoromethylation of Carbon Acids with TMSCF2Br

Article abstract of DOI:10.1002/anie.201900763

An efficient method for the selective C-difluoromethylation of carbon acids with the reagent TMSCF₂Br has been developed. A variety of structurally diverse sp³- and sp-hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, β-ketoesters, malonates, and other activated C?H nucleophiles, could be efficiently and selectively transformed into the corresponding C-difluoromethylated products under mild conditions. This protocol is also effective for the late-stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF₂Br.

Full text of DOI:10.1002/anie.201900763

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Accepted Article
Title: A General C-H Difluoromethylation Protocol for Carbon Acids
Using TMSCF2Br
Authors: Jinbo Hu, Qiqiang Xie, Ziyue Zhu, Lingchun Li, and Chuanfa
Ni
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COMMUNICATION
A General C-H Difluoromethylation Protocol for Carbon Acids
Using TMSCF Br
2
Qiqiang Xie, Ziyue Zhu, Lingchun Li, Chuanfa Ni, and Jinbo Hu*
Abstract: An efficient method for selective C-difluoromethylation of
carbon acids with TMSCF Br reagent has been developed. A variety
alkynes, their reactivity towards difluorocarbene is largely
[
12]
2
3
underexplored or unknown. Chlorodifluoromethane , N-tosyl-S-
[13]
of structurally diverse sp - and sp-hybridized carbon nucleophiles,
including esters, amides, fluorenes, terminal alkynes, β-ketoesters,
malonates, and other activated C-H nucleophiles, could be efficiently
difluoromethyl-S-phenylsulfoximine
and difluoromethyltri(n-
were used for the
[
14]
butyl)ammonium
chloride
difluoromethylation of alkynes (Scheme 1a), but these methods
suffer from several drawbacks such as low efficiency, narrow
substrate scope and/or the requirement of ozone-depleting
substance (ODS). In Shen’s work, although some examples of
oxindoles, benzofuranones and ketene silyl acetals were
showed to react with difluoromethylated sulfonium ylide (A), the
and
selectively
transformed
to
the
corresponding
C-
difluoromethylated products under mild conditions. This protocol is
also effective for the late-stage difluoromethylation of
pharmaceutically relevant molecules, and can be easily scaled up.
Moreover, ambident substrates which have more than one reactive
site towards difluorocarbene can be difluoromethylated orthogonally
[
10]
yields were typically low to moderate (Scheme 1b) . Moreover,
no examples of direct difluoromethylation of common esters or
amides were demonstrated with reagent A. Therefore, the
using TMSCF
2
Br.
Fluorinated molecules have found wide applications in
development
of
a
general
method
for
efficient
[
1]
pharmaceuticals, agrochemicals, and advanced materials.
Among them, the difluoromethyl (CF H) group is of special
interest because it is known to be isosteric to OH/SH unit and
difluoromethylation of various C-H nucleophiles with readily
available reagent is highly desirable.
[
5f,6b]
2
[
2]
can act as
a
lipophilic hydrogen bond donor.
As
a
consequence, many marketed drugs contain the CF
2
H group.
For examples, Roflumilast is an orally administered drug for the
treatment of inflammatory conditions of the lungs such as
[
3]
chronic obstructive pulmonary disease (COPD),
and
Pantoprazole is a drug used for the treatment of erosive
[
4]
esophagitis in patients with gastroesophageal reflux. Therefore,
it is of great importance to develop efficient methods to introduce
2
the CF H motif into organic molecules.
Over the past decades, numerous methods have been
[
5]
2
developed to access CF H-containing molecules. Among them,
electrophilic difluoromethylation represents a powerful strategy,
of which difluorocarbene-involved difluoromethylation has
[
6]
attracted
consideration
attention.
Difluorocarbene,
a
moderately electrophilic species, is an ideal intermediate for
difluoromethylation. Various types of difluorocarbene reagents
have been developed in recent years and their reactivity towards
[
6,7]
different nucleophiles have been studied.
Most of these
reactions are focused on 1) the difluoromethylation of
heteroatoms, such as O-, S-, N-, P- and Se-nucleophiles, and 2)
the [2+1] cycloaddition with alkenes or alkynes. However, the
difluoromethylation of C-H nucleophiles is sparse, with limited
Scheme 1. The difluoromethylation of C-H nucleophiles.
[
6d,7c]
TMSCF
2
Br, a difluorocarbene precursor developed by us
,
now is commercially available and is one of the most versatile
[
7a,8-14]
[
6]
success being reported.
β-Ketoestes and malonates are the most studied C-H
difluorocarbene reagents.
It has been applied in the
difluoromethylation of (thio)phenols, alcohols, thiols and
[
7a,8]
[
7c,7j]
[7c]
nucleophiles
, and their efficient difluoromethylation with high
amines
among others.
TMSCF Br as a versatile and robust difluorocarbene reagent,
herein, we report our recent success in the difluoromethylation
of carbon acids using TMSCF Br (Scheme 1c).
,
cyclopropa(e)nation of alkenes and alkynes
,
[
7g-h,15]
C/O selectivity were achieved very recently by the groups led by
As our continuing effort in developing
[
9]
[10]
[11]
Shibata , Shen
and Liu . However, for many other C-H
2
nucleophiles, such as common esters, amides, fluorenes and
2
At the onset of our investigation, we chose 2,2-diaryl ethyl
[*]
Q. Xie, Z. Zhu, Dr. L. Li, Dr. C. Ni, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
acetate 1a as a model substrate and dichloromethane as solvent
(
Table 1). A variety of bases (for both deprotonation of 1a and
desilylation of TMSCF Br to generate difluorocarbene) were
2
screened (Table 1, entries 1-6), and only KOtBu could give the
desired product 2a in 17% yield, together with about 1% of the
O-difluoromethylated byproduct 2a’ (entry 3). Next, we
examined the solvent effect of this reaction. When THF or DMF
was used, 2a was formed in moderate yields, and significant
345 Ling-Ling Road, Shanghai, 200032 (China)
E-mail: jinbohu@sioc.ac.cn
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
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COMMUNICATION
amounts of 2a’ were also formed (Table 1, entries 7 and 8).
hindrance of the esters does not have obvious impact on the
reaction efficiency; for instance, all of the methyl, ethyl and tert-
butyl esters gave the corresponding desired products in
excellent yields (2i-k).
When the reaction was carried out in CH
TMSCF Br was fully consumed, 2a was formed in very low yield
Table 1, entry 9). When 1,4-dioxane was used as solvent, 2a
3
CN, although
2
(
was formed in 78% yield (Table 1, entry 10), together with 2a’
being formed in 9% yield. Adding lithium iodide could decrease
the yield of byproduct 2a’ to 2% (Table 1, entry 11). To our
delight, when the reaction was carried out in toluene, 2a was
formed in 84% yield, and no 2a’ was detected (Table 1, entry
Next, we found that α-aryl amides are also suitable substrate
for this difluoromethylation reaction. However, for this type of
substrate, O-difluoromethylated byproducts were also observed
in most cases, but the C/O regioselectivity were high (86:14
to >99:1) (Scheme 3). Oxindoles, either with N-Boc or N-Me
protection, could give the desired products in moderate yields
(4a-b). Functional groups such as halogens (4c-d) are tolerated.
For morpholine- and piperidine-derived amides, the desired
products were formed in good yields (4e-g). Of special note is
that for flurbiprofen, a member of the phenylalkanoic acid family
of nonsteroidal anti-inflammatory drugs (NSAIDs), its amide
analog was successfully difluoromethylated to give 4h in 61%
yield with >99:1 C/O regioselectivity.
12).
[
a]
Table 1. Optimization of reaction conditions for the difluoromethylation of 1a.
Entry
Base [equiv]
Solvent
2a, yield
2a’,
[
c]
[%]
yield [%]
ND
ND
1
ND
ND
ND
13
18
7
9
2
1
2
3
4
5
6
7
8
9
LiOtBu (2.0)
NaOtBu (2.0)
KOtBu (2.0)
LiHMDS (2.0)
NaHMDS (2.0)
KHMDS (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
KOtBu (2.0)
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
ND (15%)
ND (60%)
17 (39%)
ND (18%)
ND (41%)
ND (7%)
64 (88%)
67 (>99%)
13 (>99%)
78 (>99%)
76 (>99%)
84 (>99%)
THF
DMF
CH
3
CN
10
11
12
1,4-dioxane
1,4-dioxane
[
b]
PhCH
3
ND
[
a] Reactions were performed on 0.2 mmol scale (1a); solvent (2 mL) was
19
used. Yields were determined by F NMR spectroscopy using PhOCF
an internal standard. [b] 0.2 equiv. of LiI was added. ND = not detected. [c]
Conversion of TMSCF Br was given in parentheses.
3
as
2
With the optimized conditions in hand (Table 1, entry 12), we
examined the scope of esters (Scheme 2). A variety of 2,2-diaryl
acetates were smoothly difluoromethylated in good yields (2a-e).
Dimethylamino group, which could react with difluorocarbene,
was tolerated under the reaction conditions, and N-
difluomethylated product was not detected (2c). Amide group
was compatible with the reaction conditions (2e). 2-Alkyl
arylacetates are also suitable substrates (2f-h); however, owing
to their relatively higher pKa value comparing to 2,2-diaryl
acetates, a mixed base of KHMDS and KOtBu were required to
achieve a full conversion of the substrates 1f-h. Notably, the
vinyl group, which could undergo [2+1] cycloaddition with
difluorocarbene species, was found to be tolerated under the
present difluoromethylation reaction conditions (2h). The steric
Scheme 3. The difluoromethylation of amides. [a] Reaction conditions: 3 (0.5
mmol, 1.0 equiv), KOtBu (2.0 equiv), TMSCF Br (2.0 equiv), PhCH (4.0 mL).
2 3
The data in parentheses refer to the ratio of C- and O-difluomethylated
19
regioisomers and was determined by F NMR spectroscopy of the crude
mixture. Isolated yield of 4 were given. [b] KHMDS (3.0 equiv) was used
instead of KOtBu (2.0 equiv), and 3.0 equiv of TMSCF Br was used.
2
Scheme 4. The reactivity of other difluorocarbene reagents towards 3g.
Inspired by these exciting results, we turned our attention to
2
the unique reactivity of TMSCF Br and carried out some
comparison experiments using other difluorocarbene sources
B1-B6 (Scheme 4). Amide 3g was selected as a model
Scheme 2. Difluoromethylation of esters. [a] Reaction conditions: 1 (0.5 mmol,
2 3
1.0 equiv), KOtBu (2.0 equiv), TMSCF Br (2.0 equiv), PhCH (4.0 mL). [b]
KOtBu (1.0 equiv) and KHMDS (1.0 equiv) were used instead of KOtBu (2.0
equiv).
substrate. As described in Scheme 3, TMSCF
2
Br can
difluoromethylate 3g to give product 4g in 72% yield. However,
[
7b,7d,10-11,16]
under the optimized and modified reaction conditions
,
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COMMUNICATION
difluorocarbene reagents B1-B6 showed low reactivity towards
(14a-d), malononitrile (14e), α-cyano esters (14f-g), β-ketoamide
(14h) and α-phosphono ester (14i) reacted smoothly, giving the
desired products in moderate to excellent yields (48%-100%). It
is noteworthy that pharmaceutically important molecules such as
phenylbutazone , a drug that has anti-inflammatory, antipyretic,
and analgesic activities, is also amenable in our protocol, and
the corresponding difluoromethylated product 14j was formed in
81% yield and with 90:10 C/O selectivity. This example shows
the potential of this difluoromethylation protocol for the late-
stage modification of other bioactive molecules.
3g, and desired product 4g was formed in low yields (0-36%),
with most of 3g being recovered. These data highlights the
unique feature and advantage of TMSCF
difluorocarbene precursor.
2
Br as a privileged
[
19]
Owing to the distinguished difluoromethylation power of
TMSCF Br reagent for esters and amides, we further extend the
2
substrate scope to other C-H carbon nucleophiles. Fluorene is
an important structure scaffold with wide application in advanced
materials because of its unique electronic and photonic
[
17]
properties.
aryl/alkyl
After brief optimization of reaction conditions, 9-
substituted fluorenes could be efficiently
difluoromethylated (Scheme 5).
Scheme 5. The difluoromethylation of fluorenes. [a] Reaction conditions: 5
2
(0.5 mmol, 1.0 equiv), KOtBu (2.0 equiv), TMSCF Br (2.0 equiv), 1,4-dioxane
(4.0 mL).
This protocol is not only useful for the difluoromethylation of
3
sp -hybridized C-H nucleophiles, but also efficient for sp-
hybridized ones. The reaction proceeded smoothly with terminal
alkynes, and a variety of difluoromethylated alkynes were
obtained (Scheme 6). Both electron-rich and electron-neutral
aryl alkynes resulted in moderate to good yields (8a-g).
Heterocycles are compatible with the reaction conditions (8h-i),
and this method is also applicable to the enyne substrate, giving
the difluoromethylated product 8j in 54% yield.
Our TMSCF
2
Br-mediated difluoromethylation protocol is also
Br than
applicable to β-ketoesters with lower loadings of TMSCF
2
[
9]
the previous report (Scheme 6). Under the aqueous basic
conditions, cyclic ketoesters (10a-g) were difluoromethylated
successfully in good yields (73%-94%) with high C/O selectivity
(
79:21 to 92:8). It is worth noting that acyclic β-ketoesters are
also suitable substrates, giving the desired product in 64% yield
and excellent C/O selectivity (10h). However, for 1,3-diketones,
such as 1,3-cyclohexanone, only O-difluoromethylated product
[
18]
was formed, which is in consistence with previous report.
Malonates also exhibited good reactivity in this
Scheme 6. The difluoromethylation of alkynes, β-ketoesters, malonates and
miscellaneous carbon acids. [a] Reaction conditions: 7, 9, 11 or 13 (0.5 mmol,
difluoromethylation reaction (Scheme 6). A variety of 2-aryl, 2-
heteroaryl, and 2–alkyl substituted malonates reacted smoothly,
affording the desired products in good to excellent yield (12a-j).
However, when un-substituted malonate (diethyl malonate) was
used as a substrate, the difluroromethylated product was formed
1
.0 equiv), KOtBu (2.0 equiv), TMSCF
2
Br (2.0 equiv), PhCH (2.0 mL); The
3
o
C/O selectivity is given in parentheses. [b] 0 C instead of RT. [c] Yield was
19
determined by F NMR spectroscopy using PhOCF
d] TMSCF Cl (2.0 equiv) was used instead of TMSCF
6.0 equiv) was used instead of KOtBu; CH Cl was used instead of PhCH
NaOtBu was used instead of KOtBu; LiI (0.2 equiv) was added; CH Cl
used instead of PhCH . [g] CH CN was used instead of PhCH . [h] LiOtBu was
. [i] LiOtBu was used
3
as an internal standard.
Br. [e] NaOH (20% aq.,
. [f]
was
[
2
2
2
2
3
1
9
in low yield (24%, determined by F NMR) and no diethyl
malonate was recovered after the reaction.
2
2
3
3
3
used instead of KOtBu; THF was used instead of PhCH
instead of KOtBu.
3
Apart from the above mentioned carbon acids, many other
carbon acids which contain an activated C-H bond could also
successfully difluoromethylated (Scheme 6). α-Sulfonyl esters
To further demonstrate the practicability of our method, the
gram-scale syntheses were performed (Scheme 7). When the
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COMMUNICATION
Scheme 8. Orthogonal transformations of ambident substrates. ND = not
detected.
reaction with complex substrate 11g was scaled up to 2.23
grams, the desired product 12g was formed in 88% yield (2.19
g). For the drug molecule 13j, 10 mmol-scale (3.08 g) reaction
could give the difluoromethylated analog 14j in 79% yield. 2-
In
difluoromethylation of a wide range of carbon acids has been
developed, using TMSCF Br as a powerful difluorocarbene
conclusion,
a
general
method
for
efficient
(
Methoxy-2-naphthyl)-propanoic acid 15 (its S-isomer is called
naproxen), a nonsteroidal anti-inflammatory drug (NSAID) used
2
[
20]
to treat pain or inflammation , could be easily transformed to
ester 16. 16 could be efficiently difluoromethylated to 17, which
underwent hydrolysis to give 18. Thus, from the racemic
naproxen, we could easily obtain the difluoromethylated
naproxen 18 in three steps with 67% overall yield. These
reagent. This protocol is easy to scale up and amenable to the
late-stage modification of bioactive compounds. Compared with
2
other difluorocarbene reagents, TMSCF Br showed unique
reactivity towards C-nucleophiles in terms of the reaction
efficiency and substrate scope. We also demonstrated the
examples
further
showcase
the
potency
of
our
2
orthogonal reactivity of TMSCF Br towards ambident substrates,
difluoromethylation protocol in the late-stage difluoromethylation
of bioactive compounds for drug discovery.
which has never been exemplified by other difluorocarbene
reagents. This work not only provides a facile approach to
3
access the difluoromethylated analog of sp - and sp-hybridized
C-nucleophiles, it also opens a new avenue for the orthogonal
reactivity study in difluorocarbene chemistry. Further
investigations in this direction are underway in our laboratory.
Acknowledgements
This work was supported by the National Key Research and
Development Programof China (Nos. 2015CB931900,
2016YFB0101200), the National Natural Science Foundation of
China (Nos. 21632009, 21421002, 21472221), the Key
Programs of the Chinese Academy of Sciences (No. KGZD-EW-
T08), the Key Research Program of Frontier Sciences of CAS
(
No. QYZDJ-SSW-SLH049), and Shanghai Science and
Technology program (No. 16QA1404600).
Scheme 7. Late-stage difluoromethylation of bioactive and complex molecules
in gram scale.
Keywords: difluorocarbene • difluoromethylation • carbon acids
•
bromodifluoromethyltrimethylsilane • synthetic method
2
Due to the unique feature of TMSCF Br that can generate
difluorocarbene under different conditions, we envisioned that its References
orthogonal reactivity towards different functional groups in
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Scheme 8). For alkyne 7b, under basic conditions, only the
difluoromethylated alkyne 8b was formed in 84% yield; while
(
o
with nBu
4
NBr being used as a catalyst at 110 C, the
[
21]
difluorocyclopropene 19 was formed exclusively in 94% yield.
[2]
For the vinyl-containing ester 1h, the acidic C-H bond was
selectively difluoromethylated to give 2h in 78% yield under
basic conditions, and the difluorocyclopropane 20 was
exclusively generated in 89% yield at high temperature under
neutral conditions. To the best of our knowledge, this type of
orthogonal reactivity has never been exhibited by other
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[
21] We carried out the reaction between (phenylethynyl)potassium
o
(
prepared in situ from phenylacetylene and KH) and TMSCF
2
Br at 0
C
for 30 min, and found that TMSCF
(
2
Br was recovered in 93% yield
determined by F NMR spectroscopy), with no other fluorinated signal
being observed. This result rules out the possibility that the current C-
difluoromethylation with TMSCF Br proceeds through stepwise
19
2
a
sequence (new C-C bond formation along with C-Br bond cleavage,
followed by C-Si bond cleavage).
[
2
22] The unique reactivity of TMSCF Br can be attributed to its multiple (and
tunable) activation modes to release difluorocarbene, such as under
strongly basic (alkoxide, hydroxide), weakly basic (NaOAc), neutral
4 2
(nBu NBr), acidic (KHF ) conditions as well as at different temperatures
(also see Ref. 7c and 7j). However, other known difluorocarbene
reagents usually have only one activation mode to generate
difluorocarbene. For difluorocarbene-involved difluoromethylation with
carbanions, basic conditions and relatively lower temperature are often
used (such as Condition A in Scheme 8); while for difluorocarbene-
involved cycloprope(a)nations with alkynes or alkenes, non-basic
conditions and sufficiently high temperature are usually required (such
as Condition B in Scheme 8). Therefore, the orthogonal reactivity of
2
TMSCF Br (as difluorocarbene reagent) towards carbanions and
unsaturated carbon-carbon bonds can be well tuned by changing the
acidity/basicity of the reaction medium as well as the reaction
temperature. For related discussions, also see Ref 6d, 7c and 7j.
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Angewandte Chemie International Edition
10.1002/anie.201900763
COMMUNICATION
COMMUNICATION
Carbene for carbon:
Qiqiang Xie, Ziyue Zhu,
Difluorocarbene (generated
from TMSCF Br) is able to
2
Lingchun, Li, Chuanfa Ni, and
Jinbo Hu*
efficiently react with various
carbon nucleophiles. This
powerful C-H
Page No. – Page No.
A General C-H
difluoromethylation protocol
provides an easy access to
C-difluoromethylated
products from corresponding
carbon acids under mild
conditions.
Difluoromethylation Protocol
for Carbon Acids Using
TMSCF Br
2
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