Aqueous Base Promoted O-Difluoromethylation of Carboxylic Acids with TMSCF2Br: Bench-Top Access to Difluoromethyl Esters

Article abstract of DOI:10.1021/acs.orglett.9b03604

A method for the O-difluoromethylation of carboxylic acids using commercially available TMSCF₂Br is disclosed. The devised benchtop reaction system is air-stable and offers mild reaction conditions while using readily available reagents and sol

Full text of DOI:10.1021/acs.orglett.9b03604

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Aqueous Base Promoted O‑Difluoromethylation of Carboxylic Acids
with TMSCF2Br: Bench-Top Access to Difluoromethyl Esters
Vinayak Krishnamurti,‡ Colby Barrett,‡ Xanath Ispizua-Rodriguez, Matthew Coe,§
and G. K. Surya Prakash*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California
90089-1661, United States
S
* Supporting Information
ABSTRACT: A method for the O-difluoromethylation of carboxylic
acids using commercially available TMSCF2Br is disclosed. The
devised benchtop reaction system is air-stable and offers mild reaction
conditions while using readily available reagents and solvents. The
method is applicable to both aliphatic and aromatic carboxylic acids
while demonstrating compatibility with a range of commonly
encountered functional groups. The difluoromethyl esters of FDA
approved drugs and pharmaceutically relevant molecules are also
presented, demonstrating the potential for late-stage functionalization.
generation of difluoromethyl esters, which could prove to be
valuable compounds. One reported approach uses fluorosulfo-
nyldifluoroacetic acid at room temperature with metal
carboxylates to form the corresponding difluoromethyl esters
in moderate to good yields, but this also generates SO2 as an
undesirable byproduct.22 Another report describes a difluor-
omethylation using Ph3P+−CF2−COO−, wherein triphenyl-
phosphine and carbon dioxide are byproducts.23 Benzoic acid
with trimethyl(trifluoromethyl)stannane has been shown to
yield difluoromethyl benzoate.24
Owing to the inherent toxicity of SO2, PPh3, and tin
compounds, an alternative difluoromethylation approach is
desirable. CF2N2 can produce −CF2− esters from the
corresponding carboxylic acids, but the hazards associated
with the synthesis and use of this gaseous and explosive reagent
render this approach less accessible.25
mong the plethora of fluorinated groups pursued for their
Aability to modify the physical and chemical properties of
molecules,1−3 the difluoromethyl group stands out as a
potentially invaluable unit in the preparation of bioisosteres
of medicinally relevant compounds, owing to its similarity to
−OH.4,5 This potential application to drug discovery has
spurred the development of novel methods for its installation,
including gem-difluorination6−8 and direct difluoromethyla-
tion9−12 reactions. An alternative approach comes in the form
of difluorocarbene. Generated from silicon-based reagents, this
intermediate has received much recent interest, having been
applied to C,13−15 N,16 B,17 O,18 S,19 Se,20 and P21 centers.
Considering the abundance of carboxylic acids in nature and in
pharmacologically relevant molecules, it is interesting that such
an approach has rarely been applied (Figure 1) for the
Silicon reagents, by virtue of their mild activation
conditions26−29 and nontoxic byproducts, provide one such
alternative. Among the various reagents used to release
difluorocarbene, TMSCF2Br, first prepared by our group,30a
stands out owing to its availability, effectiveness, and
compatibility with aqueous reaction systems.30b Using
TMSCF2Br to perform a difluoromethylation of carboxylic
acids would be a facile, accessible, and safe method to
synthesize difluoromethyl esters. Based on our previous
experience with difluorocarbene chemistry,20,21 we envisioned
a reaction system wherein the carbene generated from
TMSCF2Br would react with a carboxylate anion, yielding a
difluoromethyl ester upon protonation (Scheme 1). Benzoic
Figure 1. Prior art on the direct difluoromethylation of carboxylic
acids.
Received: October 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03604
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
acid 1a was chosen as a model for optimization studies (Table
Scheme 2. Substrate Scope
1).
Scheme 1. Mechanistic Hypothesis
Table 1. Optimization Experiments on 2a
a
b
c
trial
base (equiv)
solvent
TMSCF2Br (equiv)
2a (%)
1
2
3
4
5
6
7
NaOtBu (1.1)
KOtBu (1.1)
KOtBu (1.1)
K2CO3 (1.1)
KOH (1.1)
KOH (2.2)
KOH (2.2)
KOH (2.2)
KOH (2.2)
KOH (2.2)
triglyme
triglyme
CH3CN
CH3CN
CH3CN
DMF
CH3CN
CH3CN
CH3CN
CH3CN
2
2
2
2
2
2
2
2
3
44
39
58
27
48
10
72
72
69
66
d
8
9
d
d
10
4
a
b
Reactions performed with 0.25 mmol of 1a. 0.4 M concentration of
c
1a in solvent. Yield determined by 19F NMR using fluorobenzene as
internal standard. 100 μL of H2O added.
d
Sodium tert-butoxide (trial 1) and potassium tert-butoxide
(trial 2) proved mildly effective in facilitating this trans-
formation in triglyme. Performing the reaction in acetonitrile
increased the amount of difluoromethyl benzoate (2a)
observed (trial 3). Of the bases screened, KOH worked the
best, with 72% of 2a detected by 19F NMR (trial 5). DMF was
found to be ineffective in promoting the chemistry, with a
severely diminished yield of 2a (trial 6). It was found that
higher loadings of KOH resulted in higher yields, with the
maximum being 72% of 2a observed when 2.2 equiv of KOH
was used (trial 7). To remove the potential for variability in the
system by virtue of water absorbed by the hygroscopic KOH,
100 μL of water was added to the system, and the yield
remained unchanged (trial 8). With the optimal base and
solvent system determined, efforts were made to determine the
optimal amount of TMSCF2Br required in this system. Higher
loadings of TMSCF2Br (trials 9 and 10) did not afford
increased yields. The optimum conditions were then applied to
a series of carboxylic acids (Scheme 2).
a
Reactions performed at 1 mmol scale for isolated yields. Yields in
parentheses determined by 19F NMR at 0.25 mmol reaction scale.
b
Four equiv of TMSCF2Br.
electron deficient ester, 2h, with two trifluoromethyl groups,
was obtained in moderate yield. Among the aryl carboxylic
acids (1a−1h), it appears that the yield is directly related to
the electron density on the aryl ring: electron-donating groups
enhance the yield, while electron-withdrawing groups diminish
the yield. Under the optimized conditions, 4-chlorocinnamic
acid saw high conversion to 2i.
Aliphatic carboxylic acids were also tested under the
optimized conditions. Difluoromethyl 4-phenylbutanoate 2j
was formed with excellent conversion. The phenyl acetic acid
derivative 2k was obtained in a slightly lower yield than the
phenyl butyric acid derivative 2j, possibly due to the stronger
withdrawing effect of the phenyl group in 2k by virtue of
proximity to the carboxylic acid group. 1-Adamantyl carboxylic
1l acid was derivatized in moderate yields despite the strong
electron-donating effect of the adamantyl group. Strong steric
repulsion may be responsible for this diminished yield.
Aliphatic alcohols, despite their propensity to react with CF2
carbene,18 were found to be tolerant to the conditions: 2m was
furnished from mandelic acid in 84% yield with none of the
difluoromethyl ether observed. Thiocarboxylic acid ester 2n
was prepared in 75% conversion with the carbene showing a
preference for the S atom over the O atom (inferred from 19F
NMR and IR data, see the Supporting Information). Finally,
The model substrate 1a afforded 2a in 72% yield by 19F
NMR and was isolated in 41% yield. The reduced isolated
yield may be attributed to the volatility of the product.
Similarly, 2b was isolated in 65% yield (87% by NMR).
Haloarenes are tolerant to the reaction conditions, as is
demonstrated by 2c and 2d, which were isolated in high yields.
Compound 2e, bearing the electron-donating 4-OMe sub-
stituent, was obtained in good yield. Despite the facile nature
of difluorocarbene cyclopropanation reactions with alkenes,
substrate 1f, containing a 4-vinyl group, gave none of the
difluorocyclopropane product, instead providing only the
desired difluoromethyl ester 2f.30,31 Similarly, the terminal
alkyne unit on 2g was left untouched; no difluorocyclopropene
was observed. This exquisite selectivity could be advantageous
in the O-difluoromethylation of complex carboxylic acids. An
B
DOI: 10.1021/acs.orglett.9b03604
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disulfide containing 1o produced a 1:1 mixture of 2o and 2o′,
with <4% formation of the gem-difluoromethyl dithioacetal
(the product of CF2 insertion into the S−S bond).20
As stated previously, carboxyl groups can be found in a
number of FDA approved drugs and in biologically relevant
molecules. To test the applicability of this method on complex
molecules, acids 1p−1u were subjected to the reaction
conditions (Scheme 3).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03604.
Procedures, characterization, and images of spectra
(PDF)
Scheme 3. O-Difluoromethylation of Biologically Relevant
Carboxylic Acids
AUTHOR INFORMATION
a
■
Corresponding Author
*E-mail: gprakash@usc.edu.
ORCID
G. K. Surya Prakash: 0000-0002-6350-8325
Author Contributions
§M.C.: Undergraduate research participant.
Author Contributions
‡V.K. and C.B. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
Reactions were performed at 1 mmol scale using standard reaction
The authors thank the Loker Hydrocarbon Research Institute
for funding.
b
c
conditions. Conducted at 0.5 mmol scale. Three equivalents of
TMSCF2Br.
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