Room Temperature Deoxyfluorination of Benzaldehydes and α-Ketoesters with Sulfuryl Fluoride and Tetramethylammonium Fluoride

Article abstract of DOI:10.1021/acs.orglett.9b00054

A method for the room temperature deoxyfluorination of benzaldehydes and α-ketoesters using sulfuryl fluoride and Me₄NF is described. A large scope of aryl and heteroaryl substrates is demonstrated, and this method compares favorably to other common deoxyfluorination methods for many substrates.

Full text of DOI:10.1021/acs.orglett.9b00054

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Room Temperature Deoxyfluorination of Benzaldehydes and
α‑Ketoesters with Sulfuryl Fluoride and Tetramethylammonium
Fluoride
Patrick R. Melvin,† Devin M. Ferguson,† Sydonie D. Schimler,† Douglas C. Bland,‡
and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
‡CP PD&P Process Chemistry, Corteva Agriscience, Agriculture Division of DowDuPont, 9330 Zionsville Road, Indianapolis,
Indiana 46268, United States
S
* Supporting Information
ABSTRACT: A method for the room temperature deoxy-
fluorination of benzaldehydes and α-ketoesters using sulfuryl
fluoride and Me4NF is described. A large scope of aryl and
heteroaryl substrates is demonstrated, and this method
compares favorably to other common deoxyfluorination
methods for many substrates.
eoxyfluorination reactions are powerful methods for the
installation of fluorine atoms into organic molecules.1
We recently demonstrated that the inexpensive commodity
chemical sulfuryl fluoride (SO2F2) can be utilized for the
deoxyfluorination of phenol substrates. In combination with
tetramethylammonium fluoride (Me4NF), SO2F2 effectively
converts electronically diverse phenols to the corresponding
aryl fluorides under mild conditions.11 We hypothesized that
the inexpensive and thermally stable combination of SO2F2/
Me4NF12 should also enable other deoxyfluorination reactions,
and we initially targeted the deoxyfluorination of (hetero)-
aromatic aldehydes. This transformation is known with other
deoxyfluorinating reagents,2b,3 but it has been less extensively
studied than analogous alcohol deoxyfluorination reactions.
Indeed, many published examples are limited to simple
substrates (e.g., benzaldehyde).13 Notably, the difluorometh-
yl-substituted (hetero)arene products are of high interest in
medicinal and agricultural chemistry.14,15 Herein, we demon-
strate that the combination of SO2F2 and Me4NF is effective
for the room temperature deoxyfluorination of a wide scope of
aryl and heteroaryl aldehydes as well as α-ketoesters.
Furthermore, direct comparison to DAST reveals that
SO2F2/Me4NF affords comparable or significantly enhanced
yields for most aldehyde and α-ketoester substrates.
D
The most widely used deoxyfluorination reagent is DAST
(diethylamino sulfur trifluoride), which was originally reported
in 1973.2 Over the past four decades, a variety of next-
generation alternatives have been developed, including
Deoxofluor,3 Fluolead,4 Xtalfluor,5 PBSF6 (perfluorobutane
sulfonyl fluoride), PhenoFluor,7 DFMBA8 (N,N-diethyl-α,α-
difluoro-(m-methylbenzyl)amine), DFI9 (2,2-difluoro-1,3-
dimethylimidazolidine), and PyFluor10 (see Figure 1 for
Figure 1. (a) Common, commercially available deoxyfluorination
reagents. (b) Deoxyfluorination of benzaldehydes using SO2F2 and
Me4NF (this work).
Our initial studies focused on the conversion of 4-
bromobenzaldehyde (1a-Ald) to 1-bromo-4-(difluoromethyl)-
benzene (1a) under conditions similar to those for the
deoxyfluorination of phenols [1.5 equiv of SO2F2 (stock
solution in DMF), 3 equiv of Me4NF in DMF at 25 °C for 24
h].11b As shown in Table 1, entry 1, this reaction afforded 1a in
56% yield. While SO2F2 is an inexpensive commodity chemical,
it is also a toxic gas that can be challenging to handle on a
laboratory scale. As such, we also explored a recently reported
representative examples). All of these are highly effective for
the conversion of primary and secondary alcohols to alkyl
fluorides. Many have also been applied to the deoxyfluorina-
tion of aldehydes, ketones, and/or phenols.2b,3 However,
despite their utility, these existing deoxyfluorinating reagents
remain limited by some combination of thermal instability,
high cost, and limited substrate scope. For these reasons, they
are commonly used on a laboratory scale, but are limited in the
context of process-scale deoxyfluorination reactions.
Received: January 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00054
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Organic Letters
Letter
inert-atmosphere glovebox, the yield dropped to 42% under
otherwise analogous conditions (entry 6).
Table 1. Optimization of the Deoxyfluorination of 1a-Ald
with SO2F2 and Me4NF
Product 1a was isolated in high yield from the two-chamber
reaction following chromatographic purification on silica gel
(85% yield on 0.2 mmol scale and 80% yield on 1 mmol scale).
Furthermore, this transformation proceeds in comparable yield
using a stock solution of SO2F2 in DMF, conditions that better
reflect how these reagents would be used on process scale.17
This latter procedure afforded a 79% isolated yield of 1a on 5
mmol scale.
We next explored the substrate scope of this deoxyfluorina-
tion reaction (Scheme 1). Substitution at the ortho (products
1e−h) position as well as aryl chloride, bromide, and iodide
substituents (products 1a−c) were well-tolerated. These
features render this method complementary to many transition
metal-catalyzed cross-couplings that form such difluoromethyl
arene products.18 In addition, the simple purification
procedure offers a major advantage over cross-coupling
approaches to analogous products. The deoxyfluorination is
highly selective for aldehydes over less electrophilic carbonyl
substituents such as esters and amides (to form products 1j
and 1k). This method was also effective for aldehydes derived
from the biologically active molecules probenecid and
adapalene (1p and 1q).
a
entry
equiv of Me4NF
equiv of SO2F2
yield (%)
b
1
3
3
4
4
4
4
1.5
1.5
2
2
2
56
68
91
90
85
42
2
3
c
4
d
5
e
6
2
a
General conditions: (Chamber A) SDI (0.2 mmol, 2 equiv), KF (0.4
mmol, 4 equiv) in formic acid (0.2 mL); (Chamber B) 1a-Ald (0.1
mmol, 1 equiv), Me4NF (0.2 mmol, 2 equiv), DMF (0.5 mL) at 25
°C for 24 h. All reactions were set up under anhydrous conditions.
Yields were determined via 19F NMR spectroscopy using 4-
fluoroanisole as the internal standard. Using a stock solution of
SO2F2 (0.14 M) in DMF. Reaction time: 4 h. Isolated yield.
b
c
d
e
Reagents weighed on benchtop.
Pyridine, quinoline, and isoquinoline carboxaldehydes were
also good substrates for this transformation to form products
1r−1z. In all cases, 19F NMR spectroscopic analysis of the
crude reaction mixtures showed high conversion and yield. In a
few examples (e.g., 1r and 1v), the isolated yields were
moderate due to the volatility of the difluoromethylpyridine
products. Both electron-donating and electron-withdrawing
substituents on the pyridine ring were well tolerated (for
instance to form 1s and 1t). Halogen substituents on the
pyridine were also generally compatible (see products 1u and
1w).
procedure for the ex situ generation of SO2F2 in a two-chamber
system using commercially available 1,1′-sulfonyldiimidazole
(SDI), KF, and acid.16 As shown in Table 1, entry 2, using ex
situ SO2F2 generation under otherwise identical conditions
afforded 1a in 68% yield. DMF proved to be the optimal
solvent (see Table S1 for a solvent screen). Increasing the
equivalents of Me4NF and SO2F2 to 4 and 2, respectively,
resulted in a 91% yield of 1a (entry 3). Finally, the reaction
time could be reduced to just 4 h with minimal impact on the
yield (entry 4, 90%). Notably, it is important that this
transformation be conducted under anhydrous conditions, due
to the water sensitivity of Me4NF. For example, when the
reagents were weighed on the benchtop, rather than in an
We next examined other classes of carbonyl substrates.
Subjecting acetophenone and cyclohexanone to the standard
Scheme 1. Difluoromethylation of Benzaldehyde Substrates
a
Conditions: (Chamber A) SDI (0.4 mmol, 2.0 equiv), KF (0.8 mmol, 4.0 equiv) in formic acid (0.4 mL); (Chamber B) aldehyde (0.2 mmol, 1.0
equiv), Me4NF (0.8 mmol, 4.0 equiv) in DMF (1.0 mL) at room temperature for 4 h. Isolated yields average of two runs; yields in parentheses were
b
determined by 19F NMR spectroscopy using 4-fluoroanisole as the internal standard. Performed using 5.0 mmol of aldehyde.
B
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Letter
reaction conditions afforded decomposition of the ketone and
no detectable quantity of the difluoromethylene-containing
product. This is likely due to competitive enolate formation in
the presence of Me4NF. Benzophenone reacted to afford traces
(<5%) of difluorodiphenylmethane. The low reactivity is likely
due to the moderate electrophilicity of this substrate relative to
the aldehydes. In contrast, more electrophilic α-keto ester
derivatives proved to be excellent substrates for deoxyfluori-
nation with SO2F2/Me4NF. These reacted selectively to afford
the α-gem-difluoro esters products 1aa and bb in high yields.
Notably, these motifs are commonly assembled via Cu-
mediated cross-coupling,19 and the deoxyfluorination approach
provides a complementary route to accessing this function-
ality.20
A final set of studies focused on benchmarking this new
method relative to DAST, the most common deoxyfluorinating
reagent. All of the substrates in Scheme 1 were subjected to
conditions reported as optimal for DAST, and the yield of the
difluoromethyl product was assayed by 19F NMR spectroscopy
and compared directly to that achieved with SO2F2/Me4NF
(Scheme 2). The complete results are shown in Table S1. In
difluoromethyl- and α-gem-difluoroester-substituted (hetero)-
arene products under mild conditions. A direct comparison to
DAST shows that SO2F2/Me4NF affords comparable or
significantly enhanced yield for a number of substrate classes.
Ultimately, this feature, in combination with the relatively low
cost and high stability of SO2F2/Me4NF, renders this an
attractive method for process-scale deoxyfluorination reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00054.
Procedure details and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mssanfor@umich.edu.
ORCID
Sydonie D. Schimler: 0000-0002-7170-1643
Melanie S. Sanford: 0000-0001-9342-9436
Notes
Scheme 2. Substrates That Afforded Significantly Higher
Yields with SO2F2/Me4NF Compared to DAST
a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
DowAgrosciences is acknowledged for supporting this work.
■
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■
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