Reactions of Arylsulfonate Electrophiles with NMe4F: Mechanistic Insight, Reactivity, and Scope

Article abstract of DOI:10.1021/acs.joc.8b01762

This paper describes a detailed study of the deoxyfluorination of aryl fluorosulfonates with tetramethylammonium fluoride (NMe₄F) and ultimately identifies other sulfonate electrophiles that participate in this transformation. ¹⁹F NMR spectroscopic monitoring of the deoxyfluorination of aryl fluorosulfonates revealed the rapid formation of diaryl sulfates under the reaction conditions. These intermediates can proceed to fluorinated products; however, diaryl sulfate derivatives bearing electron-donating substituents react very slowly with NMe₄F. Based on these findings, aryl triflate and aryl nonaflate derivatives were explored, since these cannot react to form diaryl sulfates. Aryl triflates were found to be particularly effective electrophiles for deoxyfluorination with NMe₄F, and certain derivatives (i.e., those bearing electron-neutral/donating substituents) afforded higher yields than their aryl fluorosulfonate counterparts. Computational studies implicate a similar mechanism for deoxyfluorination of all the sulfonate electrophiles.

Full text of DOI:10.1021/acs.joc.8b01762

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Reactions of Arylsulfonate Electrophiles with NMe4F: Mechanistic
Insight, Reactivity, and Scope
Sydonie D. Schimler,† Robert D. J. Froese,‡ Douglas C. Bland,‡ and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
‡Core Research and Development, The Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States
S
* Supporting Information
ABSTRACT: This paper describes a detailed study of the
deoxyfluorination of aryl fluorosulfonates with tetramethyl-
ammonium fluoride (NMe4F) and ultimately identifies other
sulfonate electrophiles that participate in this transformation.
19F NMR spectroscopic monitoring of the deoxyfluorination of
aryl fluorosulfonates revealed the rapid formation of diaryl
sulfates under the reaction conditions. These intermediates can
proceed to fluorinated products; however, diaryl sulfate derivatives bearing electron-donating substituents react very slowly with
NMe4F. Based on these findings, aryl triflate and aryl nonaflate derivatives were explored, since these cannot react to form diaryl
sulfates. Aryl triflates were found to be particularly effective electrophiles for deoxyfluorination with NMe4F, and certain
derivatives (i.e., those bearing electron-neutral/donating substituents) afforded higher yields than their aryl fluorosulfonate
counterparts. Computational studies implicate a similar mechanism for deoxyfluorination of all the sulfonate electrophiles.
We recently developed a related method for the deoxy-
fluorination of phenols involving aryl fluorosulfonate inter-
mediates of general structure B (Figure 1C).13−15 Ab initio
calculations show the feasibility of a mechanism involving F−
attack at the electrophilic sulfur of B16,17 and subsequent
intramolecular delivery of fluoride to the ipso carbon via TSB
(Figure 1C). This transformation proved applicable to
electronically diverse aryl fluorosulfonate derivatives. Further-
more, in contrast to the PhenoFluor system, both the fluoride
source (NMe4F)18 and the leaving group (SO3F)19 are formed
from inexpensive commodity chemicals. Finally, the aryl
fluorosulfonates are stable, isolable intermediates, enabling
mechanistic investigations of the fluorination process.
In this Article, we probe the mechanism and side products of
reactions between aryl fluorosulfonates and NMe4F. These
investigations reveal markedly different electronic effects
relative to the PhenoFluor system. In addition, they show
that diaryl sulfates form rapidly under the reaction conditions,
and that these intermediates can have a detrimental impact on
both the reaction rate and yield. Ultimately, these insights led
to the discovery that readily available aryl triflates are also
effective electrophiles for deoxyfluorination with NMe4F under
mild conditions.
INTRODUCTION
■
Fluorinated (hetero)arenes appear in a wide variety of
pharmaceuticals and agrochemicals.1,2 Nucleophilic aromatic
substitution (SNAr) is the most common industrial method for
the formation of aromatic C−F bonds.3 SNAr fluorination
reactions typically involve the conversion of an aryl chloride or
nitroarene to the corresponding aryl fluoride via treatment
with an alkali metal fluoride salt (Figure 1A).3,4 However,
these transformations remain limited by the requirement for
high temperatures (generally >100 °C) and long reaction
times. These forcing conditions often lead to poor functional
group tolerance as well as the formation of side products.5,6 In
addition, the scope of SNAr fluorination reactions is typically
restricted to substrates bearing strongly electron-withdrawing
substituents, which are needed to stabilize the high energy
Meisenheimer intermediates/transition states (Figure 1A).3b
Recent work has demonstrated the use of soluble anhydrous
tetraalkylammonium fluoride salts to achieve the SNAr
fluorination of aryl chloride and nitroarene substrates under
milder conditions.7−9 However, these transformations still
remain limited to highly electron-deficient ArX electrophiles.
In 2011, the Ritter group showed that the combination of
PhenoFluor and CsF is effective for the conversion of phenols
to aryl fluorides (Figure 1B).10−12 This reaction represents a
major advance for the field because it proceeds under relatively
mild conditions (80−110 °C) and enables the deoxyfluorina-
tion of electronically diverse phenol derivatives. The authors
propose that these attributes derive from a novel mechanism,
involving the formation of a 2-phenoxyimidazolium bifluoride
intermediate A that undergoes concerted intramolecular
delivery of fluoride to the ipso carbon via TSA (Figure 1B).12
RESULTS AND DISCUSSION
■
Substituent Effects on Reaction Rates. We first
examined the impact of arene substitution on the rate of the
deoxyfluorination of aryl fluorosulfonates with NMe4F. Rate
studies were conducted at 80 °C in DMF, using 1 equiv of the
Received: July 11, 2018
© XXXX American Chemical Society
A
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Figure 1. Examples of nucleophilic aromatic fluorination reactions.
aryl fluorosulfonate substrate and 2 equiv of NMe4F. The
initial rate of each reaction was determined by monitoring the
first ∼10% conversion under these conditions via NMR
spectroscopy. As shown in Figure 2, a Hammett plot of these
explains why the deoxyfluorination of arylfluorosulfonates
remains slow and relatively low yielding with substrates bearing
strong electron donor substituents (e.g., para-OMe) on the
aromatic ring.
NMR Studies of Reaction Intermediates. We next
probed intermediates and side products formed during the
reaction of aryl fluorosulfonates with NMe4F. 3-Fluorophenyl
sulfofluoridate (1-OFs) was selected as the substrate for these
investigations, as it contains two fluorine substituents that can
be tracked using 19F NMR spectroscopy. In an initial
experiment, 1-OFs was combined with 1 equiv of NMe4F in
anhydrous DMF (Figure 3). After 30 min at room temper-
ature, the Caryl−F 19F NMR signal of 1-OFs (−109.9 ppm)
broadened significantly, suggesting possible equilibration with
pentacoordinate intermediate 1-Int (compare Figure 3A and
3B). Notably, an analogous pentacoordinate sulfur species has
been detected upon the treatment of SO2F2 with NMe4F.16b
After 30 min at 25 °C, a new Caryl−F 19F NMR signal was
observed at −110.6 ppm, which corresponds to the bis(3-
fluorophenyl)sulfate (1-sulfate; Figure 3B). After 24 h at room
temperature, product 1-F was observed in ∼11% yield (Caryl−F
signal at −111.4 ppm), and both 1-sulfate and the broad
resonance that is tentatively assigned to 1-OFs/1-Int remained
(Figure 3C).
We next monitored the reaction of 1-OFs with 2 equiv of
NMe4F at 80 °C (Figure 4). At this temperature, the Caryl−F
19F NMR signal corresponding to 1-OFs broadened within
minutes and subsequently disappeared. 1-Sulfate also appeared
within minutes and was then consumed over the course of 2 h.
Product 1-F was formed in 75% yield after 2 h.
A proposed pathway for the conversion of 1-OFs to 1-
sulfate is shown in Scheme 1. In the first step, aryl
fluorosulfonate 1-OFs reacts with NMe4F to form the
pentacoordinate sulfur intermediate 1-Int (step i). As detailed
below, ab initio calculations suggest that this step is
enthalpically favorable at room temperature. 1-Int can then
undergo two competing reactions: formation of the fluorinated
product 1-F (step ii) or release of SO2F2 and phenoxide 1-
O[NMe4] (step iii). The phenoxide can then attack 1 equiv of
starting material, 1-OFs, to form a new pentacoordinate sulfur
intermediate (step iv) that collapses into 1-sulfate and NMe4F
(step v).22 Thus, the equilibria proposed in Scheme 1 provide
Figure 2. Hammett plot for the reaction of aryl fluorosulfonates with
NMe4F at 80 °C.
data shows a ρ value of +6.26, with the best fit obtained using
σ− values for each of the substituents.20 This value is in striking
contrast to the much smaller ρ value observed for the
PhenoFluor reaction (ρ = +1.79, with σ values giving the best
fit).12 This ρ of +6.26 is similar to that observed for
conventional SNAr reactions (where ρ values between 3 to 8
have been reported).21 Overall, these results suggest that the
fluorosulfonate leaving groups serve to reduce the overall
barrier for nucleophilic fluorination relative to that with, for
example, chloride leaving groups. However, in contrast to
PhenoFluor, the electronic requirements of this transformation
versus SNAr fluorination of more conventional aryl chloride
substrates do not appear to fundamentally change. This likely
B
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independently synthesized tetramethylammonium 3-fluoro-
phenoxide (1-O[NMe4]) with 3-fluorophenyl sulfofluoridate
(1-OFs) afforded 1-sulfate in 64% yield within 24 h at 25 °C
(eq 1).22
We next studied the conversion of 1-sulfate to 1-F by
independently synthesizing bis(3-fluorophenyl)sulfate (1-
sulfate) and then treating it with 2 equiv of NMe4F at 80
°C. As shown in eq 2, this reaction afforded 1-F in 64% yield
within 2.5 h. As expected, an equimolar quantity of 1-
O[NMe4] was also generated under these conditions.
Figure 3. 19F NMR study of the reaction between 1-OFs and 1 equiv
of NMe4F at 25 °C. (A) Aromatic region of the 19F NMR spectrum of
a mixture of starting material 1-OFs and product 1-F. (B) Aromatic
region of the 19F NMR spectrum of the reaction between 1-OFs (0.1
mmol, 1.0 equiv) and NMe4F (0.1 mmol, 1.0 equiv) in DMF (0.2 M)
at 25 °C after 30 min. (C) Aromatic region of the 19F NMR spectrum
of the reaction between 1-OFs (0.1 mmol, 1.0 equiv) and NMe4F
(0.1 mmol, 1.0 equiv) in DMF (0.2 M) at 25 °C after 24 h.
The pathway in Scheme 1 suggests that 1-OFs might be
detectable during the fluorination of 1-sulfate. At 80 °C, the
19F NMR signal for 1-OFs is too broad to observe. However,
when the reaction was heated to 80 °C for 10 min and then
immediately cooled to 25 °C, we observed a 19F NMR signal
consistent with the aromatic fluorine of 1-OFs (−109.9 ppm)
in 10% yield, along with 1-F (9%), 1-O[NMe4] (30%), and
unreacted 1-sulfate (80%) (eq 3).
Finally, the pathway in Scheme 1 suggests that the addition
of SO2F2 should push the equilibrium between 1-sulfate and
1-Int toward 1-Int, thereby ultimately driving the reaction to
1-F. Indeed, the addition of 1 equiv of SO2F2 to the reaction of
1-sulfate with NMe4F resulted in an increase in yield of 1-F
from 64% to 110% (eq 4). This supports the proposed
Figure 4. Reaction of 1-OFs with 2 equiv of NMe4F at 80 °C.
Conditions: 1-OFs (0.1 mmol, 1.0 equiv) and NMe4F (0.2 mmol, 2.0
equiv) in DMF (0.2 M) at 80 °C. 19F NMR spectra collected every 5
min for a total of 2 h. Yields determined by 19F NMR spectroscopy
with 4-fluoroanisole as standard. 1-O[NMe4] is also produced during
the course of the reaction but is not shown in the plot.
pathway, as SO2F2 is expected to capture 1-O[NMe4], thus
producing more of the aryl fluorosulfonate 1-OFs that can
undergo the productive fluorination reaction.23
Comparison of Ar2SO4 to ArOFs Electrophiles. When
the diaryl sulfates were synthesized independently and used as
substrates for deoxyfluorination with NMe4F, they afforded
lower yields of aryl fluoride products relative to their aryl
an explanation for both the formation of 1-sulfate as well as its
ability to proceed to the fluorinated product 1-F.
Additional studies were conducted to investigate the
pathways proposed in Scheme 1. First, we examined the
feasibility of step iv. As shown in eq 1, the reaction of
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Scheme 1. Proposed Pathway for the Formation of 1-Sulfate
fluorosulfonate analogues (Table 1). Furthermore, with
electron-deficient diaryl sulfates, the yield of aryl fluoride
Table 1. Fluorination of Aryl Fluorosulfonates Compared to
a
Diaryl Sulfates
a
Conditions: Substrate (0.1 mmol, 1.0 equiv) and NMe4F (0.2 mmol,
2.0 equiv) stirred in DMF (0.2 M) at 80 °C for 24 h. Yields
determined by 19F NMR spectroscopy with 1,3,5-trifluorobenzene as
standard.
decreased with increasing reaction times, due to competing
consumption of the fluorinated product. For example, 2-sulfate
afforded 2-F in 78% yield after 15 min at 80 °C but in just 54%
yield after 24 h at 80 °C (entry 2). The corresponding diaryl
ether was observed as a byproduct in the latter reaction. The
diaryl ether likely forms via the reaction of 2-F with
tetramethylammonium 4-cyanophenoxide, which is generated
during the course of the fluorination reaction.3b,4 This
competing reaction can be suppressed by reducing the
temperature to 25 °C (resulting in 75% yield of 2-F after 24
h) or lowering the reaction time.
Electron-neutral and -rich diaryl sulfates showed particularly
low reactivity with NMe4F (entries 4 and 5). For instance, the
reaction of 5-sulfate with NMe4F afforded only 3% of 5-F
(entry 5), with >90% unreacted starting material remaining
after 24 h at 80 °C. This is likely due to the low electrophilicity
of sulfur, which slows the reaction of the sulfate with NMe4F
(step v in Scheme 1). Rate studies confirm that the diaryl
sulfates react significantly slower than the corresponding aryl
fluorosulfonates. For example, as shown in Figure 5, the initial
rate of product formation in the reaction between NMe4F and
4-sulfate is approximately an order of magnitude slower than
that for 4-OFs.
Figure 5. Initial rates of deoxyfluorination of 4-OFs and 4-sulfate at
80 °C. Conditions: Substrate (4-OFs or 4-sulfate, 0.1 mmol, 1.0
equiv) and NMe4F (0.2 mmol, 2.0 equiv) stirred in DMF (0.2 M) at
80 °C for the given time. Yields determined by 19F NMR
spectroscopy with 1,3,5-trifluorobenzene as standard. For 4-OFs, y
= 0.36x − 0.25, R2 = 0.9946. For 4-sulfate, y = 0.025x + 0.332, R2 =
0.98.
intermediates has a negative impact on the desired
deoxyfluorination reaction. We noted that aryl triflates and
nonaflates are widely used sulfonate derivatives that have
comparable electronic properties to their fluorosulfonate
analogues.24−27 However, in contrast to aryl fluorosulfonates,
these electrophiles do not contain a second leaving group on
the sulfur. As such, aryl triflates and nonaflates should not be
capable of forming Ar2SO4 intermediates.28 Triflates and
nonaflates offer the additional advantage that they can be
conveniently synthesized on laboratory scale without the need
for sulfuryl fluoride, a gas that is not readily available in some
research settings.29,30
A series of ArOFs, ArOTf,31 and ArONf32,33 analogues were
next compared as substrates for deoxyfluorination with NMe4F
(Table 2). For derivatives bearing the strongly electron-
withdrawing cyano group (entry 2), 2-OFs afforded the
highest yield of the fluorinated product 2-F (92%). Aryl triflate
Use of Aryl Triflate and Aryl Nonaflate Electrophiles.
The results above show that the formation of diaryl sulfate
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formation with ArOTf increases relative to that for ArOFs
upon moving to substrates bearing more electron-donating
substituents (i.e., moving from 3 to 4 to 5). Additionally, the
ArOTf affords a slightly higher yield than the ArOFs in all
three of these systems (Table 3, entries 3−5). Notably, diaryl
sulfate intermediates are observed at initial time points in the
reactions of 3-OFs, 4-OFs, and 5-OFs, and these intermediates
likely play a role in the slower initial rates with these substrates.
Computational Studies of ArOFs and ArOTf. We next
compared the mechanisms of the deoxyfluorination of 1−5-
OFs and 1−5-OTf using ab initio calculations.35,36 As
summarized in Scheme 2, the calculations show that the
fluorosulfonate and triflate substrates react by analogous
pathways. Binding of fluoride to sulfur to form the
pentacoordinate species, 1-Int, is enthalpically favorable in all
cases, with ΔHbind ranging from −0.3 to −4.1 kcal/mol.37
Notably, there are five possible isomers of the trigonal
bipyramidal structure 1-Int. The isomer shown in Scheme 2
[with fluorine trans to X (X = F or CF3)] is the lowest energy
in all cases. Details about the other isomers are provided in the
Supporting Information. Carbon−fluorine bond formation
then proceeds without the formation of a discrete Meisen-
heimer intermediate. Instead, the fluoride is transferred to the
ipso carbon via the transition state TS. In all cases, the
calculated value of ΔH‡ is similar between the fluorosulfonate
and triflate analogues, with the triflate derivatives being slightly
lower (by 1−3 kcal/mol) in all cases. As expected, the
calculated values of ΔH‡ vary significantly depending on
substitution patterns on the aromatic ring. The lowest barrier is
predicted (and observed experimentally) for the electron-
deficient p-CN substrates 2-OFs and 2-OTf, while the highest
is predicted (and observed experimentally) for the electron-
rich p-OPh systems 5-OFs and 5-OTf.
Table 2. Deoxyfluorination of Different Sulfonate
Electrophiles with NMe4F
a
a
Conditions: Substrate (0.1 mmol, 1.0 equiv) and NMe4F (0.2 mmol,
2.0 equiv) stirred in DMF (0.2 M) at 80 °C for 24 h. Yields
determined by 19F NMR spectroscopy with 1,3,5-trifluorobenzene as
standard.
2-OTf afforded only a modest yield (66%), and byproducts
including 4-cyanophenol were observed by GCMS. The
presence of this byproduct suggests that competing hydrolysis
of 2-OTf is occurring under the reaction conditions. The
analogous nonaflate 2-ONf afforded 73% yield of 2-F, and <5%
of hydrolysis-derived byproducts were detected in this case.
Time studies of the reactions of 2-OFs, 2-OTf, and 2-ONf
(Figure 6) show that the relative rates track with the final
yields (i.e., 2-OFs reacts to form 2-F faster than 2-ONf, which
reacts faster than 2-OTf).24,34
Substrate Scope with Aryl Triflates. With a better
understanding of the reactivity of aryl triflates, the substrate
scope for this deoxyfluorination reaction was evaluated and
compared to that of the corresponding aryl fluorosulfonates
(Figure 8). ArOTf substrates bearing strongly electron-
withdrawing substituents generally afforded lower yields than
the analogous ArOFs. This appears to be due, at least in part,
to competing hydrolysis of the aryl triflate starting materials.38
With substrates bearing electron-neutral substituents, the
difference in the yield of the fluorinated product with ArOFs
versus ArOTf becomes less pronounced. However, in general,
slightly higher yields were obtained with the ArOTf (for
example, 3−5 and 8 in Figure 8). For substrates bearing
stronger electron-donating substituents, both ArOFs and
ArOTf show modest reactivity, but higher yields were generally
obtained with the aryl fluorosulfonates (for example, 9 and 10
in Figure 8). Overall, these studies show that readily accessible
aryl triflate electrophiles exhibit comparable reactivity to their
ArOFs counterparts in deoxyfluorination with NMe4F.
Figure 6. Time study of reactions of 2-OFs, 2-OTf, and 2-ONf with
NMe4F to form 2-F. Conditions: Substrate (0.1 mmol, 1.0 equiv) and
NMe4F (0.2 mmol, 2.0 equiv) stirred in DMF (0.2 M) at 80 °C for
the given time. Yields determined by 19F NMR spectroscopy with
1,3,5-trifluorobenzene as standard.
CONCLUSIONS
■
In conclusion, this report describes studies of the mechanism
and side products involved in deoxyfluorination reactions of
aryl fluorosulfonates with NMe4F. These studies reveal
markedly different electronic effects relative to Ritter’s
PhenoFluor system. In addition, they show that aryl
fluorosulfonates are in equilibrium with diaryl sulfates under
the reaction conditions and that the formation of diaryl sulfates
can impede the productive deoxyfluorination reaction,
particularly with electron-neutral and electron-rich substrates.
In contrast, for the 4-chloro-substituted sulfonate electro-
philes, aryl triflate 3-OTf afforded a higher yield of 3-F than
aryl fluorosulfonate 3-OFs (85% versus 75%, entry 3), while
the lowest yield (64%) was obtained with the aryl nonaflate 3-
ONf. A similar trend was observed with the 4-phenyl and 4-
phenoxy derivatives (entries 4 and 5). Rate studies with these
substrates (3−5, Figure 7) show that the initial rate of product
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Figure 7. Initial rates for reaction of aryl fluorosulfonates versus the corresponding aryl triflates with NMe4F for substrates 3−5. (A) Initial rate of
product formation for reactions of 3-OFs and 3-OTf with NMe4F. (B) Initial rate of product formation for the reactions of 4-OFs and 4-OTf with
NMe4F. (C) Initial rate of product formation for the reactions of 5-OFs and 5-OTf with NMe4F.
Table 3. Computed Enthalpies of Reaction (ΔHbind) for Pentacoordinate Intermediate Formation and Enthalpies of Activation
(ΔH‡) of Different Substrates
1
MHz for 19F), a 700 MHz (699.76 MHz for H; 175.95 MHz for
Scheme 2. Energy Diagram for the Reaction of Sulfonate
Derivatives with Fluoride
13C), or a 500 MHz (499.90 MHz for H; 125.70 for 13C) NMR
1
spectrometer. H and 13C chemical shifts are reported in parts per
1
million (ppm), with the residual solvent peak used as an internal
reference (CDCl3; 1H δ 7.26 ppm; 13C δ 77.16 ppm). 19F NMR
spectra are referenced based on the internal standard 1,3,5-
trifluorobenzene, which appears at −108.33 ppm, or 4-fluoroanisole,
which appears at −125.55 ppm. 1H and 19F multiplicities are reported
as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet
(m), doublet of doublets (dd), doublet of triplets (dt). Coupling
constants (J) are reported in Hz. For GCMS analysis, the products
were separated on a crossbond 5% diphenyl-95% dimethyl
polysiloxane column (30 m length by 0.25 mm ID, 0.25 μm df).
Helium was employed as the carrier gas, with a constant column flow
of 1.5 mL/min. The injector temperature was held constant at 250
°C. The GC oven temperature program for low molecular weight
compounds was as follows: 32 °C hold 5 min, ramp 15 °C/min to 250
°C, and hold for 1.5 min. Melting points are uncorrected. High-
resolution mass spectra were recorded on a Magnetic Sector mass
spectrometer.
Commercial reagents were used as received unless otherwise noted.
Anhydrous tetramethylammonium fluoride (NMe4F) was obtained
from Sigma-Aldrich. Anhydrous N,N-dimethylformamide (DMF) was
purchased from Alfa Aesar. Phenyl trifluoromethanesulfonate (6-
OTf) was purchased from Oakwood Products and stored at −33 °C
in the freezer of a N2-filled glovebox. Sulfuryl fluoride (SO2F2) was
purchased from SynQuest Laboratories. Triflic anhydride and
perfluoro-1-butanesulfonyl fluoride were purchased from Oakwood
Products.
These insights led to the examination of other aryl sulfonate
electrophiles that cannot form diaryl sulfate intermediates.
These aryl triflates and aryl nonaflates are demonstrated to be
effective electrophiles for deoxyfluorination with NMe4F, thus
expanding the scope of substrates for these mild arene
fluorination reactions.
3-Fluorophenyl sulfofluoridate (1-OFs), 4-cyanophenyl sulfofluor-
idate (2-OFs), 4-chlorophenyl sulfofluoridate (3-OFs), [1,1′-
biphenyl]-4-yl sulfofluoridate (4-OFs), 4-phenoxyphenyl sulfofluor-
idate (5-OFs), phenyl sulfofluoridate (6-OFs), 3-methoxyphenyl
sulfofluoridate (7-OFs), m-tolylfluorosulfonate (8-OFs), p-tolylfluor-
EXPERIMENTAL SECTION
■
Materials and Methods. NMR spectra were obtained on a 400
1
MHz (400.52 MHz for H; 376.87 MHz for 19F; 100.71 MHz for
1
13C), a 500 MHz (500.01 MHz for H; 125.75 MHz for 13C; 470.56
F
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Figure 8. Substrate scope for the fluorination of aryl triflates compared to aryl fluorosulfonates. Conditions: Substrate (0.1 mmol, 1.0 equiv) and
NMe4F (0.02 mmol, 2.0 equiv) in DMF (0.2 M) at 80 °C for 24 h. Yields were determined by 19F NMR spectroscopy with 1,3,5-trifluorobenzene
a
b
c
as internal standard. 100 °C. 5 equiv NMe4F. Yield from ref 13.
osulfonate (9-OFs), and 4-methoxyphenyl sulfofluoridate (10-OFs)
were synthesized according to the literature procedures.13,39 A 1.5 wt
% solution of sulfuryl fluoride in anhydrous DMF was prepared as
described previously in the literature.13 Caution: sulfuryl fluoride is a
highly toxic gas. As such, all preparations of sulfuryl fluoride solutions
were carried out in a well-ventilated fume hood and in the presence of
a sulfuryl fluoride detector.
Synthesis of Diaryl Sulfates. Diaryl sulfates were synthesized
according to literature procedures as described below.40,41 All
products were dried under vacuum in the presence of P2O5 prior to
use in deoxyfluorination reactions.
Bis(3-fluorophenyl) Sulfate (1-sulfate). In a N2-filled drybox, a 20
mL vial equipped with a magnetic stir bar was charged with 3-
fluorophenyl sulfofluoridate (1-OFs) (194.0 mg, 1.0 mmol, 1.0
equiv), tetramethylammonium 3-fluorophenoxide (1-O[NMe4])42
(185.0 mg, 1.0 mmol, 1.0 equiv), and anhydrous DMF (5.0 mL).
The vial was sealed with a Teflon-lined cap, and the reaction mixture
was allowed to stir at room temperature overnight. The reaction
mixture was extracted with diethyl ether (10 mL) and water (20 mL).
The organic layer was washed with water (3 × 20 mL), dried over
MgSO4, and concentrated. The product was purified by column
chromatography on silica gel (eluent = 5% diethyl ether in pentane).
Product 1-sulfate was obtained as a colorless oil (182.8 mg, 64%
yield, Rf = 0.39 in 5% diethyl ether in pentane). 1H NMR (500 MHz,
CDCl3): δ 7.42 (m, 2H), 7.15−7.06 (multiple peaks, 6H). 13C{1H}
NMR (176 MHz, CDCl3): δ 160.0 (d, J = 250 Hz), 148.0 (d, J = 86
Hz), 128.4 (d, J = 9.2 Hz), 114.2 (d, J = 3.6 Hz), 112.5 (d, J = 21 Hz),
106.8 (d, J = 22 Hz). 19F NMR (376 MHz, CDCl3): δ −108.6 (m,
2F). HRMS EI (m/z): [M]+ calcd C12H8F2O4S, 286.0111; found,
286.0111.
Bis(4-chlorophenyl) Sulfate (3-sulfate). In a N2-filled drybox, a 20
mL vial equipped with a magnetic stir bar was charged with 4-
chlorophenol (1.93 g, 15.0 mmol, 3.0 equiv), Cs2CO3 (1.63 g, 5.0
mmol, 1.0 equiv), N,N′-sulfuryldiimidazole (992.0 mg, 5.0 mmol, 1.0
equiv), and THF (5.0 mL). The vial was sealed with a Teflon-lined
cap, and the reaction mixture was heated at 66 °C overnight. The
reaction solution was cooled to room temperature, filtered through
Celite, and concentrated. The crude product was purified by column
chromatography on silica gel (eluent = 10% EtOAc in hexanes).
Product 3-sulfate was obtained as a white solid (1.04 g, 66% yield, mp
= 70.0−72.0 °C, Rf = 0.66 in 10% EtOAc in hexanes). 1H NMR (500
MHz, CDCl3): δ 7.40 (d, J = 9.9 Hz, 4H), 7.25 (d, J = 9.9 Hz, 4H).
13C{1H} NMR (176 MHz, CDCl3): δ 148.7, 133.6, 130.3, 122.6.
HRMS EI (m/z): [M]+ calcd C12H8Cl2O4S, 317.9520; found,
317.9520.
Di([1,1′-biphenyl]4-yl) Sulfate (4-sulfate). In a N2-filled drybox, a
4 mL vial equipped with a magnetic stir bar was charged with 4-
phenylphenol (510.8 mg, 3.0 mmol, 3.0 equiv), Cs2CO3 (325.8 mg,
1.0 mmol, 1.0 equiv), N,N′-sulfuryldiimidazole (198.2 mg, 1.0 mmol,
1.0 equiv), and THF (1.0 mL). The vial was sealed with a Teflon-
lined cap, and the reaction mixture was heated at 66 °C overnight.
The reaction solution was cooled to room temperature, filtered
through Celite, and concentrated. The crude product was purified by
column chromatography on silica gel (eluent = 5% EtOAc in
hexanes). Product 4-sulfate was obtained as a white solid (258.2 mg,
64% yield, mp = 132.6−133.8 °C, Rf = 0.41 in 5% EtOAc in hexanes).
The 1H NMR (CDCl3) and 13C{1H} NMR (CDCl3) spectra matched
those previously reported in the literature.40 HRMS EI (m/z): [M]+
calcd C24H18O4S, 402.0926; found, 402.0924.
Bis(4-phenoxyphenyl) Sulfate (5-sulfate). In a N2-filled drybox, a
20 mL vial equipped with a magnetic stir bar was charged with 4-
phenoxyphenol (2.79 g, 15.0 mmol, 3.0 equiv), Cs2CO3 (1.63 g, 5.0
mmol, 1.0 equiv), N,N′-sulfuryldiimidazole (992.0 mg, 5.0 mmol, 1.0
equiv), and THF (5.0 mL). The vial was sealed with a Teflon-lined
cap, and the reaction mixture was heated at 66 °C overnight. The
reaction solution was cooled to room temperature, filtered through
Celite, and concentrated. The crude product was purified by column
chromatography on silica gel (eluent = 5% EtOAc in hexanes).
Product 5-sulfate was obtained as a white solid (1.82 g, 84% yield, mp
Bis(4-cyanophenyl) Sulfate (2-sulfate). A 20 mL vial equipped
with a magnetic stir bar was charged with 4-cyanophenyl
sulfofluoridate 2-OFs (300.0 mg, 1.5 mmol, 1.0 equiv), 4-((tert-
butyldimethylsilyl)oxy)benzonitrile43 (349.5 mg, 1.5 mmol, 1.0
equiv), and 8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.04 mL, 0.3
mmol, 20 mol %) in CH3CN (4.0 mL). The vial was sealed with a
Teflon-lined cap, and the reaction mixture was allowed to stir at room
temperature overnight. The reaction mixture was concentrated under
vacuum. The crude product was dissolved in CH2Cl2 (20 mL), and
the organic layer was extracted with water (1 × 20 mL). The organic
layer was dried over MgSO4, filtered, and concentrated. The product
was recrystallized from ethyl acetate and hexanes. Product 2-sulfate
was obtained as a crystalline white solid (257.9 mg, 57% yield, mp =
1
= 49.7−50.8 °C, Rf = 0.33 in 5% EtOAc in hexanes). H NMR (500
MHz, CDCl3): δ 7.36 (t, J = 7.5 Hz, 4H), 7.27 (d, J = 9.2 Hz, 4H),
7.15 (t, J = 7.5 Hz, 2H), 7.02−7.00 (multiple peaks, 8H). 13C{1H}
NMR (176 MHz, CDCl3): δ 156.7, 156.5, 146.5, 130.1, 124.2, 122.6,
119.6, 119.5. HRMS ESI+ (m/z): [M + Na]+ calcd C24H18O6SNa,
457.0716; found, 457.0716.
1
152.0−154.0 °C). H NMR (500 MHz, CDCl3): δ 7.79 (d, J = 9.0
Hz, 4H), 7.45 (d, J = 9.0 Hz, 4H). 13C{1H} NMR (176 MHz,
CDCl3): δ 152.8, 134.6, 122.1, 117.3, 112.5. HRMS EI (m/z): [M]+
calcd C14H8N2O4S, 300.0205; found, 300.0203.
Synthesis of Aryl Triflates. Aryl triflates were synthesized
according to the following procedure adapted from the literature.44
Under a N2 atmosphere, the corresponding phenol (1.0 equiv),
G
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Article
pyridine (1.5 equiv), and dichloromethane (0.3 M) were combined in
a round-bottom flask equipped with a magnetic stir bar. The flask was
cooled to 0 °C in an ice bath, and triflic anhydride (1.2 equiv) was
added dropwise. The reaction was allowed to warm to room
temperature and stirred overnight. The reaction mixture was filtered
through a plug of silica gel that was then washed with hexanes. The
resulting solution was concentrated under vacuum, and the product
was purified by column chromatography on silica gel using gradients
of either diethyl ether and pentane or hexanes and ethyl acetate as the
eluent. All products were dried under vacuum in the presence of P2O5
prior to use in deoxyfluorination reactions.
3-Fluorophenyl Trifluoromethanesulfonate (1-OTf). The reaction
was performed using 3-fluorophenol (500.0 mg, 4.5 mmol, 1.0 equiv),
pyridine (0.5 mL, 6.7 mmol, 1.5 equiv), and triflic anhydride (0.9 mL,
5.4 mmol, 1.2 equiv) in dichloromethane (15 mL) in a 50 mL flask.
Product 1-OTf was obtained as a colorless oil (541.8 mg, 50% yield,
Rf = 0.37 in pentane). 1H NMR (500 MHz, CDCl3): δ 7.45 (m, 1H),
7.15−7.10 (multiple peaks, 2H), 7.04 (dt, J = 8.5, 2.5 Hz, 1H).
13C{1H} NMR (176 MHz, CDCl3): δ 163.0 (d, J = 252 Hz), 149.8
(d, J = 10.6 Hz), 131.2 (d, J = 8.8 Hz), 118.0 (q, J = 320 Hz), 117.4
(d, J = 3.5 Hz), 115.9 (d, J = 21 Hz), 110.0 (d, J = 26 Hz). 19F NMR
(376 MHz, CDCl3): δ −72.7 (s, 3F), −108.1 (m, 1F). HRMS EI (m/
z): [M]+ calcd for C7H4F4O3S, 243.9871; found, 243.9867.
spectra matched those previously reported in the literature.45 HRMS
EI (m/z): [M]+ calcd C8H7F3O4S, 256.0017; found, 256.0027.
m-Tolyl Trifluoromethanesulfonate (8-OTf). The reaction was
performed using m-cresol (540.5 mg, 5.0 mmol, 1.0 equiv), pyridine
(0.6 mL, 7.5 mmol, 1.5 equiv), and triflic anhydride (1.0 mL, 6.0
mmol, 1.2 equiv) in dichloromethane (15.0 mL) in a 50 mL flask.
Product 8-OTf was obtained as a colorless oil (739.4 mg, 62% yield,
1
Rf = 0.68 in 5% EtOAc in hexanes). The H NMR (CDCl3) and
13C{1H} NMR (CDCl3) spectra matched those previously reported in
the literature.47 19F NMR (376 MHz, CDCl3): δ 73.0 (s, 3F). HRMS
EI (m/z): [M]+ calcd C8H7F3O3S, 240.0068; found, 240.0075.
p-Tolyl Trifluoromethanesulfonate (9-OTf). The reaction was
performed using p-cresol (1.0 g, 9.3 mmol, 1.0 equiv), pyridine (1.1
mL, 14.0 mmol, 1.5 equiv), and triflic anhydride (1.9 mL, 11.1 mmol,
1.2 equiv) in dichloromethane (30.0 mL) in a 100 mL flask. Product
9-OTf was obtained as a colorless oil (2.09 g, 94% yield, Rf = 0.38 in
1
pentane). The H NMR (CDCl3), 19F NMR (CDCl3), and 13C{1H}
NMR (CDCl3) spectra matched those previously reported in the
literature.48 HRMS EI (m/z): [M]+ calcd C8H7F3O3S, 240.0068;
found, 240.0075.
4-Methoxyphenyl Trifluoromethanesulfonate (10-OTf). The
reaction was performed using 4-methoxyphenol (620.0 mg, 5.0
mmol, 1.0 equiv), pyridine (0.6 mL, 7.5 mmol, 1.5 equiv), and triflic
anhydride (1.0 mL, 6.0 mL, 1.2 equiv) in dichloromethane (15.0 mL)
in a 50 mL flask. Product 10-OTf was obtained as a colorless oil (1.04
g, 81% yield, Rf = 0.45 in 8:1 hexanes/EtOAc). The 1H NMR
(CDCl3), 19F NMR (CDCl3), and 13C{1H} NMR (CDCl3) spectra
matched those previously reported in the literature.49 HRMS EI (m/
z): [M]+ calcd C8H7F3O4S, 256.0017; found, 256.0028.
Synthesis of Aryl Nonaflates. Aryl nonaflates were synthesized
according to procedures adapted from the literature.50 All products
were dried under vacuum in the presence of P2O5 prior to use in
deoxyfluorination reactions.
4-Cyanophenyl Trifluoromethanesulfonate (2-OTf). The reaction
was performed using 4-cyanophenol (595.6 mg, 5.0 mmol, 1.0 equiv),
pyridine (0.6 mL, 7.5 mmol, 1.5 equiv), and triflic anhydride (1.0 mL,
6.0 mmol, 1.2 equiv) in dichloromethane (15.0 mL) in a 50 mL flask.
Product 2-OTf was obtained as a colorless oil (1.01 g, 88% yield, Rf =
0.42 in 8:1 hexanes/EtOAc). The 1H NMR (CDCl3), 19F NMR
(CDCl3), and 13C{1H} NMR (CDCl3) spectra matched those
previously reported in the literature.45 HRMS EI (m/z): [M]+ calcd
for C8H4F3NO3S, 250.9864; found, 250.9862.
4-Chlorophenyl Trifluoromethanesulftonate (3-OTf). The reac-
tion was performed using 4-chlorophenol (1.0 g, 7.8 mmol, 1.0
equiv), pyridine (0.94 mL, 11.7 mmol, 1.5 equiv), and triflic
anhydride (1.57 mL, 9.3 mmol, 1.2 equiv) in dichloromethane
(30.0 mL) in a 100 mL flask. Product 3-OTf was obtained as a
3-Fluorophenyl 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonate
(1-ONf). A 50 mL round-bottom flask equipped with a magnetic
stir bar was charged with NaH (260.0 mg (60% dispersion in mineral
oil), 6.5 mmol, 1.3 equiv) and diethyl ether (4.0 mL). The flask was
cooled to 0 °C in an ice bath, and a solution of 3-fluorophenol (560.2
mg, 5.0 mmol, 1.0 equiv) in diethyl ether (2.5 mL) was added
dropwise. After 15 min, perfluoro-1-butanesulfonyl fluoride (1.3 mL,
7.0 mmol, 1.4 equiv) was added dropwise. The solution was allowed
to warm to room temperature and then stirred overnight. Water and
diethyl ether were added to the reaction mixture, and the organic layer
was separated. The aqueous layer was extracted twice with diethyl
ether. The combined organic layers were washed with 5% aqueous
NaOH and then brine, dried over MgSO4, and concentrated. The
crude product was purified by column chromatography on silica gel
(eluent = pentane). Product 3-ONf was obtained as a colorless oil
1
colorless oil (1.31 g, 65% yield, Rf = 0.48 in pentane). The H NMR
(CDCl3), 19F NMR (CDCl3), and 13C{1H} NMR (CDCl3) spectra
matched those previously reported in the literature.46 HRMS EI (m/
z): [M]+ calcd C7H4ClF3O3S 259.9522; found 259.9518.
[1,1′-Biphenyl]-4-yl Trifluoromethanesulfonate (4-OTf). The
reaction was performed using 4-phenylphenol (1.70 g, 10.0 mmol,
1.0 equiv), pyridine (1.62 mL, 20.0 mmol, 2.0 equiv), and triflic
anhydride (2.03 mL, 12.0 mmol, 1.2 equiv) in dichloromethane (20.0
mL) in a 50 mL flask. Product 4-OTf was obtained as a white solid
(2.26 g, 72% yield, mp = 47.2−48.0 °C, Rf = 0.64 in 10:1 hexanes/
1
EtOAc). The H NMR (CDCl3), 19F NMR (CDCl3), and 13C{1H}
1
(859.3 g, 44% yield, Rf = 0.53 in pentane). H NMR (500 MHz,
NMR (CDCl3) spectra matched those previously reported in the
literature.45 HRMS EI (m/z): [M]+ calcd C13H9F3O3S, 302.0224;
found, 302.0230.
CDCl3): δ 7.44 (q, J = 14.5, 8.5 Hz, 1H), 7.15−7.11 (multiple peaks,
2H), 7.06 (dt, J = 8.5, 2.5 Hz, 1H). 13C{1H} NMR (176 MHz,
CDCl3): δ 163.4 (d, J = 250 Hz), 150.0 (d, J = 10.6 Hz), 131.2 (d, J =
8.8 Hz), 117.4 (d, J = 3.5 Hz), 115.8 (d, J = 21 Hz), 110.0 (d, J = 26
Hz), 108.0−118.2 (multiple peaks, 4C). 19F NMR (376 MHz,
CDCl3): δ −80.6 (t, J = 7.5 Hz, 3F), −108.2 (q, J = 7.5 Hz, 1F),
−180.7 (m, 2F), −120.8 (m, 2F), −125.8 (m, 2F). HRMS EI (m/z):
[M]+ calcd C10H4F10O3S, 393.9721; found, 393.9736.
4-Cyanophenyl 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonate
(2-ONf). A 50 mL round-bottom flask equipped with a magnetic
stir bar was charged with 4-cyanophenol (595.6 mg, 5.0 mmol, 1.0
equiv), 4-dimethylaminopyridine (DMAP) (30.5 mg, 0.25 mmol, 0.05
equiv), iPr2NEt (1.0 mL, 6.0 mmol, 1.2 equiv), and dichloromethane
(8.0 mL). The solution was cooled to 0 °C in an ice bath. Perfluoro-1-
butanesulfonyl fluoride (1.0 mL, 5.5 mmol, 1.1 equiv) was added
dropwise. The solution was allowed to warm to room temperature
and then stirred overnight. The reaction mixture was poured into
water. The organic layer was collected, washed with brine, dried over
MgSO4, and concentrated. The crude product was purified by column
chromatography on silica gel (eluent = 20% EtOAc in hexanes).
Product 2-ONf was obtained as a white solid (1.80 g, 90% yield, mp =
4-Phenoxyphenyl trifluoromethanesulfonate (5-OTf). The reac-
tion was performed using 4-phenoxyphenol (500.0 mg, 2.7 mmol, 1.0
equiv), pyridine (0.32 mL, 4.0 mmol, 1.5 equiv), and triflic anhydride
(0.54 mL, 3.2 mL, 1.2 equiv) in dichloromethane (15.0 mL) in a 50
mL flask. Product 5-OTf was obtained as a colorless oil (751.5 mg,
1
88% yield, Rf = 0.25 in pentane). H NMR (500 MHz, CDCl3): δ
7.38 (t, J = 8.0 Hz, 2H), 7.21 (d, J = 9.1 Hz, 2H), 7.18 (t, J = 8.0 Hz,
1H), 7.03 (t, J = 9.1 Hz, 4H). 13C{1H} NMR (176 MHz, CDCl3): δ
157.5, 156.2, 144.6, 130.2, 124.5, 122.8, 119.8, 119.5, 117.0 (q, J =
320 Hz). 19F NMR (376 MHz, CDCl3): δ 72.8 (s, 3F). HRMS EI
(m/z): [M]+ calcd C13H9F3O4S, 318.0174; found, 318.0180.
3-Methoxyphenyl Trifluoromethanesulfonate (7-OTf). The re-
action was performed using 3-methoxyphenol (500.0 mg, 4.0 mmol,
1.0 equiv), pyridine (0.5 mL, 6.0 mmol, 1.5 equiv), and triflic
anhydride (0.8 mL, 4.8 mmol, 1.2 equiv) in dichloromethane (20.0
mL) in a 50 mL flask. Product 7-OTf was obtained as a pale yellow oil
(592.9 mg, 58% yield, Rf = 0.56 in 5% diethyl ether in pentane). The
1H NMR (CDCl3), 19F NMR (CDCl3), and 13C{1H} NMR (CDCl3)
H
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Article
1
32.4−34.0 °C, Rf = 0.62 in 20% EtOAc in hexanes). The H NMR
(CDCl3), 19F NMR (CDCl3), and 13C{1H} NMR (CDCl3) spectra
matched those previously reported in the literature.45 HRMS EI (m/
z): [M]+ calcd C11H4F9NO3S, 400.9768; found, 400.9765.
Computational Details. Calculations were carried out with a
modified G3MP2B3 method using the PCM solvation model in
DMF. Further details are provided in the Supporting Information.
General Procedures for Fluorination Reactions. General
Procedure A: Experimental Procedure for Initial Rates in Figures 2,
5, and 7. In a N2-filled drybox, substrate (0.1 mmol, 1.0 equiv) and
NMe4F (18.6 mg, 0.2 mmol, 2.0 equiv) were weighed into a 4 mL vial
equipped with a magnetic stir bar. Anhydrous DMF (0.5 mL) was
added, and the vial was sealed with a Teflon-lined cap. The vial was
removed from the drybox and heated at 80 °C on a preheated
aluminum heat block. After the desired reaction time, the reaction was
flash frozen in a liquid N2 bath. The vial was then warmed to room
temperature, and the reaction mixture was diluted with dichloro-
methane (2.0 mL). 1,3,5-Trifluorobenzene was added as a standard,
and the reaction was analyzed by 19F NMR spectroscopy. Yields of
product are reported as an average of three independent vial reactions.
Yield versus time data were collected from the integration of the 19F
NMR signals of product versus internal standard (1,3,5-trifluor-
obenzene) (see Supporting Information for rate data and plots). The
initial rate for each experiment was determined by a linear fit of the
appearance of fluorinated product. A plot of Hammett values (Figure
3),51 σ−, versus log (kR/kH) showed a linear correlation.
General Procedure B: Experimental Procedure for the Room
Temperature 19F NMR Spectroscopy Studies in Figure 3. In a N2-
filled drybox, a screw-cap NMR tube was charged with 1-OFs (19.4
mg, 0.1 mmol, 1.0 equiv), NMe4F (9.3 mg, 0.1 mmol, 1.0 equiv), and
anhydrous DMF (0.5 mL). The NMR tube was sealed with a Teflon-
lined cap. After 30 min at room temperature, a 19F NMR spectrum
was acquired. The NMR tube was allowed to stand at room
temperature for 24 h, and another 19F NMR spectrum was acquired. A
truncated 19F NMR spectrum is shown in Figure 3. 4-Fluoroanisole
was used as an internal standard. For comparison, an NMR tube was
prepared with 1-OFs and 1-F and a 19F NMR spectrum was acquired.
General Procedure C: Experimental Procedure for the 19F NMR
Spectra Monitoring Shown in Figure 4. In a N2-filled drybox, a
screw-cap NMR tube was charged with 1-OFs (0.1 mmol, 1.0 equiv),
NMe4F (18.6 mg, 0.2 mmol, 2.0 equiv), and anhydrous DMF (0.5
mL). The NMR tube was sealed with a Teflon-lined cap and removed
from the drybox. The NMR tube was then placed into an NMR
spectrometer where the probe had been preheated to 80 °C. The
fluorination reaction of 1-OFs to form 1-F was monitored by 19F
NMR spectroscopy at 80 °C. Yield versus time plots were acquired by
integration of the 19F NMR signals of 1-OFs, 1-sulfate, and 1-F
relative to internal standard (4-fluoroanisole).
4-Chlorophenyl 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonate
(3-ONf). A 50 mL round-bottom flask equipped with a magnetic
stir bar was charged with NaH (260.0 mg (60% dispersion in mineral
oil), 6.5 mmol, 1.3 equiv) and diethyl ether (4.0 mL). The flask was
cooled to 0 °C in an ice bath, and a solution of 4-chlorophenol (642.8
mg, 5.0 mmol, 1.0 equiv) in diethyl ether (2.5 mL) was added
dropwise. After 15 min, perfluoro-1-butanesulfonyl fluoride (1.3 mL,
7.0 mmol, 1.4 equiv) was added dropwise. The solution was allowed
to warm to room temperature and then stirred overnight. Water and
diethyl ether were added to the reaction mixture, and the organic layer
was separated. The aqueous layer was extracted twice with diethyl
ether. The combined organic extracts were washed with 5% aqueous
NaOH and then brine, dried over MgSO4, and concentrated. The
crude product was purified by column chromatography on silica gel
(eluent = pentane). Product 3-ONf was obtained as a colorless oil
1
(1.438 g, 70% yield, Rf = 0.54 in pentane). The H NMR (CDCl3)
and 13C{1H} NMR (CDCl3) spectra matched those previously
reported in the literature.50 19F NMR (376 MHz, CDCl3): δ −80.6 (t,
J = 11.3 Hz, 3F), −108.7 (m, 2F), −120.8 (m, 2F), −125.8 (m, 2F).
HRMS EI (m/z): [M]+ calcd C10H4ClF9O3S, 409.9426; found,
409.9420.
[1,1′-Biphenyl]-4-yl 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfo-
nate (4-ONf). A 50 mL round-bottom flask equipped with a magnetic
stir bar was charged with NaH (260.0 mg (60% dispersion in mineral
oil), 6.5 mmol, 1.3 equiv) and diethyl ether (4.0 mL). The flask was
cooled to 0 °C in an ice bath, and a solution of 4-phenylphenol (851.0
mg, 5.0 mmol, 1.0 equiv) in diethyl ether (2.5 mL) was added
dropwise. After 15 min, perfluoro-1-butanesulfonyl fluoride (1.3 mL,
7.0 mmol, 1.4 equiv) was added dropwise. The solution was allowed
to warm to room temperature and then stirred overnight. Water and
diethyl ether were added to the reaction mixture, and the organic layer
was separated. The aqueous layer was extracted twice with diethyl
ether. The combined organic extracts were washed with 5% aqueous
NaOH and brine, dried over MgSO4, and concentrated. The crude
product was purified by column chromatography on silica gel (eluent
= pentane). Product 4-ONf was obtained as a white solid (1.785 g,
79% yield, mp = 45.5−46.7 °C, Rf = 0.43 in pentane). 1H NMR (500
MHz, CDCl3): δ 7.66−7.63 (m, 2H), 7.56−7.54 (m, 2H), 7.48−7.45
(m, 2H), 7.43−7.34 (multiple peaks, 3H). 13C{1H} NMR (176 MHz,
CDCl3): δ 149.3, 141.8, 139.4, 129.1, 129.0, 128.2, 127.3, 121.7,
108.0−118.0 (multiple peaks, 4C). 19F NMR (376 MHz, CDCl3): δ
−80.6 (t, J = 9.8 Hz, 3F), −108.8 (m, 2F), −120.9 (m, 2F), −125.8
(m, 2F). HRMS EI (m/z): [M]+ calcd C16H9F9O3S, 452.0129; found,
452.0133.
4-Phenyoxyphenyl 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfo-
nate (5-ONf). A 50 mL round-bottom flask equipped with a magnetic
stir bar was charged with NaH (260.0 mg (60% dispersion in mineral
oil), 6.5 mmol, 1.3 equiv) and diethyl ether (4.0 mL). The flask was
cooled to 0 °C in an ice bath, and a solution of 4-phenoxyphenol
(931.1 mg, 5.0 mmol, 1.0 equiv) in diethyl ether (2.5 mL) was added
dropwise. After 15 min, perfluoro-1-butanesulfonyl fluoride (1.3 mL,
7.0 mmol, 1.4 equiv) was added dropwise. The solution was allowed
to warm to room temperature and then stirred overnight. Water and
diethyl ether were added to the reaction mixture, and the organic layer
was separated. The aqueous layer was extracted twice with diethyl
ether. The combined organic extracts were washed with 5% aqueous
NaOH and brine, dried over MgSO4, and concentrated. The crude
product was purified by column chromatography on silica gel (eluent
= 10% EtOAc in hexanes). Product 5-ONf was obtained as a colorless
oil (1.699 g, 73% yield, Rf = 0.64 in 10% ethyl acetate in hexanes).
The 1H NMR (CDCl3), 19F NMR (CDCl3), and 13C{1H} NMR
(CDCl3) spectra matched those previously reported in the
literature.45 HRMS EI (m/z): [M]+ calcd C16H9F9O4S, 468.0078;
found, 468.0080.
General Procedure D: Experimental Procedure for the 19F NMR
Study for the Observation of 1-OFs in eq 3. In a N2-filled drybox, a
screw-cap NMR tube was charged with 1-sulfate (28.6 mg, 0.1 mmol,
1.0 equiv), NMe4F (18.6 mg, 0.2 mmol, 2.0 equiv), and anhydrous
DMF (0.5 mL). The NMR tube was sealed with a Teflon-lined cap
and removed from the drybox. The NMR tube was placed into a
preheated oil bath at 80 °C such that the solution was completely
immersed in the heated oil. After 10 min, the NMR tube was removed
from the oil bath, flash frozen in a liquid N2 bath, and then warmed to
room temperature to acquire a 19F NMR spectrum. 4-Fluoroanisole
was used as an internal standard.
General Procedure E: Experimental Procedure for the Effect of
Exogenous SO2F2 on Reaction of 1-Sulfate in eq 4. In a N2-filled
drybox, 1-sulfate (20.1 mg, 0.05 mmol, 1.0 equiv) and NMe4F (9.3
mg, 0.1 mmol, 2.0 equiv) were weighed into a 4 mL vial equipped
with a magnetic stir bar. A solution of SO2F2 in anhydrous DMF (0.36
mL of 0.14 M solution, 0.05 mmol, 1.0 equiv) was added, and the vial
was quickly sealed with a Teflon-lined cap. The reaction was heated at
80 °C for 24 h. The reaction mixture was cooled to room temperature
and then diluted with dichloromethane (2.0 mL). 1,3,5-Trifluor-
obenzene was added as an internal standard, and the reaction was
analyzed by 19F NMR spectroscopy. The yield in eq 2 represents the
average of two runs (100% and 120%).
General Procedure F: Experimental Procedure for the Fluorina-
tion of Aryl Fluorosulfonates, Diaryl Sulfates, Aryl Triflates, and
Aryl Nonaflates in Tables 1−2. In a N2-filled drybox, substrate (0.1
mmol, 1.0 equiv) and NMe4F (18.6 mg, 0.2 mmol, 2.0 equiv) were
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weighed into a 4 mL glass vial equipped with a microsized magnetic
stir bar. Anhydrous DMF (0.5 mL) was added, and the vial was sealed
with a Teflon-lined cap. The reaction mixture was allowed to stir at 80
°C for 24 h. The reaction was then diluted with dichloromethane (2.0
mL). 1,3,5-Trifluorobenzene was added as an internal standard, and
the reaction was analyzed by 19F NMR spectroscopy and GCMS. For
reactions with diaryl sulfates, the yield was determined based on 0.1
mmol of starting material producing 0.1 mmol fluorinated product.
The yields reported in Tables 1 and 2 represent an average of two
reactions.
General Procedure G: Experimental Procedure for the Reaction
Profiles in Figure 6. In a N2-filled drybox, substrate 2-X (0.1 mmol,
1.0 equiv, X = OFs, OTf, ONf) and NMe4F (18.6 mg, 0.2 mmol, 2.0
equiv) were weighed into a 4 mL glass vial equipped with a magnetic
stir bar. Anhydrous DMF (0.5 mL) was added, and the vial was sealed
with a Teflon-lined cap. The reaction mixture was allowed to stir at 80
°C for the given time. The reaction was then cooled in an ice bath and
diluted with dichloromethane (2.0 mL). 1,3,5-Trifluorobenzene was
added as an internal standard, and the reaction was analyzed by 19F
NMR spectroscopy.
determined by 19F NMR spectroscopic analysis of the crude reaction
mixture. The 19F NMR spectral data matched those of an authentic
sample (Matrix, m, −116.7 ppm). The identity of the product was
further confirmed by GCMS analysis (m/z = 172). The yield reported
in Figure 8 is an average of two runs [86% and 87%].
General procedure H was followed using [1,1′-biphenyl]-4-yl
sulfofluoridate 4-OFs (25.3 mg, 0.1 mmol, 1.0 equiv) at 80 °C,
providing 4-F in 80% yield as determined by 19F NMR spectroscopic
analysis of the crude reaction mixture. The 19F NMR spectral data
matched those of an authentic sample (Matrix, m, −116.7 ppm). The
identity of the product was further confirmed by GCMS analysis (m/z
= 172). The yield reported in Figure 8 is an average of two runs [80%
and 73%].
1-Fluoro-4-phenoxybenzene (5-F). General procedure H was
followed using 4-phenoxyphenyl trifluoromethanesulfonate 5-OTf
(31.8 mg, 0.1 mmol, 1.0 equiv) at 80 °C, providing 5-F in 33% yield
as determined by 19F NMR spectroscopic analysis of the crude
reaction mixture. The product showed a 19F NMR signal at −121.1
ppm in DCM (lit. −120.1 ppm in CDCl3).13 The identity of the
product was further confirmed by GCMS analysis (m/z = 188). The
yield reported in Figure 8 is an average of two runs [33% and 34%].
General procedure H was followed using 4-phenoxyphenyl
sulfofluoridate 5-OFs (26.8 mg, 0.1 mmol, 1.0 equiv) at 80 °C,
providing 5-F in 30% yield as determined by 19F NMR spectroscopic
analysis of the crude reaction mixture. The product showed a 19F
NMR signal at −121.1 ppm in DCM (lit. −120.1 ppm in CDCl3).13
The identity of the product was further confirmed by GCMS analysis
(m/z = 188). The yield reported in Figure 8 is an average of two runs
[30% and 28%].
Fluorobenzene (6-F). General procedure H was followed using
phenyl trifluoromethanesulfonate 6-OTf (22.6 mg, 0.1 mmol, 1.0
equiv) at 80 °C, providing product 6-F in 56% yield as determined by
19F NMR spectroscopic analysis of the crude reaction mixture. The
19F NMR spectral data matched those of an authentic sample (Matrix,
m, −114.1 ppm). The yield reported in Figure 8 is an average of two
runs [56% and 60%].
General Procedure H: Experimental Details for the 19F NMR
Yields Reported in Figure 8. Yields for the fluorination reactions of
aryl fluorosulfonates 1-OFs, 2-OFs, 7-OFs, 8-OFs, 9-OFs, and 10-
OFs are from ref 13.
In a N2-filled drybox, NMe4F (18.6 mg, 0.2 mmol, 2 equiv) and the
aryl triflate or aryl fluorosulfonate substrate (0.1 mmol, 1 equiv) were
weighed into a 4 mL glass vial equipped with a magnetic stir bar.
Anhydrous DMF (0.5 mL) was added, and the vial was sealed with a
Teflon-lined cap. The reaction mixture was allowed to stir at the given
temperature for 24 h. The resulting solution was diluted with
dichloromethane (2 mL), and a standard (1,3,4-trifluorobenzene or 4-
fluoroanisole, 100 μL of a 0.5 M solution in toluene) was added. An
aliquot was removed for analysis by 19F NMR spectroscopy and
GCMS.
Product Synthesis and Characterization. 1,3-Difluoroben-
zene (1-F). General procedure H was followed using 3-fluorophenyl
trifluoromethanesulfonate 1-OTf (24.4 mg, 0.1 mmol, 1.0 equiv) at
80 °C, providing product 1-F in 80% yield as determined by 19F NMR
spectroscopic analysis of the crude reaction mixture. The 19F NMR
spectral data matched those of an authentic sample (Matrix, m,
−110.9 ppm). The yield reported in Figure 8 is an average of two runs
[80% and 71%].
General procedure H was followed using phenyl sulfofluoridate 6-
OFs (17.6 mg, 0.1 mmol, 1.0 equiv) at 80 °C, providing product 6-F
in 55% yield as determined by 19F NMR spectroscopic analysis of the
crude reaction mixture. The 19F NMR spectral data matched those of
an authentic sample (Matrix, m, −114.1 ppm). The yield reported in
Figure 8 is an average of two runs [55% and 48%].
4-Fluorobenzonitrile (2-F). General procedure H was followed
using 4-cyanophenyl trifluoromethanesulfonate 2-OTf (25.1 mg, 0.1
mmol, 1.0 equiv) at 80 °C, providing product 2-F in 65% yield as
determined by 19F NMR spectroscopic analysis of the crude reaction
mixture. The 19F NMR spectral data matched those of an authentic
sample (Oakwood Chemicals, m, −103.89 ppm). The identity of the
product was further confirmed by GCMS analysis (m/z = 121). The
yield reported in Figure 8 is an average of two runs [65% and 66%].
1-Chloro-4-fluorobenzene (3-F). General procedure H was
followed using 4-chlorophenyl trifluoromethanesulfonate 3-OTf
(26.0 mg, 0.1 mmol, 1.0 equiv) at 80 °C, providing product 3-F in
85% yield as determined by 19F NMR spectroscopic analysis of the
crude reaction mixture. The 19F NMR spectral data matched those of
an authentic sample (Oakwood Products, m, −116.7 ppm). The
identity of the product was further confirmed by GCMS analysis (m/z
= 130). The yield reported in Figure 8 is an average of two runs [85%
and 85%].
General procedure H was followed using 4-chlorophenyl
sulfofluoridate 3-OFs (21.0 mg, 0.1 mmol, 1.0 equiv) at 80 °C,
providing product 3-F in 77% yield as determined by 19F NMR
spectroscopic analysis of the crude reaction mixture. The 19F NMR
spectral data matched those of an authentic sample (Oakwood
Products, m, −116.7 ppm). The identity of the product was further
confirmed by GCMS analysis (m/z = 130). The yield reported in
Figure 8 is an average of two runs [77% and 73%].
3-Fluoroanisole (7-F). General procedure H was followed using 3-
methoxyphenyl trifluoromethanesulfonate 7-OTf (25.6 mg, 0.1 mmol,
1.0 equiv) at 100 °C, providing 7-F in 22% yield as determined by 19F
NMR spectroscopic analysis of the crude reaction mixture. The 19F
NMR spectral data matched those of an authentic sample (Sigma-
Aldrich, m, −112.9 ppm). The identity of the product was further
confirmed by GCMS analysis (m/z = 126). The yield reported in
Figure 8 is an average of two runs [22% and 19%].
3-Fluorotoluene (8-F). General procedure H was followed using m-
tolyl trifluoromethanesulfonate 8-OTf (24.0 mg, 0.1 mmol, 1.0 equiv)
at 100 °C, providing 8-F in 43% yield as determined by 19F NMR
spectroscopic analysis of the crude reaction mixture. The 19F NMR
spectral data matched those of an authentic sample (Matrix, m,
−115.2 ppm). The yield reported in Figure 8 is an average of two runs
[43% and 46%].
4-Fluorotoluene (9-F). General procedure H was followed using p-
tolyl trifluoromethanesulfonate 9-OTf (24.0 mg, 0.1 mmol, 1.0 equiv)
and NMe4F (46.5 mg, 0.5 mmol, 5.0 equiv) at 100 °C, providing
product 9-F in 23% yield as determined by 19F NMR spectroscopic
analysis of the crude reaction mixture. The 19F NMR spectral data
matched those of an authentic sample (Matrix Scientific, m, −119.5
ppm). The identity of the product was further confirmed by GCMS
analysis (m/z = 110). The yield reported in Figure 8 is an average of
two runs [12% and 12%].
4-Fluoroanisole (10-F). General procedure H was followed using
4-methoxyphenyl trifluoromethanesulfonate 10-OTf (25.6 mg, 0.1
mmol, 1.0 equiv) and NMe4F (46.5 mg, 0.5 mmol, 5.0 equiv) at 100
4-Fluoro-1,1′-biphenyl (4-F). General procedure H was followed
using [1,1′-biphenyl]-4-yl trifluoromethanesulfonate 4-OTf (30.2 mg,
0.1 mmol, 1.0 equiv) at 80 °C, providing 4-F in 86% yield as
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°C, providing none of the desired product 10-F as determined by 19
NMR spectroscopic analysis of the crude reaction mixture.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01762.
■
S
NMR spectral data of substrates, NMR spectral data for
reaction monitoring, summary of kinetic data and plots,
and computational details (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: mssanfor@umich.edu.
■
(8) (a) Allen, L. J.; Muhuhi, J. M.; Bland, D. C.; Merzel, D.; Sanford,
M. S. Mild Fluorination of Chloropyridines with in Situ Generated
Anhydrous Tetrabutylammonium Fluoride. J. Org. Chem. 2014, 79,
5827−5833. (b) Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford, M.
S. Acyl Azolium Fluorides for Room Temperature Nucleophilic
Aromatic Fluorination of Chloro- and Nitroarenes. Org. Lett. 2015,
17, 1866−1869. (c) Cismesia, M. A.; Ryan, S. J.; Bland, D. C.;
Sanford, M. S. Multiple Approaches to the In Situ Generation of
Anhydrous Tetraalkylammonium Fluoride Salts for SNAr Fluorination
Reactions. J. Org. Chem. 2017, 82, 5020−5026.
(9) Schimler, S. D.; Ryan, S. J.; Bland, D. C.; Anderson, J. E.;
Sanford, M. S. Anhydrous Tetramethylammonium Fluoride for
Room-Temperature SNAr Fluorination. J. Org. Chem. 2015, 80,
12137−12145.
(10) Tang, P.; Wang, W.; Ritter, T. Deoxyfluorination of Phenols. J.
Am. Chem. Soc. 2011, 133, 11482−11484.
(11) (a) Fujimoto, T.; Becker, F.; Ritter, T. PhenoFluor: Practical
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(12) Neumann, C. N.; Hooker, J. M.; Ritter, T. Concerted
Nucleophilic Aromatic Substitution with 19F− and 18F−. Nature
2016, 534, 369−373.
(13) Schimler, S. D.; Cismesia, M. A.; Hanley, P. S.; Froese, R. D. J.;
Jansma, M. J.; Bland, D. C.; Sanford, M. S. Nucleophilic
Deoxyfluorination of Phenols via Aryl Fluorosulfonate Intermediates.
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(14) For the reaction of phenols with SOF4 to afford aryl fluorides in
low yields, see: Cramer, R.; Coffman, D. D. New Synthesis of Aryl
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ORCID
Sydonie D. Schimler: 0000-0002-7170-1643
Melanie S. Sanford: 0000-0001-9342-9436
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by The Dow Chemical Company.
Dr. Megan Cismesia (University of Michigan), Cristina Garcia
■
́
Morales (University of Michigan), and Dr. Patrick Hanley
(The Dow Chemical Company) are acknowledged for
synthetic contributions. Michael Wade Wolfe (University of
Michigan) is acknowledged for preliminary Hammett studies.
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−
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