Multiple Approaches to the in Situ Generation of Anhydrous Tetraalkylammonium Fluoride Salts for SNAr Fluorination Reactions

Article abstract of DOI:10.1021/acs.joc.7b00481

This article focuses on the development of practical approaches to the in situ generation of anhydrous fluoride salts for applications in nucleophilic aromatic substitution (S_NAr) reactions. We report herein that a variety of combinations of inexpensive nucleophiles (e.g., tetraalkylammonium cyanide and phenoxide salts) and fluorine-containing electrophiles (e.g., acid fluoride, fluoroformate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives) are effective for this transformation. Ultimately, we demonstrate that the combination of tetramethylammonium 2,6-dimethylphenoxide and sulfuryl fluoride (SO₂F₂) serves as a particularly practical route to anhydrous tetramethylammonium fluoride. This procedure is applied to the S_NAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as nitroarenes.

Full text of DOI:10.1021/acs.joc.7b00481

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pubs.acs.org/joc
Multiple Approaches to the In Situ Generation of Anhydrous
Tetraalkylammonium Fluoride Salts for SNAr Fluorination Reactions
Megan A. Cismesia,† Sarah J. Ryan,† 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 & Development, The Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States
S
* Supporting Information
ABSTRACT: This article focuses on the development of practical
approaches to the in situ generation of anhydrous fluoride salts for
applications in nucleophilic aromatic substitution (SNAr) reactions.
We report herein that a variety of combinations of inexpensive
nucleophiles (e.g., tetraalkylammonium cyanide and phenoxide salts)
and fluorine-containing electrophiles (e.g., acid fluoride, fluorofor-
mate, benzenesulfonyl fluoride, and aryl fluorosulfonate derivatives)
are effective for this transformation. Ultimately, we demonstrate that the combination of tetramethylammonium 2,6-
dimethylphenoxide and sulfuryl fluoride (SO2F2) serves as a particularly practical route to anhydrous tetramethylammonium
fluoride. This procedure is applied to the SNAr fluorination of a range of electron-deficient aryl and heteroaryl chlorides as well as
nitroarenes.
temperature. This reagent proved highly reactive for the SNAr
fluorination of electron-deficient aryl chlorides and nitro-
arenes.13,14 However, widespread application of this method
remains limited by both cost (C6F6) and toxicity (NBu4CN)
considerations.
Our overall objective is to develop more practical and
potentially scalable approaches to the in situ generation of
anhydrous fluoride salts for SNAr reactions (Scheme 1c). We
report herein that a variety of combinations of inexpensive
nucleophiles and fluorine-containing electrophiles are effective
for this transformation. Ultimately, we demonstrate that the
reaction of tetramethylammonium 2,6-dimethylphenoxide with
sulfuryl fluoride (SO2F2) serves as a particularly practical route
to anhydrous tetramethylammonium fluoride (NMe4F). This
procedure is applied to the in situ generation of NMe4F and
subsequent SNAr fluorination of a range of electron-deficient
aryl and heteroaryl chlorides as well as nitroarenes.
INTRODUCTION
■
Fluorinated arenes and heteroarenes appear in a variety of
pharmaceuticals and agrochemicals.1 In many cases, the
replacement of a C−H bond with a C−F bond is used to
increase the bioavailability, metabolic stability, and/or lip-
ophilicity of these biologically active molecules.2 However,
despite their prevalence, many aryl and heteroaryl fluorides
remain challenging to synthesize, particularly under mild
conditions and with inexpensive reagents.
One of the most common methods for the formation of aryl
fluorides is nucleophilic aromatic substitution (SNAr fluorina-
tion). These transformations typically involve the reaction of an
aryl chloride or nitroarene with an alkali metal fluoride salt
(MF).3,4 Elevated temperatures (>100 °C) and long reaction
times are often required,5 mainly due to the low solubility of
MF under the anhydrous reaction conditions.6 This can result
in poor functional group tolerance and undesired side reactions.
As such, significant recent effort has focused on developing
inexpensive and practical routes to more soluble anhydrous
fluoride sources for SNAr fluorination reactions (Scheme 1a).
Tetraalkylammonium fluoride salts are attractive targets as
anhydrous fluoride sources for this application.7−10 However,
these salts are generally synthesized under aqueous conditions,
resulting in strongly hydrated (and thus weakly nucleophilic)
NR4F.11 Furthermore, the elevated temperatures required to
dehydrate NR4F·(H2O)n often lead to decomposition via E2 or
SN2 reactions of the NR4 cation.11,12 In an effort to address
these challenges, DiMagno pioneered the in situ formation of
anhydrous NR4F starting from a tetraalkylammonium nucleo-
phile and a fluorine-containing electrophile.13 As shown in
Scheme 1b, DiMagno’s original report involved the combina-
tion of tetrabutylammonium cyanide (NBu4CN) and hexa-
fluorobenzene (C6F6) to generate anhydrous NBu4F at room
RESULTS AND DISCUSSION
■
The 5-chloropicolinate 1-Cl was selected as a model SNAr
substrate for our initial investigations. The resulting fluorinated
product 1-F is a close analogue of several agrochemicals.15
Furthermore, 1-Cl has been used as a substrate for our previous
studies of SNAr fluorination,8,14,16,17 thus enabling a direct
comparison to the current systems. We first evaluated the SNAr
fluorination of 1-Cl using the combination of acid fluoride A-1
and a variety of neutral nucleophiles, which were expected to
form fluoride salts of general structure B (Table 1).16,18 For the
initial screening, equimolar quantities of the acid fluoride A-1
and the nucleophile were combined in anhydrous DMF, and
Received: February 28, 2017
© XXXX American Chemical Society
A
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this mixture was allowed to stir for 15 min. Substrate 1-Cl was
then added, and the reaction was stirred at room temperature
for an additional 24 h and then analyzed by 19F NMR
spectroscopy to determine the yield of 1-F. Among the
nucleophiles examined, only the N-heterocyclic carbene C-1
formed a reactive fluorinating reagent under these conditions,19
affording 89% yield of 1-F.16 In contrast, <1% of 1-F was
formed using the amine, phosphine, and pyridine derivatives in
Table 1. In all these systems, significant quantities of acid
fluoride (>90%) remained at the end of the reaction, suggesting
that very little of B is formed.
Scheme 1. Methods for the In Situ Generation of Anhydrous
Fluoride for SNAr Fluorination
We next examined the reactions of A-1 with tetraalkylam-
monium (NR4) salts of anionic nucleophiles in an effort to
form anhydrous NR4F (Table 2). This in situ generated
Table 2. Reaction of A-1 with Anionic Nucleophiles To
Generate Anhydrous NR4F for the SNAr Fluorination of 1-
a
Cl
Table 1. Reaction of A-1 with Neutral Nucleophiles To
Generate Anhydrous Fluoride for the SNAr Fluorination of
a
1-Cl
a
Conditions: A-1 (2 equiv) and nucleophile (2 equiv) stirred in DMF
for 15 min at rt; then 1-Cl (1 equiv) added and reaction stirred for an
additional 24 h at rt. Yields of 1-F determined by 19F NMR
spectroscopy.
fluoride was then utilized for the SNAr fluorination of 1-Cl.
Whereas NMe4OAc was ineffective for this transformation, the
more nucleophilic salts NBu4CN and NMe4OPh led to 75 and
65% yield of 1-F, respectively. In the latter transformation, the
major side product was 1-OPh, which results from an SNAr
reaction between the residual nucleophile and either the
starting material 1-Cl or the fluorinated product 1-F.20 We
hypothesized that this side product could be limited (and thus
the yield of 1-F could be improved) through the use of a more
hindered phenoxide. Indeed, under otherwise identical
conditions, tetramethylammonium 2,6-dimethylphenoxide (D-
1) afforded 92% yield of 1-F, along with <10% of 1-OAr (Ar =
2,6-dimethylphenoxide).21 The formation of 1-OAr could be
further minimized by changing the ratio of A-1 to 2,6-
dimethylphenoxide from 1:1 to 1.3:1. Using these optimized
a
Conditions: A-1 (2 equiv) and nucleophile (2 equiv) stirred in DMF
for 15 min at rt; 1-Cl (1 equiv) added and stirred for an additional 24
b
h at rt. Yield of 1-F determined by 19F NMR spectroscopy. Yield
from ref 16.
B
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conditions, 1-OAr was not detected, and product 1-F was
formed in >95% yield as determined by 19F NMR spectroscopy
and isolated in 89% yield.
Table 4. Reaction of Different Fluorine-Containing
Electrophiles A with D-1 To Generate Anhydrous NMe4F for
a
the SNAr Fluorination of 1-Cl
We next applied the combination of A-1 and tetramethy-
lammonium 2,6-dimethylphenoxide (D-1) to the SNAr
fluorination of several other substrates and compared the
results to those reported in the literature (Table 3). As shown
Table 3. Comparison with Other SNAr Fluorination Methods
a
Conditions: A-1 (2 equiv) and D-1 (1.5 equiv) stirred in DMF for 15
min at rt; then substrate (1 equiv) added and reaction stirred for a
b
a
further 24 h at rt. Isolated yields are reported. Isolated yields from ref
Conditions: A (2 equiv) and D-1 (2 equiv) stirred in DMF for 15
c
16. Isolated yields from ref 8.
min at rt; then substrate (1 equiv) added and reaction stirred for a
further 24 h at rt. Yields of 1-F determined by 19F NMR spectroscopy.
in Table 3, column 1, the SNAr fluorination of 1-Cl with A-1/
D-1 afforded an isolated yield comparable to that with the in
situ generated acyl azolium fluoride (B with Nu = C-1)16 or
with isolated anhydrous NMe4F8 (89, 87, and 82% yield,
respectively). These three methods also provided comparable
isolated yields for the fluorodenitration of 2-NO2 (column 2) as
well as the halex fluorination of 2-chloroquinoline (3-Cl,
column 3).
We next probed a series of fluorine-containing electrophiles
that could react with tetramethylammonium 2,6-dimethylphen-
oxide (D-1) to release NMe4F. These reactions were conducted
by stirring 2 equiv of A and 2 equiv of D-1 in DMF for 15 min
at room temperature, followed by the addition of 1 equiv of 1-
Cl. As shown in Table 4, methyl fluoroformate (A-2),
benzenesulfonyl fluoride (A-3),22 and 4-methoxyphenyl sulfur-
ofluoridate (A-4) were all effective precursors to anhydrous
fluoride under these conditions, affording 1-F in 49, 57, and
62% yield, respectively. However, the best results were obtained
with sulfuryl fluoride (A-5), which afforded >95% yield of 1-
F.23 This is a particularly significant result because sulfuryl
fluoride is an inexpensive commercial insecticide that is
produced on multi-ton scale annually.24 As such, this method
serves as a practical and potentially scalable route to anhydrous
NMe4F.
NO2, and 3-Cl all reacted under our standard conditions to
afford 1-F, 2-F, and 3-F in 95, 91, and 81% isolated yield,
respectively. Other heteroaryl chlorides, including quinolines 4-
Cl and 5-Cl as well as pyridazine 6-Cl, underwent SNAr
fluorination in 81, 75, and 74% isolated yield, respectively. This
method was also effective for the SNAr fluorination of aryl
chlorides and nitroarenes bearing electron-withdrawing cyano
(7-Cl, 9-NO2, and 11-NO2), ester (8-NO2), and amide (10-
NO2) substituents. Finally, this method enabled the synthesis
of 4-fluoro-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-
(pyridin-2-yl)benzamide (MPPF, 10-F), a serotonin 1A
receptor ligand, and 3-fluoro-5-(pyridin-2-ylethynyl)-
benzonitrile (PEB-F, 11-F), a metabotropic glutamate receptor
subtype 5 ligand. Both of these are analogues to positron
emission tomography (PET) radiotracers.
CONCLUSION
■
Overall, this report demonstrates that a variety of different
combinations of nucleophiles and electrophilic fluorine sources
can be used to generate anhydrous fluoride at room
temperature. In particular, the combination of tetramethylam-
monium 2,6-dimethylphenoxide (D-1) and sulfuryl fluoride (A-
5) rapidly generates anhydrous tetramethylammonium fluoride,
which can then be employed for the SNAr fluorination of a
variety of different substrates. This method offers the
advantages that it employs inexpensive, readily available
reagents and that it is operationally straightforward. As such,
we anticipate that it has the potential for applications in
pharmaceutical and agrochemical syntheses.
We next used the combination of tetramethylammonium 2,6-
dimethylphenoxide (D-1) and sulfuryl fluoride (A-5) for the
SNAr fluorination of a variety of different substrates. Notably, in
most cases, prestirring the tetramethylammonium 2,6-dime-
thylphenoxide and sulfuryl fluoride was found to be
unnecessary. As such, the standard conditions involved
combining 2 equiv of D-1, 3 equiv of A-5,25 and 1 equiv of
substrate in a single pot and then stirring for 24 h at room
temperature. As summarized in Table 5, substrates 1-Cl, 2-
C
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A 1.5 wt % solution of sulfuryl fluoride in DMF was prepared by
bubbling sulfuryl fluoride through a 100 mL AcroSeal bottle of dry
DMF for 15 min or until 1.5 g of sulfuryl fluoride was added. Excess
sulfuryl fluoride was passed through a knockout pot containing an
aqueous 1 M NaOH solution. 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.
Table 5. Substrate Scope for SNAr Fluorination with
Tetramethylammonium 2,6-Dimethylphenoxide (D-1) and
a
Sulfuryl Fluoride (A-5)
4-Methoxybenzoyl fluoride (A-1). Spray-dried potassium fluoride
(1.63 g, 28.1 mmol, 2 equiv) was suspended in anhydrous acetonitrile
(10 mL). 4-Methoxybenzoyl chloride (1.9 mL, 14.0 mmol, 1 equiv)
was added, and the reaction was stirred vigorously for 3 days. The
reaction mixture was then filtered through a silica plug and
concentrated in vacuo to yield the product as a clear oil (1.94 g,
1
90% yield, Rf = 0.60 in 5:1 pentane/diethyl ether). H, 13C, and 19F
NMR characterization data match those reported in the literature.29
HRMS ESI (m/z): [M]+ calcd for C8H7FO2 154.0430; found
154.0434.
Tetramethylammonium Phenoxide. Phenol (726 mg, 7.7 mmol, 1
equiv) was dissolved in water (5 mL). Tetramethylammonium
hydroxide (25 wt % in H2O, 2.8 g, 7.7 mmol, 1 equiv) was added,
and the reaction was stirred for 1 min before the water was removed in
vacuo. The resulting salt was dried at 70 °C under vacuum for 3 days
and then overnight at room temperature in the presence of P2O5 to
yield the product as an off-white solid (1.3 g, quantitative yield, mp =
69.5−70.8 °C). The salt was stored in a drybox. 1H NMR (500 MHz,
DMSO-d6): δ 6.78 (t, J = 7.5 Hz, 2H), 6.24 (d, J = 7.0 Hz, 2H), 6.03
(m, 1H), 3.10 (s, 12H). 13C NMR (126 MHz, DMSO-d6): δ 169.0,
128.7, 118.0, 108.9, 55.28 (t, J = 3.9 Hz).
Tetramethylammonium 2,6-Dimethylphenoxide (D-1). Under a
N2 atmosphere, tetramethylammonium hydroxide (25 wt % in H2O,
7.2 mL, 20 mmol, 1 equiv) was added to a round-bottom flask
containing 2,6-dimethylphenol (2.5 g, 20 mmol, 1 equiv). The reaction
was stirred until it became homogeneous, and then the water was
removed in vacuo. The resulting salt was dried at 70 °C under vacuum
for 3 days and then overnight at room temperature in the presence of
P2O5 to yield the product as an off-white solid (3.8 g, 96% yield, mp =
decomp). The salt was stored in a drybox. 1H NMR (500 MHz,
DMSO-d6): δ 6.54 (d, J = 7.0 Hz, 2H), 5.61 (t, J = 7.0 Hz, 1H), 3.09
(s, 12H), 1.88 (s, 6H). 13C NMR (126 MHz, DMSO-d6): δ 170.1,
126.9, 123.1, 103.8, 51.5 (t, J = 3.9 Hz), 18.7. HRMS EI (m/z): [M]−
calcd for C8H9O 121.0659, found 121.0655. HRMS EI (m/z): [M]+
calcd for C4H12N 74.0964, found 74.0969.
Methyl Fluoroformate (A-2). Spray-dried potassium fluoride (3.0 g,
52 mmol, 2 equiv) was suspended in anhydrous acetonitrile (12 mL).
Methyl chloroformate (2.1 mL, 27 mmol, 1 equiv) was added, and the
reaction was stirred vigorously for 4 days. The reaction mixture was
filtered through a cotton pipet plug to remove most of the KCl
byproduct. Distillation of the resulting solution at 90 °C under N2
yielded the product as a 27 wt % solution in acetonitrile (2.44 g, 31%
yield). 1H NMR (500 MHz, CDCl3): δ 3.88 (s, 3H, A-2), 1.90 (s, 3H,
MeCN). 13C NMR (126 MHz, CDCl3): δ 145.9 (d, J = 280.9 Hz, A-
2), 116.5 (MeCN), 57.5 (A-2), 1.5 (MeCN). 19F NMR (470 MHz,
CDCl3): δ −18.42 (s, 1 F). 19F NMR characterization data match
those reported in the literature.30
General Procedures of Fluorination Reactions. General
Procedure A: Reactions Reported in Tables 1 and 2. In a drybox,
4-methoxybenzoyl fluoride (A-1, 0.2 mmol, 2 equiv), nucleophile (0.2
mmol, 2 equiv), and DMF (0.5 mL) were added to a 1 dram vial
equipped with a stir bar. This mixture was stirred for 15 min at rt, and
then 1-Cl (0.1 mmol, 1 equiv) was added. The vial was sealed with a
Teflon-lined cap and removed from the drybox, and then the reaction
was stirred for 24 h at rt. The reaction was then diluted with
dichloromethane, and a standard (25 μL of 4-fluoroanisole) was
added. An aliquot was removed for analysis by 19F NMR spectroscopy.
General Procedure B: Reactions Reported in Table 3. In a drybox,
4-methoxybenzoyl fluoride (A-1, 0.4 mmol, 2 equiv), tetramethylam-
monium 2,6-dimethylphenoxide (D-1, 0.3 mmol, 1.5 equiv), and DMF
(1.0 mL) were combined in a 1 dram vial equipped with a stir bar.
This mixture was stirred for 15 min at rt, and then the substrate (0.2
a
Conditions: A-5 (3 equiv) in a DMF solution was added to the
substrate (1 equiv) and D-1 (2 equiv) and stirred for 24 h at rt.
Isolated yields are reported. (Hetero)aryl chloride was used as the
substrate. Nitroarene was used as the substrate. With 15 min prestir
of A-5/D-1 salt before substrate addition. Conducted at 100 °C with
b
c
d
e
f
6 equiv of A-5 and 4 equiv of D-1. Conducted at 80 °C for 4 h.
EXPERIMENTAL SECTION
■
Materials and Methods. NMR spectra were obtained on a 400
MHz (400.52 MHz for 1H, 376.87 MHz for 19F, 100.71 MHz for 13C)
or a 500 MHz (500.01 MHz for 1H, 470.56 MHz for 19F, 125.75 MHz
for 13C) NMR spectrometer. 1H, 19F, and 13C NMR chemical shifts are
reported in parts per million (ppm) relative to the residual solvent
peak (CDCl3: 1H δ 7.26 ppm, 13C δ 77.16 ppm; DMSO-d6: 1H δ 2.50
ppm, 13C δ 39.52 ppm). Multiplicities are reported as follows: singlet
(s), doublet (d), triplet (t), quartet (q), heptet (hept), multiplet (m),
doublet of doublets (dd), double of doublet of doublets (ddd).
Coupling constants (J) are reported in hertz (Hz). Melting points are
uncorrected. High-resolution mass spectra were recorded on a
Magnetic Sector mass spectrometer.
Commercial reagents and solvents were used as received unless
otherwise stated. Anhydrous acetonitrile and anhydrous N,N-
dimethylformamide were purchased from Alfa Aesar. Spray-dried
potassium fluoride was received from The Dow Chemical Company.
Sulfuryl fluoride was purchased from SynQuest Laboratories. 1,3-Di-
isopropyl-4,5-dimethyl-1H-imidazol-3-ium-2-ide,16 isopropyl 5-chloro-
6-phenylpicolinate,14 4-methoxyphenyl sulfurofluoridate,26 N-(2-(4-(2-
methoxyphenyl)piperazin-1-yl)ethyl)-4-nitro-N-(pyridin-2-yl)-
benzamide,27 and 3-nitro-5-(pyridin-2-ylethynyl)benzonitrile28 were
prepared as previously described. Phenol and 2,6-dimethylphenol were
purified by column chromatography before use. Nitroarenes and
(hetero)aryl chlorides were dried under vacuum in the presence of
P2O5 overnight before use. All fluorination reactions were set up in a
drybox due to the sensitivity of this system to water.8
D
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mmol, 1 equiv) was added. The vial was sealed with a Teflon-lined cap
and removed from the drybox, and then the reaction was stirred for 24
h at rt. The reaction mixture was diluted with diethyl ether (10 mL),
and the organic layer was washed with water (3 × 10 mL), dried over
magnesium sulfate, and concentrated in vacuo. The crude reaction
mixture was purified by flash column chromatography on silica gel
using a gradient of hexane and ethyl acetate or pentane and diethyl
ether.
colorless oil (23.0 mg, 78% yield). The yield reported in Table 5
(81%) represents an average of two runs (78 and 84%).
1-Fluoroisoquinoline (4-F). General procedure D was followed
using 2-chloroisoquinoline (32.9 mg, 0.2 mmol, 1 equiv), D-1 (78.5
mg, 0.4 mmol, 2 equiv), and A-5 (4.3 mL of a 0.14 M solution in
DMF, 3 equiv), providing 4-F as a colorless oil (23.7 mg, 80% yield, Rf
= 0.48 in 5:1 pentane/diethyl ether). 1H, 13C, and 19F NMR
characterization data match those reported in the literature.16 HRMS
ESI (m/z): [M + H]+ calcd for C9H7FN 148.0557, found 148.0557.
The yield reported in Table 5 (81%) represents an average of two runs
(80 and 82%).
4-Fluoro-7-(trifluoromethyl)quinoline (5-F). General procedure D
was followed, with the exception that D-1 and A-5 were stirred
together at rt for 15 min prior to addition of 5-Cl, using 4-chloro-7-
(trifluoromethyl)quinoline (46.4 mg, 0.2 mmol, 1 equiv), D-1 (78.4
mg, 0.4 mmol, 2 equiv), and A-5 (4.3 mL of a 0.14 M solution in
DMF, 3 equiv), providing 5-F as a white solid (31.9 mg, 74% yield, Rf
= 0.26 in 5:1 pentane/diethyl ether, mp = 81.6−82.3 °C). 1H, 13C, and
19F NMR experimental data match those reported in the literature.14
HRMS ESI (m/z): [M + H]+ calcd for C10H6F4N 216.0431, found
216.0432. The yield reported in Table 5 (75%) represents an average
of two runs (74 and 75%).
3-Fluoro-6-phenylpyridazine (6-F). General procedure D was
followed using 3-chloro-6-phenylpyridazine (38.2 mg, 0.2 mmol, 1
equiv), D-1 (78.1 mg, 0.4 mmol, 2 equiv), and A-5 (4.3 mL of a 0.14
M solution in DMF, 3 equiv), providing 6-F as a white solid (25.1 mg,
72% yield, Rf = 0.14 in 5:1 pentane/diethyl ether, mp = 127.2−128.4
°C). 1H, 13C, and 19F NMR characterization data match those
reported in the literature.8 HRMS ESI (m/z): [M + H]+ calcd for
C10H8FN2 175.0666, found 175.0666. The yield reported in Table 5
(74%) represents an average of two runs (72 and 76%).
General Procedure C: Reactions Reported in Table 4. In a drybox,
the fluoride source (A, 0.2 mmol, 2 equiv), D-1 (0.2 mmol, 2 equiv),
and DMF (0.5 mL) were combined in a 1 dram vial equipped with a
stir bar. For the reaction with A-5 (sulfuryl fluoride solution in DMF),
no additional DMF was added. The reaction was stirred for 15 min at
rt, and then 1-Cl (0.1 mmol, 1 equiv) was added. The vial was sealed
with a Teflon-lined cap and removed from the drybox, and the
reaction was stirred for 24 h at rt. The reaction was then diluted with
dichloromethane, and a standard (25 μL of 4-fluoroanisole) was
added. An aliquot was removed for analysis by 19F NMR spectroscopy.
General Procedure D: Reactions Reported in Table 5. In a drybox,
substrate (0.2 mmol, 1 equiv), D-1 (0.4 mmol, 2 equiv), and sulfuryl
fluoride (A-5, 4.3 mL of a 0.14 M solution in DMF, 3 equiv) were
added to a 2 dram vial equipped with a stir bar. The vial was sealed
with a Teflon-lined cap and removed from the drybox, and the
reaction was stirred for 24 h at rt. The reaction mixture was then
diluted with diethyl ether (10 mL), and the organic layer was washed
with water (3 × 10 mL), dried over magnesium sulfate, and
concentrated in vacuo. The crude reaction mixture was purified by
flash column chromatography on silica gel using a gradient of hexane
and ethyl acetate or pentane and diethyl ether.
Product Synthesis and Characterization. Isopropyl 5-Fluoro-6-
phenylpicolinate (1-F). General procedure B was followed using
isopropyl 5-chloro-6-phenylpicolinate (1-Cl) (55.1 mg, 0.2 mmol, 1
equiv), A-1 (62.2 mg, 0.4 mmol, 2 equiv), and D-1 (58.8 mg, 0.3
mmol, 1.5 equiv), providing 1-F as a colorless oil (45.1 mg, 87% yield,
Rf = 0.40 in 5:1 pentane/diethyl ether). 1H, 13C, and 19F NMR
characterization data match those reported in the literature.14 HRMS
ESI (m/z): [M + H]+ calcd for C15H15FNO2 260.1081, found
260.1082. The yield reported in Table 3 (89%) represents an average
of two runs (87 and 90%).
3-Chloro-4-Fluorobenzonitrile (7-F). General procedure D was
followed using 3,4-dichlorobenzonitrile (34.6 mg, 0.2 mmol, 1 equiv),
D-1 (78.5 mg, 0.4 mmol, 2 equiv), and A-5 (4.3 mL of a 0.14 M
solution in DMF, 3 equiv), providing 7-F as a white solid (24.8 mg,
79% yield, Rf = 0.57 in 5:1 pentane/diethyl ether, mp = 65.7−66.2
1
°C). H NMR (500 MHz, CDCl3): δ 7.74 (dd, J = 6.7, 2.0 Hz, 1H),
7.58 (ddd, J = 8.5, 4.3, 2.0 Hz, 1H), 7.27 (t, J = 8.5 Hz, 1H). 13C NMR
(126 MHz, CDCl3): δ 160.9 (d, J = 259.0 Hz), 134.8, 132.7 (d, J = 8.5
Hz), 123.0 (d, J = 19.0 Hz), 118.0 (d, J = 22.6 Hz), 116.9, 109.7 (d, J =
4.4 Hz). 19F NMR (470 MHz, CDCl3) δ −104.8 (m, 1F). HRMS EI
(m/z): [M]+ calcd for C7H3ClFN 154.9938, found 154.9943. The
yield reported in Table 5 (82%) represents an average of two runs (79
and 85%).
General procedure D was followed using isopropyl 5-chloro-6-
phenylpicolinate (1-Cl) (55.1 mg, 0.2 mmol, 1 equiv), D-1 (78.0 mg,
0.4 mmol, 2 equiv), and A-5 (4.3 mL of a 0.14 M solution in DMF, 3
equiv), providing 1-F as a colorless oil (47.8 mg, 92% yield). The yield
reported in Table 5 (95%) represents an average of two runs (92 and
98%).
Ethyl-4-fluorobenzoate (8-F). General procedure D was followed
using ethyl-4-nitrobenzoate (39.1 mg, 0.2 mmol, 1 equiv), D-1 (78.3
mg, 0.4 mmol, 2 equiv), and A-5 (4.3 mL of a 0.14 M solution in
DMF, 3 equiv), providing 8-F as a colorless oil (30.1 mg, 89% yield, Rf
= 0.71 in 5:1 pentane/diethyl ether). 1H, 13C, and 19F NMR
characterization data match those reported in the literature.16 HRMS
EI (m/z): [M]+ calcd for C9H9FO2 168.0587, found 168.0594. The
yield reported in Table 5 (86%) represents an average of two runs (89
and 82%).
4-Fluorobenzonitrile (9-F). General procedure D was followed
using 4-nitrobenzonitrile (29.3 mg, 0.2 mmol, 1 equiv), D-1 (78.0 mg,
0.4 mmol, 2 equiv), and A-5 (4.3 mL of a 0.14 M solution in DMF, 3
equiv), providing 9-F as a white solid (13.6 mg, 57% yield, Rf = 0.57 in
5:1 pentane/diethyl ether, mp = 32.7−33.3 °C). 1H, 13C, and 19F
NMR characterization data match those reported in the literature.31
HRMS EI (m/z): [M]+ calcd for C7H4FN 121.0328, found 121.0326.
The yield reported in Table 5 (60%) represents an average of two runs
(57 and 62%).
4-Fluoro-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(pyri-
din-2-yl)benzamide (10-F). General procedure D was followed using
N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-4-nitro-N-(pyridin-2-
yl)benzamide (46.3 mg, 0.1 mmol, 1 equiv), D-1 (78.1 mg, 0.4 mmol,
4 equiv), and A-5 (4.3 mL of a 0.14 M solution in DMF, 6 equiv). The
reaction was heated to 100 °C for 24 h, and the workup was
conducted using dichloromethane in place of diethyl ether (6 × 10
mL) to afford 10-F as a brown oil (22.3 mg, 51% yield, Rf = 0.29 in
4-Fluorobenzophenone (2-F). General procedure B was followed
using 4-nitrobenzophenone (45.4 mg, 0.2 mmol, 1 equiv), A-1 (61.7
mg, 0.4 mmol, 2 equiv), and D-1 (58.7 mg, 0.3 mmol, 1.5 equiv),
providing 2-F as a white solid (29.5 mg, 74% yield, Rf = 0.63 in 5:1
1
pentane/diethyl ether, mp = 42.0−43.9 °C). H, 13C, and 19F NMR
characterization data match those reported in the literature.16 HRMS
ESI (m/z): [M + H]+ calcd for C13H10FO 201.0710, found 201.0712.
The yield reported in Table 3 (76%) represents an average of two runs
(74 and 77%).
General procedure D was followed using 4-nitrobenzophenone
(45.6 mg, 0.2 mmol, 1 equiv), D-1 (78.4 mg, 0.4 mmol, 2 equiv), and
A-5 (4.3 mL of a 0.14 M solution in DMF, 3 equiv), providing 2-F as a
white solid (31.8 mg, 89% yield). The yield reported in Table 5 (91%)
represents an average of two runs (89 and 93%).
2-Fluoroquinoline (3-F). General procedure B was followed using
2-chloroquinoline (32.5 mg, 0.2 mmol, 1 equiv), A-1 (62.8 mg, 0.4
mmol, 2 equiv), and D-1 (58.9 mg, 0.3 mmol, 1.5 equiv), providing 3-
F as a colorless oil (19.3 mg, 66% yield, Rf = 0.51 in 5:1 pentane/
diethyl ether). 1H, 13C, and 19F NMR characterization data match
those reported in the literature.14 HRMS ESI (m/z): [M + H]+ calcd
for C9H7FN 148.0557, found 148.0557. The yield reported in Table 3
(70%) represents an average of two runs (66 and 73%).
General procedure D was followed using 2-chloroquinoline (32.8
mg, 0.2 mmol, 1 equiv), D-1 (78.2 mg, 0.4 mmol, 2 equiv), and A-5
(4.3 mL of a 0.14 M solution in DMF, 3 equiv), providing 3-F as a
E
DOI: 10.1021/acs.joc.7b00481
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The Journal of Organic Chemistry
Featured Article
diethyl ether). 1H, 13C, and 19F NMR characterization data match
those reported in the literature.9 HRMS ESI (m/z): [M + H]+ calcd
for C24H28FN4O2 435.2191, found 435.2190. The yield reported in
Table 5 (52%) represents an average of two runs (51 and 53%).
3-Fluoro-5-(pyridin-2-ylethynyl)benzonitrile (11-F). General pro-
cedure D was followed using 3-nitro-5-(pyridin-2-ylethynyl)-
benzonitrile (49.4 mg, 0.2 mmol, 1 equiv), D-1 (78.1 mg, 0.4 mmol,
2 equiv), and A-5 (4.3 mL of a 0.14 M solution in DMF, 3 equiv). The
reaction was heated to 80 °C for 4 h and provided 11-F as a white
solid (30.0 mg, 68% yield, Rf = 0.80 in diethyl ether, mp = 95.7−96.7
°C). 1H, 13C, and 19F NMR characterization data match those
reported in the literature.26,32 HRMS ESI (m/z): [M + H]+ calcd for
C14H8FN2 223.0666, found 223.0663. The yield reported in Table 5
(71%) represents an average of two runs (68 and 73%).
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ASSOCIATED CONTENT
* Supporting Information
■
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S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00481.
NMR spectral data for all new substrates and for isolated
products (PDF)
(14) Allen, L. J.; Muhuhi, J. M.; Bland, D. C.; Merzel, R.; Sanford, M.
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AUTHOR INFORMATION
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(19) We cannot exclude the possibility of a covalent C−F bond
formed between C-1 and A-1 as the active fluorinating reagent.
(20) Peaks corresponding to starting material 1-Cl (m/z = 275) and
side product 1-OPh (m/z = 333) were observed by GCMS.
(21) A peak corresponding to side product 1-OAr (m/z = 361) was
observed by GCMS.
Corresponding Author
*E-mail: mssanfor@umich.edu.
ORCID
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.
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