Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination

Article abstract of DOI:10.1021/acs.joc.5b02075

This paper describes the room-temperature S_NAr fluorination of aryl halides and nitroarenes using anhydrous tetramethylammonium fluoride (NMe₄F). This reagent effectively converts aryl-X (X = Cl, Br, I, NO₂, OTf) to aryl-F under mild conditions (often room temperature). Substrates for this reaction include electron-deficient heteroaromatics (22 examples) and arenes (5 examples). The relative rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO₂ or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe₄F is generally more cost-effective than fluorination with CsF.

Full text of DOI:10.1021/acs.joc.5b02075

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Article
pubs.acs.org/joc
Anhydrous Tetramethylammonium Fluoride for Room-Temperature
SNAr Fluorination
Sydonie D. Schimler,† Sarah J. Ryan,† Douglas C. Bland,‡ John E. Anderson,‡ and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
‡Process Science, Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States
S
* Supporting Information
ABSTRACT: This paper describes the room-temperature
SNAr fluorination of aryl halides and nitroarenes using
anhydrous tetramethylammonium fluoride (NMe4F). This
reagent effectively converts aryl-X (X = Cl, Br, I, NO2, OTf)
to aryl-F under mild conditions (often room temperature).
Substrates for this reaction include electron-deficient hetero-
aromatics (22 examples) and arenes (5 examples). The relative
rates of the reactions vary with X as well as with the structure of the substrate. However, in general, substrates bearing X = NO2
or Br react fastest. In all cases examined, the yields of these reactions are comparable to or better than those obtained with CsF at
elevated temperatures (i.e., more traditional halex fluorination conditions). The reactions also afford comparable yields on scales
ranging from 100 mg to 10 g. A cost analysis is presented, which shows that fluorination with NMe4F is generally more cost-
effective than fluorination with CsF.
Scheme 1. Soluble Anhydrous Fluoride Sources for Room-
Temperature SNAr Fluorination
INTRODUCTION
■
Fluorinated arenes and heteroarenes are finding increasing
application in agrochemicals and pharmaceuticals.1 The
substitution of a hydrogen atom with a fluorine atom in
biologically active molecules often imparts improvements in
bioavailability and/or metabolic stability.2 However, despite the
importance of the incorporation of fluorine into organic
molecules, there are relatively few selective and mild synthetic
methods for C−F bond formation, particularly on a process
scale.
One of the most common reactions for the industrial
preparation of aryl and heteroaryl fluorides is nucleophilic
aromatic fluorination (SNAr).3 This involves the reaction of an
electron-deficient (hetero)aryl halide or nitroarene with a
nucleophilic fluoride source to generate the corresponding aryl
fluoride.3,4 Anhydrous alkali metal fluorides (MF) are most
typically employed as the fluoride source. However, these salts
are poorly soluble in organic solvents. As a result, high
temperatures and long reaction times are necessary to obtain
high conversions. These forcing conditions often limit
functional group tolerance and lead to the formation of
undesired side products.3
Several recent reports have shown that replacing alkali metal
fluorides with more soluble, anhydrous fluoride reagents can
enable SNAr fluorination to proceed under significantly milder
conditions. For example, DiMagno and co-workers have shown
that anhydrous (anh) tetrabutylammonium fluoride (NBu4F)
can be generated in situ from tetrabutylammonium cyanide
(TBACN) and hexafluorobenzene (C6F6).5 This NBu4F (anh)
participates in SNAr fluorination reactions with chloro- and
nitroarenes at room temperature (Scheme 1a).5,6 Similarly, our
group has recently reported that the combination of acid
fluorides and N-heterocyclic carbenes (NHCs) produces
anhydrous acyl azolium fluorides that effect room-temperature
SNAr fluorinations (Scheme 1b).7,8 However, both of these
methods are limited by the requirement for expensive
stoichiometric reagents (C6F6, NHCs) that preclude imple-
mentation in an industrial-process scale.
To address this challenge, we have pursued anhydrous
tetramethylammonium fluoride (NMe4F) as a more practical
Received: September 4, 2015
© XXXX American Chemical Society
A
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source of soluble anhydrous fluoride for SNAr fluorination.
NMe4F (anh) offers the advantage that it can be prepared from
inexpensive precursors (e.g., from NMe4Cl and KF or from
NMe4OH and HF).9 Furthermore, it can be rigorously dried at
elevated temperatures (unlike NBu4F, which is susceptible to
Hoffman elimination upon heating).10 Grushin and Marshall
have reported that NMe4F (anh) reacts with unactivated aryl
bromides in DMSO at 90−110 °C to form regioisomeric
mixtures of fluoroarene products in 10−65% yield.11 However,
this transformation is proposed to proceed via an aryne
mechanism rather than SNAr. Clark has demonstrated a variety
of examples of SNAr fluorodenitration reactions using
anhydrous NMe4F.12,13 These reactions are typically conducted
at temperatures ranging from 60 to 100 °C, and a variety of side
products (e.g., arylethers, phenols) are formed in these systems.
In contrast, there are very few literature reports of halide
substitution with NMe4F (anh), and the scope of these
transformations has not been extensively explored.13a,b,14
Indeed, in some cases, the conversion of aryl chlorides to aryl
fluorides is reported as an undesired side reaction during
fluorodenitration processes.13a,b
Herein, we demonstrate the room-temperature SNAr
fluorination of a variety of aryl halides and nitroarenes using
anhydrous tetramethylammonium fluoride (Scheme 1c). We
show that the reaction rates vary dramatically as a function of
the leaving group, with nitroarenes and aryl bromides providing
the fastest reactions. We demonstrate that NMe4F (anh) is
effective for the SNAr fluorination of industrially relevant
chloropicolinates as well as other electron-deficient (hetero)-
aromatic substrates. The reactions generally proceed in
excellent yield on scales ranging from 100 mg to 10 g, and
the mild temperature limits the formation of side products
derived from competing transesterification and/or deprotona-
tion pathways. Finally, we provide a comparative cost analysis,
which shows that SNAr fluorination with NMe4F (anh) is more
cost-effective than analogous reactions with CsF.
Table 1. SNAr Fluorination of 1 with NMe4F (anh)
a
b
entry
equiv of NMe4F
temp
% conversion
% yield
1
2
3
4
5
6
7
2
2
2
2
2
140 °C
100 °C
60 °C
40 °C
rt
100
100
100
100
100
0
66
73
85
95
99
<1
80
c
2
rt
1
rt
80
a
Conditions: Substrate 1 (0.1 mmol) and anhydrous NMe4F were
b
stirred in DMF for 24 h. Yield determined by 19F NMR spectroscopy
using 1,3,5-trifluorobenzene as a standard. NMe4F·4H2O was used in
c
place of anhydrous NMe4F.
We hypothesized that competing side product formation
could be limited by lowering the reaction temperature (entries
2−5). Gratifyingly, at room temperature we observed full
conversion of 1, along with a quantitative yield of 2 (entry
5). Furthermore, with only 1 equiv of anhydrous NMe4F, the
SNAr fluorination of 1 proceeded to 80% yield at room
temperature (entry 7). These results demonstrate that NMe4F
(anh) has comparable reactivity to previously reported
anhydrous NBu4F6 and acyl azolium fluoride7 reagents.
The use of NMe4F·4H2O under otherwise analogous
conditions afforded none of the fluorinated product (Table 1,
entry 6). On the basis of this result, we next systematically
explored the effect of H2O on the room-temperature reaction
of 1 with NMe4F (anh). In this study, various quantities of
water were added to reactions that were set up under
anhydrous conditions (Table 2). The addition of 1 equiv of
Table 2. Effect of Water on the Reaction of 1 with NMe4F
RESULTS AND DISCUSSION
■
Our initial investigations focused on the use of NMe4F (anh)
for the SNAr fluorination of 5-chloropicolinate 1, a structural
motif found in many Dow AgroSciences products.15 This
transformation was initially examined at 140 °C (i.e, elevated
temperature conditions similar to those commonly employed
for SNAr fluorination).3,16 As shown in Table 1, the reaction of
1 with 2 equiv of anhydrous NMe4F at 140 °C led to complete
conversion of 1 but afforded only 66% yield of the
fluoropicolinate product 2 (entry 1). At 100 °C, the conversion
of 1 was again quantitative, but the yield of 2 was only 73%
(entry 2). The major side products observed in these
transformations are the carboxylic acid 2-CO2H, the isopropyl
ether 1-iPrO, and CH3F17 (eq 1).
a
b
entry
equiv of H2O
% yield
1
2
3
4
0
1
2
5
99
76
1
<1
a
Conditions: Substrate 1 (0.1 mmol) and anhydrous NMe4F (0.2
mmol) were combined in a 4 mL vial. DMF (0.2 M) and water were
combined and added as a solution to the solids. The reaction was
b
stirred at room temperature for 24 h. Yield was determined by 19F
NMR spectroscopy using 1,3,5-trifluorobenzene as an internal
standard.
water resulted in an approximately 25% reduction in the
reaction yield (from 99% to 76%, entries 1 and 2, respectively).
However, the addition of ≥2 equiv of water completely shut
−
down the reaction (entries 3 and 4). Bifluoride (HF2 ) was the
major species detected by 19F NMR spectroscopic analysis
under the conditions in entries 3 and 4 (19F NMR resonance at
−152.0 ppm in CH2Cl2).
We next examined the scope of leaving groups that can be
employed in this SNAr fluorination with NMe4F (anh). Our
B
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first study focused on a series of commercially available 2-
substituted-benzonitrile substrates with Cl, Br, I, NO2, and OTf
as leaving groups (3a−e). Compounds 3a−e react slowly with
2 equiv of NMe4F (anh) at room temperature, affording 4 in
2−95% yield after 48 h (Table 3). In most cases, significantly
Table 3. Comparison of Reactions of 3a−e with NMe4F
(anh) and CsF
Figure 1. Reaction profiles for the reactions of 3a−e with anhydrous
NMe4F to form 4. Conditions: Substrate (0.1 mmol, 1 equiv) and
anhydrous NMe4F (0.2 mmol, 2 equiv) were stirred in DMF (0.2 M)
at 80 °C for the given time. Yields determined by 19F NMR
spectroscopy using 1,3,5-trifluorobenzene as a standard.
% yield
a
b
c
of the crude reaction mixture). Such side products are common
in fluorodenitration reactions, as the displaced nitrite ion can
act as a nucleophile.12,13 Finally, aryl triflate 3e afforded a
significantly better yield with CsF at 140 °C (73%) than with
NMe4F (anh) at 80 °C (8%). Overall, these results highlight
the advantages of the current method as well as its
complementarity to more conventional SNAr fluorination with
CsF.
We conducted an analogous set of studies with the 2-
substituted pyridines 5a−e. Similar to our results using 3a−e,
the reactions of 2-chloro, 2-bromo, 2-iodo, and 2-nitropyridine
(5a−d) with NMe4F (anh) at 80 °C afforded 2-fluoropyridine
6 in good to excellent yield (72−98%) (Table 4, entries 1−4).
entry
substrate
24 h, 25 °C
3 h, 80 °C
CsF, 140 °C
1
2
3
4
5
3a
3b
3c
3d
3e
32
48
8
94
95
88
97
8
52
49
22
73
73
95
2
a
Conditions: Substrate (0.1 mmol) and anhydrous NMe4F (0.2
mmol) stirred in DMF (0.2 M) at 25 °C for 24 h. Conditions:
Substrate (0.1 mmol) and anhydrous NMe4F (0.2 mmol) stirred in
b
c
DMF (0.2 M) at 80 °C for 3 h. Conditions: Substrate (0.1 mmol) and
CsF (0.2 mmol) stirred in DMF (0.2 M) at 140 °C for 24 h. All yields
were determined by 19F NMR spectroscopy using 1,3,5-trifluoroben-
zene as an internal standard.
Table 4. Comparison of Reactions of 5a−e with NMe4F
(anh) and CsF
faster rates were observed at 80 °C, and 3a−d reacted to afford
4 in 88−97% yield after 3 h at 80 °C (Table 3, entries 1−4). In
contrast, aryl triflate 3e showed minimal reactivity at 80 °C,
even at reaction times up to 48 h (entry 5). Notably, aryl
bromides and aryl iodides have previously been reported as
poor substrates for SNAr fluorination reactions.18 However, the
current study shows that they can react with NMe4F (anh) to
afford comparable yields of the fluorinated product.
Time studies were conducted to obtain more detailed insight
into the relative rates of fluorination of substrates 3a−e.
Notably, there are relatively few systematic studies of the rate of
SNAr fluorination reactions as a function of leaving group, and
most of these have been conducted in the context of
radiofluorination.19 As shown in Figure 1, the relative rates
were NO2 ≫ Br > Cl > I ≫ OTf. 2-Nitrobenzonitrile 3d
reacted to afford a nearly quantitative yield of 4 in just 5 min at
80 °C, while all three of the halide substrates afforded
quantitative conversion within 3 h under otherwise analogous
conditions.
We also compared the reactions of 3a−e with NMe4F (anh)
to those with CsF, a more traditional reagent for SNAr
fluorination. In all cases, CsF afforded <5% yield of the
fluorinated product 4 after 24 h at 80 °C. At 140 °C (more
typical conditions for CsF halex reactions),3,20 the aryl halides
3a−c reacted with CsF to form 4 in moderate yields after 24 h
(22−52%, entries 1−3). In all of these reactions, unreacted
starting material remained after 24 h at 140 °C. The
fluorodenitration of 2-nitrobenzonitrile (3d) with CsF at 140
°C afforded 4 in 73% yield (entry 4). In this case, the
conversion of 3d was quantitative, but a variety of aryl ether
side products were formed (as determined by GCMS analysis
% yield
a
b
entry
substrate
4 h, 80 °C
CsF, 140 °C
1
2
3
4
5
5a
5b
5c
5d
5e
72
96
91
98
43
9
17
19
100
87
a
Conditions: Substrate (0.1 mmol) and anhydrous NMe4F (0.2
b
mmol) stirred in DMF (0.2 M) at 80 °C for 4 h. Conditions:
Substrate (0.1 mmol) and CsF (0.2 mmol) stirred in DMF (0.2 M) at
140 °C for 24 h. All yields were determined by 19F NMR spectroscopy
using 1,3,5-trifluorobenzene as an internal standard.
In all of these cases, the results compare favorably to those
obtained with CsF at 140 °C (9−100% yield for 5a−d, Table
4). Pyridin-2-yl trifluoromethanesulfonate (5e) underwent
fluorination with NMe4F (anh) to afford 6 in moderate 43%
yield. With this substrate, side products (most significantly aryl
ether derivatives) were detected by GCMS. Interestingly, the
CsF conditions afforded a significantly improved yield of 87%
C
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with substrate 5e. These data suggest that (hetero)aryl triflates
are particularly good substrates for CsF halex reactions.
Time studies for the reactions of 5a−e with NMe4F (anh)
are shown in Figure 2. In this system, the impact of leaving
meta-positioned electron-withdrawing groups do not activate
aryl rings for SNAr reactions.5a While ethyl 4-chlorobenzoate
and 4-chlorobenzophenone are not sufficiently activated for the
SNAr fluorination with NMe4F (even at 80 °C), the nitro
analogs react to afford high yields of the fluorinated products at
room temperature (30 and 31).
Finally, we conducted a cost analysis in order to compare
NMe4F (anh) to CsF for process scale SNAr fluorinations.23
The cost of manufacturing (COM) for each of the cases studied
was computed using the equation shown below:24−26
COM = raw material cost + waste treatment cost
+ conversion cost
The calculations were performed for several different
substrates 3a, 5b, 5d, in order to demonstrate how the reaction
yield impacts this analysis. All calculations were performed by
assuming a product volume of 200 t per year. The results are
summarized in Table 5.
With substrates 3a and 5b, the yield of fluorinated product is
much higher with NMe4F (anh). As a result, the use of CsF is
3−10-fold more costly and thus not economically competitive.
For substrate 5d, the reaction yields are similar to the two
fluorinating reagents. Here, NMe4F (anh) still offers a
significant advantage over CsF, since the mass of CsF required
to achieve high yield is quite large. As such, the mass (and thus
cost) required to deliver each fluorinating equivalent is higher
than that with NMe4F (anh). Overall, for difficult fluorinations,
NMe4F (anh) appears to offer a cost-effective alternative to
CsF.
Figure 2. Reaction profiles for the reaction 5a−e with anhydrous
NMe4F to form 6. General conditions: Substrate (0.1 mmol, 1 equiv)
and anhydrous NMe4F (0.2 mmol, 2 equiv) were stirred in DMF (0.2
M) at 80 °C for the given time. Yield was determined by 19F NMR
spectroscopy using 1,3,5-trifluorobenzene as a standard.
group on reaction rate is slightly different from that observed
for 3a−e, with the order of reactivity being NO2 ≫ Br ≈ I > Cl
> OTf. Notably, the initial rate with triflate substrate 5e is
actually comparable to that of the aryl bromide; however, the
reaction stalls after about 20 min. A related time study of SNAr
fluorination as a function of leaving group has been reported for
the radiofluorination of 2-substituted pyridines with K18F.
Similar to our observations, this study showed that 2-
nitropyridine and 2-bromopyridine reacted faster than the
other 2-halopyridines.19d Overall, a key finding from the time
studies in Figures 1 and 2 is that leaving-group effects on
reaction rates are substrate-dependent.
The substrate scope of SNAr fluorination with NMe4F (anh)
was next investigated. As shown in Chart 1, a variety of
monochloropicolinates and dichloropicolinates react to afford
the corresponding mono- and difluorinated products 2 and 7−
11 in good to excellent isolated yields. These transformations
were all conducted at room temperature over 24 h, and the
reactions of dichloropicolinate substrates required only 1.5
equiv of NMe4F per chloride. The fluorination of 1 has been
conducted on a 138 mg, a 2 g, and a 10 g scale. Comparable
yields were obtained in all of these cases [82% (isolated), 93%
(in pot), and 85% (isolated), respectively].
Chloroquinoline, chloroisoquinoline, and chloropyridazine
substrates also undergo room-temperature fluorination to form
12−16 in excellent yields. The high-yielding synthesis of 8-
(benzyloxy)-2-fluoroquinoline (15) is particularly noteworthy,
as 18F-15 has been used for the PET imaging of amyloid
plaques.21,22 Methoxy, cyano, and trifluoromethyl substituents
are compatible with the reaction conditions (products 8, 11, 13,
and 17−21). In addition, halide (Cl, Br, and I) and nitro
substituents at less-activated positions in the molecule are well-
tolerated, even in the presence of excess NMe4F (products 7,
10, and 23−26). Less-activated aryl chlorides require higher
temperatures to form the desired product (products 4, 28, and
29). SNAr fluorination with NMe4F (anh) can be used to
produce 2- and 4-fluorobenzonitrile (4 and 29) in excellent
yields, while 3-fluorobenzonitrile 28 is formed in low yield. This
latter result is consistent with previous reports showing that
CONCLUSION
■
This report describes the use of NMe4F (anh) as a broadly
useful reagent for low-temperature SNAr fluorination reactions.
We demonstrate that diverse aryl halides and nitroarenes react
with NMe4F (anh) to yield aryl fluoride products at
temperatures ranging from room temperature to 80 °C. The
relative rates vary as a function of leaving group and substrate,
but aryl bromide and nitroarene substrates generally afford the
fastest rates and highest yields in these transformations. NMe4F
(anh) has been compared directly to CsF, and it generally
affords comparable or enhanced reaction yields and smaller
quantities of byproducts. This latter effect is likely due to the
lower operating temperature required for SNAr fluorinations
with NMe4F (25−80 °C) versus with CsF (140 °C). A cost
analysis projects that NMe4F (anh) is economically superior to
CsF for the SNAr reactions presented herein. Overall, the use of
NMe4F (anh) addresses many of the prior limitations of
process-scale SNAr fluorination reactions (e.g., high temper-
atures, side product formation, and costly reagents).
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),
1
a 500 MHz (500.01 MHz for H, 125.75 MHz for 13C, 470.56 MHz
for 19F), a 700 MHz (699.76 MHz for 1H, 175.95 MHz for 13C), or a
1
500 MHz (499.90 MHz for H, 125.70 for 13C) NMR spectrometer.
1H and 13C chemical shifts are reported in parts per million (ppm)
relative to TMS, 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 to the internal standard 1,3,5-trifluorobenzene,
which appears at −108.33 ppm. 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
D
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a
Chart 1. Substrate Scope for SNAr Fluorination with NMe4F (anh)
a
b
c
Conditions: anhydrous NMe4F (2 equiv) and substrate (1 equiv) were stirred in DMF at 25 °C for 24 h. With 3 equiv of anhydrous NMe4F. The
d
corresponding nitroarene was used as the substrate. Yield determined by 19F NMR spectroscopy using 1,3,5-trifluorobenzene as a standard.
e
Reaction was stirred at 80 °C for 24 h.
Table 5. Cost Analysis for SNAr Fluorination of 3a, 5b, and 5d with CsF and NMe4F (anh)
fluorinating agent
%
consumption of fluorinating agent
cost contribution of fluorinating agent
total estimated cost
($/kg product)
(equiv)
substrate yield
(kg/kg product)
($/kg product)
NMe4F (2)
CsF (2)
3a
3a
3a
3a
5b
5b
5d
5d
94
52
1.6
4.8
53
237
32
74
260
53
NMe4F (1)
CsF (1)
78
0.99
2.56
2.0
51
121
65
143
127
1185
214
297
NMe4F (2)
CsF (2)
96
17
18.42
1.96
3.13
902
64
NMe4F (2)
CsF (2)
98
100
153
reported in hertz. For GCMS analysis, the products were separated on
a crossbond 5% diphenyl−95% dimethyl polysiloxane column (30 m
length by 0.25 mm i.d., 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 for 5 min, ramp 15 °C/min to 250 °C, and hold for 1.5 min. The
GC oven temperature program for medium molecular weight
compounds was as follows: 60 °C, hold for 4 min, ramp 15 °C/min
to 250 °C. 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 was obtained from Sigma-
Aldrich. Anhydrous N,N-dimethylformamide was obtained from Alfa
Aesar. Isopropyl chloroarylpicolinates were prepared using previously
described methods.6 2-Cyanophenyl trifluoromethanesulfonate,27
E
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pyridine-2-yl trifluoromethanesulfonate,28 and 8-(benzyloxy)-2-chlor-
oquinoline21 were prepared using literature procedures and dried over
P2O5 prior to use.
added. An aliquot was removed for analysis by 19F NMR spectroscopy
and GCMS.
Product Synthesis and Characterization. Isopropyl 5-Fluoro-6-
phenylpicolinate (2). General procedure D was followed using
isopropyl 5-chloro-6-phenylpicolinate (1) (138 mg, 0.5 mmol, 1
equiv), providing 2 as a colorless oil (106 mg, 82% yield, Rf = 0.61 in
General Procedures for Fluorination Reactions. General
Procedure A: Experimental Details for Fluorination Reactions
Reported in Table 1. In a drybox, substrate 1 (0.1 mmol, 1.0 equiv)
and anhydrous tetramethylammonium fluoride (NMe4F) were
weighed into a 4 mL vial equipped with a microsized stir bar. DMF
(0.5 mL) was added, and the reaction vial was sealed with a Teflon-
lined cap, removed from the drybox, and stirred at the designated
temperature for 24 h. The reaction was then cooled to room
temperature and diluted with dichloromethane (2.5 mL), and an
internal standard (1,3,5-trifluorobenzene, 100 μL of a 0.5 M solution
in toluene) was added. An aliquot was removed for analysis by 19F
NMR spectroscopy.
1
70% hexanes/30% Et2O). H, 13C, and 19F NMR experimental data
match those reported in the literature.6 HRMS ESI+ (m/z): [M + H]+
calcd for C15H15FNO2 260.1081, found 260.1080. The yield reported
in Chart 1 (82%) represents an average of two runs (82% and 81%).
Isopropyl 5-Fluoro-6-phenylpicolinate (2) on a 10 g Scale. A 250
mL three-necked round-bottom flask equipped with a magnetic stir bar
was evacuated and purged about three times with nitrogen. The vessel
was charged with isopropyl 5-chloro-6-phenylpicolinate (10.11 g,
36.67 mmol, 1 equiv) and then anhydrous DMF (100 mL) was added
by cannula transfer under vacuum. Anhydrous NMe4F (5.02 g, 53.92
mmol, 1.47 equiv) was added in a single portion, and the mixture was
allowed to stir overnight (23 h) at ambient temperature. The reaction
mixture was filtered and the filtrate was partitioned between 200 mL of
distilled water and 120 mL of toluene in a 1 L separatory funnel. The
bottom cloudy aqueous layer was separated and then subsequently
extracted with two 50 mL portions of toluene. The three organic layers
were combined and then washed with two 50 mL portions of distilled
water. The upper toluene layer was separated and concentrated under
vacuum. Purification by column chromatography provided the product
as a colorless oil (8.04 g, 85% yield, CombiFlash using a 220 g RediSep
Silica column, 90% hexanes/10% ethyl acetate). 1H, 13C, and 19F NMR
experimental data match those reported in the literature.6
General Procedure B: Experimental Details for Fluorination
Reactions Reported in Table 2. A solution of anhydrous DMF (2 mL)
and deionized water that was sparged with N2 was prepared in a
Schlenk flask and sparged with N2 for 15 min. The Schlenk tube was
then pumped into a drybox. In a drybox, substrate 1 (0.1 mmol, 1.0
equiv) and anhydrous NMe4F (0.2 mmol, 2.0 equiv) were weighed
into a 4 mL vial equipped with a microsized stir bar. The water−DMF
solution was then added (0.5 mL), and the reaction vial was sealed
with a Teflon-lined cap, removed from the drybox, and stirred at room
temperature for 24 h. The reaction was then diluted with
dichloromethane (2.5 mL), and an internal standard (1,3,5-
trifluorobenzene, 100 μL of a 0.5 M solution in toluene) was added.
An aliquot was removed for analysis by 19F NMR spectroscopy.
General Procedure C: Experimental Details for Fluorination
Reactions Reported in Tables 3 and 4 and Figures 1 and 2. For
reactions with anhydrous NMe4F, in a drybox, substrate 3a−e or 5a−e
(0.1 mmol, 1.0 equiv) and anhydrous NMe4F (0.2 mmol, 2 equiv)
were weighed into a 4 mL vial equipped with a microsized stir bar.
DMF (0.5 mL) was added, and the reaction vial was sealed with a
Teflon-lined cap, removed from the drybox, and stirred at the given
temperature for the given time. The reactions were cooled at 0 °C and
diluted with dichloromethane (2.5 mL), and an internal standard
(1,3,5-trifluorobenzene, 100 μL of a 0.5 M solution in toluene) was
added. An aliquot was removed for analysis by 19F NMR spectroscopy.
For reactions with CsF, in a drybox, substrate 3a−e or 5a−e (0.1
mmol, 1.0 equiv) and CsF (0.2 mmol, 2 equiv) were weighed into a 4
mL vial equipped with a microsized stir bar. DMF (0.5 mL) was
added, and the reaction vial was sealed with a Teflon-lined cap,
removed from the drybox, and stirred at 140 °C for 24 h. The
reactions were cooled to room temperature and diluted with
dichloromethane (2.5 mL), and an internal standard (1,3,5-
trifluorobenzene, 100 μL of a 0.5 M solution in toluene) was added.
An aliquot was removed for analysis by 19F NMR spectroscopy.
General Procedure D: Experimental Details for Isolated Yields
Reported in Chart 1. In a drybox, anhydrous NMe4F (93 mg, 1 mmol,
2 equiv) and the appropriate aryl chloride or nitroarene substrate (0.5
mmol, 1 equiv) were weighed into a 4 mL vial equipped with a
microsized stir bar. DMF (2.5 mL) was added, and the reaction vial
was sealed with a Teflon-lined cap, removed from the drybox, and
stirred at room temperature for 24 h. The reaction was then diluted
with dichloromethane (15 mL) and transferred to a separatory funnel.
The organic layer was washed with water (3 × 25 mL) and brine (1 ×
25 mL), dried over magnesium sulfate, and concentrated in vacuo. The
crude mixture was purified by flash column chromatography on silica
gel using gradients of hexanes and either diethyl ether or ethyl acetate
as eluent.
Isopropyl 5-Fluoro-6-(p-chlorophenyl)picolinate (7). General
procedure D was followed using isopropyl 5-chloro-6-(p-
chlorophenyl)picolinate (122 mg, 0.5 mmol, 1 equiv), providing 7
as a white solid (122 mg, 83% yield, Rf = 0.59 in 70% hexanes/30%
1
Et2O, mp = 73−76 °C). H, 13C, and 19F NMR experimental data
match those reported in the literature.7 HRMS ESI+ (m/z): [M + H]+
calcd for C15H14ClFNO2 294.0692, found 294.0689. The yield
reported in Chart 1 (85%) represents an average of two runs (83%
and 87%).
Isopropyl 5-Fluoro-6-(p-methoxyphenyl)picolinate (8). General
procedure D was followed using isopropyl 5-chloro-6-(p-
methoxyphenyl)picolinate (153 mg, 0.5 mmol, 1 equiv), providing 8
as a white solid (138 mg, 96% yield, Rf = 0.38 in 70% hexanes/30%
1
Et2O, mp = 46−48 °C). H, 13C, and 19F NMR experimental data
match those reported in the literature.7 HRMS ESI+ (m/z): [M + H]+
calcd for C16H17FNO3 290.1187, found 290.1185. The yield reported
in Chart 1 (93%) represents an average of two runs (96% and 90%).
Isopropyl 4,5-Difluoro-6-phenylpicolinate (9). General procedure
D was followed using isopropyl 4,5-dichloro-6-phenylpicolinate (155
mg, 0.5 mmol, 1 equiv) and anhydrous NMe4F (140 mg, 1.5 mmol, 3
equiv), providing 9 as a colorless oil (121 mg, 87% yield, Rf = 0.64 in
1
70% hexanes/30% Et2O). H, 13C, and 19F NMR experimental data
match those reported in the literature.6 HRMS ESI+ (m/z): [M + H]+
calcd for C15H14F2NO2 278.0987, found 278.0986. The yield reported
in Chart 1 (88%) represents an average of two runs (87% and 88%).
Isopropyl 4,5-Difluoro-6-(p-chlorophenyl)picolinate (10). General
procedure D was followed using isopropyl 4,5-dichloro-6-(p-
chlorophenyl)picolinate (172 mg, 0.5 mmol, 1 equiv) and anhydrous
NMe4F (140 mg, 1.5 mmol, 3 equiv), providing 10 as a white solid
(138 mg, 89% yield, Rf = 0.69 in 70% hexanes/30% Et2O, mp = 74−76
°C). 1H, 13C, and 19F NMR experimental data match those reported in
the literature.6 HRMS ESI+ (m/z): [M + H]+ calcd for
C15H13ClF2NO2 312.0597, found 312.0597. The yield reported in
Chart 1 (84%) represents an average of two runs (89% and 79%).
Isopropyl 4,5-Difluoro-6-(p-methoxyphenyl)picolinate (11). Gen-
eral procedure D was followed using isopropyl 4,5-dichloro-6-(p-
methoxyphenyl)picolinate (170 mg, 0.5 mmol, 1 equiv) and
anhydrous NMe4F (140 mg, 1.5 mmol, 3 equiv), providing 11 as a
white solid (136 mg, 89% yield, Rf = 0.61 in 70% hexanes/30% Et2O,
General Procedure E: General Experimental Details for NMR
Yields Reported in Chart 1. In a drybox, anhydrous NMe4F (18.6 mg,
0.2 mmol, 2 equiv) and the appropriate aryl chloride or nitroarene
substrate (0.1 mmol, 1 equiv) were weighed into a 4 mL vial equipped
with a microsized stir bar. DMF (0.5 mL) was added, and the reaction
vial was sealed with a Teflon-lined cap, removed from the drybox, and
stirred at room temperature unless otherwise noted for 24 h. The
reaction was cooled to room temperature and an internal standard
(1,3,5-trifluorobenzene, 100 μL of a 0.5 M solution in toluene) was
1
mp = 37−38 °C). H, 13C, and 19F NMR experimental data match
those reported in the literature.6 HRMS ESI+ (m/z): [M + H]+ calcd
F
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
for C16H16F2NO3 308.1093, found 308.1091. The yield reported in
Chart 1 (89%) represents an average of two runs (89% and 88%).
2-Fluoroquinoline (12). General procedure D was followed using 2-
chloroquinoline (82 mg, 0.5 mmol, 1 equiv), providing 12 as a
colorless oil (56 mg, 77% yield, Rf = 0.51 in 70% hexanes/30% Et2O).
1H, 13C, and 19F NMR experimental data match those reported in the
literature.6 HRMS ESI+ (m/z): [M + H]+ calcd for C9H7FN 148.0557,
found 148.0555. The yield reported in the text (79%) represents an
average of two runs (77% and 80%).
matched that of an authentic sample (Synthonix; s, −64.94 ppm). The
identity of the product was further confirmed by GCMS analysis (m/z
= 122). The yield reported in Chart 1 (95%) represents an average of
two runs (100% and 89%).
2-Fluoro-3-cyanopyridine (20). General procedure E was followed
using 2-chloro-3-cyanopyridine (13.8 mg, 0.1 mmol, 1 equiv),
providing 20 in 93% yield as determined by 19F NMR spectroscopic
analysis of the crude reaction mixture. The product showed a 19F
NMR signal at −62.66 ppm in DCM (lit.29 −60.0 ppm in CDCl3).
The identity of the product was further confirmed by GCMS analysis
(m/z = 122). The yield reported in Chart 1 (91%) represents an
average of two runs (93% and 88%).
2-Fluoro-5-cyanopyridine (21). General procedure E was followed
using 2-chloro-5-cyanopyridine (13.8 mg, 0.1 mmol, 1 equiv),
providing 21 in 87% yield as determined by 19F NMR spectroscopic
analysis of the crude reaction mixture. The 19F NMR spectral data
matched that of an authentic sample (Matrix Scientific; s, −59.41
ppm). The identity of the product was further confirmed by GCMS
analysis (m/z = 122). The yield reported in the text (94%) represents
an average of two runs (87% and 100%).
2-Fluoropyrazine (22). General procedure E was followed using 2-
chloropyrazine (11.4 mg, 0.1 mmol, 1 equiv), providing 22 in 99%
yield as determined by 19F NMR spectroscopic analysis of the crude
reaction mixture. The product showed a 19F NMR signal at −81.00
ppm in DCM (lit.5a −80.4 ppm in DMSO). The identity of the
product was further confirmed by GCMS analysis (m/z = 98). The
yield reported in Chart 1 (92%) represents an average of two runs
(99% and 84%).
2-Fluoro-3-chloropyridine (23). General procedure E was followed
using 2-nitro-3-chloropyridine (15.8 mg, 0.1 mmol, 1 equiv), providing
23 in 94% yield as determined by 19F NMR spectroscopic analysis of
the crude reaction mixture. The product showed a 19F NMR signal at
−72.54 ppm in DCM (lit.5a −73.03 ppm in DMSO). The identity of
the product was further confirmed by GCMS analysis (m/z = 131).
The yield reported in Chart 1 (94%) represents an average of two runs
(94% and 94%).
2-Fluoro-5-iodopyridine (24). General procedure E was followed
using 2-chloro-5-iodopyridine (23.9 mg, 0.1 mmol, 1 equiv), providing
24 in 85% yield as determined by 19F NMR spectroscopic analysis of
the crude reaction mixture. The 19F NMR spectral data matched that
of an authentic sample (Sigma-Aldrich; m, −71.28 ppm). The identity
of the product was further confirmed by GCMS analysis (m/z = 223).
The yield reported in Chart 1 (86%) represents an average of two runs
(85% and 87%).
2-Fluoro-5-nitropyridine (25). General procedure E was followed
using 2-chloro-5-nitropyridine (15.8 mg, 0.1 mmol, 1 equiv), providing
25 in 70% yield as determined by 19F NMR spectroscopic analysis of
the crude reaction mixture. The 19F NMR spectral data matched that
of an authentic sample (Oakwood Chemicals; s, −59.14 ppm). The
identity of the product was further confirmed by GCMS analysis (m/z
= 142). The yield reported in Chart 1 (73%) represents an average of
two runs (70% and 76%).
2-Fluoro-5-bromopyridine (26). General procedure E was followed
using 2-chloro-5-bromopyridine (19.1 mg, 0.1 mmol, 1 equiv),
providing 26 in 100% yield as determined by 19F NMR spectroscopic
analysis of the crude reaction mixture. The 19F NMR spectral data
matched that of an authentic sample (Oakwood Products; s, −71.69
ppm). The identity of the product was further confirmed by GCMS
analysis (m/z = 175). The yield reported in Chart 1 (94%) represents
an average of two runs (100% and 88%).
4-Fluoro-7-(trifluoromethyl)quinoline (13). General procedure D
was followed using 4-chloro-7-(trifluoromethyl)quinoline (116 mg, 0.5
mmol, 1 equiv), providing 13 as a white solid (88 mg, 82% yield, Rf =
1
0.38 in 70% hexanes/30% Et2O, mp = 84−86 °C). H, 13C, and 19F
NMR experimental data match those reported in the literature.6
HRMS ESI+ (m/z): [M + H]+ calcd for C10H6F4N 216.0431, found
216.0430. The yield reported in Chart 1 (79%) represents an average
of two runs (82% and 75%).
1-Fluoroisoquinoline (14). General procedure D was followed
using 1-chloroisoquinoline (82 mg, 0.5 mmol, 1 equiv), providing 14
as a colorless oil (59 mg, 80% yield, Rf = 0.53 in 70% hexanes/30%
Et2O). 1H, 13C, and 19F NMR experimental data match those reported
in the literature.7 HRMS ESI+ (m/z): [M + H]+ calcd for C9H7FN
148.0557, found 148.0555. The yield reported in Chart 1 (78%)
represents an average of two runs (80% and 76%).
8-(Benzyloxy)-2-fluoroquinoline (15). General procedure D was
followed using 8-(benzyloxy)-2-chloroquinoline (134.5 mg, 0.1 mmol,
1 equiv), providing 15 as a white solid (120 mg, 95% yield, Rf = 0.38 in
70% hexanes/30% Et2O, mp = 67−69 °C). 1H and 19F NMR
experimental data match those reported in the literature.22 13C NMR
(125.75 MHz, CDCl3): δ 161.5 (d, J = 242 Hz), 153.4, 142.0 (d, J =
9.5 Hz), 138.7, 137.6 (d, J = 15.3 Hz), 136.8, 128.6, 128.0 (d, J = 1.9
Hz), 127.0, 126.9, 126.1 (d, J = 2.9 Hz), 119.6, 111.6, 110.6 (d, J =
42.9 Hz), 70.7. HRMS ESI+ (m/z): [M + H]+ calcd for C16H13FNO
254.0976, found 254.0975. The yield reported in Chart 1 (91%)
represents an average of two runs (95% and 86%).
3-Fluoro-6-phenylpyridazine (16). General procedure D was
followed using 3-chloro-6-phenylpyridzaine (95 mg, 0.5 mmol, 1
equiv), providing 16 as a white solid (79 mg, 91% yield, Rf = 0.38 in
1
70% hexanes/30% Et2O, mp = 129−131 °C). H NMR (500 MHz,
CDCl3): δ 8.01−7.98 (multiple peaks, 3H), 7.53−7.49 (multiple
peaks, 3H), 7.29 (dd, J = 9.5, 2.0 Hz, 1H). 13C NMR (175.95 MHz,
CDCl3): δ 166.7 (d, J = 245 Hz), 159.2 (d, J = 3.5 Hz), 135.1 (d, J =
2.1 Hz), 130.2, 129.5 (d, J = 7.6 Hz), 129.0, 127.0, 116.1 (d, J = 33.4
Hz). 19F NMR (100 MHz, CDCl3): − 84.8 (d, J = 1.5 Hz). IR (cm−1):
1584, 1556, 1450, 1427, 1278, 1108, 852, 778, 739. HRMS ESI+ (m/
z): [M + H]+ calcd for C10H7FN2 175.0666, found 175.0663. The
yield reported in Chart 1 (90%) represents an average of two runs
(91% and 88%).
2-Fluoro-3-(trifluoromethyl)pyridine (17). General procedure E
was followed using 2-chloro-3-(trifluoromethyl)pyridine (18.1 mg, 0.1
mmol, 1 equiv), providing 17 in 100% yield as determined by 19F
NMR spectroscopic analysis of the crude reaction mixture. The
product showed a 19F NMR signals at −63.42 (3F) and −68.06 (1F)
ppm in DCM [lit.5a −60.62 (3F), −63.01 (1F) ppm in DMSO]. The
identity of the product was further confirmed by GCMS analysis (m/z
= 165). The yield reported in Chart 1 (97%) represents an average of
two runs (100% and 94%).
2-Fluoro-5-(trifluoromethyl)pyridine (18). General procedure E
was followed using 2-chloro-5-(trifluoromethyl)pyridine (18.1 mg, 0.1
mmol, 1 equiv), providing 18 in 95% yield as determined by 19F NMR
spectroscopic analysis of the crude reaction mixture. The product
showed 19F NMR signals at −62.68 (3F) and −63.51 (1F) ppm in
DCM [lit.5a −60.62 (3F), −63.01 (1F) ppm in DMSO]. The identity
of the product was further confirmed by GCMS analysis (m/z = 165).
The yield reported in Chart 1 (98%) represents an average of two runs
(95% and 100%).
2,6-Difluoropyridine (27). General procedure E was followed using
2,6-dichloropyridine (14.7 mg, 0.1 mmol, 1 equiv) and anhydrous
NMe4F (28 mg, 0.3 mmol, 3 equiv), providing 27 in 91% yield as
determined by 19F NMR spectroscopic analysis of the crude reaction
mixture. The 19F NMR spectral data matched that of an authentic
sample (Alfa Aesar; m, −68.91 ppm). The identity of the product was
further confirmed by GCMS analysis (m/z = 115). The yield reported
in Chart 1 (93%) represents an average of two runs (91% and 95%).
2-Fluorobenzonitrile (4). General procedure E was followed using
2-chlorobenzonitrile (13.7 mg, 0.1 mmol, 1 equiv) at 80 °C, providing
2-Fluoro-4-cyanopyridine (19). General procedure E was followed
using 2-chloro-4-cyanopyridine (13.8 mg, 0.1 mmol, 1 equiv),
providing 19 in 100% yield as determined by 19F NMR spectroscopic
analysis of the crude reaction mixture. The 19F NMR spectral data
G
DOI: 10.1021/acs.joc.5b02075
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The Journal of Organic Chemistry
Article
4 in 98% yield as determined by 19F NMR spectroscopic analysis of
the crude reaction mixture. The 19F NMR spectral data matched that
of an authentic sample (Ark Pharm; m, −108.02 ppm). The identity of
the product was further confirmed by GCMS analysis (m/z = 121).
The yield reported in Chart 1 (94%) represents an average of three
runs (98%, 83%, and 100%).
reaction). In Industrial Chemistry Library; Jean-Roger, D., Serge, R.,
Eds.; Elsevier: New York, 1996; pp 244−292. (c) Champagne, P. A.;
Desroches, J.; Hamel, J.-D.; Vandamme, M.; Paquin, J.-F. Chem. Rev.
2015, 115, 9073. (d) Clark, J. H.; Wails, D.; Bastock, T. W. Aromatic
Fluorination; CRC Press: Boca Raton, FL, 1996.
(4) For fluorodenitration reactions, see the following: Kuduk, S. D.;
3-Fluorobenzonitrile (28). General procedure E was followed using
3-chlorobenzonitrile (13.7 mg, 0.1 mmol, 1 equiv) at 80 °C, providing
28 in 6% yield as determined by 19F NMR spectroscopic analysis of
the crude reaction mixture. The 19F NMR spectral data matched that
of an authentic sample (Oakwood Chemicals; m, −111.18 ppm). The
identity of the product was further confirmed by GCMS analysis (m/z
= 121). The yield reported in Chart 1 (7%) represents an average of
two runs (6% and 7%).
DiPardo, R. M.; Bock, M. G. Org. Lett. 2005, 7, 577.
(5) (a) Sun, H.; DiMagno, S. G. Angew. Chem., Int. Ed. 2006, 45,
2720. (b) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050.
(c) DiMagno, S. G.; Sun, H. Anhydrous Fluoride Salts and Reagents
and Methods for Their Production. Patent US20060089514A1, April
27, 2006.
(6) Allen, L. J.; Muhuhi, J. M.; Bland, D. C.; Merzel, R.; Sanford, M.
S. J. Org. Chem. 2014, 79, 5827.
4-Fluorobenzonitrile (29). General procedure E was followed using
4-chlorobenzonitrile (13.7 mg, 0.1 mmol, 1 equiv) at 80 °C, providing
29 in 79% yield as determined by 19F NMR spectroscopic analysis of
the crude reaction mixture. The 19F NMR spectral data matched that
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 Chart 1 (80%) represents an average of
two runs (79% and 81%).
Ethyl 4-Fluorobenzoate (30). General procedure D was followed
using ethyl 4-nitrobenzoate (98 mg, 0.5 mmol, 1 equiv), providing 30
as a colorless oil (51 mg, 61% yield, Rf = 0.58 in 90% hexanes/10%
EtOAc). 1H, 13C, and 19F NMR experimental data match those
reported in the literature.7 HRMS ESI+ (m/z): [M]+ calcd for
C9H9FO2 168.0587, found 168.0584. The yield reported in Chart 1
(63%) represents an average of two runs (61% and 65%).
(7) Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford, M. S. Org. Lett.
2015, 17, 1866.
(8) The deoxyfluorination reagent Phenofluor converts phenols to
(hetero)aryl fluorides via a proposed SNAr pathway. These reactions
generally proceed at temperatures (≥80 °C) and require the addition
of an excess of CsF: (a) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem.
Soc. 2011, 133, 11482. (b) Fujimoto, T.; Becker, F.; Ritter, T. Org.
Process Res. Dev. 2014, 18, 1041. (c) Fujimoto, T.; Ritter, T. Org. Lett.
2015, 17, 544.
(9) NMe4F can be synthesized from NMe4Cl and KF or NMe4OH
and HF: (a) Dermeik, S.; Sasson, Y. J. Org. Chem. 1989, 54, 4827.
(b) Tunder, R.; Siegel, B. J. Inorg. Nucl. Chem. 1963, 25, 1097.
(c) Christe, K. O.; Wilson, W. W.; Wilson, R. D.; Bau, R.; Feng, J. J.
Am. Chem. Soc. 1990, 112, 7619. (d) Christe, K. O.; Wilson, W. W.
Anhydrous, chlorine- and bifluoride-free tetramethylammonium
fluoride. Patent EP0457966A1, November 27, 1991. (e) Urban, G.;
4-Fluorobenzophenone (31). General procedure D was followed
using 4-nitrobenzophenone (114 mg, 0.5 mmol, 1 equiv), providing 31
as a white solid (89 mg, 89% yield, Rf = 0.54 in 90% hexanes/10%
Dotzer, R. Method of producing onium fluorides selected from the
̈
group consisting of nitrogen, antimony, boron, and arsenic. Patent
US3388131A1, June 11, 1968.
1
EtOAc, mp = 47−48 °C). H, 13C, and 19F NMR experimental data
match those reported in the literature.7 HRMS ESI+ (m/z): [M + H]+
calcd for C13H10FO 201.0710, found 201.0708. The yield reported in
Chart 1 (90%) represents an average of two runs (89% and 90%).
(10) Sharma, R. K.; Fry, J. L. J. Org. Chem. 1983, 48, 2112.
(11) Grushin, V. V.; Marshall, W. J. Organometallics 2008, 27, 4825.
(12) (a) Boechat, N.; Clark, J. H. J. Chem. Soc., Chem. Commun. 1993,
921. (b) Adams, D. J.; Clark, J. H.; McFarland, H. J. Fluorine Chem.
1998, 92, 127. (c) Clark, J. H.; Wails, D. J. Fluorine Chem. 1995, 70,
201. (d) Clark, J. H.; Wails, D. Tetrahedron Lett. 1993, 34, 3901.
(e) Clark, J. H.; Wails, D.; Jones, C. W.; Smith, H.; Boechat, N.;
Mayer, L. U.; Mendonca, J. S. J. Chem. Res. 1994, 478.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02075.
■
S
(13) (a) Adams, D. J.; Clark, J. H.; Nightingale, D. J. Tetrahedron
1999, 55, 7725. (b) Adams, D. J.; Clark, J. H.; McFarland, H.;
Nightingale, D. J. J. Fluorine Chem. 1999, 94, 51. (c) Maggini, M.;
Passudetti, M.; Gonzales-Trueba, G.; Prato, M.; Quintily, U.; Scorrano,
G. J. Org. Chem. 1991, 56, 6406.
(14) (a) Filatov, A. A.; Boiko, V. N.; Yagupolskii, Y. L. J. Fluorine
Chem. 2012, 143, 123. (b) Smyth, T.; Carey, A. Tetrahedron 1995, 51,
8901.
Further description of the cost analysis and NMR spectra
of isolated products 2, 7−16, 30, and 31 (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: mssanfor@umich.edu
■
Notes
(15) (a) Eckelbarger, J. D.; Epp, J. B.; Schmitzer, P. R.; Siddall, T. L.
3-Alkenyl-6-halo-4-aminopicolinates and their use as herbicides. Patent
US20120190548A1, July 26, 2012. (b) Whiteker, G. T.; Arndt, K. E.;
Renga, J. M.; Yuanming, Z.; Lowe, C. T.; Siddall, T. L.; Podhorez, D.
E.; Roth, G. A.; West, S. P.; Arndt, C. Process for the preparation of 4-
amino-5-fluoro-3-halo-6-(substituted)picolinates. Patent
US20120190860, July 26, 2012. (c) Yerkes, C. N.; Lowe, C. T.;
Eckelbarger, J. D.; Epp, J. B.; Guenthenspberger, K. A.; Siddall, T. L.;
Schmitzer, P. R. Arylalkyl esters of 4-amino-6-(substitutedphenyl)-
picolinates and 6-amino-2-(substitutedphenyl)-4-pyrimidinecarboxy-
lates and their use as selective herbicides for crops. Patent
US20150025238A1, January 22, 2015. (d) Eckelbarger, J. D.; Epp, J.
B.; Schmitzer, P. R. 6-Amino-2-substituted-5-vinylsilylpyrimidine-4-
carboxylic acids and esters and 4-amino-6-substituted-3-vinylsilylpyr-
idine-2-carboxylic acids and esters as herbicides. Patent
US20120190549A1, July 26, 2012. (e) Epp, J. B.; Schmitzer, P. R.;
Balko, T. W.; Ruiz, J. M.; Yerkes, C. N.; Siddall, T. L.; Lo, W. C. 2-
Substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-pyrimidinecarboxylic
acids and 6-substituted-4-amino-3-alkyl, alkenyl and alkynyl picolinic
acids and their use as herbicides. Patent US20090088322A1, April 2,
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Dow Chemical.
■
REFERENCES
(1) (a) Wang, J.; San
■
́
chez-Rosello,
́
M.; Acena, J. L.; del Pozo, C.;
̃
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev.
2014, 114, 2432. (b) Jeschke, P. Pest Manage. Sci. 2010, 66, 10.
(c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320. (d) Muller, K.; Faeh, C.; Diederich, F. Science
̈
2007, 317, 1881. (e) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
(2) (a) Special Issue: Fluorine in the Life Sciences ChemBioChem
2004, 5, 557−726.10.1002/cbic.v5:5 (b) Smart, B. E. J. Fluorine Chem.
2001, 109, 3.
(3) (a) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225.
(b) Langlois, B.; Gilbert, L.; Forat, G. Fluorination of aromatic
compounds by halogen exchange with fluoride anions (“halex”
H
DOI: 10.1021/acs.joc.5b02075
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2009. (f) Walsh, T. A.; Hicks, G.; Honma, M.; Davies, J. P. Resistance
to auxinic herbicides. Patent US20070220629A1, September 20, 2007.
(16) Allen, L. J.; Lee, S. H.; Cheng, Y.; Hanley, P. S.; Muhuhi, J. M.;
Kane, E.; Powers, S. L.; Anderson, J. E.; Bell, B. M.; Roth, G. A.;
Sanford, M. S.; Bland, D. C. Org. Process Res. Dev. 2014, 18, 1045.
(17) We assign the 19F NMR signal appearing at −267.9 ppm (q) as
CH3F, on the basis of the following literature report: Weigert, F. J. J.
Org. Chem. 1980, 45, 3476.
(18) (a) Furuya, T.; Klein, J. E. M. N.; Ritter, T. Synthesis 2010, 11,
1804. (b) Miller, J. Aromatic Nucleophilic Substitution; Elsevier:
London, 1968. (c) Terrier, F. Modern Nucleophilic Aromatic
Substitution; Wiley-VCH: Weinheim, Germany, 2013.
(19) For examples of rate studies in the radiofluorination of aryl
halides and nitroarenes, see the following: (a) Karramkam, M.;
Hinnen, F.; Berrehouma, M.; Hlavacek, C.; Vaufrey, F.; Halldin, C.;
́
McCarron, J. A.; Pike, V. W.; Dolle, F. Bioorg. Med. Chem. 2003, 11,
2769. (b) Al-Labadi, A.; Zeller, K.-P.; Machulla, H.-J. J. Radioanal.
Nucl. Chem. 2006, 270, 313. (c) Guo, N.; Alagille, D.; Tamagnan, G.;
Price, R. R.; Baldwin, R. M. Appl. Radiat. Isot. 2008, 66, 1396.
(d) Dolci, L.; Dolle, F.; Jubeau, S.; Vaufrey, F.; Crouzel, C. J. Labelled
Compd. Radiopharm. 1999, 42, 975.
(20) (a) Kobayashi, Y.; Okumura, K. Fluorinated aniline derivatives
and their preparation. Patent JP2011153115A, August 11, 2011.
(b) Aoki, Y.; Kobayashi, Y.; Daido, H.; Katsuta, H.; Tsukada, H.;
Hirabayashi, A.; Takahashi, Y.; Nomura, M.; Kawahara, A. Methods for
producing N-phenyl-3- (benzamido or 3-pyridylcarbonylamino)-
benzamide derivatives. Patent US20140296560A1, October 2, 2014.
(c) Sakai, T.; Iikura, H.; Hyoudoh, I.; Aoki, T.; Furuichi, N.;
Matsushita, M.; Watanabe, F.; Ozawa, S.; Sakaitani, M.; Ho, P.-S.;
Tomii, Y.; Takanashi, K.; Harada, N. Preparation of 2-oxo-2H-
benzopyran derivatives and benzo[e][1,3]oxazine-2,4-dione derivatives
as P27 protein inducers. Patent US20110009398A1, January 13, 2014.
(d) Hyohdoh, I.; Furuichi, N.; Aoki, T.; Itezono, Y.; Shirai, H.; Ozawa,
S.; Watanabe, F.; Matsushita, M.; Sakaitani, M.; Ho, P.-S.; Takanashi,
K.; Harada, N.; Tomii, Y.; Yoshinari, K.; Ori, K.; Tabo, M.; Aoki, Y.;
Shimma, N.; Iikura, H. ACS Med. Chem. Lett. 2013, 4, 1059.
(e) Finger, G. C.; Kruse, C. W. J. Am. Chem. Soc. 1956, 78, 6034.
(21) (a) Hicken, E. J.; Marmsater, F. P.; Munson, M. C.; Schlachter,
S. T.; Robinson, J. E.; Allen, S.; Burgess, L. E.; DeLisle, R. K.; Rizzi, J.
P.; Topalov, G. T.; Zhao, Q.; Hicks, J. M.; Kallan, N. C.; Tarlton, E.;
Allen, A.; Callejo, M.; Cox, A.; Rana, S.; Klopfenstein, N.; Woessner,
R.; Lyssikatos, J. P. ACS Med. Chem. Lett. 2014, 5, 78. (b) Duncan, K.
W.; Chesworth, R.; Boriack-Sjodin, P. A.; Munchhof, M. J.; Jin, L.
Prmt5 inhibitors containing a dihydro- or tetrahydroisoquinoline and
uses thereof. Patent WO2014100730A1, June 26, 2014.
(22) Vasdev, N.; Cao, P.; van Oosten, E. M.; Wilson, A. A.; Houle, S.;
Hao, G.; Sun, X.; Slavine, N.; Alhasan, M.; Antich, P. P.; Bonte, F. J.;
Kulkarni, P. MedChemComm 2012, 3, 1228.
(23) Notably, a similar cost comparison of NBu4F (anh) was not
possible because bulk pricing for C6F6 was not readily available. The
single supplier identified for this reagent provided a price indication of
over $600/kg of C6F6 (compared to approximately $33/kg of NMe4F
and $49/kg of CsF).
(24) Commercial prices for raw materials were obtained from John
Kantzes of SACHEM, Inc. and from SRI’s 2014 Yearbook.
(25) Consultation with waste treatment experts at Dow Chemical,
Midland, MI.
(26) See the Supporting Information for a more detailed discussion
of the cost analysis.
(27) Qin, L.; Ren, X.; Lu, Y.; Li, Y.; Zhou, J. Angew. Chem., Int. Ed.
2012, 51, 5915.
(28) Xu, X.-H.; Wang, X.; Liu, G.-K.; Tokunaga, E.; Shibata, N. Org.
Lett. 2012, 14, 2544.
(29) Umemoto, T.; Tomizawa, G. J. Org. Chem. 1989, 54, 1726.
I
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