Mild fluorination of chloropyridines with in situ generated anhydrous tetrabutylammonium fluoride

Article abstract of DOI:10.1021/jo5003054

This paper describes the fluorination of nitrogen heterocycles using anhydrous NBu₄F. Quinoline derivatives as well as a number of 3- and 5-substituted pyridines undergo high-yielding fluorination at room temperature using this reagent. These results with anhydrous NBu₄F compare favorably to traditional halex fluorinations using alkali metal fluorides, which generally require temperatures of ≥100 °C.

Full text of DOI:10.1021/jo5003054

Note
pubs.acs.org/joc
Mild Fluorination of Chloropyridines with in Situ Generated
Anhydrous Tetrabutylammonium Fluoride
Laura J. Allen,† Joseck M. Muhuhi,‡ Douglas C. Bland,‡ Rachel Merzel,† and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 N. 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 fluorination of nitro-
gen heterocycles using anhydrous NBu4F. Quinoline deriva-
tives as well as a number of 3- and 5-substituted pyridines
undergo high-yielding fluorination at room temperature using
this reagent. These results with anhydrous NBu4F compare
favorably to traditional halex fluorinations using alkali metal fluorides, which generally require temperatures of ≥100 °C.
luorinated pyridines are widely prevalent in commercial
agrochemicals and pharmaceuticals,1 and pyridines con-
taining a fluorine substituent at the 3- and/or 5-position are
particularly common in biologically active molecules (Figure
1).2−5 However, the carbon−fluorine bond in such molecules is
Scheme 1. Fluorination of 1 via (A) Traditional Halex
Fluorination with CsF and (B) Proposed Room-
Temperature Fluorination with Anhydrous TBAF
F
We aimed to use anhydrous TBAF to achieve both mild and
high-yielding fluorinations of challenging 3- and 5-chloropyr-
idine substrates (Scheme 1B). We report herein a convenient
adaptation of DiMagno’s anhydrous TBAF fluorination
procedure that enables the room-temperature fluorination of
a variety of nitrogen heterocycles. This method offers the
additional advantages that it can be performed in one pot and
that a variety of solvents can be used.
Our initial studies focused on the fluorination of 5-
chloropicolinate 1, a structural motif that appears in a variety
of Dow Agrosciences products.12 As shown in Table 1, the
reaction of 1 with a preformed solution of anhydrous TBAF (1
equiv generated from 0.167 equiv of C6F6 and 1 equiv of
NBu4CN in DMSO per DiMagno’s procedure)7 resulted in
82% yield of fluoropicolinate 2 within 24 h at room
temperature (Table 1, entry 2). The yield of this transformation
increased to near quantitative with 2 equiv or more of the
preformed anhydrous TBAF (entries 3, 4). Furthermore, with 2
equiv of anhydrous TBAF, the fluorination of 1 proceeded to
84% yield within 30 min at room temperature (entry 5).
Importantly, these conditions compare favorably to the
Figure 1. Examples of biologically active molecules containing 3- or 5-
fluoropyridines.
often challenging to install. The most common method for
fluorinating pyridine derivatives involves nucleophilic halide
exchange (halex) between the corresponding aryl chloride and
an alkali metal fluoride salt (MF).6−8 Since the 3- and 5-
positions of pyridine are relatively electron-rich sites, such
transformations generally require forcing conditions (≥100 °C)
and often involve the use of expensive CsF. For instance, as
shown in Scheme 1A, the fluorination of 5-chloropicolinate 1
with 2 equiv of CsF requires 24 h at 100 °C to proceed to
completion.
An attractive alternative to high-temperature halex reactions
with metal fluorides involves the use of anhydrous
tetrabutylammonium fluoride.9 Sun and DiMagno have
shown that anhydrous TBAF can participate in SNAr reactions
with a variety of electron-deficient arene substrates at room
temperature.10 Furthermore, this reagent can be preformed
through the combination of tetrabutylammonium cyanide
(TBACN) and hexafluorobenzene (C6F6) in DMSO.11
Received: February 13, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5003054 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2, entries 5−13). The use of MeCN at room temperature is
particularly appealing from a process chemistry perspective.13
We next investigated the scope of this room-temperature
fluorination reaction with various chloropyridine and chlor-
oquinoline derivatives (Table 3). In order to avoid competing
Table 1. Fluorination of 1 with Preformed Anhydrous TBAF
Table 3. Substrate Scope for in Situ Generated Fluorination
with Anhydrous TBAF
a
b
entry
equiv NBu4F
time
24 h
yield (%)
1
2
3
4
5
6
0.5
1
43
82
24 h
24 h
2
>99
>99
84
4
24 h
2
30 min
5 min
2
53
a
Conditions: C6F6 and NBu4CN stirred for 1 h in DMSO at 25 °C,
b
and then substrate 1 added to this solution. Yield determined by 19F
NMR spectroscopy using trifluorotoluene as a standard.
requirements for the corresponding reaction with CsF (100 °C
for 24 h, Scheme 1A).
Further investigations revealed that preformation of anhy-
drous TBAF is not necessary to achieve room temperature
fluorination of 1. Simply weighing the substrate and TBACN
into the reaction vessel followed by the addition of DMSO and
C6F6 furnished 2 in quantitative yield within 6 h (Table 2,
Table 2. One-Pot Room-Temperature Fluorination of 1 with
Anhydrous TBAF in a Variety of Solvents
a
b
c,d
entry
solvent
time
yield 2 (%)
yield 2-CN (%)
1
2
3
DMSO
DMSO
DMSO
DMSO
DMF
10 min
6 h
66
>99
>99
70
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
<1
24 h
24 h
10 min
6 h
a
e
Conditions: C6F6 and NBu4CN were stirred for 5 min in DMSO at
4
25 °C, and then the chloropyridine or chloroquinoline substrate was
added to this solution. The resulting reaction mixtures were then
stirred for 24 h at 25 °C. Two equivalents of anhydrous TBAF were
5
95
6
DMF
>99
>99
87
7
DMF
24 h
10 min
6 h
b
added per chlorine on the pyridine/quinolone ring. Yield determined
by 19F NMR spectroscopy using trifluorotoluene as a standard; n.d. =
8
DMAc
DMAc
DMAc
MeCN
MeCN
MeCN
c
d
9
98
<1
not detected. Isolated yield. Reaction time was 60 h.
10
11
12
13
24 h
10 min
6 h
>99
5
<1
n.d.
n.d.
n.d.
cyanation (which was problematic with a few of the more
activated substrates), we used a general procedure that involves
prestirring a DMSO solution of 2 equiv of NBu4CN and 0.33
equiv of C6F6 for 5 min and then adding the chloropyridine
substrate. Both monofluorination of electron-deficient 3- or 5-
chloropyridines (to afford 2−5) and difluorination of electron-
deficient 4,5-dichloropyridines (to afford 6−8) proceeded in
high yield. The fluorination of ethyl 3-chloro-6-phenyl-
picolinate to form 5 is particularly remarkable, since this
product was obtained in low yield under more traditional halex
conditions with CsF. For instance, the reaction of ethyl 3-
chloro-6-phenylpicolinate with 2 equiv of CsF in DMSO for 24
h at 130 °C afforded only 35% yield of 5 along with unreacted
starting material. Fluorination also proceeded smoothly when
the ester group of 5, 6, and 8 was replaced with a CN
substituent (products 16−18). Furthermore, difluorination of
57
24 h
>99
a
Conditions: all reagents combined together in the appropriate solvent
b
and stirred at 25 °C for 10 min to 24 h. Yield determined by 19F
c
NMR spectroscopy using trifluorotoluene as a standard. Yields
determined by GC using 2-phenylpyridine as a standard. n.d. = not
detected. NBu3MeCN was used in place of NBu4CN.
d
e
entries 2 and 3). No cyanation to form 2-CN was observed
under these conditions. Good results were also obtained using
less expensive NBu3MeCN in place of NBu4CN (70% yield
after 24 h at 25 °C, entry 4). In addition, the one-pot
generation of anhydrous TBAF could be applied to achieve
rapid, high-yielding, room-temperature fluorination of 1 in a
variety of solvents, including DMF, DMAc, and MeCN (Table
B
dx.doi.org/10.1021/jo5003054 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
69.8, 22.0. HRMS ESI+ (m/z): [M + H]+ calcd for C15H15ClNO2
276.0786; found 276.0794.
the isopropyl ester of the broad leaf herbicide chlopyralid
proceeded to form 9 in high yield. Importantly, all of these
difluorination reactions were carried out using 2 equiv of
anhydrous TBAF per chloride in the starting material.
Isopropyl 4,5-Dichloro-6-phenylpicolinate. A 300 mL 3-neck
round bottomed flask equipped with a mechanical overhead stirrer
was charged with CsF (8.19 g, 53.9 mmol), tap water (40 mL),
acetonitrile (120 mL), phenylboronic acid (4.39 g, 36.0 mmol), and
isopropyl 4,5,6-trichloropicolinate (5.44 g, 18.8 mmol, 92% purity).
The resulting suspension was sparged with N2 gas for 15 min, and then
bis(triphenylphosphine) palladium dichloride (0.51 g, 0.72 mmol) was
added. The resulting bright yellow suspension was sparged with N2 for
an additional 15 min, and then the mixture was heated to 55 °C. After
24 h, the heating mantle was removed, and the mixture was cooled to
ambient temperature and then diluted with EtOAc (150 mL) and
water (40 mL). The layers were separated, and SiO2 (30 g) was added
to the organic layer. The solvent was then removed by rotary
evaporation. The product was purified by semiautomated silica gel
chromatography (column: RediSep Silica 330 g; mobile phase:
hexanes/EtOAc gradient elution from 0% to 10% EtOAc; flow rate:
200 mL/min) to afford a white solid (5.50 g, 95% yield, mp = 95 °C).
1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.74−7.71 (m, 2H),
7.49−7.46 (m, 3H), 5.31 (hept, J = 6.4 Hz, 1H), 1.41 (d, J = 6.4 Hz,
6H, CH3); 13C NMR (100.6 MHz, CDCl3) 163.2, 158.8, 146.7, 144.5,
137.7, 132.3, 129.7, 129.5, 128.2, 125.1, 70.3, 21.9. IR (cm−1): 3067,
2986, 1715, 1309, 1216, 817. HRMS ESI+ (m/z): [M + Na]+ calcd for
C15H13Cl2NNaO2 332.0216; found 332.0240.
As anticipated on the basis of DiMagno’s earlier work,8 less
activated 3- and 3,5-chloropyridine substrates afforded modest
yields under these conditions. For example, only 7% of 12 was
detected after 24 h. However, increasing the reaction time to 60
h resulted in 54% yield of 12. Finally, chloroquinoline
derivatives were also good substrates for these room-temper-
ature fluorination reactions, and 13−15 were formed in >99%
yield from the reactions of anhydrous TBAF with the
corresponding chloroquinolines.
In conclusion, this report describes the nucleophilic
fluorination of chloropyridine and chloroquinoline substrates
using anhydrous NBu4F. A variety of 3- and 5-chloropyridines
undergo high-yielding fluorination at room temperature using
this reagent. These results compare very favorably to traditional
alkali metal fluoride halex fluorinations of these challenging
substrates, which typically require temperatures of ≥100 °C.
EXPERIMENTAL SECTION
■
Isopropyl 4,5-Dichloro-6-(p-methoxyphenyl)picolinate. A 300 mL
3-necked round bottomed flask equipped with a mechanical overhead
stirrer was charged with CsF (8.19 g, 53.9 mmol), tap water (40 mL),
acetonitrile (120 mL), 4-methoxyphenylboronic acid (4.23 g, 27.8
mmol), and isopropyl 5,6-dichloropicolinate (5.44 g, 18.8 mmol, 92%
purity). The resulting suspension was sparged with N2 gas for 15 min,
and then bis(triphenylphosphine) palladium dichloride (0.51 g, 0.72
mmol) was added. The resulting bright yellow suspension was sparged
with N2 for an additional 15 min, and then the mixture was heated to
55 °C. After 6 h, the heating mantle was removed, and the mixture was
cooled to ambient temperature. The reaction was diluted with EtOAc
(150 mL) and water (40 mL). The layers were separated, and SiO2 (31
g) was added to the organic layer. The solvent was then removed by
rotary evaporation. The product was purified by semiautomated silica
gel chromatography (column: RediSep Silica 220 g; mobile phase:
hexanes/EtOAc gradient elution from 5% to 15% EtOAc; flow rate:
150 mL/min) to afford a white solid (5.70 g, 89% yield, mp = 105−
Materials and Methods. NMR spectra were recorded on a 700
1
MHz (699.76 MHz for H; 175.95 MHz for 13C), 500 MHz (500.10
MHz for 1H; 125.75 MHz for 13C, 470.56 MHz for 19F), or 400 MHz
1
(400.52 MHz for H; 100.71 for 13C; 376.87 MHz for 19F) NMR
spectrometer with the residual solvent peak (CDCl3; 1H δ = 7.26 ppm,
13C δ = 77.16 ppm) used as the internal reference unless otherwise
noted. Chemical shifts are reported in parts per million (ppm) (δ)
relative to tetramethylsilane. Multiplicities are reported as follows: br
(broad resonance), s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet). Coupling constants (J) are reported in hertz. Infrared (IR)
spectroscopy peaks are reported in cm−1. Melting points are
uncorrected. All stock solutions were made using volumetric glassware.
All liquid reagents were dispensed by difference from syringes. All
reagents were weighed out in a nitrogen-filled drybox with exclusion of
air and moisture, unless otherwise noted. All reagents were purchased
from common suppliers and dried over P2O5 prior to use unless
otherwise noted. Tetrabutylammonium cyanide was dried at 40 °C
under vacuum for 12 h before use.7 Thin layer chromatography (TLC)
1
106 °C). H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.74 (dt, J =
8.8, 2.4 Hz, 2H), 6.99 (dt, J = 8.8, 2.4 Hz, 2H), 5.30 (hept, J = 6.0 Hz,
1H), 3.87 (s, 3H, OCH3), 1.41 (d, J = 6.0 Hz, 6H, CH3); 13C NMR
(100.6 MHz, CDCl3) δ 163.3, 160.7, 158.3, 146.5, 144.4, 131.9, 131.4,
130.1, 124.6, 113.5, 70.2, 55.5, 21.9. IR (cm−1): 3061, 2980, 2837,
1717, 1214, 1179, 1104, 825. HRMS ESI+ (m/z): [M + Na]+ calcd for
C16H15Cl2NNaO3 362.0321; found 362.0331.
was performed on plates precoated with silica gel 60 F254
.
Substrate Synthesis. Isopropyl 5-Chloro-6-phenylpicolinate (1).
A 500 mL 3-neck round bottomed flask equipped with a mechanical
overhead stirrer was charged with KF·2H2O (18.1 g, 192.6 mmol), tap
water (70 mL), and acetonitrile (280 mL). The mixture was stirred
until all of the solids dissolved. To this biphasic mixture was added
phenylboronic acid (9.39 g, 77.1 mmol) and then isopropyl 5,6-
dichloropicolinate (15.0 g, 64.2 mmol). The resulting suspension was
sparged with N2 for 15 min, and then bis(triphenylphosphine)
palladium dichloride (1.13 g, 1.61 mmol) was added. The resulting
bright yellow suspension was sparged with N2 for an additional 15 min,
and then the mixture was heated to 65 °C. After 6 h, the heating
mantle was removed, and the mixture was cooled to ambient
temperature. The reaction was diluted with EtOAc (150 mL) and
water (50 mL). The layers were separated, and SiO2 (48 g) was added
to the organic layer. The solvent was then removed by rotary
evaporation. The product was purified by semiautomated silica gel
chromatography (column: RediSep Silica 330 g; mobile phase:
hexanes/EtOAc gradient elution from 5% to 20% EtOAc; flow rate:
200 mL/min) to afford a thick oil (15.63 g, 88% yield). Crystallization
was induced by seeding with a pure crystal to afford an off-white
crystalline solid (15.03 g, 85% yield, mp = 43−45 °C). 1H NMR (400
MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H),
7.80−7.77 (m, 2H), 7.49−7.44 (m, 3H), 5.31 (hept, J = 6.4 Hz, 1H),
1.41 (d, J = 6.4 Hz, 6H, CH3); 13C NMR (100.6 MHz, CDCl3) δ
164.0, 156.7, 146.8, 138.8, 137.6, 133.5, 129.8, 129.2, 128.1, 124.2,
Isopropyl 4,5-Dichloro-6-(p-chlorophenyl)picolinate. A 300 mL 3-
neck round bottomed flask equipped with a mechanical overhead
stirrer was charged with CsF (8.19 g, 53.9 mmol), tap water (40 mL),
acetonitrile (120 mL), 4-chlorophenylboronic acid (4.22 g, 27.0
mmol), and isopropyl 5,6-dichloropicolinate (5.00 g, 18.0 mmol, 96%
purity). The resulting suspension was sparged with N2 gas for 15 min,
and then bis(triphenylphosphine) palladium dichloride (0.47 g, 0.67
mmol) was added. The resulting bright yellow suspension was sparged
with N2 for an additional 15 min, and then the mixture was heated to
55 °C. After 5 h, the mixture was cooled to ambient temperature. The
reaction was diluted with EtOAc (120 mL) and water (40 mL). The
layers were separated, and SiO2 (34 g) was added to the organic layer.
The solvent was then removed by rotary evaporation. The product was
purified by semiautomated silica gel chromatography (column:
RediSep Silica 330 g; mobile phase: hexanes/EtOAc gradient elution
from 5% to 15% EtOAc; flow rate: 200 mL/min) to afford a white
1
solid (4.90 g, 79% yield, mp = 134−138 °C). H NMR (400 MHz,
CDCl3) δ 8.13 (s, 1H), 7.69 (dt, J = 8.8, 2.4 Hz, 2H), 7.90 (dt, J = 8.8,
2.4 Hz, 2H), 5.31 (hept, J = 6.4 Hz, 1H), 1.41 (d, J = 6.0 Hz, 6H,
CH3); 13C NMR (100.6 MHz, CDCl3) δ 163.1, 157.5, 146.8, 144.7,
136.0, 135.8, 132.2, 131.2, 128.5, 125.3, 70.4, 21.9. IR (cm−1): 3069,
C
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The Journal of Organic Chemistry
Note
2990, 1717, 1312, 1216, 830, 820. HRMS ESI+ (m/z): [M + Na]+
calcd for C15H12Cl3NNaO2 365.9826; found 332.9830.
Et3N); flow rate: 200 mL/min) to give a white solid (1.32 g, 73%
1
yield, mp = 99−101 °C). H NMR (400 MHz, CDCl3) δ 8.01−7.99
Ethyl 3,6-Dichloropicolinate. This compound was prepared using a
modification of a literature procedure.14 3,6-Dichloropicolinic acid
(12.0 g, 62.5 mmol, 1.0 equiv) was weighed into a 100 mL round
bottomed flask equipped with a magnetic stir bar. Absolute ethanol
(25 mL) and sulfuric acid (0.5 mL) were added, and a reflux
condenser was attached. The reaction was heated at reflux for 5 h.
After completion, the reaction mixture was cooled to room
temperature, diluted with Na2CO3 (5% aqueous solution, 100 mL),
and transferred to a separatory funnel. The crude material was diluted
with ethyl acetate (50 mL), and the organic layer was washed with
brine (1 × 50 mL), dried over sodium sulfate, and concentrated in
vacuo to provide the product as a colorless oil (12.0 g, 73% yield, Rf =
0.59 in 70% hexanes/30% Et2O). 1H NMR (700 MHz, CDCl3) δ 7.74
(d, J = 8.5 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H),
1.42 (t, J = 7.1 Hz, 3H). 13C NMR (700 MHz, CDCl3) δ 163.3, 149.0,
147.9, 141.0, 129.4, 127.1, 62.6, 14.1. HRMS ESI+ (m/z): [M + H]+
calcd for C8H8Cl2NO2 219.9927; found 219.9926.
(m, 2H), 7.89 (d, J = 0.4 Hz, 2H), 7.52−7.48 (m, 3H). 13C NMR
(100.6 MHz, CDCl3) δ 157.0, 138.3, 136.2, 134.1, 132.9, 130.6, 129.2,
127.1, 124.2, 115.0. IR (cm−1): 3077, 3061, 2239, 1573, 1547, 1451,
1434, 1364, 1304, 1251, 1185, 1159, 1076, 1040, 840, 773, 744, 698,
692, 650, 606. HRMS calcd for C12H7ClN2 [M + H]+: 215.0376;
found 215.0388.
4,5-Dichloro-6-phenylpicolinonitrile. To a 125 mL round
bottomed flask were added potassium fluoride (4.20 g, 72.3 mmol),
H2O (20 mL), MeCN (60 mL), 4,5,6-trichloro-2-pyridinecarbonitrile
(5.00 g, 24.1 mmol), and phenylboronic acid (4.41 g, 36.2 mmol). The
resulting colorless solution was sparged with N2 for 20 min, and then
bis(triphenylphosphine)palladium(II) chloride (845 mg, 1.2 mmol)
was added. The yellow solution was sparged for 15 min and then
heated to 45 °C for 21 h. To the reaction mixture were added
additional phenylboronic acid (200 mg, 1.64 mmol) and additional
bis(triphenylphosphine)palladium dichloride (35 mg, 0.05 mmol).
The mixture was then stirred for an additional 4 h at 45 °C. The
mixture was allowed to cool to room temperature and then diluted
with H2O (75 mL) and EtOAc (150 mL). The layers were separated,
and the aqueous layer was extracted with EtOAc (2 × 60 mL). The
organic layers were combined, and SiO2 (58 g) added. The solvent was
removed under vacuum, and the crude product was purified by
semiautomated silica gel chromatography (column: RediSep Silica 330
g; mobile phase: hexanes/EtOAc (0.1% Et3N) gradient elution from
0% to 15% EtOAc (0.1% Et3N); flow rate: 200 mL/min) to give a
Ethyl 3-Chloro-6-phenylpicolinate. Phenylboronic acid (381 mg,
3.13 mmol, 1.2 equiv), Pd(PPh3)4 (75 mg, 0.065 mmol, 0.025 equiv),
and potassium fluoride (500 mg, 8.61 mmol, 3.3 equiv) were
combined in a Schlenk flask equipped with a magnetic stir bar. The
flask was evacuated and backfilled with nitrogen three times. Ethyl 3,6-
dichloropicolinate (576 mg, 2.6 mmol, 1.0 equiv) was added as a
solution in toluene (10.5 mL, purged with N2), and the resulting
reaction mixture was refluxed at 120 °C for 12 h. Upon cooling, the
mixture was diluted with ethyl acetate and transferred to a separatory
funnel. The organic layer was washed with water (2 × 50 mL) and
brine (1 × 50 mL), dried over sodium sulfate, and concentrated in
vacuo. The resulting residue was purified by flash column
chromatography using a gradient elution of 0−20% EtOAc in hexanes,
providing the product as a colorless oil (355 mg, 52% yield, Rf = 0.65
1
white solid (5.38 g, 90% yield, mp = 100−103 °C). H NMR (400
MHz, CDCl3) δ 7.77 (s, 1H), 7.71−7.68 (m, 2H), 7.52−7.49 (m, 2H).
13C NMR (100.6 MHz, CDCl3) δ 160.4, 144.9, 136.5, 133.4, 131.4,
130.2, 129.4, 128.4, 128.1, 115.8. IR (cm−1): 3107, 3054, 2245 1532,
1497, 1450, 1283, 1159, 1123, 1037, 902, 885, 815, 778, 778, 744, 686,
641, 599. HRMS calcd for C12H6Cl2N2 [M + H]+: 248.9986; found
248.9996.
1
in 70% hexanes/30% Et2O). H NMR (700 MHz, CDCl3) δ 8.00−
7.99 (multiple peaks, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4
Hz, 1H), 7.47−7.43 (multiple peaks, 3H), 4.51 (q, J = 7.1 Hz, 2H),
1.46 (t, J = 7.1 Hz, 3H). 13C NMR (700 MHz, CDCl3) δ 165.1, 155.5,
148.4, 139.0, 137.4, 129.8, 129.0, 128.6, 127.2, 122.8, 62.3, 14.3.
HRMS ESI+ (m/z): [M + H]+ calcd for C14H13ClNO2 262.06291;
found 262.0629.
2-Phenyl-3-chloropyridine. 2,3-Dichloropyridine (500 mg, 3.38
mmol, 1.0 equiv), phenylboronic acid (494 mg, 4.05 mmol, 1.2 equiv),
Pd(PPh3)4 (98 mg, 0.085 mmol, 0.025 equiv), and potassium fluoride
(648 mg, 11.15 mmol, 3.3 equiv) were combined in a Schlenk flask
equipped with a magnetic stir bar. The flask was evacuated and
backfilled with nitrogen three times. Toluene (10.5 mL, purged with
N2) was added, and the mixture was refluxed at 120 °C for 12 h. Upon
cooling, the mixture was diluted with ethyl acetate and transferred to a
separatory funnel. The organic layer was washed with water (2 × 50
mL) and brine (1 × 50 mL), dried over sodium sulfate, and
concentrated in vacuo. The residue was purified by flash column
chromatography using a gradient elution of 0−20% EtOAc in hexanes
to provide the product as a colorless oil (396 mg, 62% yield, Rf = 0.65
in 70% hexanes/30% Et2O). The 1H and 13C NMR spectroscopic data
match that reported in the literature.15
3-Chloro-6-phenylpicolinonitrile. To a 125 mL round bottomed
flask were added potassium fluoride (1.46 g, 18.9 mmol), H2O (13
mL), MeCN (50 mL), 3,6-dichloro-2-pyridinecarbonitrile (1.45 g, 8.4
mmol), and phenylboronic acid (1.54 g, 12.6 mmol). The resulting
colorless solution was sparged with N2 for 20 min, and then
bis(triphenylphosphine)palladium dichloride (296 mg, 0.44 mmol)
was added. The yellow solution was sparged for 15 min and then
heated to 40 °C for 24 h. The mixture was then cooled to room
temperature and diluted with H2O (30 mL) and EtOAc (100 mL).
The layers were separated, and the aqueous layer extracted with
EtOAc (2 × 50 mL). The organic layers were combined, and SiO2 (35
g) was added. The solvent was removed under vacuum, and the crude
product was purified by semiautomated silica gel chromatography
(column: RediSep Silica 330 g; mobile phase: hexanes/EtOAc (with
0.1% Et3N) gradient elution from 0% to 15% EtOAc (with 0.1%
4,5-Dichloro-6-(4-chlorophenyl)picolinonitrile. To a 125 mL
round bottomed flask were added potassium fluoride (840 mg, 14.5
mmol), H2O (5 mL), MeCN (20 mL), 4,5,6-trichloro-2-pyridine-
carbonitrile (1.00 g, 4.82 mmol), and 4-chlorophenyboronic acid (1.13
g, 7.23 mmol). The resulting colorless solution was sparged with N2
for 20 min, and then bis(triphenylphosphine)palladium dichloride
(169 mg, 0.24 mmol) was added. The yellow solution was sparged for
15 min and then heated to 40 °C for 21 h. The mixture was allowed to
cool to room temperature and then was diluted with H2O (25 mL)
and EtOAc (75 mL). The layers were separated, and the aqueous layer
was extracted with EtOAc (2 × 25 mL). The organic layers were
combined, and SiO2 (18.2 g) was added. The solvent was removed
under vacuum, and the crude product was purified by semiautomated
silica gel chromatography (column: RediSep Silica 120 g; mobile
phase: hexanes/EtOAc (0.1% Et3N) gradient elution from 0% to 25%
EtOAc (0.1% Et3N); flow rate: 85 mL/min) to give a white solid (0.99
g, 72% yield, mp = 132−134 °C). 1H NMR (400 MHz, CDCl3) δ 7.78
(s, 1H), 7.67 (dt, J = 8.8, 2.2 Hz, 2H), 7.48 (dt, J = 8.6, 2.2 Hz, 2H);
13C NMR (100.6 MHz, CDCl3) δ 159.1, 145.2, 136.6, 134.8, 133.3,
131.5, 131.0, 128.7, 128.3, 115.7. IR (cm−1): 3110, 3061, 2235, 1593,
1533, 1489, 1371, 1323, 1286, 1217, 1159, 1371, 1323, 1286, 1217,
1159, 1124, 1090, 1040, 1031, 1019, 903, 883, 820, 760, 717, 640, 604,
586. HRMS calcd for C12H5Cl3N2 [M + H]+: 282.9597; found
282.9607.
General Procedures for Fluorination Reactions. General
Procedure A: Experimental Details for Fluorination Reactions
Reported in Table 1. In a drybox, tetrabutylammonium cyanide
(TBACN) was weighed into a 4 mL vial (Vial 1). DMSO (0.5 mL)
was added, and the mixture was stirred at room temperature until all of
the TBACN dissolved (<5 min). Hexafluorobenzene (0.167 equiv
with respect to TBACN) was then added, resulting in a rapid color
change from light yellow to dark red/brown. This solution was stirred
at room temperature for 1 h. Substrate 1 (0.1 mmol, 1.0 equiv) was
weighed into a separate 4 mL vial equipped with a micro stirbar, and
the appropriate amount of preformed anhydrous TBAF from vial 1
(0.5−4.0 equiv) was added via syringe. The reaction vial was sealed
D
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Note
with a Teflon-lined cap, removed from the drybox, and stirred at room
temperature for the indicated time. The reaction was then diluted with
dichloromethane (2.5 mL), and an internal standard (trifluorotoluene,
10 mL, 0.081 mmol, 0.81 equiv) was added. An aliquot (∼0.6 mL) was
removed for analysis by 19F NMR spectroscopy.
1313, 1285, 1213, 1138, 1101, 1052, 909, 795, 723, 692. HRMS ESI+
(m/z): [M + H]+ calcd for C15H15FNO2 260.1081; found 260.1084.
Isopropyl 5-Fluoropicolinate (3). General procedure C was
followed using isopropyl 5-chloropicolinate (100 mg, 0.5 mmol, 1.0
equiv) with a reaction time of 24 h, providing 3 as a white solid (78
mg, 85% yield, Rf = 0.44 in 70% hexanes/30% Et2O, mp = 36−38 °C).
1H NMR (700 MHz, CDCl3) δ 8.60 (d, J = 2.8 Hz, 1H), 8.17 (dd, J =
8.4, 4.2 Hz, 1H), 7.51 (ddd, J = 8.4, 8.4, 2.8 Hz, 1H), 5.33 (septet, J =
6.3 Hz, 1H), 1.42 (d, J = 6.3 Hz, 6H). 13C NMR (700 MHz, CDCl3):
163.6, 161.0 (d, J = 160 Hz), 144.8 (d, J = 4.0 Hz), 138.4 (d, J = 25
Hz), 126.8 (d, J = 5.0 Hz), 123.3 (d, J = 19 Hz), 69.7, 21.8. 19F NMR
(470 MHz, CDCl3) δ −120.40 (m). IR (cm−1): 1716, 1584, 1480,
1374, 1353, 1294, 1227, 1137, 1100, 908, 856, 725, 697. HRMS ESI+
(m/z): [M + Na]+ calcd for C9H10FNO2Na 206.0588; found
206.0589.
Methyl 5-Fluoropicolinate (4). General procedure C was followed
using methyl 5-chloropicolinate (86 mg, 0.5 mmol, 1.0 equiv) with a
reaction time of 24 h, providing 4 as a white solid (55 mg, 71% yield,
Rf = 0.29 in 70% hexanes/30% Et2O, mp = 30−32 °C). 1H NMR (700
MHz, CDCl3) δ 8.55 (d, J = 2.8 Hz, 1H), 8.16 (dd, J = 8.4, 4.9 Hz,
1H), 7.50 (ddd, J = 8.4, 8.4, 2.8 Hz, 1H), 3.97 (s, 3H). 13C NMR (700
MHz, CDCl3) δ 164.5, 161.1 (d, J = 260 Hz), 144.1 (d, J = 4.0 Hz),
138.5 (d, J = 24 Hz), 126.9 (d, J = 5.0 Hz), 123.5 (d, J = 18 Hz), 53.0.
19F NMR (470 MHz, CDCl3) δ −119.73 (m). IR (cm−1): 2362, 2337,
1717, 1700, 1653, 1559, 1437, 1314, 1228, 1197, 1129, 1100, 854, 790,
692. HRMS ESI+ (m/z): [M + H]+ calcd for C7H7FNO2 156.0455;
found 156.0454.
General Procedure B: Experimental Details for Fluorination
Reactions Reported in Table 2. In a drybox, substrate 1 (0.1 mmol,
1.0 equiv) and tetrabutylammonium cyanide (0.2 mmol, 2.0 equiv)
were combined in a 4 mL vial equipped with a micro stir bar. Solvent
(0.5 mL) was added, and the mixture was stirred at room temperature
until all of the solids dissolved (<5 min). Hexafluorobenzene (3.8 μL,
0.033 mmol, 0.33 equiv) was then added via microliter syringe,
resulting in a rapid color change from light yellow to dark red/brown.
The reaction vial was sealed with a Teflon-lined cap, removed from the
drybox, and stirred at room temperature for the indicated time. The
reaction was then diluted with dichloromethane (2.5 mL), and internal
standards (both trifluorotoluene, 10 mL, 0.081 mmol, 0.81 equiv and
2-phenylpyridine, 14.3 mL, 0.1 mmol, 1.0 equiv) were added. An
aliquot (∼0.6 mL) was removed for analysis by both 19F NMR
spectroscopy and gas chromatography. The reaction with NBu3MeCN
(entry 4) was carried out on a slightly larger scale (0.18 mmol of 1,
0.36 mmol NBu3MeCN, 0.06 mmol C6F6, 0.75 mL DMSO) but under
otherwise identical conditions.
General Procedure C: Experimental Details for Isolated Yields
Reported in Table 3. In a drybox, tetrabutylammonium cyanide (268
or 536 mg, 1.0 or 2.0 mmol, 2.0 or 4.0 equiv) was weighed into 4 mL
vial equipped with a micro stir bar. DMSO (2.5 mL) was added, and
the mixture was stirred at room temperature until all of the solids
dissolved (<5 min). Hexafluorobenzene (31 or 63 mg, 0.17 or 0.33
mmol, 0.33 or 0.67 equiv) was then added, resulting in a rapid color
change from light yellow to dark red/brown. The reaction mixture was
stirred at room temperature for ∼5 min. The appropriate
chloropyridine or chloroquinoline substrate (0.5 mmol, 1.0 equiv)
was then added, and the reaction vial was sealed with a Teflon-lined
cap, removed from the drybox, and stirred at room temperature for the
indicated time. 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 sodium sulfate, and concentrated in vacuo. The crude mixture
was purified by flash column chromatography using gradients of
hexanes and either diethyl ether or ethyl acetate as eluent.
General Procedure D: General Experimental Details for NMR
Yields Reported in Table 3. In a drybox, tetrabutylammonium cyanide
(54 or 108 mg, 0.2 or 0.4 mmol, 2.0 or 4.0 equiv) was weighed into 4
mL vial equipped containing a micro stir bar. DMSO (0.5 mL) was
added, and the mixture was stirred at room temperature until all of the
solids dissolved (<5 min). Hexafluorobenzene (6.1 or 12.4 mg, 0.033
or 0.066 mmol, 0.33 or 0.67 equiv) was then added, resulting in a rapid
color change from light yellow to dark red/brown. The reaction
mixture was stirred at room temperature for 5 min. The appropriate
chloropyridine or chloroquinoline substrate (0.1 mmol, 1.0 equiv) was
then added, and the reaction vial was sealed with a Teflon-lined cap,
removed from the drybox, and stirred at room temperature for the
indicated time. The reaction was then diluted with dichloromethane
(2.5 mL), and an internal standard (trifluorotoluene, 10 mL, 0.81
equiv) was added. An aliquot (∼0.6 mL) was removed for analysis by
19F NMR spectroscopy.
Ethyl 3-Fluoro-6-phenylpicolinate (5). General procedure C was
followed using ethyl 3-chloro-6-phenylpicolinate (125 mg, 0.5 mmol, 1
equiv) with a reaction time of 24 h, providing 5 as a colorless oil (80
1
mg, 65% yield, Rf = 0.49 in 70% hexanes/30% Et2O). H NMR (700
MHz, CDCl3): 7.99 (m, 2H), 7.88 (dd, J = 8.7, 3.4 Hz, 1H), 7.58 (dd,
J = 9.5, 8.7 Hz, 1H), 7.47 (m, 2H) 7.42 (m, 1H), 4.50 (q, J = 7.1 Hz,
2H), 1.46 (t, J = 7.1 Hz, 3H). 13C NMR (700 MHz, CDCl3) δ 163.4,
158.3 (d, J = 270 Hz), 153.4 (d, J = 4.0 Hz), 137.5, 136.8 (d, J = 10
Hz), 129.3, 128.8, 127.0, 126.0 (d, J = 21 Hz), 124.7 (d, J = 5.0 Hz),
62.0, 14.2. 19F NMR (470 MHz, CDCl3) δ −121.96 (m). IR (cm−1):
1729, 1459, 1313, 1254, 1216, 1094, 907, 725, 692. HRMS ESI+ (m/
z): [M + H]+ calcd for C14H13FNO2 246.0925; found 246.0926.
Isopropyl 4,5-Difluoro-6-phenylpicolinate (6). General procedure
C was followed using isopropyl 4,5-difluoro-6-phenylpicolinate (155
mg, 0.5 mmol, 1.0 equiv) with a reaction time of 24 h, providing 6 as a
colorless oil (88 mg, 63% yield, Rf = 0.75 in 70% hexanes/30% Et2O).
1H NMR (700 MHz, CDCl3) δ 8.04 (m, 2H), 7.89 (dd, J = 9.4, 5.2
Hz, 1H), 7.53−7.45 (multiple peaks, 3H), 5.31 (septet, J = 6.3 Hz,
1H), 1.42 (d, J = 6.3 Hz, 6H). 13C NMR (700 MHz, CDCl3) δ 162.8
(d, J = 4.0 Hz), 156.7 (dd, J = 260, 12 Hz), 148.5 (d, J = 8.0 Hz), 148.0
(dd, J = 270, 10 Hz), 145.4 (t, J = 6.0 Hz), 133.8 (dd, J = 5.0, 3.0 Hz),
130.1, 129.0 (d, J = 6.0 Hz), 128.6, 113.5 (d, J = 16 Hz), 70.1, 21.8. 19F
NMR (470 MHz, CDCl3) δ −125.2 (m), −144.7 (m). IR (cm−1):
1742, 1714, 1605, 1576, 1471, 1435, 1417, 1371, 1226, 1135, 1094,
974, 909, 879, 730, 713, 690. HRMS ESI+ (m/z): [M + H]+ calcd for
C15H14F2NO2 278.0987; found 278.0992.
Isopropyl 4,5-Difluoro-6-(p-methoxyphenyl)picolinate (7). Gen-
eral procedure C was followed using isopropyl 4,5-dichloro-6-(p-
methoxyphenyl)picolinate (170 mg, 0.5 mmol, 1.0 equiv) with a
reaction time of 24 h, providing 7 as a colorless oil (90 mg, 57% yield,
Rf = 0.56 in 70% hexanes/30% Et2O). 1H NMR (700 MHz, CDCl3) δ
8.04 (m, 2H), 7.82 (dd, J = 9.4, 5.2 Hz, 1H), 7.00 (m, 2H), 5.29
(septet, J = 6.3 Hz, 1H), 3.86 (s, 3H), 1.41 (d, J = 6.3 Hz, 6H). 13C
NMR (700 MHz, CDCl3) δ 162.9 (d, J = 3.0 Hz), 161.2, 156.6 (dd, J
= 260, 13 Hz), 148.0 (d, J = 8.0 Hz), 147.7 (dd, J = 270, 11 Hz), 145.1
(t, J = 7.0 Hz), 130.4 (d, J = 7.0 Hz), 126.4 (dd, J = 6.0, 3.0 Hz), 114.0,
112.8 (d, J = 16 Hz), 70.0, 55.3, 21.8. 19F NMR (470 MHz, CDCl3) δ
−125.7 (m), −145.3 (m). IR (cm−1): 1741, 1714, 1598, 1517, 1464,
1411, 1371, 1222, 1179, 1133, 1107, 1091, 1029, 973, 880, 834, 786,
729, 697. HRMS ESI+ (m/z): [M + H]+ calcd for C16H16F2NO3
308.1093; found 308.1096.
Product Synthesis and Characterization. Isopropyl 5-Fluoro-6-
phenylpicolinate (2). General procedure C was followed using
isopropyl 5-chloro-6-phenylpicolinate (1) (138 mg, 0.5 mmol, 1
equiv) with a reaction time of 24 h, providing 2 as a colorless oil (121
1
mg, 91% yield, Rf = 0.61 in 70% hexanes/30% Et2O). H NMR (700
MHz, CDCl3) δ 8.05−8.03 (multiple peaks, 3H), 7.54 (dd, J = 10.5,
8.4 Hz, 1H), 7.49−7.46 (m, 2H), 7.45−7.42 (m, 1H) 5.31 (septet, J =
6.3 Hz, 1H), 1.41 (d, J = 6.3 Hz, 6H). 13C NMR (700 MHz, CDCl3) δ
163.7, 159.0 (d, J = 270 Hz), 146.2 (d, J = 11 Hz), 144.4 (d, J = 4.0
Hz), 134.5 (d, J = 5.0 Hz), 129.6, 129.0 (d, J = 6.0 Hz), 128.4, 125.3
(d, J = 6.0 Hz), 124.5 (d, J = 21 Hz), 69.3, 21.8. 19F NMR (470 MHz,
CDCl3) δ −117.8 (m). IR (cm−1): 1734, 1712, 1463, 1438, 1358,
Isopropyl 4,5-Difluoro-6-(p-chlorophenyl)picolinate (8). General
procedure C was followed using isopropyl 4,5-dichloro-6-(p-
E
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Note
chlorophenyl)picolinate (172 mg, 0.5 mmol, 1 equiv) with a reaction
reaction time of 24 h, providing 14 as a colorless oil (50 mg, 68% yield,
Rf = 0.44 in 70% hexanes/30% Et2O). 1H and 13C NMR experimental
data match those reported in the literature.13 1H NMR (700 MHz,
CDCl3) δ 8.16 (d, J = 8.3 Hz, 1H), 8.05 (m, 1H), 7.86 (d, J = 8.2 Hz,
1H), 7.76 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.52
(d, J = 5.7 Hz, 1H). 13C NMR (176 MHz, CDCl3) δ 160.0 (d, J =
246.5 Hz), 139.7 (d, J = 5.9 Hz), 139.3 (d, J = 16.1 Hz), 131.6, 128.0,
126.4 (d, J = 3.8 Hz), 123.2, 119.4 (d, J = 4.9 Hz), 117.8 (d, J = 32.4
Hz). 19F NMR (470 MHz, CDCl3) δ −71.3 (s). IR (cm−1): 1637,
1591, 1573, 1497, 1371, 1348, 1269, 1051, 819, 749, 720, 658. HRMS
ESI+ (m/z): [M + H]+ calcd for C9H7FN 148.0557; found 148.0554.
4-Fluoro-7-(trifluoromethyl)quinoline (15). General procedure C
was followed using 4-chloro-7-(trifluoromethyl)quinoline (116 mg, 0.5
mmol, 1.0 equiv) with a reaction time of 24 h, providing 15 as a white
solid (68 mg, 64% yield, Rf = 0.33 in 70% hexanes/30% Et2O, mp =
54−56 °C). 1H NMR (700 MHz, CDCl3) δ 8.92 (ddd, J = 8.1, 5.0, 2.0
Hz, 1H), 8.39 (s, 1H), 8.16 (dd, J = 8.7, 2.8 Hz, 1H), 7.73 (dd, J = 8.7,
2.1 Hz, 1H), 7.17 (ddd, J = 9.4, 4.9, 2.1 Hz, 1H). 13C NMR (700
MHz, CDCl3) δ 164.9 (d, J = 170 Hz 152.9 (d, J = 8.0 Hz), 149.3 (d, J
= 4.0 Hz), 132.3 (q, J = 33 Hz), 126.7 (quin, J = 4.0 Hz), 123.5 (q, J =
260 Hz), 122.5 (d, J = 2.0 Hz), 121.9 (d, J = 5.0 Hz), 121.1 (d, J = 120
Hz), 107.3 (d, J = 14 Hz). 19F NMR (470 MHz, CDCl3) δ −63.1 (s),
−111.6 (m). IR (cm−1): 1616, 1562, 1512, 1456, 1383, 1367, 1322,
1297, 1250, 1172, 1109, 1090, 904, 844, 831, 683. HRMS ESI+ (m/z):
[M + H]+ calcd for C10H6F4N 216.0431; found 216.0430.
time of 24 h, providing 8 as a white solid (75 mg, 48% yield, Rf = 0.61
1
in 70% hexanes/30% Et2O, mp = 46−48 °C). H NMR (700 MHz,
CDCl3) δ 8.01 (m, 2 H), 7.90 (dd, J = 9.0, 4.9 Hz, 1 H), 7.48 (m, 2
H), 5.31 (septet, J = 5.6 Hz, 1 H), 1.42 (d, J = 6.3 Hz, 6 H). 13C NMR
(700 MHz, CDCl3) δ 162.7 (d, J = 3.0 Hz), 156.7 (dd, J = 270, 13
Hz), 148.0 (dd, J = 270, 11 Hz), 147.0 (d J = 9.0 Hz), 145.5 (t, J = 7.0
Hz), 136.4, 132.2 (dd, J = 5.0, 3.0 Hz), 130.3 (d, J = 6.0 Hz), 128.9,
113.8 (d, J = 16 Hz), 70.2, 21.8. 19F NMR (470 MHz, CDCl3) δ
−124.7 (m), −144.4 (m). IR (cm−1): 1714, 1593, 1462, 1393, 1371,
1239, 1221, 1103, 1089, 1014, 974, 909, 877, 829, 788, 753, 736.
HRMS ESI+ (m/z): [M + H]+ calcd for C15H13ClF2NO2 312.0601;
found 312.0601.
Ethyl 3,6-Difluoropicolinate (9). General procedure C was followed
using ethyl 3,6-dichloropicolinate (110 mg, 0.5 mmol, 1 equiv) with a
reaction time of 24 h, providing 9 as a white solid (49 mg, 53% yield,
Rf = 0.20 in 70% hexanes/30% Et2O, mp = 24−27 °C). 1H NMR (700
MHz, CDCl3) δ 7.66 (app. td, J = 8.4, 5.6 Hz, 1H), 7.14 (ddd, J = 8.4,
4.2, 2.8, 1H), 4.43 (q, J = 7.0 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H). 13C
NMR (700 MHz, CDCl3) δ 161.8 (d, J = 6.0 Hz), 157.7 (dd, J = 240, J
= 6.0 Hz), 157.2 (dd, J = 270, 4.0 Hz), 133.5 (t, J = 13 Hz), 131.4 (dd,
J = 24, 8.0 Hz), 115.3 (dd, J = 36, 6.0 Hz), 62.4, 14.2. 19F NMR (470
MHz, CDCl3) δ −69.4 (m), −122.5 (m). IR (cm−1): 1729, 1459,
1418, 1228, 1084, 1018, 912, 834, 766, 722, 662. HRMS ESI+ (m/z):
[M + H]+ calcd for C8H8F2NO2 188.0518; found 188.0518.
2-Phenyl-3-fluoropyridine (10). General procedure D was followed
using 2-phenyl-3-chloropyridine (18.9 mg, 0.1 mmol, 1.0 equiv) with a
reaction time of 60 h, providing 10 in 13% yield as determined by 19F
NMR spectroscopy. The identity of 10 was confirmed by synthesis of
an authentic sample from arylation of 2-chloro-3-fluoropyridine with
3-Fluoro-6-phenyl-2-pyridinecarbonitrile (16). General procedure
C was followed using 3-chloro-6-phenyl-2-pyridinecarbonitrile (680
mg, 3.15 mmol, 1.0 equiv) with a reaction time of 15 h. The mixture
was purified by semiautomated silica gel chromatography. First
purification (column: RediSep Silica 40 g; mobile phase: hexanes/
EtOAc gradient elution from 0% to 10% EtOAc; flow rate: 40 mL/
min) provided 249 mg of 16. Remaining fractions were concentrated,
and the residue was purified a second time by semiautomated silica gel
chromatography (column: RediSep Silica 40 g; mobile phase:
hexanes/EtOAc gradient elution from 0% to 4.8% EtOAc; flow rate:
40 mL/min) providing an additional 117 mg of 16 (total: 366 mg,
1
phenylboronic acid. H and 13C NMR data match those previously
reported in the literature.16 1H NMR (700 MHz, CDCl3) δ 8.51 (dt, J
= 4.5, 1.6 Hz, 1H), 8.01 (dt, J = 8.1, 1.4 Hz, 2H), 7.50 (td, J = 7.0, 1.6
Hz, 2H), 7.44 (m, 2H), 7.20 (ddd, J = 8.3, 4.5, 3.8 Hz, 1H). 13C NMR
(176 MHz, CDCl3) δ 157.5 (d, J = 260.7 Hz), 146.2 (d, J = 10.2 Hz),
145.4 (d, J = 5.4 Hz), 135.4 (d, J = 5.6 Hz), 129.2, 128.8 (d, J = 5.7
Hz), 128.5, 124.0 (d, J = 20.6 Hz), 123.4 (d, J = 3.9 Hz). 19F NMR
(400 MHz, CDCl3) δ −122.9 (m). IR (cm−1): 1595, 1444, 1430, 1249,
1187, 1101, 907, 798, 728, 691. HRMS ESI+ (m/z): [M + H]+ calcd
for C11H9FN 174.0714; found 174.0716.
3-Fluoropyridine (11). General procedure D was followed using 3-
chloropyridine (9.7 mg, 0.1 mmol, 1.0 equiv) with a reaction time of
24 h. None of product 11 was detected by 19F NMR spectroscopy in
the crude reaction mixture by comparison to an authentic sample of 11
[19F NMR (470 MHz, CH2Cl2) δ −128.1 (m)].
1
59% yield, mp = 114−115 °C). H NMR (400 MHz, CDCl3) δ) δ
7.99−7.95 (multiple peaks, 3H), 7.65 (dd, J = 9.0, 7.9 Hz, 1H), 7.52−
7.45 (multiple peaks, 3H). 13C NMR (101 MHz, CDCl3) δ 160.6 (d, J
= 269.3 Hz), 155.4 (d, J = 4.3 Hz), 136.4, 130.2, 129.2, 127.0, 125.6
(d, J = 4.5 Hz), 125.4 (d, J = 18.2 Hz), 122.3 (d, J = 15.5 Hz), 113.3
(d, J = 5.1 Hz). 19F NMR (376 MHz, CDCl3) δ −119.7. IR (cm−1):
3074, 2236, 1462, 1453, 1269, 1119, 776, 743. HRMS ESI+ (m/z): [M
+ H]+ calcd for C12H8FN2 199.0666; found 199.0665.
4,5-Difluoro-6-phenyl-2-pyridinecarbonitrile (17). General proce-
dure C was followed using 4,5-dichloro-6-phenyl-2-pyridinecarboni-
trile (500 mg, 2.01 mmol, 1.0 equiv) with a reaction time of 24 h. The
mixture was purified by semiautomated silica gel chromatography
(column: RediSep Silica 80 g; mobile phase: hexanes/EtOAc gradient
elution from 0% to 1.5% EtOAc; flow rate: 60 mL/min), providing 17
as a white solid (177 mg, 44% yield, mp = 73−74 °C). 1H NMR (400
MHz, CDCl3) δ 8.00 (m, 2H), δ 7.53 (multiple peaks, 4H). 13C NMR
(101 MHz, CDCl3) δ 156.6 (dd, J = 267.5, 13.0 Hz), 150.9 (dd, J =
8.8, 2.0 Hz), 148.3 (dd, J = 271.7, 10.5 Hz), 132.8 (dd, J = 5.2, 3.1
Hz), 131.1, 130.0 (dd, J = 8.9, 7.8 Hz), 129.1 (d, J = 6.2 Hz), 129.0,
117.1 (d, J = 17.6 Hz), 115.9 (d, J = 3.8 Hz). 19F NMR (376 MHz,
CDCl3) δ −122.5 (d, J = 19.2 Hz), −141.3 (d, J = 19.1 Hz). IR
(cm−1): 3097, 2240, 1594, 1573, 1431, 1235, 977, 790. HRMS ESI+
(m/z): [M + H]+ calcd for C12H7F2N2 217.0572; found 217.0572.
4,5-Difluoro-6-(p-chlorophenyl)-2-pyridinecarbonitrile (18). Gen-
eral procedure C was followed using 4,5-dichloro-6-(4-chlorophenyl)-
2-pyridinecarbonitrile (1.00 g, 3.54 mmol, 1.0 equiv) with a reaction
time of 22 h. The mixture was purified by semiautomated silica gel
chromatography (column: RediSep Silica 80 g; mobile phase:
hexanes/EtOAc gradient elution from 0% to 2.1% EtOAc; flow rate:
60 mL/min)providing 18 as a white solid (333 mg, 38% yield, mp =
88−89 °C). 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2H), 7.54 (dd, J
= 8.2, 5.0 Hz, 1H), 7.49 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
156.6 (dd, J = 267.8, 13.1 Hz), 150.0−146.6 (m, 2 carbons), 137.6,
131.1 (dd, J = 5.4, 3.2 Hz), 130.4 (d, J = 6.7 Hz), 130.1 (dd, J = 9.0,
3-Chloro-5-fluoropyridine (12a) and 3,5-Difluoropyridine (12b).
General procedure D was followed using 3,5-dichloropyridine (15 mg,
0.1 mmol, 1.0 equiv) with a reaction time of 24 h, providing 12a in 7%
yield as determined by 19F NMR spectroscopy (none of product 12b
was detected). The same reaction was repeated with a reaction time of
60 h, providing the fluorinated products as a mixture of 12a and 12b in
54% and 5% yield as determined by 19F NMR spectroscopy. The 19F
NMR spectral data for 12a and 12b matched those of authentic
samples [12a, 19F NMR (400 MHz, CH2Cl2) δ −126.5 (d, J = 8.3
Hz); 12b, 19F NMR (400 MHz, CH2Cl2) δ −124.9 (d, J = 8.6 Hz)].
2-Fluoroquinoline (13). General procedure C was followed using 2-
chloroquinoline (82 mg, 0.5 mmol, 1 equiv) with a reaction time of 24
h, providing 13 as a colorless oil (61 mg, 83% yield, Rf = 0.50 in 70%
hexanes/30% Et2O). 1H and 13C experimental data match those
reported in the literature.17 1H NMR (700 MHz, CDCl3) δ 8.19 (t, J =
8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.80 (m, 1H), 7.70 (m, 1H),
7.50 (m, 1H), 7.03 (dd, J = 8.7, 2.8 Hz, 1H). 13C NMR (176 MHz,
CDCl3) δ 161.2 (d, J = 242.1 Hz), 145.8 (d, J = 16.8 Hz), 142.0 (d, J =
10.0 Hz), 130.7, 128.1 (d, J = 1.2 Hz), 127.6, 126.9 (d, J = 1.9 Hz),
126.2 (d, J = 2.4 Hz), 110.0 (d, J = 42.4 Hz). 19F NMR (400 MHz,
CDCl3) δ −61.7. IR (cm−1): 1620, 1593, 1579, 1507, 1472, 1428,
1309, 1230, 1205, 1107, 967, 906, 815, 777, 753, 727, 705. HRMS ESI
+ (m/z): [M + H]+ calcd for C9H7FN 148.0557; found 148.0554.
1-Fluoroisoquinoline (14). General procedure C was followed
using 1-chloroisoquinoline (82 mg, 0.5 mmol, 1.0 equiv) with a
F
dx.doi.org/10.1021/jo5003054 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
7.7 Hz), 129.3, 117.29 (d, J = 17.5 Hz), 115.7 (d, J = 3.7 Hz). 19F
NMR (376 MHz, CDCl3) δ −122.0 (d, J = 19.1 Hz), −140.9 (d, J =
19.1 Hz). IR (cm−1): 3075, 2246, 1738, 1596, 1583, 1461, 1237, 1092,
980, 843. HRMS ESI+ (m/z): [M + H]+ calcd for C12H6ClF2N2
251.0182; found 251.0185.
U.S. Patent Appl. US20120190549 A1, July 26, 2012. (e) Balko, T. W.;
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Yerkes, C. N. 2-Substituted-6-amino-5-alkyl, alkenyl or alkynyl-4-
pyrimidinecarboxylic acids and 6-substituted-4-amino-3- alkyl, alkenyl,
or alkynyl picolinic acids and their use as herbicides. U.S. Patent Appl.
US20090088322 A1, Apr 2, 2009. (f) Davies, J.; Hicks, G.; Honma,
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(13) Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fevig, T.; Jennings, S.;
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(14) Zhang, J.; Shen, T.; Xu, L.; Shen, F.; Qin, Q.; Ma, C.; Song, Q.
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ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectral data for all new substrates and for isolated
products 2−17. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mssanfor@umich.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by Dow Chemical.
■
REFERENCES
■
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