Synthesis of 3-Fluoropyridines via Photoredox-Mediated Coupling of α,α-Difluoro-β-iodoketones with Silyl Enol Ethers

Article abstract of DOI:10.1021/acs.joc.7b02467

A method for the synthesis of diversely substituted 3-fluoropyridines from two ketone components is described. The reaction involves photoredox coupling of α,α-difluoro-β-iodoketones with silyl enol ethers catalyzed by fac-Ir(ppy)₃ under blue LED irradiation with subsequent one-pot condensation with ammonium acetate. Based on cyclic voltammetry studies, it was determined that α,α-difluoro-β-iodoketones are reduced notably easier compared to 2,2,2-trifluoro-1-iodoethane, which may be ascribed to the influence of the carbonyl group.

Full text of DOI:10.1021/acs.joc.7b02467

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Synthesis of 3‑Fluoropyridines via Photoredox-Mediated Coupling of
α,α-Difluoro-β-iodoketones with Silyl Enol Ethers
Sofya I. Scherbinina,†,‡ Oleg V. Fedorov,† Vitalij V. Levin,† Vladimir A. Kokorekin,†,§
Marina I. Struchkova,† and Alexander D. Dilman*,†
†N. D. Zelinsky Institute of Organic Chemistry, Leninsky prosp. 47, 119991 Moscow, Russian Federation
‡D. Mendeleev University of Chemical Technology of Russia, Higher Chemical College, Miusskaya sq. 9, 125047 Moscow, Russian
Federation
§I. M. Sechenov First Moscow State Medical University, Trubetskaya st. 8-2, 119991 Moscow, Russian Federation
S
* Supporting Information
ABSTRACT: A method for the synthesis of diversely
substituted 3-fluoropyridines from two ketone components is
described. The reaction involves photoredox coupling of α,α-
difluoro-β-iodoketones with silyl enol ethers catalyzed by fac-
Ir(ppy)3 under blue LED irradiation with subsequent one-pot
condensation with ammonium acetate. Based on cyclic
voltammetry studies, it was determined that α,α-difluoro-β-
iodoketones are reduced notably easier compared to 2,2,2-trifluoro-1-iodoethane, which may be ascribed to the influence of the
carbonyl group.
Scheme 1. Synthesis of 3-Fluoropyridines
INTRODUCTION
■
The pyridine unit plays an important role in medicinal
chemistry with inclusion in more than 100 approved drugs.1
Introduction of a single fluorine atom into a molecule can
significantly modify its biological properties, and this tool is
frequently used during the search of active compounds.2 In
particular, while substitution of hydrogen by fluorine may incur
little steric effect, the fluorine substituent can decrease basicity
of a nitrogen (for example, of the pyridine fragment) or
increase metabolic stability by slowing down the rate of
oxidation.
Concerning fluorinated pyridines,3 2- and 4-substituted
derivatives are notably more susceptible to nucleophilic
substitution of fluorine4 compared to 3-fluoropyridines.
Correspondingly, the 3-fluoropyridine fragment is a frequently
utilized unit for the design of pharmaceuticals.5
experimental step.14 In this protocol, the key C−C bond-
forming event involving a reaction of the iodide 1 with silyl
enol ethers is performed under photoredox conditions. The use
of visible light in combination with a photocatalyst15 is the key
feature of the method.
Existing methods toward 3-fluoropyridines3 rely on sub-
stitution of the diazonium group (Balz−Schiemann reaction),6
whereas other transformations such as electrophilic fluorination
of organometallics,7 deoxofluorination,8 and nucleophilic
fluorination (transition-metal-catalyzed,9 iodine(III) substitu-
tion,10 uncatalyzed halogen substitution11) have been occa-
sionally used. Several ring-forming reactions of narrow scope
have also been described.12 In this regard, reactions which
provide diverse 3-fluoropyridines from readily available starting
materials would be highly desirable.
RESULTS AND DISCUSSION
■
Because of the electron-withdrawing effect of fluorine atoms,
perfluorinated compounds are good substrates for photoredox
catalysis.16,17 In particular, photoredox-mediated alkylation of
enol ethers with perfluoroalkyl iodides (RfI)18 or with iodides
bearing proximal difluoromethylene fragment (RCF2I)17e were
described.19 However, moving two fluorine atoms away from
iodine, as in compounds 1, would likely decrease the efficiency
of the reductive radical generation step.20 As a starting point of
our work, iodide 1a and silyl enol ether 2a, both originating
Recently, we demonstrated that ketones can be easily
transformed into α,α-difluoro-β-iodoketones 1 according to a
halogenative difluorohomologation process13 (Scheme 1).
Herein, we report that ketones 1 can be coupled with another
ketones and ammonia affording 3-fluoropyridines within one
Received: September 28, 2017
Published: November 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02467
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from acetophenone, were selected as model substrates, and
their coupling was evaluated (Table 1). The mixture containing
Table 2. Optimization of Cyclization Reaction
Table 1. Optimization of Photoredox Reaction
a
additive
(equiv)
time
(h)
yield of 3a
a
T
time
(h)
yield
(%)
no.
cat.
Ir(ppy)3
solvent
MeCN
(%)
no.
1
reagents (equiv)
solvent
MeCN
(°C)
1
2
3
4
5
3.5
3.5
3.5
15
81
97
30
47
<5
AcONH4 (1.3), K2CO3
(2.5)
80
2
<5
Ir(ppy)3
MeCN PPh3 (0.25)
MeCN PPh3 (0.25)
MeCN PPh3 (0.25)
MeCN PPh3 (0.25)
MeCN PPh3 (0.25)
Ru(bpy)3(BF4)2
2
3
4
5
6
AcONH4 (2.5), K2CO3 (4)
AcONH4 (6)
DMF
DMF
MeCN
DMF
DMF
80
120
80
2
3
2
2
1
55
b
b
Na2-Eosin Y
98 (90 )
15
HMDS (3.5), K2CO3 (2.5)
HMDS (3.5), K2CO3 (2.5)
<5
71
<5
c
6
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
15
140
140
7
DMF
DMF
DMF
DMF
DMF
DMF
PPh3 (0.25)
PPh3 (0.25)
3.5
0.5
0.5
15
99
69
40
30
47
HMDS (3.5)
8
a
b
Isolated yield. Yield based on iodide 1a in one-pot reaction.
9
10
11
photoredox coupling performed in DMF, afforded pyridine 4a
in 90% isolated yield based on iodide 1a (entry 3). In fact, the
opportunity to avoid the isolation of intermediate ketone 3a
greatly simplifies the procedure. Concerning the mechanism of
the pyridine ring formation, we believe that ammonia attacks at
the carbonyl groups followed by temperature promoted
elimination of water and dehydrofluorination.
PPh3 (0.5)
15
c
12
PPh3 (0.25)
15
a
Determined by 19F NMR of reaction mixtures with 4-fluorotoluene as
an internal standard. 5 mol %. In the dark.
b
c
0.3 mol % of an iridium complex, fac-Ir(ppy)3, was exposed to
blue LED irradiation, and the reaction temperature was
maintained at 25 °C by external cooling. Acetonitrile was
used as solvent for primary optimization. Propylene oxide (PO)
was added as a scavenger of iodotrimethylsilane (Me3SiI),17e,21
a highly reactive byproduct that can trigger side condensation
reactions of diketone 3a. After 3.5 h, the expected product 3a
was formed in good yield, though 19% of starting iodide 1a
remained unaffected (entry 1). Rewardingly, the addition of
substoichiometric amounts (0.25 equiv) of triphenylphosphine
provided notable acceleration leading to complete conversion
of iodide 1a (entry 2). Other photocatalysts such as
Ru(bpy)3(BF4)2 and Eosin Y were less effective (entries 3
and 4). For further applications of ketone 3a under one-pot
conditions (see below), we evaluated the photoredox coupling
in dimethylformamide (DMF) as solvent. Fortunately, the
reaction proceeded faster, leading to a virtually quantitative
yield of the product as determined by 19F NMR of the reaction
mixture (entry 7). The phosphine has accelerating effect even
in DMF, which is observable in experiments at reduced reaction
time (see entries 8 and 9). Interestingly, in DMF the reaction
can work even without the iridium catalyst, albeit at a slower
rate (entries 10 and 11). To purify ketone 3a, we had to
recourse to preparative HPLC, since conventional flash
chromatography did not allow to get rid of acetophenone
formed after hydrolysis of excess of starting silyl enol ether
2a.22
Silyl enol ethers 2 can be obtained from ketones using a
combination of chlorosilane/sodium iodide/triethylamine.24
For some ketones, the isolation of enol ethers 2 by distillation
is simple and can be performed on a gram scale, and these
individual enol ethers were used for the synthesis of pyridines
according to the optimized one-pot procedure (Table 3). For
the generality, the photoredox reactions were performed for a
longer time (15 h), which is required for less reactive
substrates.
Given that silylation is a virtually quantitative process, we
decided to develop a procedure in which the crude unpurified
silyl enol ether is directly involved into the synthesis of
fluoropyridines (Table 4). The advantage of the latter protocol
is that it can be conveniently performed on a millimole scale of
the ketone. As follows from the results presented in Tables 3
and 4, the reaction is quite general. Various iodides 1 bearing
iodine at the primary or secondary carbon were employed
effectively. The macrocyclic iodide 1g furnished product 4t
featuring a bridge-type ring junction. Concerning the ketone
component, methyl-substituted ketones uniformly provided
good yields of 5-unsubstituted 3-fluoropyridines 4 (R3 = H for
structure 4 in the scheme of Table 4). The ketone can have
aromatic or heteroaromatic (furyl, thienyl, pyridyl) groups.
Notably, the ester group remained unaffected in the presence of
ammonia (Table 4, entry 9). The reaction of benzalacetone
gave the expected product with the erosion of the double-bond
geometry, which can be associated with reversible conjugate
addition of ammonia under forcing conditions (Table 4, entry
3). However, for ketones leading to enol ethers with terminally
substituted double bond, the photoredox step turned out to be
less predictable. Thus, enol ethers derived from α-tetralone,
indanone and propiophenone afforded corresponding pyridines
4f,i,o in decreased yields of 56−60%. At the same time, in
photoredox reactions of silyl enolates of cyclohexanone,
Then, the transformation of ketone 3a into fluoropyridine 4a
was studied (Table 2). The reaction in DMF proceeded
significantly faster than in acetonitrile (entries 1 and 2), and
elevated temperatures were required for complete formation of
the pyridine product.23 Finally, the optimal conditions include
the use of excess of ammonium acetate without base at 120 °C
for 3 h. Importantly, a one-pot protocol, in which ammonium
acetate was simply added to the reaction mixture from the
B
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To confirm the radical character of the process, the
photoredox reaction of 1a and 2a was performed in the
presence of 1 equiv of TEMPO. The desired reaction was
completely blocked, as no expected product 3a was observed.
Instead, a compound arising from the trapping of difluorinated
radical 5 by TEMPO was detected by 19F NMR and GC−MS.
Furthermore, the interaction of the photoexcited iridium
catalyst with iodoketone 1a was confirmed by Stern−Volmer
fluorescence quenching experiments.
Table 3. Synthesis of Pyridines 4 from Iodide 1a
The accelerating effect of triphenylphosphine deserves a
special comment. Previously, we observed such an effect, which
on the basis of electrochemical data, was ascribed to reductive
quenching of the excited state by the phosphine leading to a
2+
stronger reductive complex (for Ru(bpy)3 photocata-
lyst).17b,25 However, for fac-Ir(ppy)3, the reductive quenching
of the photoexited complex by triphenylphosphine seems
unlikely because of the mismatch of reduction potentials
(Ir(III)*/Ir(II) + 0.31 V;26 Ph3P/Ph3P+• + 1.10 V vs SCE; see
the Supporting Information for cyclic voltammetry).
Another opportunity is the formation of halogen-bonded
species between iodide 1 and the phosphine followed by light-
promoted homolysis and/or reduction of C−I bond.27
However, for an equimolar mixture of iodide 1a and
triphenylphosphine, there were no signs of complex formation
according to 19F and 31P NMR and UV−vis spectroscopy. For
compound 1a, the reduction potential of −1.20 V (vs SCE) was
determined by cyclic voltammetry (CV), and the CV curve of
1a was unaffected by the addition of a stoichiometric amount of
triphenylphosphine. For comparison, the reduction potential of
2,2,2-trifluoro-1-iodoethane (CF3CH2I) was found to be −1.70
V. Apparently, more facile reduction of 1a relative to CF3CH2I
is associated with the presence of the benzoyl group.28 Since we
could not detect associative interaction between 1a and the
phosphine, the latter would likely not affect the electron
transfer event. Similarly, no interaction between triphenylphos-
phine and silyl enol ether 2a was observed by 31P NMR.
In summary, a convenient protocol for the synthesis of
diversely substituted 3-fluoropyridines is described. The
method is based on the visible-light-mediated coupling of two
derivatives of ketones followed by condensation with ammonia,
and the whole sequence can be performed in a one-pot manner.
Given that starting difluorinated iodides themselves are readily
obtained from ketones by halogenative difluorocarbene
insertion, the presented method allows for assembling of the
3-fluoropyridine structure from two simple ketones.
a
Isolated yield.
cyclododecanone, and propionaldehyde, less than 25% of
diketones were formed. These results may be explained by
decreased reactivity of corresponding enol ethers toward
addition of the fluorinated radicals. Indeed, in photoredox
reactions of these enol ethers, noticeable amounts of
protodeiodinated products were observed resulting from the
hydrogen atom transfer to the free radicals either from allylic
position of the silyl enol ether or from solvent.
The proposed mechanism of photoredox reaction is shown
in Scheme 2. The reduction of idodide 1 by the photoexited
iridium(III) catalyst generates radical 5, which adds across the
enol ether double bond. Silyloxy-substituted radical 6 is then
oxidized by iridium(IV) to cation 7, which expels the silyl group
leading to diketone 3.
Scheme 2. Proposed Photoredox Cycle
EXPERIMENTAL SECTION
■
Dimethylformamide (under vacuum) and acetonitrile were distilled
from CaH2 and stored over MS 4A. High-resolution mass spectra
(HRMS) were measured using electrospray ionization (ESI) and time-
of-flight (TOF) mass analyzer. The measurements were done in a
positive-ion mode (interface capillary voltage −4500 V) or in a
negative ion mode (3200 V); mass range from m/z 50 to 3000.
Column chromatography was carried out employing silica gel 230−
400 mesh. Precoated silica gel plates F-254 were used for thin-layer
analytical chromatography visualizing with UV and/or acidic aq.
KMnO4 solution. For preparative HPLC, a reversed-phase column
(C18-kromasil, 5 μ, 21.2 × 250 mm) was used. For irradiation, a strip
of light-emitting diodes (2835-120LED 1M-Blue, 12 V) was used.
Compounds 1b,f13a and 2a−f24 were prepared according to literature
procedures.
Measurement of Redox Potentials by Cyclic Voltammetry.
Voltammetric studies were carried out in a temperature-controlled (25
°C) cell (V = 10 mL) under nitrogen atmosphere with a scan rate of
C
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Table 4. Synthesis of Pyridines from Iodides 1 and Ketones
a
b
Isolated yield. E/Z mixture, ratio 70:30.
0.1 V·s−1. A glassy carbon disk (diameter 2 mm) was used as a working
electrode. Experiments were performed with the concentration of a
studied compound of 1 mM in dry acetonitrile containing Et4NClO4
(0.1 M). A saturated calomel electrode (SCE) separated from the
solution being studied by a salt bridge filled with the supporting
electrolyte (0.1 M Et4NClO4) was used as a reference electrode. A
platinum plate (S = 3 cm2) was used as a counter electrode.
filled with argon. Then, MeCN (1 mL), Me3SiCF2Br (305 mg, 1.5
mmol, 1.5 equiv), and Bu4NBr (64.5 mg, 0.2 mmol, 0.2 equiv) were
successively added at room temperature. The mixture was stirred for
1.5 h at 80 °C, and then cooled to room temperature. Iodine
monochloride (0.68 mL, 1.3 mmol, 1.3 equiv) was added, and the
mixture was stirred for 10 min at room temperature. For the workup,
the mixture was diluted with saturated solution of Na2SO3 (8 mL), and
the aqueous phase was extracted with hexane (3 × 5 mL). The
combined organic layers were filtered through Na2SO4 and
Preparation of α,α-Difluoro-β-iodoketones 1a,c−e,g. The
tube containing silyl enol ether 2 (1 mmol, 1 equiv) was evacuated and
D
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concentrated under vacuum, and the residue was purified by column
chromatography.
−100.8 (t, J = 17.6 Hz, 2F). Anal. Calcd for C17H14F2O2 (288.10): C,
70.83; H, 4.90. Found: C, 70.81; H, 4.85.
Preparation of 3-Fluoropyridines 4 (General Procedure). Silyl
Enol Ethers 2. For experiments listed in Table 3, enol ethers 2 were
obtained according to the literature procedure.24 For experiments
listed in Table 4, the following protocol was used: Sodium iodide (420
mg, 2.8 mmol, 1.4 equiv) was placed in a tube and dried under vacuum
using heat gun. After being cooled to room temperature, the tube was
filled with argon. Then MeCN (2 mL), ketone (2 mmol, 1 equiv), and
triethylamine (304 mg, 3 mmol, 1.5 equiv) were successively added.
The mixture was cooled with an ice/water bath, and chlorotrime-
thylsilane (3.32 mL, 2.6 mmol, 1.3 equiv) was added at 0 °C. The
cooling bath was removed, and the mixture was stirred for 12 h at
room temperature. Then the volatile components were evaporated
under vacuum (a vacuum of about 10−20 Torr was applied with
heating in a water bath at about 50 °C). The solid residue was washed
with hexane (3 × 15 mL) (the hexane layers were decanted and
filtered through a cotton plug). The combined filtrates were
concentrated under vacuum using a rotary evaporator, furnishing the
crude silyl enol ether, which was used in photoredox reaction without
purification.
Reaction of Iodoketones 1 with Silyl Enol Ethers 2. A reaction
tube with a stir bar was evacuated and filled with argon. Then,
iodoketone 1 (1 mmol, 1 equiv), DMF (2 mL), PPh3 (65.5 mg, 0.25
mmol, 0.25 equiv), propylene oxide (69.6 mg, 1.2 mmol, 1.2 equiv),
fac-Ir(ppy)3 (0.2 mg, 0.003 mmol, 0.003 equiv), and silyl enol ether 2
[1.6 mmol of purified enol ether (Table 3); crude enol ether prepared
from 2 mmol of ketone (Table 4)] were successively added at room
temperature. The reaction vessel was irradiated with a strip of blue
LED for 15 h; during irradiation, the mixture was cooled with room
temperature water. Then ammonium acetate (462 mg, 6 mmol, 6
equiv) was added, and the mixture was stirred for 3 h at 120 °C and
then cooled to room temperature. DMF was evaporated under
reduced pressure, and the residue was purified by flash chromatog-
raphy.
2,2-Difluoro-3-iodo-1-phenylpropan-1-one (1a). Yield: 290 mg
1
(98%). Colorless oil. Rf: 0.30 (hexane/EtOAc, 30/1). H NMR (300
MHz, CDCl3) δ: 8.09 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H),
7.49 (t, J = 7.7 Hz, 2H), 3.76 (t, J = 16.0 Hz, 2H). 13C{1H} NMR (75
MHz, CDCl3) δ: 186.9 (t, J = 31.3 Hz), 134.9, 131.4, 130.3, 128.9,
115.7 (t, J = 255.1 Hz), 0.9 (t, J = 27.3 Hz). 19F NMR (282 MHz,
CDCl3) δ: −95.2 (t, J = 16.0 Hz, 2F). HRMS (ESI): calcd C9H8F2IO
(M + H) 296.9582, found 296.9583.
1-(4-Chlorophenyl)-2,2-difluoro-3-iodopropan-1-one (1c). Yield:
294 mg (89%). White crystals. Mp: 52−53 °C. Rf: 0.28 (hexane/
1
EtOAc, 20/1). H NMR (300 MHz, CDCl3) δ: 8.04 (d, J = 8.5 Hz,
2H), 7.49 (d, J = 8.5 Hz, 2H), 3.75 (t, J = 15.9 Hz, 2H). 13C{1H}
NMR (75 MHz, CDCl3) δ: 185.9 (t, J = 31.8 Hz), 141.7, 131.7 (t, J =
3.3 Hz), 129.7 (t, J = 3.1 Hz), 129.4, 115.7 (t, J = 255.0 Hz), 0.4 (t, J =
27.3 Hz). 19F NMR (282 MHz, CDCl3) δ: −95.2 (t, J = 15.9 Hz, 2F).
HRMS (ESI): calcd for C9H ClF2IONa (M + Na) 352.9012, found
6
352.9010.
2,2-Difluoro-3-iodo-1-phenylbutan-1-one (1d). Yield: 273 mg
(88%). Colorless oil. Rf: 0.23 (hexane/EtOAc, 28/1).1H NMR (300
MHz, CDCl3) δ: 8.08 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H),
7.50 (t, J = 7.6 Hz, 2H), 4.68 (ddq, J = 15.4, 12.7, 7.2 Hz, 1H), 1.99 (d,
J = 7.2 Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ: 187.6 (t, J = 30.6
Hz), 134.7, 132.3 (t, J = 2.3 Hz), 130.2 (t, J = 3.4 Hz), 129.0, 116.8 (t,
J = 257.5 Hz), 21.0 (t, J = 3.4 Hz), 19.4 (t, 25.3 Hz). 19F NMR (282
MHz, CDCl3) δ: −97.3 (dd, J = 272.8, 12.7 Hz, 1F), −103.4 (dd, J =
272.8, 15.4 Hz, 1F). HRMS (ESI): calcd for C10H10F2IO (M + H)
310.9739, found 310.9742.
1-(2,4-Dimethylphenyl)-2,2-difluoro-3-iodopropan-1-one (1e).
Yield: 217 mg (67%). White crystals. Mp: 51−52 °C. Rf: 0.25
1
(hexane/EtOAc, 25/1). H NMR (300 MHz, CDCl3) δ: 7.81 (d, J =
8.0 Hz, 1H), 7.16−7.05 (m, 2H), 3.75 (t, J = 15.3 Hz, 2H), 2.50 (s,
3H), 2.37 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ: 189.5 (t, J =
29.5 Hz), 143.9, 141.0, 133.1, 130.1 (t, J = 6.1 Hz), 128.6, 126.3, 115.5
(t, J = 256.7 Hz), 21.6, 21.4, 1.0 (t, J = 28.0 Hz). 19F NMR (282 MHz,
CDCl3) δ: − 94.9 (t, J = 15.3 Hz, 2F). HRMS (ESI): calcd for
C11H11F2IONa (M + Na) 346.9715, found 346.9704.
3-Fluoro-2,6-diphenylpyridine (4a). Yield: 224 mg (90%). White
1
crystals. Mp: 66−67 °C. Rf: 0.42 (hexane/EtOAc, 20/1). H NMR
(300 MHz, CDCl3) δ: 8.20 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 7.2 Hz,
2H), 7.7 (dd, J = 8.6, 3.2 Hz, 1H), 7.62−7.41 (m, 7H). 13C{1H} NMR
(75 MHz, CDCl3) δ: 157.0 (d, J = 260.8 Hz), 152.9 (d, J = 4.6 Hz),
145.0 (d, J = 10.6 Hz), 138.6, 135.7 (d, J = 5.8 Hz), 129.3, 129.0,
129.0, 128.9, 128.8, 128.5, 126.9, 124.9 (d, J = 21.5 Hz), 120.1 (d, J =
4.3 Hz). 19F NMR (282 MHz, CDCl3) δ: −127.1 (d, J = 10.5 Hz, 1F).
HRMS (ESI): calcd for C17H 13FN (M + H) 250.1027, found
250.1021.
2,2-Difluoro-3-iodocyclotridecan-1-one (1g). Yield: 354 mg
1
(99%). White crystals. Mp: 58−59 °C. Rf: 0.10 (hexane). H NMR
(300 MHz, CDCl3) δ: 4.23 (dd, J = 28.7, 9.8 Hz, 1H), 2.99 (ddt, J =
19.5, 10.3, 2.1 Hz, 1H), 2.64 (ddd, J = 19.2, 7.1, 1.8 Hz, 1H), 2.02−
1.82 (m, 1H), 1.82−1.50 (m, 4H), 1.50−1.05 (m, 13H). 13C{1H}
NMR (75 MHz, CDCl3) δ: 200.1 (dd, J = 32.3, 27.3 Hz), 115.8 (dd, J
= 259.7, 254.3 Hz), 36.7, 31.7 (d, J = 3.3 Hz), 29.6 (dd, J = 24.9, 22.8
Hz), 26.4, 25.6, 25.3, 24.6, 24.6, 24.2, 23.2, 21.2. 19F NMR (282 MHz,
CDCl3) δ: −87.6 (d, J = 239.4 Hz, 1F), −119.4 (dd, J = 239.3, 28.7
Hz, 1F). HRMS (ESI): calcd for C13H21F2IONa (M + Na) 381.,497;
found 381.0482.
3-Fluoro-6-(4-methoxyphenyl)-2-phenylpyridine (4b). Yield: 228
mg (82%). White crystals. Mp: 72−73 °C. Rf: 0.17 (hexane/EtOAc,
20/1). 1H NMR (300 MHz, CDCl3) δ: 8.14 (d, 8.2 Hz, 2H), 8.04 (d, J
= 8.8, 2H), 7.62 (dd, J = 8.6, 3.2 Hz, 1H), 7.57−7.42 (m, 4H), 7.01 (d,
J = 8.8 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ:
160.6, 156.7 (d, J = 259.7 Hz), 152.7 (d, J = 4.6 Hz), 144.9 (d, J = 10.6
Hz), 135.9 (d, J = 6.1 Hz), 131.4, 129.3, 129.0 (d, J = 6.2 Hz), 128.5,
128.2, 125.0 (d, J = 21.6 Hz), 119.4 (d, J = 4.0 Hz), 114.2, 55.5. 19F
NMR (282 MHz, CDCl3, 1F) δ: −128.3 (d, J = 9.4 Hz). Anal. Calcd
for C18H14FNO (279.31): C, 77.40; H, 5.05; N, 5.01. Found: C, 77.40;
H, 5.01; N, 5.03.
2,2-Difluoro-1,5-diphenylpentane-1,5-dione (3a). A reaction tube
with a stir bar was evacuated and filled with argon. Then, iodoketone
1a (296 mg, 1 mmol, 1 equiv), MeCN (2 mL), PPh3 (65.5 mg, 0.25
mmol, 0.25 equiv), propylene oxide (69.6 mg, 1.2 mmol, 1.2 equiv),
fac-Ir(ppy)3 (0.2 mg, 0.003 mmol, 0.003 equiv), and silyl enol ether 2a
(307 mg, 1.6 mmol, 1.6 equiv) were successively added at room
temperature. The reaction vessel was irradiated with a strip of blue
LED for 15 h; during irradiation, the mixture was cooled with room
temperature water. The reaction mixture was quenched with water and
extracted with MTBE (3 × 5 mL), and the combined organic layers
were filtered through Na2SO4 and concentrated under vacuum. Crude
product was purified by flash chromatography (hexane/EtOAc, 15/1)
followed by purification by preparative HPLC (22% water in
acetonitrile, retention time 10.4 min). Yield: 230 mg (80%). White
6-(4-Chlorophenyl)-3-fluoro-2-phenylpyridine (4c). Yield: 224 mg
1
(79%). Colorless oil. Rf: 0.25 (hexane/EtOAc, 20/1). H NMR (300
MHz, CDCl3) δ: 8.12 (d, J = 7.8 Hz, 2H), 8.06 (d, J = 7.8 Hz, 2H),
7.69 (dd, J = 8.6, 3.2 Hz, 1H), 7.59−7.39 (m, 6H). 13C{1H} NMR (75
MHz, CDCl3) δ: 157.0 (d, J = 260.9 Hz), 153.0 (d, J = 4.7 Hz), 143.8
(d, J = 10.4 Hz), 138.4, 135.4, 134.2 (d, J = 6.1 Hz), 130.3 (d, J = 6.8
Hz), 129.1, 128.9, 128.7, 126.9, 125.1 (d, J = 21.6 Hz), 120.5 (d, J =
4.2 Hz). 19F NMR (282 MHz, CDCl3) δ: −126.8 (d, J = 10.8 Hz, 1F).
Anal. Calcd for C17H11ClFN (283.73): C, 71.96; H, 3.91; N, 4.94.
Found: C, 71.84; H, 3.79; N, 4.87.
1
crystals. Mp: 55−56 °C. H NMR (300 MHz, CDCl3) δ: 8.13 (d, J =
7.7 Hz, 2H), 7.96 (d, J = 7.7 Hz, 2H), 7.67−7.34 (m, 6H), 3.28 (t, J =
7.6 Hz, 2H), 2.70 (tt, J = 17.6, 7.59 Hz, 2H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 197.3, 189.0 (t, J = 31.0 Hz), 136.4, 134.4, 133.3, 131.8,
130.2 (t, J = 3.2 Hz), 128.7, 128.7, 128.0, 119.6 (t, J = 253.1 Hz), 30.9
(t, J = 4.0 Hz), 28.6 (t, J = 23.3 Hz). 19F NMR (282 MHz, CDCl3) δ:
3-Fluoro-6-(naphthalen-1-yl)-2-phenylpyridine (4d). Yield: 170
mg (57%). White crystals. Mp: 135−136 °C. Rf: 0.18 (hexane/EtOAc,
1
25/1). H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.28 (d, J = 8.6
Hz, 1H), 8.23 (d, J = 7.3 Hz, 2H), 8.08−7.87 (m, 3H), 7.80 (dd, J =
E
DOI: 10.1021/acs.joc.7b02467
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1
8.6, 3.1 Hz, 1H), 7.65−7.46 (m, 6H). 13C{1H} NMR (75 MHz,
CDCl3) δ 157.1 (d, J = 260.9 Hz), 152.8 (d, J = 4.6 Hz), 145.2 (d, J =
10.8 Hz), 135.9, 135.8 (d, J = 5.8 Hz), 133.7 (d, J = 7.3 Hz), 129.4,
129.1, 129.1, 128.8, 128.6, 128.5, 127.8, 126.6, 126.4, 126.2, 125.0 (d, J
= 21.6 Hz), 124.7, 120.4 (d, J = 4.1 Hz). 19F NMR (282 MHz, CDCl3)
δ −127.0 (d, J = 10.4 Hz, 1F). HRMS (ESI): calcd for C21H 15FN (M
+ H) 300.1183, found 300.1178.
White crystals. Mp: 138−139 °C. H NMR (300 MHz, CDCl3) δ:
8.10 (d, J = 8.4 Hz, 2H), 7.79 (s, 4H), 7.56 (dd, J = 8.4, 2.9 Hz, 1H),
7.51−7.41 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ: 160.6, 156.9 (d, J = 260.8 Hz), 151.5 (d, J
= 4.7 Hz), 144.9 (d, J = 10.5 Hz), 138.1, 137.9, 130.4 (d, J = 6.7 Hz),
128.6, 128.1 (d, J = 5.9 Hz), 124.9 (d, J = 21.7 Hz), 119.1 (d, J = 4.2
Hz), 113.9, 95.2, 55.4. 19F NMR (282 MHz, CDCl3) δ: −126.4 (d, J =
8.4 Hz, 1F). HRMS (ESI): calcd for C18H14FINO (M + H) 406.0099,
found 406.0100.
3-Fluoro-6-(furan-2-yl)-2-phenylpyridine (4e). Yield: 143 mg
1
(60%). yellow oil. Rf: 0.29 (hexane/EtOAc, 22/1). H NMR (300
5-Fluoro-6-(4-methoxyphenyl)-2,3′-bipyridine (4k). Yield: 234 mg
(84%). White crystals. Mp: 85−86 °C. Rf: 0.18 (hexane/EtOAc, 3/2).
1H NMR (300 MHz, CDCl3) δ: 9.24 (br s, 1H), 8.62 (br d, J = 4.4 Hz,
1H), 8.34 (dt, J = 8.0, 1.9 Hz, 1H), 8.09 (dd, J = 8.9, 1.3 Hz, 2H), 7.61
(dd, J = 8.5, 3.2 Hz, 1H), 7.49 (dd, J = 10.8, 8.5 Hz, 1H), 7.37 (dd, J =
7.9, 4.8 Hz, 1H), 7.05−6.98 (m, 2H), 3.85 (s, 3H). 13C{1H} NMR (75
MHz, CDCl3) δ: 160.7, 157.1 (d, J = 261.3 Hz), 150.0 (d, J = 4.8 Hz),
149.8, 148.2, 145.3 (d, J = 10.6 Hz), 134.2, 134.2 (d, J = 7.0 Hz), 130.3
(d, J = 6.8 Hz), 127.8 (d, J = 5.9 Hz), 125.0 (d, J = 21.8 Hz), 123.6,
119.4 (d, J = 4.3 Hz), 113.9, 55.4. 19F NMR (282 MHz, CDCl3) δ:
−125.8 (d, J = 10.8 Hz, 1F). HRMS (ESI): calcd for C17H14FN2O (M
+ H) 281.1085, found 281.1084.
MHz, CDCl3) δ: 8.10 (d, J = 7.1 Hz, 2H), 7.65 (dd, J = 8.6, 3.2 Hz,
1H), 7.59−7.39 (m, 5H), 7.13 (d, J = 3.2 Hz, 1H), 6.59−6.51 (m,
1H). 13C{1H} NMR (75 MHz, CDCl3) δ: 156.4 (d, J = 260.2 Hz),
153.4, 145.6, 143.2, 135.5, 129.4, 129.1, 129.0, 128.5, 124.8 (d, J = 21.9
Hz), 118.5, 112.2, 108.6. 19F NMR (282 MHz, CDCl3) δ: −126.2 (d, J
= 9.6 Hz). HRMS (ESI): calcd for C15H11FNO (M + H) 240.0819,
found 240.0813.
3-Fluoro-5-methyl-2,6-diphenylpyridine (4f). Crude product was
purified by flash chromatography (hexane/EtOAc, 30/1) followed by
purification preparative HPLC (11% water in acetonitrile, retention
time 12.3 min). Yield 158 mg (60%). White crystals. Mp: 92−93 °C.
1H NMR (300 MHz, CDCl3) δ: 8.11 (d, J = 7.8 Hz, 2H), 7.67−7.60
(m, 2H), 7.55−7.38 (m, 7H), 2.43 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 156.5 (d, J = 260.9 Hz), 154.4 (d, J = 4.5 Hz), 142.6 (d, J =
10.3 Hz), 140.1, 135.6 (d, J = 5.8 Hz), 131.8 (d, J = 4.0 Hz), 129.3,
128.9, 128.8 (d, J = 6.0 Hz), 128.5, 128.2, 128.1, 126.3 (d, J = 20.5
Hz), 19.9. 19F NMR (282 MHz, CDCl3) δ: −128.2 (d, J = 11.2 Hz,
1F). HRMS (ESI): calcd for C18H15FN (M + H) 264.1183, found
264.1187.
4-(5-Fluoro-6-phenylpyridin-2-yl)benzonitrile (4g). Yield: 186 mg
(68%). White crystals. Mp: 118−119 °C. Rf: 0.14 (hexane/EtOAc, 25/
1). 1H NMR (300 MHz, CDCl3) δ: 8.19 (d, J = 8.2, 2H), 8.10 (d, J =
7.5, 2H), 7.85−7.68 (m, 3H), 7.66−7.44 (m, 4H). 13C{1H} NMR (75
MHz, CDCl3) δ: 157.6 (d, J = 263.6 Hz), 150.6 (d, J = 5.0 Hz), 145.9
(d, J = 11.5 Hz), 142.6, 135.2 (d, J = 5.5 Hz), 132.7, 129.7, 129.0 (d, J
= 6.1 Hz), 128.6, 127.4, 125.3 (d, J = 21.8 Hz), 120.7 (d, J = 4.5 Hz),
118.9, 112.5. 19F NMR (282 MHz, CDCl3) δ: −124.6 (d, J = 8.2 Hz,
1F). HRMS (ESI): calcd for C18H11FN2Na (M + Na) 297.0798, found
297.0787.
2-(4-Chlorophenyl)-3-fluoro-6-(thiophene-2-yl)pyridine (4l).
Yield: 164 mg (57%). Pale yellow oil. Rf: 0.21 (hexane/EtOAc, 25/
1
1). H NMR (300 MHz, CDCl3) δ: 8.1 (d, J = 8.5, 2H), 7.60−7.34
(m, 6H), 7.11 (t, J = 4.2 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ:
156.4 (d, J = 260.7 Hz), 148.6 (d, J = 4.8 Hz), 144.1, 143.4 (d, J = 10.7
Hz), 135.5, 133.6 (d, J = 6.0 Hz), 130.2 (d, J = 7.0 Hz), 128.7, 128.1,
127.8, 125.2 (d, J = 22.2 Hz), 124.6 (d, J = 1.0 Hz), 118.8 (d, J = 4.4
Hz). 19F NMR (282 MHz, CDCl3) δ: −126.1 (d, J = 10.3 Hz, 1F).
HRMS (ESI): calcd for C15H10ClFNS (M + H) 290.0201, found
290.0196.
6-tert-Butyl-2-(4-chlorophenyl)-3-fluoropyridine (4m). Yield: 160
mg (61%). White crystals. Mp: 60−61 °C. Rf: 0.16 (hexane). 1H NMR
(300 MHz, CDCl3) δ: 8.06 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz,
2H), 7.41−7.25 (m, 2H), 1.41 (s, 9H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 164.9 (d), 156.0 (d, J = 258.6 Hz), 142.1 (d, J = 9.2 Hz),
135.1, 134.7 (d, J = 6.3 Hz), 130.2 (d, J = 7.0 Hz), 128.7, 124.4 (d, J =
21.0 Hz), 119.4 (d, J = 3.8 Hz), 37.6, 30.5. 19F NMR (282 MHz,
CDCl3) δ: −129.3 (d, J = 10.4 Hz, 1F). HRMS (ESI): calcd for C15H
16ClFN (M + H) 264.0950, found 264.0950.
3-Fluoro-2-phenyl-6-styrylpyridine (4h). Crude product was
purified by flash chromatography (hexane/EtOAc, 20/1) followed
by purification preparative HPLC (20% water in acetonitrile).
Retention time: E-isomer, 12.2 min; Z-isomer, 10.6 min. E-Isomer.
Methyl 4-(5-Fluoro-4-methyl-6-phenylpyridin-2-yl)benzoate (4n).
Yield: 244 mg (76%). White crystals. Mp: 136−137 °C. Rf: 0.23
1
1
Yield: 146 mg (53%). Colorless oil. H NMR (300 MHz, CDCl3) δ:
(hexane/EtOAc, 11/1). H NMR (300 MHz, CDCl3) δ: 8.16−8.14
8.04 (d, J = 6.9 Hz, 2H), 7.70−7.23 (m, 11H), 7.17 (dd, J = 16.1, 1.1
Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ: 156.6 (d, J = 260.9 Hz),
151.6 (d, J = 4.9 Hz), 145.6 (d, J = 11.0 Hz), 136.8, 135.7 (d, J = 5.6
Hz), 132.9, 129.3, 129.1, 129.0, 128.8, 128.5, 128.4, 127.2, 124.6 (d, J
= 21.6 Hz), 121.7 (d, J = 4.0 Hz). 19F NMR (282 MHz, CDCl3) δ:
−126.4 (d, J = 8.1 Hz, 1F). HRMS (ESI): calcd for C19H15FN (M +
H) 276.1183, found 276.1180. Z-Isomer. Yield: 63 mg (23%).
(m, 4H), 8.13−8.09 (m, 2H), 7.58 (d, J = 4.8 Hz, 1H), 7.55−7.41 (m,
3H), 3.95 (s, 3H), 2.42 (d, J = 1.7 Hz, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 167.0, 156.6 (d, J = 259.9 Hz), 150.9 (d, J = 5.7 Hz), 145.0
(d, J = 12.2 Hz), 142.9, 135.6 (d, J = 7.11 Hz), 135.8 (d, J = 4.90 Hz),
130.2, 130.1, 129.3, 129.1 (d, J = 6.1 Hz), 128.5, 126.8, 122.6 (d, J =
2.0 Hz), 52.3, 14.9 (d, J = 4.8 Hz). 19F NMR (282 MHz, CDCl3) δ:
−131.8 (s, 1F). HRMS (ESI): calcd for C20H17FNO2 (M + H)
322.1238, found 322.1230.
1
Colorless oil. H NMR (300 MHz, CDCl3) δ: 7.92 (d, J = 7.5, 2H),
7.53−7.40 (m, 3H), 7.40−7.23 (m, 6H), 7.14 (dd, J = 8.5, 3.4 Hz,
1H), 6.90 (d, J = 12.4 Hz, 1H), 6.77 (d, J = 12.4 Hz, 1H). 13C{1H}
NMR (75 MHz, CDCl3) δ: 156.2 (d, J = 261.0 Hz), 152.1 (d, J = 5.1
Hz), 145.4 (d, J = 10.6 Hz), 137.1, 135.5 (d, J = 5.5 Hz), 133.4, 129.7,
129.2, 129.1, 128.9, 128.51, 128.48, 127.7, 124.1 (d, J = 17.1 Hz),
124.0. 19F NMR (282 MHz, CDCl3) δ: −126.3 (d, J = 9.5 Hz, 1F).
HRMS (ESI): calcd for C19H15FN (M + H) 281.1083, found
276.1186.
3-Fluoro-4-methyl-2-phenyl-5,6-dihydrobenzo[h]quinolone (4o).
Yield: 162 mg (56%). White crystals. Mp: 106−107 °C. Rf: 0.31
1
(hexane/EtOAc, 20/1). H NMR (300 MHz, CDCl3) δ: 8.46 (d, J =
7.3 Hz, 1H), 8.14 (d, J = 7.0 Hz, 2H), 7.62−7.19 (m, 6H), 2.91−3.06
(m, 4H), 2.37 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ:155.9 (d, J
= 257.9 Hz), 147.4 (d, J = 5.1 Hz), 142.4 (d, J = 12.8 Hz), 137.2, 136.4
(d, J = 5.8 Hz), 134.7, 132.3 (d, J = 15.9 Hz), 131.7, 129.04, 128.95,
128.8, 128.4, 127.6, 127.2, 125.5, 27.8, 24.4, 10.9 (d, J = 6.4 Hz). 19F
NMR (282 MHz, CDCl3) δ: −130.9 (s, 1F). HRMS (ESI): calcd for
C20H17FN (M + H) 290.1340, found 290.1347.
2-(2,4-Dimethylphenyl)-3-fluoro-6-(4-fluorophenyl)pyridine (4p).
Crude product was purified by flash chromatography (hexane/EtOAc,
30/1) followed by purification preparative HPLC (5% water in
acetonitrile, retention time 9.2 min). Yield: 204 mg (69%). Colorless
oil. 1H NMR (300 MHz, CDCl3) δ: 8.09−7.96 (m, 2H), 7.67 (dd, J =
8.6, 3.5 Hz, 1H), 7.53 (t, J = 8.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H),
7.20−7.09 (m, 4H), 2.42 (s, 3H), 2.35 (s, 3H). 13C{1H} NMR (75
MHz, CDCl3) δ: 163.5 (d, J = 248.2 Hz), 156.4 (d, J = 257.0 Hz),
151.9 (d, J = 4.7 Hz), 147.8 (d, J = 15.3 Hz), 138.9, 136.7, 134.8 (d, J
3-Fluoro-2-phenyl-5H-indeno[1,2-b]pyridine (4i). Yield: 154 mg
(59%). Pale yellow crystals. Mp: 152−153 °C. Rf: 0.22 (hexane/
1
EtOAc, 20/1). H NMR (300 MHz, CDCl3) δ 8.14 (d, J = 7.4 Hz,
1H), 8.09 (d, J = 7.8 Hz, 2H), 7.52 (m, 7H), 3.90 (s, 2H). 13C{1H}
NMR (75 MHz, CDCl3) δ 156.8 (d, J = 256.9 Hz), 156.6 (d, J = 3.7
Hz), 144.0, 140.4, 137.3 (d, J = 5.2 Hz), 136.1 (d, J = 5.1 Hz), 129.1,
129.1, 129.0, 128.5, 127.5, 125.3, 121.1, 121.1, 120.8, 34.4. 19F NMR
(282 MHz, CDCl3) δ: −127.7 (d, J = 9.0 Hz, 1F). HRMS (ESI): calcd
for C18H 13FN, (M + H) 262.1027, found 262.1031.
3-Fluoro-6-(4-iodophenyl)-2-(4-methoxyphenyl)pyridine (4j). The
crude product was recrystallized from methanol. Yield: 324 mg (80%).
F
DOI: 10.1021/acs.joc.7b02467
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Featured Article
= 3.2 Hz), 132.4 (d, J = 4.0 Hz), 131.4, 130.1 (d, J = 1.9 Hz), 128.8 (d,
J = 8.3 Hz), 126.6, 124.2 (d, J = 21.1 Hz), 119.9 (d, J = 3.8 Hz), 115.7
(d, J = 21.6 Hz), 21.7, 19.9 (d, J = 2.9 Hz). 19F NMR (282 MHz,
CDCl3) δ: −119.4 (m, 1F), −131.2 (d, J = 7.7 Hz, 1F). HRMS (ESI):
calcd for C19H15F2NNa (M + Na) 318.1065, found 318.1066.
6-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2-(2,4-dimethylphenyl)-
3-fluoropyridine (4q). Yield: 255 mg (76%). White crystals. Mp: 116−
117 °C. Rf: 0.13 (hexane/EtOAc, 15/1). 1H NMR (300 MHz, CDCl3)
δ: 7.67−7.57 (m, 2H), 7.56−7.43 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H),
7.17 (s, 1H) 7.14 (d, J = 7.7 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 4.34−
4,29 (m, 4H), 2.41 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 156.1 (d, J = 256.2 Hz), 152.3 (d, J = 4.7 Hz), 147.5 (d, J =
15.0 Hz), 144.5, 143.8, 138.7, 136.7, 132.6 (d, J = 4.0 Hz), 132.4,
131.3, 130.1, 126.5, 124.1 (d, J = 21.1 Hz), 120.2, 119.5 (d, J = 3.7
Hz), 117.5, 116.0, 64.6, 64.4, 21.4, 19.94 (d, J = 2.8 Hz). 19F NMR
(282 MHz, CDCl3) δ: −126.8 (d, J = 7.3 Hz, 1F). HRMS (ESI): calcd
for C21H19FNO2 (M + H) 336.1394, found 336.1384.
6-(2,4-Dimethylphenyl)-3-fluoro-2-(naphthalen-2-yl)pyridine
(4r). Yield: 203 mg (62%). White crystals. Mp: 111−112 °C. Rf: 0.31
(hexane/EtOAc, 25/1). 1H NMR (300 MHz, CDCl3) δ: 8.65 (s, 1H),
8.31 (d, J = 8.6 Hz, 1H), 8.05−7.88 (m, 3H), 7.64−7.50 (m, 3H), 7.46
(d, J = 7.6 Hz, 1H), 7.40 (dd, J = 8.4, 3.2 Hz, 1H), 7.24−7.12 (m, 2H),
2.54 (s, 3H), 2.45 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ: 156.7
(d, J = 260.3 Hz), 155.9 (d, J = 5.0 Hz), 144.6 (d, J = 10.0 Hz), 138.3,
136.9, 136.0, 133.7, 133.3, 133.1 (d, J = 5.8 Hz), 131.8, 129.8, 129.0,
128.9, 128.0, 127.7, 126.8 (d, J = 2.5 Hz), 126.2, 126.3, 124.7, 124.4,
123.9 (d, J = 3.9 Hz), 21.7, 20.8. 19F NMR (282 MHz, CDCl3) δ:
−127.2 (s, 1F). HRMS (ESI): calcd for C23H18FNNa (M + Na)
350.1315, found 350.1318.
ORCID
Alexander D. Dilman: 0000-0001-8048-7223
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Russian Science Foundation
(Project No. 17-13-01041).
REFERENCES
■
(1) (a) Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013, 9,
2265−2319. (b) Kishbaugh, T. L. S. Curr. Top. Med. Chem. 2016, 16,
3274−3302. (c) Wu, Y.-J. In Progress in Heterocyclic Chemistry; Gribble,
G. W., Joule, J. A., Eds.; Elsevier: Amsterdam, 2012; Vol. 24, pp 1−53.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320−330. (b) Gillis, E. P.; Eastman, K. J.; Hill, M.
D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315−
8359. (c) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
̈
Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637−
̈
643. (d) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881−
̈
1886.
(3) (a) Dolbier, W. R. In Pyridines: from Lab to Production; Scriven, E.
F. V., Ed.; Academic Press: Oxford, 2013; pp 497−516. (b) Shesto-
palov, A. M.; Rodinovskaya, L. A.; Mortikov, V. Y.; Fedorov, A. E. In
Fluorine in Heterocyclic Chemistry; Nenajdenko, V., Ed.; Springer:
Cham, 2014; Vol. 2, pp 1−58.
6-(2-Bromophenyl)-3-fluoro-2-(naphthalen-2-yl)pyridine (4s).
Yield 332 mg (88%). White crystals. Mp 109−110 °C. Rf: 0.44
(hexane/EtOAc, 20/1). 1H NMR (300 MHz, CDCl3) δ: 8.58 (s, 1H),
8.25 (dt, J = 8.7, 1.7 Hz, 1H), 8.01−7.91 (m, 2H), 7.93−7.85 (m, 1H),
7.72 (dd, J = 8.0, 0.9 Hz, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.61 (s,
1H), 7.59 (d, J = 0.6 Hz, 1H), 7.57−7.48 (m, 2H), 7.44 (td, J = 7.5, 1.0
Hz, 1H), 7.30 (dd, J = 7.8, 1.6 Hz, 1H). 13C{1H} NMR (75 MHz,
CDCl3) δ: 157.1 (d, J = 261.6 Hz), 154.0 (d, J = 8.0 Hz), 145.1 (d, J =
10.8 Hz), 140.5, 133.7, 133.5, 133.3, 132.7 (d, J = 5.4 Hz), 131.7,
129.9, 129.0, 128.9, 128.1, 127.7 (d, J = 4.38 Hz), 126.9, 126.2, 126.3,
124.6 (d, J = 3.6 Hz), 124.3, 124.0, 122.0. 19F NMR (282 MHz,
CDCl3) δ: −125.7. (t, J = 6.4 Hz, t, 1F). HRMS (ESI): calcd for
C21H14BrFN (M + H) 378.0288, 380.0269, found 378.0279, 380.0262.
16-Fluoro-14-pyridin-2-yl-13-azabicyclo[10.3.1]hexadeca-1-
(16),12,14-triene (4t). Yield: 287 mg (92%) White crystals. Mp: 53−
54 °C. Rf: 0.23 (hexane/EtOAc, 8/1). 1H NMR (300 MHz, CDCl3) δ:
8.62 (d, J = 4.3 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 5.4 Hz,
1H), 7.76 (t, J = 7.7 Hz, 1H), 7.23 (s, 1H), 3.12−2.74 (m, 4H), 2.00−
1.76 (m, 4H), 1.39−1.23 (m, 4H), 1.18−1.02 (m, 4H), 0.96−0.70 (m,
4H). 13C{1H} NMR (75 MHz, CDCl3) δ: 158.0 (d, J = 253.4 Hz),
156.2, 151.2 (d, J = 5.4 Hz), 149.9 (d, J = 18.1 Hz), 149.1, 138.8 (d, J
= 15.9 Hz), 136.95, 123.3, 121. Four (d, J = 2.7 Hz), 121.2, 31.5 (d, J =
2.1 Hz), 28.6 (d, J = 1.4 Hz), 27.3, 27.2 (d, J = 1.1 Hz), 27.1, 26.8 (d, J
= 1.4 Hz), 26.6, 26.5, 26.4, 26.3. 19F NMR (282 MHz, CDCl3) δ:
−131.8 (s, 1F). HRMS (ESI): calcd for C20H25FN2Na (M + Na)
335.1894, found 335.1881.
(4) (a) Schlosser, M.; Rausis, T. Helv. Chim. Acta 2005, 88, 1240−
1249. (b) Schlosser, M.; Rausis, T.; Bobbio, C. Org. Lett. 2005, 7,
127−129. (c) Schlosser, M.; Ruzziconi, R. Synthesis 2010, 2010, 2111−
2123.
(5) (a) David, T. K.; Prashanth, N. K.; Rajendraswami, M.; Pallalu,
D.; Castelhano, A. L.; Kates, M. J.; Blobaum, A. L.; Jones, C. K.;
Emmitte, K. A.; Conn, P. J.; Lindsley, C. W. Tetrahedron Lett. 2017,
58, 3554−3558. (b) Wilsily, A.; Mennen, S. M.; Cosbie, A.; Milne, J. E.
Org. Process Res. Dev. 2017, 21, 1286−1293. (c) 3-Fluoropyridine
subunit is present in a series of fluoroquinolone antibiotics; see: Anon,
J.; Tillotson, G. Antibiotiques 2008, 10, 199−208.
(6) (a) Fukuhara, T.; Yoneda, N.; Suzuki, A. J. Fluorine Chem. 1988,
38, 435−438. (b) Dobele, M.; Vanderheiden, S.; Jung, N.; Brase, S.
̈
̈
Angew. Chem., Int. Ed. 2010, 49, 5986−5988. (c) Timperley, C. M.;
Banks, R. E.; Young, I. M.; Haszeldine, R. N. J. Fluorine Chem. 2011,
132, 541−547.
(7) (a) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860−2863.
(b) Dubbaka, S. R.; Narreddula, V. R.; Gadde, S.; Mathew, T.
Tetrahedron 2014, 70, 9676−9681. (c) Yamada, S.; Gavryushin, A.;
Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 2215−2218.
(d) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2010, 49, 2219−2222.
(8) (a) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133,
11482−11484. (b) Neumann, C. N.; Hooker, J. M.; Ritter, T. Nature
2016, 534, 369−373. (c) Schimler, S. D.; Cismesia, M. A.; Hanley, P.
S.; Froese, R. D. J.; Jansma, M. J.; Bland, D. C.; Sanford, M. S. J. Am.
Chem. Soc. 2017, 139, 1452−1455.
(9) Lee, H. G.; Milner, P. J.; Buchwald, S. L. Org. Lett. 2013, 15,
5602−5605.
(10) (a) Rotstein, B. H.; Stephenson, N. A.; Vasdev, N.; Liang, S. H.
Nat. Commun. 2014, 5, 4365. (b) Petersen, I. N.; Kristensen, J. L.;
Herth, M. M. Eur. J. Org. Chem. 2017, 2017, 453−458. (c) Chun, J.-H.;
Pike, V. W. Chem. Commun. 2012, 48, 9921−9923.
(11) (a) Allen, L. J.; Muhuhi, J. M.; Bland, D. C.; Merzel, R.; Sanford,
M. S. J. Org. Chem. 2014, 79, 5827−5833. (b) Schimler, S. D.; Ryan, S.
J.; Bland, D. C.; Anderson, J. E.; Sanford, M. S. J. Org. Chem. 2015, 80,
12137−12145. (c) Ryan, S. J.; Schimler, S. D.; Bland, D. C.; Sanford,
M. S. Org. Lett. 2015, 17, 1866−1869.
(12) (a) Pews, R. G.; Lysenko, Z. J. Org. Chem. 1985, 50, 5115−
5119. (b) Dolbier, W. R.; Xu, Y.-L. J. Fluorine Chem. 2003, 123, 71−
73. (c) Chen, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2015, 17,
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02467.
NMR spectra for all compounds, CV curves for studied
compounds, and Stern−Volmer plot for fluorescence
quenching studies (PDF)
AUTHOR INFORMATION
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Corresponding Author
*E-mail: adil25@mail.ru.
G
DOI: 10.1021/acs.joc.7b02467
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
2567−2569. (d) Chen, Z.; Zhu, J.; Xie, H.; Li, S.; Wu, Y.; Gong, Y.
Org. Biomol. Chem. 2011, 9, 5682−5691.
(24) Cazeau, P.; Duboudin, F.; Moulines, F.; Babot, O.; Dunogues, J.
Tetrahedron 1987, 43, 2075−2088.
(13) (a) Fedorov, O. V.; Kosobokov, M. D.; Levin, V. V.; Struchkova,
M. I.; Dilman, A. D. J. Org. Chem. 2015, 80, 5870−5876. For relevant
difluorohomologation reactions, see: (b) Kosobokov, M. D.; Levin, V.
V.; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2015, 17, 760−763.
(c) Fedorov, O. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem.
2016, 81, 9455−9460.
(25) Yasui, S.; Tsujimoto, M.; Shioji, K.; Ohno, A. Chem. Ber. 1997,
130, 1699−1707.
(26) Kelly, C. B.; Patel, N. R.; Primer, D. N.; Jouffroy, M.; Tellis, J.
C.; Molander, G. A. Nat. Protoc. 2017, 12, 472−492.
(27) For visible-light-mediated reactions of halogen-bonded com-
plexes, see: (a) Sun, X.; Wang, W.; Li, Y.; Ma, J.; Yu, S. Org. Lett. 2016,
18, 4638−4641. (b) Wang, Y.; Wang, J.; Li, G.-X.; He, G.; Chen, G.
Org. Lett. 2017, 19, 1442−1445.
(28) In fact, CF3CH2I can couple with silyl enol ethers under our
photoredox conditions, though the reaction is slower than that of
iodoketones 1. Thus, only 81% conversion was noted for the coupling
of CF3CH2I with enol ether 2a (19F NMR control). In the literature,
the photoredox reaction of CF3CH2I with silyl enol ethers was
described, though a combination of an iridium catalyst with Hunig’s
base was used to effect the reductive quenching of excited
photocatalyst generating a stronger reducing species; see: Huang,
M.; Li, L.; Zhao, Z.-G.; Chen, Q.-Y.; Guo, Y. Synthesis 2015, 47, 3891−
3900.
(14) For applications of α,α-difluoro-β-bromoketones (bromo
analogues of iodoketones 1) in the synthesis of heterocycles, see:
(a) Fedorov, O. V.; Struchkova, M. I.; Dilman, A. D. J. Org. Chem.
2017, 82, 3270−3275. (b) Fedorov, O. V.; Levin, V. V.; Volodin, A.
D.; Struchkova, M. I.; Korlyukov, A. A.; Dilman, A. D. Tetrahedron
Lett. 2016, 57, 3639−3642.
(15) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322−5363. (b) Shaw, M. H.; Twilton, J.; MacMillan, D.
W. C. J. Org. Chem. 2016, 81, 6898−6926. (c) Tucker, J. W.;
Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617−1622. (d) Schultz,
D. M.; Yoon, T. P. Science 2014, 343, 1239176.
(16) For reviews on the application of perfluorinated halides in
photoredox processes, see: (a) Chatterjee, T.; Iqbal, N.; You, Y.; Cho,
E. J. Acc. Chem. Res. 2016, 49, 2284−2294. (b) Koike, T.; Akita, M.
Acc. Chem. Res. 2016, 49, 1937−1945. (c) Barata-Vallejo, S.; Bonesi, S.
M.; Postigo, A. Org. Biomol. Chem. 2015, 13, 11153−11183.
(d) Dagousset, G.; Carboni, A.; Masson, G.; Magnier, E. In Modern
Synthesis Processes and Reactivity of Fluorinated Compounds; Leroux, F.
R., Tressaud, A., Eds.; Elsevier: Amsterdam, 2017; pp 389−426.
(17) For recent light-mediated reactions from our group, see:
(a) Panferova, L. I.; Tsymbal, A. V.; Levin, V. V.; Struchkova, M. I.;
Dilman, A. D. Org. Lett. 2016, 18, 996−999. (b) Panferova, L. I.;
Smirnov, V. O.; Levin, V. V.; Kokorekin, V. A.; Struchkova, M. I.;
Dilman, A. D. J. Org. Chem. 2017, 82, 745−753. (c) Panferova, L. I.;
Struchkova, M. I.; Dilman, A. D. Synthesis 2017, 49, 4124−4132.
(d) Supranovich, V. I.; Levin, V. V.; Struchkova, M. I.; Korlyukov, A.
A.; Dilman, A. D. Org. Lett. 2017, 19, 3215−3218. (e) Chernov, G. N.;
Levin, V. V.; Kokorekin, V. A.; Struchkova, M. I.; Dilman, A. D. Adv.
Synth. Catal. 2017, 359, 3063−3067.
(18) Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C. Angew. Chem.,
Int. Ed. 2011, 50, 6119−6122.
(19) For nonphotoredox fluoroalkylation of silyl enol ethers, see:
(a) Ge, W.-Z.; Wu, Y.-M.; Huang, W.-Y. Chin. J. Chem. 1991, 9, 527−
535. (b) Sato, K.; Higashinagata, M.; Yuki, T.; Tarui, A.; Omote, M.;
Kumadaki, I.; Ando, A. J. Fluorine Chem. 2008, 129, 51−55. (c) Sato,
K.; Yamazoe, S.; Akashi, Y.; Hamano, T.; Miyamoto, A.; Sugiyama, S.;
Tarui, A.; Omote, M.; Kumadaki, I.; Ando, A. J. Fluorine Chem. 2010,
131, 86−90. (d) Miura, K.; Takeyama, Y.; Oshima, K.; Utimoto, K.
Bull. Chem. Soc. Jpn. 1991, 64, 1542−1553. (e) Katayev, D.; Vaclavik,
J.; Bruning, F.; Commare, B.; Togni, A. Chem. Commun. 2016, 52,
4049−4052.
(20) Photoredox reactions of CF3CH2I have been reported.
Mechanistically, these processes may involve prior reductive
quenching of the photocatalyst by base, thereby leading to a stronger
reducing species; see: (a) Li, L.; Huang, M.; Liu, C.; Xiao, J.-C.; Chen,
Q.-Y.; Guo, Y.; Zhao, Z.-G. Org. Lett. 2015, 17, 4714−4717. (b) Roh,
G.; Iqbal, N.; Cho, E. J. Chin. J. Chem. 2016, 34, 459−464. (c) Zhu,
M.; Han, X.; Fu, W.; Wang, Z.; Ji, B.; Hao, X.-Q.; Song, M.-P.; Xu, C. J.
Org. Chem. 2016, 81, 7282−7287.
(21) For the interaction of silylating agents with epoxides, see:
Kricheldorf, H. R.; Morber, G.; Regel, W. Synthesis 1981, 1981, 383−
̈
384.
(22) Enol acetates were notably less reactive compared to silyl enol
ethers. For example, photoredox reaction isopropenyl acetate with
iodoketone 1a under the optimized conditions gave only 45%
conversion according to 19F NMR control.
(23) Monitoring of the reaction progress by 19F NMR and GC−MS
suggests that consumption of starting diketone proceeds faster
compared to the formation of the final pyridine product. This
means that the elimination of water or hydrogen fluorinde is the rate
limiting step.
H
DOI: 10.1021/acs.joc.7b02467
J. Org. Chem. XXXX, XXX, XXX−XXX