Synthesis of 2-Arylpyridines and 2-Arylbipyridines via Photoredox-Induced Meerwein Arylation with in Situ Diazotization of Anilines

Article abstract of DOI:10.1021/acs.joc.9b03306

We report herein a sustainable method for the preparation of 2-arylpyridines through C-H arylation of pyridines using in situ formed diazonium salts (from commercially available aromatic amines) in the presence of a photoredox catalyst under blue light-emitting diode (LED) irradiation. The reaction is tolerant to a wide range of functional groups (e.g., halogen, nitrile, formyl, acetyl, ester). Applications to the C-H bond arylation of bipyridine ligands is also presented.

Full text of DOI:10.1021/acs.joc.9b03306

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Article
Synthesis of 2-Arylpyridines and 2-Arylbipyridines via Photoredox-
Induced Meerwein Arylation with in-situ Diazotization of Anilines
Wided Hagui, and Jean-François Soulé
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03306 • Publication Date (Web): 10 Feb 2020
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Synthesis of 2-Arylpyridines and 2-Arylbipyridines via Photoredox-Induced Meerwein
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Arylation with in-situ Diazotization of Anilines
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Wided Hagui and Jean-François Soulé*
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Univ Rennes, CNRS UMR6226, F-3500 Rennes, France jean-francois.soule@univ-rennes1.fr
Abstract: We report herein a sustainable method for the preparation of 2-arylpyridines through
C−H arylation of pyridines using in-situ formed diazonium salts (from commercially available
aromatic amines) in the presence of a photoredox catalyst under blue LEDs irradiation. The
reaction is tolerant to a wide range of functional groups (e.g., halogen, nitrile, formyl, acetyl,
ester). Applications to the C–H bond arylation of bipyridine ligands is also presented.
Introduction
The 2-arylpyridine derivatives are one of the essential scaffolds for the preparation of
organometallic complexes with catalytic or material uses (Figure1). For example, fac-Ir(ppy)3
with three 2-phenylpyridine is often employed as photoredox catalyst.1 FIrPic with two 2-(2,4-
difluorophenyl)pyridine is an highly phosphorescent bis-cyclometalated iridium complexes
employed in OLEDs’ manufacture.2 Moreover, 2-arylpyridine is a common unit widely
embedded in pharmaceutical drugs. For example, Enpiroline is an antimalarial agent.
F
CF3
N
Ir
N
N
O
N
F
F
Ir
N
N
O
N
H
N
OH
F3C
F
fac-Ir(ppy)3
Enpiroline
FIrPic
Figure 1. Representative 2-Arylpyridine in Organometallics and Pharmaceuticals.
Traditionally, 2-arylpyridines were synthesized from 2-halopyridines through cross-coupling
reactions with aryl pseudo-halides as coupling partners in the presence of palladium catalysts3
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or from metalated pyridines and aryl pseudo-halides.4 Among these protocols, the use of 2-
(tributylstannyl)pyridine remains the most employed starting materials, albeit it is a hazardous
and harmful reagent (Figure 2a). More sustainable approaches based on transition-metal
catalyzed C–H bond arylation of pyridines were often carried out under harsh reaction
conditions and displayed a poor substrate scope,5 or required the prior oxidation of pyridines to
N-oxide pyridines.6 Recently, photoredox catalysis has emerged as an eco-friendly alternative
to build C–C bond from C(sp2)–H bond under mild reaction conditions.7 In 2014, Xue and co-
workers reported the photoredox-catalyzed C–H bond arylation of pyridine derivatives at C2
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2+
or/and C4 positions with aryldiazonium salts using Ru(bpy)3 (Figure 2b).8 This Merwein-
type arylation of pyridines was also developed using different photosensitizers.9 In 2017,
Heinrich and co-workers demonstrated that the arylation of heteroarenes with aryldiazonium
salts could also proceed in the absence of an external photosensitizer.10 The reaction involves
the formation of charge-transfer complexes11 between the electron-poor aryl diazonium salts
with electron-rich (hetero)aromatics. In the case of pyridine, only 3-hydroxypyridine has been
arylated owing to its specific electronic nature, which allows the formation of charge-transfer
complexes with aryl diazonium and is a good aryl radical acceptor. Besides the regioselectivity
issue due to the low control of the radical additions, an additional challenge is the handling of
the potentially unstable aryldiazonium precursors. In 2014, to avoid the use of such hazardous
chemicals and employed commercially available chemicals, Martín, Carrillo, and co-workers
have developed C–H bond arylation of (hetero) arenes using in-situ diazotization from anilines
with tert-butyl that is promoted by catalytic amounts of L-ascorbic acid, with no heating or
irradiation.12 However, these protocols were limited to the direct arylation of 5-membered ring
heteroarenes, electron-rich arenes and N-oxide pyridines (Figure 2c). The reaction can be also
promoted by a mild base (Na2CO3),13 or polyamine.14 Later, Horan’s group showed that the
reaction can also proceed at 40 ºC in the absence of L-ascorbic acid.15 In 2015, Frutos, Kappe,
and co-workers also demonstrated that the C–H bond arylation of (hetero) arenes using in-situ
diazotization from anilines with tert-butyl could proceeded at room temperate under visible-
light irradiation.16 Again, the scope of the reaction is limited to heteroarenes, electron-rich
arenes and N-oxide pyridines.
To the best of our knowledge, there is no example of (photoredox-initiated) C–H bond arylation
pyridines using anilines trough the in-situ generation of diazonium slats, albeit it might provide
practical and sustainable access to 2-arylpyridine derivatives in one-step from commercially
available starting materials (Figure 2b). In addition, there is no example of direct arylation of
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bipyridines (even using aryldiazonium salts) although they are useful precursors for the
preparation of CNN-cyclometalated complexes.
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Figure 2. Synthesis of 2-Arylpyridines
Results & Discussion
Firstly, we selected 4-cyanopyridine and 4-aminobenzonitrile as model substrates. During the
reaction development, we determined that Meerwein-type arylation reaction of pyridine ring
was efficient in CH3CN containing 2 mol% [Ru(bpy)3[PF6]2 and 1.2 equivalent of tert-butyl
nitrite (tBuONO) and 6.5 equivalents of CF3CO2H (1.6 equivalents by pyridine) under blue
LEDs irradiation, affording the C2-arylated pyridine 1 in 72% isolated yield after 3 h (Table 1,
entry 1). Other metal-based photoredox catalyst, such as fac-Ir(ppy)3 or (Ir[ppy]2(dtbbpy))PF6,
gave lower yield in 1, while a similar yield was observed with (Ir[dF(CF3)ppy]2(dtbpy))PF6.
The use of eosin Y as organic dye afforded 1 in only 21% yield (Table 1, entries 2-5). Moreover,
the arylated pyridine 1 is obtained in a low yield without photoredox catalyst (Table 1, entry
6). The presence of acid is required to obtain a good yield (Table 1, entries 7 and 8). As
explained by Opatz and co-workers, DFT-calculation shows that the use of acid allows the
protonation of the pyridine lowering the energy of its LUMO and facilitating the radical
addition.17 A slightly larger amount of acid compared to pyridine is required owing that acid
is also essential for the generation of the aryldiazonium salts from aniline and tBuONO. The
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reaction can be performed in DMSO or water solvents, albeit in slightly lower yields (Table 1,
entries 9 and 10). Control experiments showed that blue LEDs are mandatory, as 1 was not
obtained when the reaction is carried out using white light or in the dark (Table 1, entries 11
and 12). As expected, no reaction occurred when the reaction is set up without tBuONO (Table
1, entry 13). Usually, a fan is used to keep the temperature at 30- 35 ºC. Without a fan, the
temperature reached 65 ºC due to the heat released from the LEDs; but this higher temperate
has no effect on the production of 1 (Table1, entry 14). A shorter reaction time (1h) gave a
partial conversation, while longer reaction time (12 h) did not affect the chemical yield (Table
1, entries 15 and 16). The conditions reported by Carrillo’s group for the C–H bond arylation
of heteroarenes and N-oxide pyridines with L-ascorbic acid as catalyst in absence of light was
inefficient with 4-cyanopyridine (Table 1, entry 17).15
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Table 1. Reaction Development and Control Experiments
CN
NH2
[Ru(bpy)3][PF6]2
(2 mol%)
CN
+
tBuONO (1.2 equiv.)
CF3CO2H (6.5 equiv.)
CH3CN, Ar, rt, 3 h
Blue LEDs
N
N
CN
(1 equiv.)
CN
(4 equiv.)
1
Entry
1
Variation from above conditions
–
Yield in 1 (%)[a]
81 (72%)
2
fac-Ir(ppy)3 as catalyst
(Ir[ppy]2(dtbbpy))PF6 as catalyst
(Ir[dF(CF3)ppy]2(dtbpy))PF6 as catalyst
Eosin Y as catalyst
65
58
80
21
15
45
15
76
67
0
3
4
5
6
without photoredox catalyst
CF3CO2H (4 equiv.)
7
8
Without CF3CO2H
9
Using DMSO instead of CH3CN
Using water instead of CH3CN
Using white light
10
11
12
13
In the dark
0
Without tBuONO
0
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At 65 ºC
1 h
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12 h
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L-ascorbic acid (10 mol%), without light
[a] The yield was determined by GC-analysis using n-dodecane as internal standard, the isolated
yield is shown in parentheses.
With the optimized conditions in hands, we turned our attention to the scope of the reaction
with the respect of pyridine (Scheme 1). Firstly, we investigated a set of 4-substituted pyridines
to avoid the formation of other regioisomers.8 4-Methylpyridine, an electron-rich pyridine,
exhibited a slightly lower reactivity with 4-aminobenzonitrile, affording the 2-arylated pyridine
2 in 64% yield. Nicotinaldehyde was arylated at C2 position with 4-chloroanaline to give 3 in
78% without deformylation. Interestingly, the reaction was tolerant to C–Br bond on the
pyridine unit, as the coupling reaction between 4-bromopyridine and 4-chloroaniline afforded
the C2-arylated pyridine 4 in 76% yield without the cleavage of both C–Br and C–Cl bonds
providing the possibility for further diversification via Pd-catalyzed selective cross-coupling
reactions. 4-(Trifluoromethyl)pyridine and 4-acetylpyridine were also arylated at C2-position
using in-situ diazotization of p-anisidine or 4-chloroaniline in 73% and 82% yield, respectively.
Disubstituted pyridines can also be employed. From 2,4-lutidine, the C6-arylated pyridine 7
was isolated in 56% yield as a single regioisomer. In contrast, when the reaction is carried out
with 2,4-dichloropyridine, a mixture of C6 and C3 arylated pyridines 8a and 8b, which can be
isolated separately, are obtained in 14% and 52% yield, respectively. The formation of 8b as
the major product might be attributed to the high electrophilic character of the carbon atom
flanked by the two chlorine atoms. The arylation of 2,6-lutidine took place at C4 position
affording 9 in 82% yield. Reaction with unsubstituted pyridine provided a mixture of C2 and
C4 arylated products 10a and 10b with are isolated in 39% and 12% yield, respectively; but
both isomers can be isolated separately by column chromatography. From 2-bromopyridine,
C6 and C4 regioisomers 11a and 11b were isolated separately in 36% and 32% yield,
respectively. We then carried out the reaction with 3-bromopyridine and we isolated the C2,
C4 and C6 regioisomers 12a, 12b, 12c in 35%, 22% and 15% yield, respectively. The
regioselectivities observed are similar to those observed with aryldiazonium salts,8-9 and more
generally with those observed for radical addition to pyridines.18 The LUMO coefficients at C-
2 and C-4 of pyridine derivatives are often very similar, which explained the formation of the
mixtures of regioisomers if at least one position is not blocked.17
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Scheme 1. Scope of Pyridine in C–H Bond Arylation with in-situ Diazotization of Anilines
under Photoredox Catalysis
Next, we moved to the scope of anilines for the C2-arylation of 4-acetylpyridine under
photoredox conditions (Scheme 2). From, 4-bromoaniline, the reaction was chemoselective
and occurred only via diazonium coupling affording the C2-arylated pyridine 13 in 84% yield,
while the C–Br bond remains untouched. para-substituted anilines by an electron-withdrawing
group (e.g., ester, acetyl, trifluoromethyl) smoothly underwent in-situ diazotization–
photoredox-triggered radical arylation to afford the C2-arylated pyridines 14-16 in 63-78%
yields. Electron-rich p-anisidine was efficiently coupled to give 17 in 70% yield. Meta-
substituted anilines such as 3,5-difluoroanilne, 3,5-bis(trifluoromethyl)aniline, and 3-fluoro-5-
(trifluoromethyl)aniline were successfully employed to prepare the corresponding C2-arylated
pyridines 18-20 in 45-56% yield. The reaction is more sensitive to the presence of an ortho-
substituent, as the coupling between 4-acetylpyridine and 2-fluoroaniline led to the formation
of 21 in only 34% yield.
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O
Me
NH2
O
Me
[Ru(bpy)3][PF6]2
(2 mol%)
+
tBuONO (1.2 equiv.)
CF3CO2H (6.5 equiv.)
CH3CN, Ar, rt, 3 h
N
R
R
N
(4 equiv.)
Me
(1 equiv.)
Blue LEDs
O
Me
O
Me
O
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N
N
N
Me
CO2Et
Br
15 71%
O
13 84%
Me
14 78%
Me
O
Me
O
O
F
N
N
N
CF3
OMe
F
18 56%
17 70%
16 63%
Me
O
O
Me
O
Me
F
CF3
CF3
N
N
N
CF3
F
19 52%
20 45%
21 34%
Scheme 2. Scope of Anilines in C–H Bond Arylation of Pyridine with in-situ Diazotization of
Anilines under Photoredox Catalysis
2-Arylbipyrines (precursor of CNN ligands) are generally prepared using a two-steps procedure
with aryl lithium reagents under cryogenic conditions,19 via transition metal-catalyzed C–H
bond functionalization using organometallic reagents (e.g., diaryl zinc or aryl boronic acids),20
or by C–H bond borylation of bipyridine followed by Suzuki reaction.21 To the best of our
knowledge, no example of Meerwein-type arylation reaction of bipyridines is reported, yet.
Although it will be a sustainable synthetic pathway to a wide variety of CNN pro-ligands,
including some bearing a sensitive functional group toward organometallic reagents. Therefore,
we also investigated the reactivity of 4,4'-di-tert-butyl-2,2'-bipyridine (Scheme 3). The
coupling reaction between 4,4'-di-tert-butyl-2,2'-bipyridine (4 equiv.) and of 4-chloroaniline (1
equiv.) –in a mixture of CH3CN/TFA (8:1) solvent containing 2 mol% [Ru(bpy)3[PF6]2 and 1.2
equivalents of tBuONO under blue LEDs irradiation– afforded 22 in 24% yield. The use of 1
mol% (Ir[dF(CF3)ppy]2(dtbpy))PF6, which displayed a lower redox potential [Ir(III)/Ir(II) = -
1.37 V vs Ru(II)/Ru(I) = -1.33 V] allowed the formation of 22 in 61% yield. From 4-
bromopyridine and 4,4'-di-tert-butyl-2,2'-bipyridine the functionalized CNN pro-ligand 23 is
obtained in 58%. Notably, this bipyridine could not be obtained using previous protocols due
to the lithiation reaction. 3-Fluoro-5-(trifluoromethyl)aniline was efficiently coupled to give
the 2-arylbipyridine 24 in 45% yield. 4,4'-Dimethyl-2,2'-bipyridine was also arylated at C2
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position using in-situ diazotization of 4-bromoaniline leading to the formation of 25 in 48%
5
6
yield.
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8
R1
R1
9
R1
R1
N
N
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(Ir[dF(CF3)ppy]2(dtbpy))PF6
(4 equiv.)
+
(1 mol%)
N
N
tBuONO (1.2 equiv.)
CF3CO2H (6.5 equiv.)
CH3CN, Ar, rt, 12 h
Blue LEDs
H2N
R2
(1 equiv.)
R2
tBu
tBu
tBu
tBu tBu
tBu
N
N
N
N
N
N
F
24 45%
F3C
23 58%
22 61%
(24%)[a]
Cl
Br
Me
Me
[a] using 2 mol%
[Ru(bpy)3][PF6]2
N
N
25 48%
Br
Scheme 3. Application de the Late-Stage Modification of Bipyridine Ligands
To have a better understanding of the mechanism, a radical control experiment was carried out
in the presence of a radical scavenger (Figure 3a). When two equivalents of 2,2,6,6-
tetramethylpiperidine1-oxyl (TEMPO) was added to the reaction mixture under the standard
conditions, no desired product 1 was detected. However, we have observed the formation of
the 4-benzonitrile–TEMPO adduct 26 (determined by GC−MS), which arises from radical
deamination of the aniline through the in-situ formation of diazonium salts.22 Also, we
conducted two competitive reactions to probe the substituent preference for such couplings
(Figure 3b). From an equimolar ratio of 4-cyanopyridine (4 equiv.) and 4-methylpyridine (4
equiv.) in the presence of 4-aminobenzonitrile (1 equiv.), we observed the formation of a
mixture of 1 and 2 in a 77:23 ratio suggesting that an electron-withdrawing substituent on the
pyridine ring favor the reaction. This result is in line with the aryl radical addition onto the
pyridine ring. From an equimolar ratio of p-anisidine (1 equiv.) and ethyl 4-aminobenzoate (1
equiv.) in the presence of 1 equivalent of tBuONO and 4-acetylpyridine (4 equiv.), we observed
the formation of a mixture of 14 and 17 in a 9:91 ratio suggesting that electron-rich anilines
react faster with tBuONO. Moreover, KIE value of 1.1 was determined from parallel
completion reactions, suggesting that the C–H bond cleavage event is not involved in a rate-
determining step (RDS) (Figure 3c).23
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a) Radical Scavenger Experiment
O•
N
5
6
7
8
(2 equiv.)
N
CN
NH2
O
[Ru(bpy)3][PF6]2
(2 mol%)
1
+
+
tBuONO (1.2 equiv.)
CF3CO2H (6.5 equiv.)
CH3CN, Ar, rt, 3 h
Blue LEDs
traces
N
9
CN
(1 equiv.)
CN
(4 equiv.)
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26 (detected
byGC-MS)
b) Competitive Parallel Experiments
R
N
NH2
CN
Me
[Ru(bpy)3][PF6]2
(2 mol%)
+
+
tBuONO (1.2 equiv.)
CF3CO2H (6.5 equiv.)
CH3CN, Ar, rt, 3 h
Blue LEDs
N
N
CN
CN
conv = 100%[a]
(4 equiv.) (4 equiv.) (1 equiv.)
1 / 2 = 77 : 23[a]
O
O
NH2
NH2
[Ru(bpy)3][PF6]2
(2 mol%)
+
+
N
tBuONO (1.2 equiv.)
CF3CO2H (6.5 equiv.)
CH3CN, Ar, rt, 3 h
Blue LEDs
N
OMe
CO2Et
R
conv = 100%[a]
(4 equiv.) (1 equiv.) (1 equiv.)
14 / 17 = 9 : 91[a]
c) Kinetic Isotope Effect (KIE) Experiment
NH2
[Ru(bpy)3][PF6]2
D
(2 mol%)
D
D
D
D
or
+
10a+10b
tBuONO (1.2 equiv.)
N
N
CF3CO2H (6.5 equiv.) KIE = 1.1
CH3CN, Ar, rt, 3 h
OMe
(1 equiv.)
(4 equiv.)
(4 equiv.)
Blue LEDs
[a] Determined by GC-MS analysis using n-dodecane as internal standard
Figure 3. Mechanistic Investigation
Based on the above experimental results and literature on photoredox-catalyzed C–H bond
arylations,8, 24 a plausible mechanism is illustrated in Figure 4. Firstly, under acidic conditions
aniline derivatives reacted with tBuONO to generate aryl diazonium salts. Upon the generation
of excited state catalyst *PC from ground state of [Ru(bpy)3[]PF6]2 or
(Ir[dF(CF3)ppy]2(dtbpy))PF6 by blue LEDs irradiation, a single electron transfer (SET) occurs
from *[PC] to the aryl diazonium salts leading to the formation of a free aryl radical (Ar) –
after the extrusion of dinitrogen– among with the oxidized catalyst [PC+]. Then, the aryl radical
adds to the protonated pyridine at C2 or/and C4 position(s) –depending on its substitution
patterns– yielding the pyridine radical-cation intermediate (A). Then, A is subsequently
transformed into a carbocation intermediate B via a SET from [Ir2+] with the loss of a proton.
Finally, the rearomatization gives the desired arylated pyridine.
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Figure 4. Proposed Mechanism
Conclusion
In summary, a highly effective visible light-promoted C–H bond arylation of pyridines has been
developed. The reaction proceeds at room temperature with [Ru(bpy)3[]PF6]2 as a
photosensitizer with commercially available anilines as safe aryl radical precursors via in-situ
diazotization using tert-butyl nitrite. A wide variety of substituted pyridines and anilines have
been efficiently coupled under these reaction conditions affording only the monoarylated
products with different regioselectivities. Moreover, bipyridines have been arylated at the C2
position using or (Ir[dF(CF3)ppy]2(dtbpy))PF6 as a photosensitizer. This procedure is a practical
and sustainable method for the synthesis of nitrogen ligands useful for the preparation of novel
organometallics.
Experimental Section
General Remarks: All reactions were run in Schlenk tubes under argon atmosphere.
Commercial pyridines and anilines were used after purification according the literature
(distillation or recrystallisation). The reactions were followed by GC and NMR. 1H and 13C
spectra were recorded with a Bruker 400 MHz spectrometer in CDCl3 solutions. Chemical shifts
are reported in ppm relative to CDCl3 (7.26 for 1H NMR and 77.0 for 13C NMR). Flash
chromatography was performed on silica gel (230–400 mesh). GC-MS analyses were
performed with a GCMS-QP2010S (Shimadzu) instrument with a GC-2010 equipped with a 30
m capillary column (Supelco, SLBTM- 5ms, fused silica capillary column, 30 m x 0.25 mm x
0.25 mm film thickness), which was used with helium as the vector gas. The following GC
conditions were used: initial temperature 80 ºC for 5 minutes, then rate 20 ºC/min until 280 ºC
and 280 ºC for 28 minutes. HRMS were recorded on a Waters Q-Tof 2 mass spectrometer at
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the corresponding facilities of the CRMPO, Centre Régional de Mesures Physiques de l’Ouest,
Université de Rennes 1.
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General Procedure for C–H bond arylation of pyrdines: To a 15 mL oven dried Schlenk
tube, [Ru(bpy)3][PF6]2 (10.3 mg, 0.012 mmol, 2 mol%) or (Ir[dF(CF3)ppy]2(dtbpy))PF6 (6.6
mg, 0.006 mmol, 1 mol%), pyridine (2.4 mmol, 4 equiv.), aniline (0.6 mmol, 1 equiv), CH3CN
(1.2 mL), TFA (0.3 mL) were successfully added under an argon atmosphere. Then, tBuONO
(88 μL, 0.62 mmol, 1.2 equiv.) was slowly added. The Schlenk was positioned on a stir plate
approximately 2 – 3 cm from two ABI PAR38 (24W) LED lamp supplying blue light (λ = 440-
460 nm). Fans were used for cooling. After irradiation for 3 hours, the reaction mixture was
poured in a saturated aqueous solution of K2CO3 (10 mL), and extracted several times with
AcOEt (4x 15 mL). The solvent was removed under reduced pressure, and the residue was
purified by flash chromatography (petroleum ether/ethyl acetate) to afford the desired product.
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2-(4-Cyanophenyl)isonicotinonitrile (1): Following the general procedure using
isonicotinonitrile (250 mg, 2.4 mmol) and 4-aminobenzonitrile (70 mg, 0.6 mmol), the residue
was purified by flash chromatography on silica gel (heptane-EtOAc, 90-10) to afford the
desired compound 1 (89 mg, 72%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d,
J = 5.0 Hz, 1H), 8.61 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.3 Hz, 2H), 7.91 (d, J =
5.0, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 155.6, 151.4, 141.5, 133.3, 128.0, 125.7,
123.6, 121.3, 119.0, 117.2, 112.9. HRMS (ESI) Calcd for: C13H8N3: 206.0713; Found:
206.0712 [M+H]+.
4-(4-Methylpyridin-2-yl)benzonitrile (2): Following the general procedure using 4-
methylpyridine (233 μL, 2.4 mmol) and 4-aminobenzonitrile (70 mg, 0.6 mmol), the residue
was purified by flash chromatography on silica gel (heptane-EtOAc, 95-5) to afford the desired
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compound 2 (75 mg, 64%) as a white solid. H NMR (300 MHz, CDCl3) δ 8.59 (d, J = 5.0 Hz,
1H), 8.12 (d, J = 7.8 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 7.60 (s, 1H), 7.15 (d, J = 4.8 Hz, 1H),
2.46 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 154.8, 149.7, 148.0, 143.7, 132.6, 127.3,
124.2, 121.7, 118.8, 111.9, 21.2. The NMR data are identical to those reported in the literature.25
2-(4-Chlorophenyl)isonicotinaldehyde (3): Following the general procedure using
isonicotinaldehyde (210 μL, 2.4 mmol) and 4-chloroaniline (76 mg, 0.6 mmol), the residue was
purified by flash chromatography on silica gel (heptane-EtOAc, 95-5) to afford the desired
compound 3 (101 mg, 78%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 8.96
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(d, J = 4.9 Hz, 1H), 8.12 (s, 1H), 8.04 (d, J = 7.8 Hz, 2H), 7.67 (d, J = 4.9, 1H), 7.50 (d, J = 7.9
Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 191.4, 157.8, 151.1, 142.5, 136.6, 135.9, 129.1,
128.2, 120.9, 118.4. HRMS (ESI) Calcd for: C12H9NO35Cl: 218.0367; Found: 218.0367
[M+H]+.
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4-bromo-2-(4-chlorophenyl)pyridine (4): Following the general procedure using 4-
bromopyridine (466 mg, 2.4 mmol) and 4-chloroaniline (76 mg, 0.6 mmol), the residue was
purified by flash chromatography on silica gel (heptane-EtOAc, 99-1) to afford the desired
compound 4 (122 mg, 76%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 5.2
Hz, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.89 (s, 1H), 7.47 (d, J = 8.4, 2H), 7.43 (d, J = 6.6 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 157.6, 150.4, 136.4, 135.8, 133.6, 129.0, 128.2, 125.5,
123.6. HRMS (ESI) Calcd for: C11H8N35Cl79Br: 267.9523; Found: 267.9526 [M+H]+.
2-(4-methoxyphenyl)-4-(trifluoromethyl)pyridine (5): Following the general procedure
using 4-(trifluoromethyl)pyridine (257 μL, 2.4 mmol) and 4-methoxyaniline (74 mg, 0.6 mmol),
the residue was purified by flash chromatography on silica gel (heptane-EtOAc, 96-4) to afford
1
the desired compound 5 (113 mg, 73%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.83
(d, J = 5.0 Hz, 1H), 8.02 (d, J = 8.9 Hz, 2H), 7.88 (s, 1H), 7.40 (d, J = 5.7 Hz, 1H), 7.04 (d, J
= 8.9 Hz, 2H), 3.90 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.1, 158.3, 150.4, 139.0
(q, J = 33.7 Hz), 130.6, 128.3, 123.0 (q, J = 273.2 Hz), 116.7 (q, J = 3.4 Hz), 115.1 (q, J = 3.6
Hz), 114.3, 55.3. The NMR data are identical to those reported in the literature.8
1-(2-(4-chlorophenyl)pyridin-4-yl)ethan-1-one (6): Following the general procedure using 4-
acetylpyridine (264 μL, 2.4 mmol) and 4-chloroaniline (76 mg, 0.6 mmol), the residue was
purified by flash chromatography on silica gel (heptane-EtOAc, 95-5) to afford the desired
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compound 6 (114 mg, 86%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 5.0
Hz, 1H), 8.13 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 6.4 Hz, 1H), 7.46 (d, J = 8.6 Hz,
2H), 2.68 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.2, 157.5, 150.8, 143.8, 136.9,
135.7, 129.0, 128.2, 120.0, 117.6, 26.7. The NMR data are identical to those reported in the
literature.26
2-(4-Methoxyphenyl)-4,6-dimethylpyridine (7): Following the general procedure using 2,4-
lutidine (277 μL, 2.4 mmol) and 4-methoxyaniline (74 mg, 0.6 mmol), the residue was purified
by flash chromatography on silica gel (heptane-EtOAc, 95-5) to afford the desired compound
7 (73 mg, 56%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 8.6 Hz, 1H), 7.30
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(s, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.90 (s, 1H), 3.87 (s, 3H), 2.58 (s, 3H), 2.37 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 160.1, 157.9, 156.5, 147.6, 132.5, 128.2, 121.9, 117.9, 113.9, 55.3,
24.5, 21.0. The NMR data are identical to those reported in the literature8
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2,4-dichloro-6-(4-methoxyphenyl)pyridine
(8a)
and
2,4-dichloro-3-(4-
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methoxyphenyl)pyridine (8b): Following the general procedure using 2,4-dichloropyridine
(354 mg, 2.4 mmol) and 4-methoxyaniline (74 mg, 0.6 mmol), the residue was purified by flash
chromatography on silica gel (heptane-EtOAc, 98-2) to afford the desired compounds 8a (22
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mg, 14%) as a white solid and 8b (81 mg, 52%) as a white solid. 8a H NMR (400 MHz,
CDCl3) δ 8.34 (s, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 3.89 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 160.0, 150.6, 150.1, 144.1, 135.1, 130.7, 126.5, 124.7,
114.0, 55.4. 8b 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 5.3 Hz, 1H), 7.40 (d, J = 5.3 Hz,
1H), 7.24 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 3.89 (s, 3H). 13C{1H} NMR (75 MHz,
CDCl3) δ 159.8, 152.3, 148.1, 145.7, 135.7, 130.6, 126.9, 123.8, 113.9, 55.2. HRMS (ESI)
Calcd for: C12H9NO35Cl2Na: 275.9953; Found: 275.9953 [M+Na]+.
4-(4-Methoxyphenyl)-2,6-dimethylpyridine (9): Following the general procedure using 2,6-
lutidine (277 μL, 2.4 mmol) and 4-methoxyaniline (74 mg, 0.6 mmol), the residue was purified
by flash chromatography on silica gel (heptane-EtOAc, 80-20) to afford the desired compound
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9 (105 mg, 82%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.8 Hz, 2H),
7.17 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 2.59 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 160.3, 158.0, 148.5, 130.9, 128.1, 117.8, 114.3, 55.3, 24.5. HRMS (ESI) Calcd for:
C14H16NO: 214.1226; Found: 214.1226 [M+H]+.
2-(4-methoxyphenyl)pyridine (10a) and 4-(4-methoxyphenyl)pyridine (10b): Following
the general procedure using pyridine (193 μL, 2.4 mmol) and 4-methoxyaniline (74 mg, 0.6
mmol), the residue was purified by flash chromatography on silica gel (heptane-EtOAc, 70-30)
to afford the desired compounds 10a (43 mg, 39%) as a white solid and 8b (13 mg, 12%) as a
white solid. 10a 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.7 Hz, 1H), 7.98 (d, J = 8.9 Hz,
2H), 7.76–7.66 (m, 2H), 7.20 (m, 1H), 7.02 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H). 10b 1H NMR (400
MHz, CDCl3) δ 8.64 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 6.0 Hz, 1H),
7.04 (d, J = 8.8 Hz, 1H), 3.90 (s, 1H). The NMR data are identical to those reported in the
literature.8
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2-Bromo-6-(4-chlorophenyl)pyridine (11a) and 2-bromo-4-(4-chlorophenyl)pyridine
(11b): Following the general procedure using 2-bromopyridine (229 μL, 2.4 mmol) and 4-
chloroaniline (76 mg, 0.6 mmol), the residue was purified by flash chromatography on silica
gel (heptane-EtOAc, 70-30) to afford the desired compounds11a (58 mg, 36%) as a white solid
and 11b (51 mg, 32%) as a white solid. 11a 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.5 Hz,
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2H), 7.68 (d, J = 7.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.48 – 7.42 (m, 3H). C NMR (400
MHz, CDCl3) δ 157.3, 142.2, 139.1, 136.0, 135.9, 129.0, 128.2, 126.6, 118.8. The NMR data
are identical to those reported in the literature.27 11b 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J
= 5.1 Hz, 1H), 7.70 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 5.1
Hz, 1H). 13C NMR (400 MHz, CDCl3) δ 150.5, 150.0, 143.1, 136.1, 135.1, 129.5, 128.3, 125.7,
120.6. The NMR data are identical to those reported in the literature.28
3-Bromo-2-(4-chlorophenyl)pyridine (12a), 3-bromo-4-(4-chlorophenyl)pyridine and 5-
bromo-2-(4-chlorophenyl)pyridine (12c): Following the general procedure using 3-
bromopyridine (231 μL, 2.4 mmol) and 4-chloroaniline (76 mg, 0.6 mmol), the residue was
purified by flash chromatography on silica gel (heptane-EtOAc, 70-30) to afford the desired
compounds 12a (56 mg, 35%) as a white solid, 12b (35 mg, 22%) as a white solid and 12c (26
mg, 16%) as a white solid. 12a 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 2.4 Hz, 1H), 7.93 (d,
J = 8.6 Hz, 2H), 7.89 (dd, J = 2.4, 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.4 Hz,
2H). 13C NMR (400 MHz, CDCl3) δ 154.6, 150.8, 139.4, 136.6, 135.5, 129.1, 128.0, 121.4,
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119.6. The NMR data are identical to those reported in the literature.29 12b H NMR (400
MHz, CDCl3) δ 8.89 – 8.80 (m, 1H), 8.62 – 8.53 (m, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.40 (d, J =
8.4 Hz, 2H), 7.31 – 7.24 (m, 1H). 13C NMR (400 MHz, CDCl3) δ 152.6, 148.5, 148.4, 136.5,
135.1, 130.8, 130.2, 128.7, 128.2, 125.4. HRMS (ESI) Calcd for: C11H8N35Cl79Br: 267.9524;
Found: 267.9526 [M+H]+. 12c 1H NMR (400 MHz, CDCl3) δ 8.64 (dd, J = 1.5, 4.7 Hz, 1H),
8.01 (dd, J = 1.5, 8.1 Hz, 1H), 7.72 – 7.61 (m, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.17 (dd, J = 4.6,
13
8.1 Hz, 1H). C NMR (400 MHz, CDCl3) δ 157.0, 148.2, 141.4, 137.9, 134.9, 130.8, 128.2,
127.0, 123.5, 119.7. HRMS (ESI) Calcd for: C11H8N35Cl79Br: 267.9526; Found: 267.9526
[M+H]+.
1-(2-(4-Bromophenyl)pyridin-4-yl)ethan-1-one (13): Following the general procedure using
4-acetylpyridine (264 μL, 2.4 mmol) and 4-bromoaniline (103 mg, 0.6 mmol), the residue was
purified by flash chromatography on silica gel (heptane-EtOAc, 95-5) to afford the desired
1
compound 13 (139 mg, 84%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.86 (d, J = 5.0
Hz, 1H), 8.14 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 5.0 Hz, 1H), 7.63 (d, J = 8.6 Hz,
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2H), 2.68 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.2, 157.5, 150.9, 143.8, 137.4, 132.0,
128.5, 124.1, 120.0, 117.5, 26.7. The NMR data are identical to those reported in the literature.26
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Ethyl 4-(4-acetylpyridin-2-yl)benzoate (14): Following the general procedure using 4-
acetylpyridine (264 μL, 2.4 mmol) and ethyl 4-aminobenzoate (99 mg, 0.6 mmol), the residue
was purified by flash chromatography on silica gel (heptane-EtOAc, 80-20) to afford the
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desired compound 14 (126 mg, 18%) as a white solid. H NMR (400 MHz, CDCl3) δ 8.89 (d,
J = 5.0 Hz, 1H), 8.20 (s, 1H), 8.16 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 5.0
Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 197.1, 166.2, 157.5, 150.9, 143.8, 142.4, 131.2, 130.0, 126.8, 120.4, 118.2,
61.1, 26.7, 14.3. HRMS (ESI) Calcd for: C16H15NO3Na: 292.0944; Found: 292.0944 [M+Na]+.
1-(2-(4-Acetylphenyl)pyridin-4-yl)ethan-1-one (15): Following the general procedure using
4-acetylpyridine (264 μL, 2.4 mmol) and 4'-aminoacetophenone (81 mg, 0.6 mmol), the residue
was purified by flash chromatography on silica gel (heptane-EtOAc, 90-10) to afford the
1
desired compound 15 (102 mg, 71%) as a white solid. H NMR (400 MHz, CDCl3) δ 8.94 (d,
J = 4.9 Hz, 1H), 8.25 (s, 1H), 8.19 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 5.0
Hz, 1H), 2.72 (s, 3H), 2.69 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.7, 197.1, 157.4,
151.0, 143.8, 142.7, 137.6, 128.9, 127.1, 120.5, 118.3, 77.3, 26.7. HRMS (ESI) Calcd for:
C15H13NO2Na: 262.0839; Found: 262.0840 [M+Na]+.
1-(2-(4-(Trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-one (16): Following the general
procedure using 4-acetylpyridine (264 μL, 2.4 mmol) and 4-(trifluoromethyl)aniline (96 mg,
0.6 mmol), the residue was purified by flash chromatography on silica gel (heptane-EtOAc, 96-
1
4) to afford the desired compound 16 (100 mg, 63%) as a yellow solid. H NMR (400 MHz,
CDCl3) δ 8.94 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 8.20 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.2 Hz,
2H), 7.74 (d, J = 5.0 Hz, 1H), 2.72 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.1, 157.2,
151.1, 143.9, 141.8, 131.3 (q, J = 32.5 Hz), 127.3, 125.8 (q, J = 3.8 Hz), 120.7, 124.1 (q, J =
272.2 Hz), 118.2, 26.8. HRMS (ESI) Calcd for: C14H10NOF3Na: 288.0607; Found: 288.0607
[M+Na]+.
1-(2-(4-Methoxyphenyl)pyridin-4-yl)ethan-1-one (17): Following the general procedure
using 4-acetylpyridine (264 μL, 2.4 mmol) and 4-methoxyaniline (74 mg, 0.6 mmol), the
residue was purified by flash chromatography on silica gel (heptane-EtOAc, 85-15) to afford
1
the desired compound 17 (95 mg, 70%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.83
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(d, J = 5.0 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 5.0 Hz, 1H), 7.03 (d, J
= 8.9 Hz, 2H), 3.89 (s, 3H), 2.68 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.6, 160.9,
158.4, 150.6, 143.6, 131.1, 128.3, 118.9, 117.1, 114.2, 55.3, 26.7. The NMR data are identical
to those reported in the literature.26
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1-(2-(3,5-difluorophenyl)pyridin-4-yl)ethan-1-one (18): Following the general procedure
using 4-acetylpyridine (264 μL, 2.4 mmol) and 3,5-difluoroaniline (77 mg, 0.6 mmol), the
residue was purified by flash chromatography on silica gel (heptane-EtOAc, 96-4) to afford the
1
desired compound 18 (78 mg, 56%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.89 (d,
J = 5.0 Hz, 1H), 8.14 (s, 1H), 7.73 (d, J = 5.0, 1H), 7.64 – 7.60 (m, 2H), 6.91 (tt, J = 8.6, 2.3
Hz, 1H), 2.71 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 196.9, 163.5 (dd, J = 248.4, 12.7
Hz), 156.1, 150.9, 143.9, 141.8 (t, J = 9.3 Hz), 120.8, 117.8, 109.9 (d, J = 26.6 Hz), 104.7 (t, J
= 25.4 Hz), 26.7. HRMS (ESI) Calcd for: C13H9NOF2Na: 256.0544; Found: 256.0545 [M+Na]+.
1-(2-(3,5-bBs(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-one (19): Following the general
procedure using 4-acetylpyridine (264 μL, 2.4 mmol) and 3,5-bis(trifluoromethyl)aniline (93
μL, 0.6 mmol), the residue was purified by flash chromatography on silica gel (heptane-EtOAc,
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96-4) to afford the desired compound 19 (104 mg, 52%) as a yellow solid. H NMR (400 MHz,
CDCl3) δ 8.97 (d, J = 5.0 Hz, 1H), 8.56 (s, 2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.80 (d, J = 6.4 Hz,
13
1H), 2.74 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 196.8, 155.4, 151.3, 144.2, 140.1, 132.3
(q, J = 33.7 Hz), 123.0, 127.1, 123.3 (q, J = 273.3 Hz), 121.4, 117.6, 26.8. HRMS (ESI) Calcd
for: C15H10NOF6: 334.0661; Found: 334.0659 [M+H]+.
1-(2-(3-Fluoro-5-(trifluoromethyl)phenyl)pyridin-4-yl)ethan-1-one (20): Following the
general procedure using 4-acetylpyridine (264 μL, 2.4 mmol) and 3-fluoro-5-
(trifluoromethyl)aniline (76 μL, 0.6 mmol), the residue was purified by flash chromatography
on silica gel (heptane-EtOAc, 95-5) to afford the desired compound 20 (76 mg, 45%) as a
1
yellow solid. H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 5.0 Hz, 1H), 8.40 (dd, J = 7.1, 2.3 Hz,
1H), 8.29 (s, 1H), 7.77 (d, J = 6.6 Hz, 1H), 7.75 – 7.68 (m, 1H), 7.39 – 7.31 (m, 1H), 2.71 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 197.0, 162.2 (d, J = 256.2 Hz), 153.2 (d, J = 2.5
Hz), 151.1, 143.6, 128.8 (q, J = 3.9 Hz), 128.1 (dq, J = 3.6, 9.9 Hz), 127.3 (d, J = 12.6 Hz),
123.7 (q, J = 272.1 Hz), 122.1 (d, J = 10.3 Hz), 120.7, 117.2 (d, J = 24.6 Hz), 26.8. HRMS
(ESI) Calcd for: C14H9NOF4Na: 306.0513; Found: 306.0515 [M+Na]+.
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1-(2-(2-Fluorophenyl)pyridin-4-yl)ethan-1-one (21): Following the general procedure using
4-acetylpyridine (264 μL, 2.4 mmol) and 2-fluoroaniline (57 μL, 0.6 mmol), the residue was
purified by flash chromatography on silica gel (heptane-EtOAc, 95-5) to afford the desired
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compound 21 (44 mg, 34%) as a yellow solid. H NMR (400 MHz, CDCl3) δ 8.91 (d, J = 5.0
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Hz, 1H), 8.24 (s, 1H), 8.01 (td, J = 7.9, 1.7 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.44 – 7.41 (m,
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1H), 7.34 – 7.27 (m, 1H), 7.25 – 7.17 (m, 1H), 2.68 (s, 3H). C{1H} NMR (101 MHz, CDCl3)
δ 197.4, 160.5 (d, J = 250.1 Hz), 154.9, 150.8, 143.4, 131.0 (d, J = 4.6 Hz), 131.0 (d, J = 1.1
Hz), 126.8 (d, J = 11.3 Hz), 124.6 (d, J = 3.6 Hz), 122.2 (d, J = 9.4 Hz), 119.8, 116.3 (d, J =
22.9 Hz), 26.8. HRMS (ESI) Calcd for: C13H10NOFNa: 238.0639; Found: 238.0637 [M+Na]+.
4,4'-Di-tert-butyl-6-(4-chlorophenyl)-2,2'-bipyridine (22): Following the general procedure
using 4,4'-di-tert-butyl-2,2'-bipyridine (634 mg, 2.4 mmol) and 4-chloroaniline (76 mg, 0.6
mmol), the residue was purified by flash chromatography on silica gel (heptane-EtOAc, 99-1)
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to afford the desired compound 22 (139 mg, 61%). H NMR (400 MHz, CDCl3) δ 8.64 (d, J =
5.3 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.12 (d, J = 8.6 Hz, 2H), 7.76 (s, 1H), 7.52 (d, J = 8.6
13
Hz, 2H), 7.35 (d, J = 4.5 Hz, 1H), 1.47 (s, 9H), 1.44 (s, 9H). C{1H} NMR (101 MHz, CDCl3)
δ 161.9, 160.8, 156.4, 156.3, 155.2, 148.9, 138.4, 134.8, 128.8, 128.3, 120.8, 118.4, 117.1,
35
117.0, 35.2, 34.9, 30.7, 30.6. HRMS (ESI) Calcd for: C24H28N2 Cl: 379.1936; Found:
379.1936 [M+H]+.
6-(4-Bromophenyl)-4,4'-di-tert-butyl-2,2'-bipyridine (23): Following the general procedure
using 4,4'-di-tert-butyl-2,2'-bipyridine (634 mg, 2.4 mmol) and 4-bromoaniline (103 mg, 0.6
mmol), the residue was purified by flash chromatography on silica gel (heptane-EtOAc, 99-1)
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to afford the desired compound 23 (147 mg, 58%) as a white solid. H NMR (400 MHz, CDCl3)
δ 8.64 (d, J = 5.2 Hz, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.75 (s, 1H), 7.67
(d, J = 8.5 Hz, 2H), 7.35 (d, J = 5.2 Hz, 1H), 1.47 (s, 9H), 1.44 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 161.9, 160.9, 156.4, 156.2, 155.3, 148.9, 138.9, 131.8, 128.6, 123.1, 120.8,
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118.4, 117.1, 117.1, 35.2, 34.9, 30.7, 30.6. HRMS (ESI) Calcd for: C24H27N2 BrNa: 445.1250;
Found: 445.1250 [M+Na]+.
4,4'-di-tert-butyl-6-(3-fluoro-5-(trifluoromethyl)phenyl)-2,2'-bipyridine (24): Following
the general procedure using 4,4'-di-tert-butyl-2,2'-bipyridine (634 mg, 2.4 mmol) and 3-fluoro-
5-(trifluoromethyl)aniline (76 μL, 0.6 mmol), the residue was purified by flash chromatography
on silica gel (heptane-EtOAc, 99-1) to afford the desired compound 24 (116 mg, 45%) as a
1
yellow solid. H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 5.2 Hz, 1H), 8.62 – 8.60 (m, 2H), 8.48
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(s, 1H), 7.91 (s, 1H), 7.71 – 7.67 (m, 1H), 7.38 – 7.31 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H).
13C{1H} NMR (101 MHz, CDCl3) δ 162.4 (d, J = 254.6 Hz), 161.9, 161.0, 156.4, 156.2, 150.7
(d, J = 3.0 Hz), 149.0, 129.1 (q, J = 4.1 Hz), 128.5 (d, J = 12.5 Hz), 127.3 – 126.9 (m), 123.9
(q, J = 272.0 Hz), 121.5 (d, J = 10.4 Hz), 121.0, 118.4, 117.5, 117.0 (d, J = 24.9 Hz), 25.2, 35.0,
30.7, 30.5. HRMS (ESI) Calcd for: C25H27N2F4: 431.2105; Found: 431.2105 [M+H]+.
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6-(4-Bromophenyl)-4,4'-dimethyl-2,2'-bipyridine (25): Following the general procedure
using 4,4'-dimethyl-2,2'-bipyridine (442 mg, 2.4 mmol) and 4-bromoaniline (103 mg, 0.6
mmol), the residue was purified by flash chromatography on silica gel (heptane-EtOAc, 98-2)
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to afford the desired compound 25 (98 mg, 48%). H NMR (400 MHz, CDCl3) δ 8.57 (d, J =
4.9 Hz, 1H), 8.42 (s, 1H), 8.24 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.57
(s, 1H), 7.17 (d, J = 4.3 Hz, 1H), 2.52 (s, 3H), 2.50 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 156.0, 155.8, 155.3, 148.9, 148.8, 148.1, 138.4, 131.8, 128.6, 124.7, 123.2, 122.1, 121.0,
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120.7, 21.4, 21.3. HRMS (ESI) Calcd for: C18H15N2 BrNa: 361.0311; Found: 361.0312
[M+Na]+.
ASSOCIATED CONTENT
1
13
The Supporting Information is available free of charge on the ACS Publications website. H and C
NMR spectra for all new compounds. Details for tempo-trapping and KIE experiments.
AUTHOR INFORMATION
Corresponding Author
jean-francois.soule@univ-rennes1.fr
ACKNOWLEDGMENT
Financial support from CNRS, Univ. Rennes 1, Rennes Métropole, and Région Bretagne
(Boost’Europe 18003332) is acknowledged.
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