Photoarylation of Pyridines Using Aryldiazonium Salts and Visible Light: An EDA Approach

Article abstract of DOI:10.1021/acs.joc.9b01879

A metal-free methodology for the photoarylation of pyridines, in water, is described giving 2 and 4-arylated-pyridines in yields up to 96percent. The scope of the aryldiazonium salts is presented showing important results depending on the nature and position of the substituent group in the diazonium salt, that is, electron-donating or electron-withdrawing in the ortho, meta, or para positions. Further heteroaromatics were also successfully photoarylated. Mechanistic studies and comparison between our methodology and similar metal-catalyzed procedures are presented, suggesting the occurrence of a visible-light EDA complex which generates the aryl radical with no need for an additional photocatalyst.

Full text of DOI:10.1021/acs.joc.9b01879

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Article
Photoarylation of Pyridines using Aryldiazonium
Salts and Visible Light: An EDA Approach
Aloisio de Andrade Bartolomeu, Rodrigo Costa Silva, Timothy
J Brocksom, Timothy Noël, and Kleber Thiago de Oliveira
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 19 Jul 2019
Downloaded from pubs.acs.org on July 19, 2019
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Photoarylation of Pyridines using Aryldiazonium Salts and
Visible Light: An EDA Approach
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Aloisio de A. Bartolomeu,1,2 Rodrigo C. Silva, Timothy J. Brocksom, Timothy Noël,
1
1
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and Kleber T. de Oliveira1*
1. Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP,
13565-905, Brazil.
2
. Department of Chemical Engineering and Chemistry, Sustainable Process
Engineering, Micro Flow Chemistry & Synthetic Methodology, Eindhoven
University of Technology, De Rondom 70 (Helix, STO 1.37), 5612 AP Eindhoven,
The Netherlands.
*E-mail: kleber.oliveira@ufscar.br
Graphical Abstract
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Abstract
A metal-free methodology for the photoarylation of pyridines, in water, is described giving
2 and 4-arylated-pyridines in yields up to 96%. The scope of the aryldiazonium salts is
presented showing important results depending on the nature and position of the
substituent group in the diazonium salt, i.e., electron-donating or electron-withdrawing in
the ortho, meta or para positions. Further heteroaromatics were also successfully
photoarylated. Mechanistic studies and comparison between our methodology and
similar metal-catalyzed procedures are presented, suggesting the occurrence of a visible
light EDA complex which generates the aryl radical with no need for additional
photocatalyst.
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Introduction
Pyridine moieties are common in natural products, agrochemicals,1-3 and drugs
approved by the FDA.4,5 Moreover, relevant clinical drugs such as Crizotinib, Enasidenib,
Vismodegib, Nilotinib, Etoricoxib, Atazanavir, and Nevirapine, contain the pyridine
nucleus directly linked/fused to aryl or heteroaryl units (Figure 1).4-8 Therefore, the
development of new and efficient methodologies for the direct C–H arylation or
heteroarylation of this electron-deficient heterocycle is of great interest.
1
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Cl
N
Cl
N
N
Cl
O
F
HN
CF3
Cl
O
NH
N
N
N
N
O
H
N
CF3
H N
2
N
N
N
S
O
HO
H
Crizotinib (Xalkori)
Enasidenib (Idhifa)
Vismodegib (Erivedge)
Anticancer
Pfizer
Anticancer
Celgene
Anticancer
Genentech
Approved in 2011
Approved in 2017
Approved in 2012
O
N
N
S
O
N
H
N
N
Cl
O
OH
O
N
H
H
N
N
N
O
N
N
O
N
N
H
H
O
N
CF3
O
O
H
N
Nilotinib (Tasigna)
Etoricoxib (Arcoxia)
Atazanavir (Reyataz)
Antiviral
Anticancer
Novartis
Anti-inflammatory
Merck Sharp & Dohme
Bristol-Myers Squibb
Approved in 2003
Approved in 2007
Approved in many countries
O
HN
Nevirapine (Viramune)
Antiretroviral
N
N
N
Boehringer Ingelheim
Approved in 1996
Figure 1. Structures of drugs which contain the pyridine nucleus (in blue).
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The synthesis of biaryls containing a pyridine motif can be efficiently carried out by
9
Baran’s methodology (Scheme 1, Eq a), in which silver nitrate and potassium persulfate
are used for aryl-radical generation from boronic acids, and subsequent arylation of a
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variety of N-heterocycles. Classical cross-coupling reactions such as Suzuki-Miyaura,10-
14
Negishi,15-17 Stille,13,18,19 Hiyama,20,21 and Kumada22,23 have been developed (Scheme
1, Eq. b) and proved to be similarly efficient. These structures can also be synthesized by
C–H activation reactions (Scheme 1, Eq. c),24-26 oxidative cross-coupling reactions
(
Scheme 1, Eq. d),27-29 and alternatively by radical-based methodologies,30,31 which have
received much attention recently in studies involving photocatalysis.32-39 Such
photocatalyzed reactions have been performed with various aryl radical precursors such
as aryldiazonium40-49 and diaryliodonium salts,50,51 aryl carboxylic acids,52
53
benzenesulfonyl chlorides (not tested with a pyridine nucleus), arylazosulfones (tested
with the pyrazolopyridine nucleus),54,55 diazoanhydrides (with pyridine N-oxide),56 and
halo(hetero)arenes57-59 in the presence of ruthenium complexes,41,43,44,51 iridium
complexes,50,52,57 organic dyes,47-49,58,59 metal oxides,40,42,46 and other (photo)catalysts
(
Scheme 1, Eq. e).60,61 However, the radical arylation of arenes and heteroarenes has
been achieved with only a few aryl radical precursors, even in the absence of a
photocatalyst.50,55,56,62
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(
a) Baran's methodology
R1
R
1
B(OH)
2 TFA, AgNO , K S O
R2
3
3
2
2
8
+
DCM:H O
2
2
N
N
R2
3-12 h
0
.25 mmol
32 examples
-96% yield
0.375 mmol
5
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(b) Arylation of pyridine nucleus via Suzuki-Miyaura cross-coupling
B(OH)2
Pd(PPh ) /K CO )
R
3
3 4
2
3
3
2
Br + R
2
dioxane/H O, 90 °C
2
N
N
1
mmol
3 mmol
continuous flow
12 examples
45-93% yield
R = H, NO , CN, Me, OMe
2
(c) Pd-catalyzed C3-selective arylation of pyridine nucleus
Y
Pd(OAc) / Phen
R
2
+
R
Cs CO 140 °C
2
3,
N
48 or 96 h
16 examples
ca. 37 mmol
0.5 mmol
N
N
58-86% yield
Y = Br, I R = H, CF , CN, Me, OMe, Ph, etc
3
(d) Metal-catalyzed oxidative cross-coupling reactions
Y
titanate
R
X + R
Co or Fe [O]
different conditions
N
2
.5 or 3 mmol 2.5 or 3 mmol
6
5
examples
5-96% yield
X, Y = MgBr, MgCl R = H, Br, CN, OMe, CO Et, Ph (Np)
2
(
e) Blue-light-mediated arylation of pyridine nucleus using immobilized TiO2
N BF
2
4
TiO2
Blue LED
+
R
N
EtOH, 20 °C
continuous flow
R
N
ca. 618 mmol
5 mmol
7 examples
75-99% yield
R = F, Cl, CF , NO , OMe, OEt
3
2
(f) Our Photocatalyzed approach
N BF
2
4
4
X
X
R
Blue LED

R
HCl +
2
H O, O , r.t., 48 h
2
2
N
N
7.5 mmol
0.5 mmol
2
1 examples
12-96% yield
R = H, F, CF , NO , Et, OMe, etc
3
2
X = C or N
No additional photocatalyst
Scheme 1. Selected approaches for the synthesis of biaryls with one pyridine nucleus.
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In 2017, Heinrich and co-workers reported that the arylation of some arenes and
heteroarenes with p-substituted aryl diazonium salts does not require the use of an
additional photocatalyst and other additives, and can be conducted under simple UV-
photocatalysis (250W, iron lamp, black glass filter), UV-Vis (250W, iron lamp, no filter) or
visible-light (10W, blue LED lamp) irradiation using an argon or air atmosphere. They
postulated that these arylations can be achieved by simple photoinduced radical
generation from a CT complex, but no further mechanistic insights were reported. They
also have shown the direct C–H arylation of 3-hydroxypyridine with some aryldiazonium
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salts, in 50-62% yields. However, this methodology does not work for the aryldiazonium
salt bearing a para-methoxy group even when an electron-rich (hetero)arene was
employed as substrate (<10% isolated yields).
We now report a protocol for the direct C–H arylation of the pyridine nucleus and
other N-heteroarenes, in water, with several aryldiazonium tetrafluoroborates substituted
by electron-donor, -neutral and -acceptor groups and with no base or additives, at room
temperature, and using visible-light irradiation (blue-LED) in the absence of
photocatalysts (Scheme 1, Eq. f). We postulate the occurrence of a visible light EDA for
1
1
15
the aryl radical generation which is supported by UV-Vis and H and H- N NMR.
Results and discussion
We started our investigation with pyridine hydrochloride (1a) and 4-
methoxybenzenediazonium tetrafluoroborate (2a) as the model substrates using a
homemade batch photoreactor with blue or white 30W LEDs (see details of the
photoreactor setup in the Supporting Information). First, the reaction between (1a) (7.5
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mmol) and 2a (0.5 mmol) in MeOH (1.5 mL) was tested at r.t., under an O atmosphere
2
and in the dark, but only traces of the 2-arylated-regioisomer 3a could be detected by
GC-MS after 48 h (Table 1, entry 1). Subsequently, we performed the reaction in the
same conditions but in the presence of blue light (blue LEDs) obtaining a mixture of 2-
aryl/4-aryl substituted pyridines (3a) in 84% yield (Table 1, entry 2).
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We also evaluated whether the activation of the pyridine moiety as the
hydrochloride is needed, and carried out the same reaction with 7.5 mmol of free base
pyridine and irradiation by blue LED resulting in a 20% yield of a mixture of the 2- and 4-
arylated-regioisomers 3a (Table 1, entry 3); this experiment allowed us to conclude that
the use of pyridinium salts is essential in this protocol. Changing the amount of pyridine
hydrochloride (1a) relative to the diazonium salt 2a we found 41 to 90% yields of 3a (Table
1, entries 4 and 5). Keeping 7.5 mmol of 1a and increasing 2a to 1 mmol also resulted in
a lower yield (51%) (Table 1, entry 6) showing that high excesses of 1a relative to 2a are
important for the efficiency of the protocol. Although the reaction with 10 mmol of 1a
significantly improved the yield of 3a (Table 1, entry 5), we decided to continue the
screening of conditions using 7.5 mmol of this substrate. It is important to highlight that
this excess of pyridinium salt is necessary and will be clarified in the section of
mechanistic studies.
The influence of the atmosphere, reaction time, and LED light source was also
evaluated (Table 1, entries 7-9, respectively). It was observed that the yield of 3a
decreased when the reaction was performed under an argon atmosphere (75% yield,
entry 7 vs 2) or when a shorter reaction time (24 h) was considered (72% yield, entry 8).
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Additionally, when white LEDs were employed under the same reaction conditions (entry
9) a lower yield (59%) was obtained.
We also investigated the effect of other solvents (EtOH, DMF, DMSO and H O) or
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mixtures of solvents (DMF/MeOH, 1:1 or 1:2, v/v) on the yield of 3a (Table 1, entries 10-
5). To our delight, when H O was used as the solvent, the desired product 3a was
1
2
obtained in 96% yield under identical conditions (entry 15). It is worth noting that the yield
of the arylated product 3a increased with the increase in polarity of the solvent used in
the reaction (Table 1, entries 11, 10, 2 and 15, respectively). The only exception was the
reaction carried out in DMSO (entry 14). The robustness of the protocol (entry 16) was
also tested reacting 2 mmols of 2a in the same optimized conditions (entry 15), giving the
product 3a in 79% yield (0.3 g-scale). Finally, we checked the optimized reaction condition
for the pyridine arylation (entry 15) in the absence of light, and again only traces of the 2-
arylated-regioisomer 3a could be detected by GC-MS after 48 h (entry 17). These results
showed that these arylation reactions are promoted by visible-light irradiation and do not
require a photocatalyst to occur under mild and environmentally friendly conditions.
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Table 1. Screening of the reaction conditions.[a]
N BF
2
4
4
Visible light

HCl +
OMe
2
N
Solvent, O , r.t.
2
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OMe
1a
3a
2a
1a
2a
Light source
Time
(h)
2-aryl:4-
aryl[e]
Overall Yield
3a [f]
Entry
Solvent
(mmol) (mmol)
(30W)
1
2
7.5
7.5
7.5[b]
5
0.5
0.5
0.5
0.5
0.5
1
None
MeOH
MeOH
48
48
48
48
48
48
48
24
48
48
48
48
48
48
48
48
48
-
Trace
84
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
White LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
Blue LED
none
71:29
68:32
67:33
67:33
68:32
71:29
72:28
73:27
67:33
77:23
71:29
69:31
73:27
71:29
67:33
-
3
MeOH
20
4
MeOH
41
5
10
MeOH
90
6
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
7.5
30
MeOH
55
7[c]
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
MeOH
75
MeOH
72
9
MeOH
59
10
11
12
13
EtOH
69
DMF
64
DMF/MeOH (1:1)
DMF/MeOH (1:2)
DMSO
63
71
14
15
82
H
H
H
2
2
2
O
O
O
96
16[d]
79
17
7.5
0.5
Trace
[
a] Reaction conditions: pyridine hydrochloride (1a) (5, 7.5 and 10 mmol), 4-methoxybenzenediazonium
tetrafluoroborate (2a) (0.5 and 1 mmol) in solvent (1.5 mL) at r.t. under an O atmosphere for 24 or 48 h.
b] With 7.5 mmol of free base pyridine. [c] Previously deoxygenated and maintained under argon
2
[
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
atmosphere. [d] scaled-up reaction performed in the same reaction conditions of entry 15, but in 6 mL of
H
2
O with 3a obtained in 0.3 g-scale. [e] Determined after isolation. [f] Isolated yields
With the optimized reaction conditions in hands (Table 1, entry 15), we proceeded
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
to evaluate the diazonium salt scope. As shown in Scheme 2, several aryldiazonium salts
with different substitution patterns, substituted pyridines, quinoline and quinoxaline are
compatible with our arylation protocol.
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N BF
4
2
4
X
N
X
R
Blue LED
H O, O , r.t., 48 h

HCl + R
2
2
2
N
1
a-g, X = C or N
2a-r
3b-x
7
.5 mmol
0.5 mmol
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
F
4
4
4
4
4
F
Cl
F
2
2
2
2
2
N
N
N
N
N
3c, 80%
3
d, 53%
3e, 58%
2-aryl/4-aryl, 62:38 2-aryl/4-aryl, 64:36
3f, 31%
3
b, 62%
2-aryl/4-aryl, 59:41
2
-aryl/4-aryl, 71:29 2-aryl/4-aryl, 68:32
CF3
4
CF3
4
4
NO2
4
NO2
4
NO2
2
2
2
2
2
N
N
N
N
N
3g, 49%
3h
3i, 66%
3j, 49%
3k, 52%
2-aryl/4-aryl, 63:37 2-aryl = 23%, 4-aryl = 0% 2-aryl/4-aryl, 64:36
2
-aryl/4-aryl, 61:39 2-aryl/4-aryl, 60:40
4
OMe
4
OMe
4
4
Me
Et
2
2
2
2
N
N
N
N
3
l, 80%
3
m, 13%
3n, 57%
3o, 75%
2-aryl/4-aryl, 68:32
2
-aryl/4-aryl, 68:32
2
-aryl/4-aryl, 67:33
2-aryl/4-aryl, 66:34
Me
Me
N
4
Et
Et
Et
Me
Me
4
4
Et
N
2
N
2
2
OH
N
OH
4, 55%
N
Cl
6, 13%
3r
5
, 56%
3q, 0%
2
-aryl = 14%, 4-aryl = 0%
3p, 0%
CF3
OMe
4
OMe
2
MeO
N
N
N
N
S
3
v, 38%
OMe
OMe
3u, 15%
3
s, 41%
3t, 12%
2
-aryl/4-aryl, 60:40
4
OMe
N
OMe
obtained from
pyridine-2-thiol
2
N
N
3w, 72%
3x, 71%
OMe
2
-aryl/4-aryl, 41:59
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 2. Evaluation of the reaction scope. All reactions were carried out on a scale of
7
.5 mmol of 1a-g and 0.5 mmol of 2a-r in H O (1.5 mL). Isolated yields with ratio
2
determined after column chromatography.
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8
9
0
1
2
3
4
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8
9
0
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2
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5
6
7
8
9
0
1
2
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8
9
0
1
2
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4
5
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0
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Among the aryldiazonium tetrafluoroborate salts tested for the direct arylation of
the pyridine moiety, electron-donor (Scheme 2, 3l and 3o) and neutral-4-substituted
aryldiazonium salts (Scheme 2, 3b and 3c) were more efficient than electron-acceptor-4-
substituted groups (Scheme 2, 3d and 3i). However, the reaction with the aryldiazonium
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
salt 2r, which contains the π-donor group 4-N(Me) , provided the 2-arylated pyridine (3r)
2
in only 14% yield, and the diazo-substituted product 6 in 13% yield.
In the work reported by Heinrich and co-workers (2016),63 an aryldiazonium
chloride salt containing the same 4-dimethylamino group was not successful in the radical
arylation of 3-hydroxypyridine mediated by TiCl , which suggests incompatibility of this
3
type of substrate with radical C–H arylation protocols.
Intriguingly, the aryldiazonium salts 2p (R = 3-Ethyl) and 2q (R = 2-Ethyl) also
underwent substitution reactions by hydroxyl groups (from the solvent water) to give the
phenols 4 and 5 in yields of 55% and 56%, respectively. The use of π-acceptor (NO ) or
2
donor (OMe) substituents at the 2 and 3 positions of the aryldiazonium ring decreased
the yield of products compared with the same substituents at the 4-position of the
diazonium salts. However, this effect was more pronounced for the methoxy donor
substituent (Scheme 2, 3m and 3n) than for the nitro acceptor (Scheme 2, 3i-3k).
Furthermore, lower yields were observed when σ-acceptors (F and CF ) groups were
3
present at the 2 and 3- positions of the aryldiazonium rings (see Scheme 2, 3e vs 3f and
3g vs 3h).
Sakakura64
reported
that
some
diazonium
salts
such
as
3-
methoxybenzenediazonium (2m) and certain heteroarenediazonium tetrafluoroborates
are known to decompose when dried, which may explain the observed low yield obtained
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
for biaryl 3m (13%). Indeed, Heinrich and co-workers 63 also reported problems with the
use of an aryldiazonium chloride containing the meta-methoxy group, which partially
decomposed before the addition to the reaction mixture. In the case of compounds 3e-3h
0
1
2
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4
5
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8
9
0
1
2
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9
0
1
2
3
4
5
6
7
8
9
0
bearing σ-acceptors (F and CF ) groups, the difference in yields between the ortho and
3
meta derivatives can be due to steric and/or electronic factors. However, we do not rule
out the possibility that the yields of these and other reactions (such as Scheme 2, 3p,3q)
are correlated with the (photo)stability of the corresponding aryldiazonium salts. As well
as the nature of the counter-ion, it is known that the substituent nature and position on
the cation are of the greatest importance for the stability of the aryldiazonium salt.65,66
We also included additional N-heterocycles (Scheme 2) as scope with the 4-
trifluoromethyl-pyridine (giving 3s in 41% yield), 4-methoxy-pyridine (giving 3t in 12%
yield), 2-methoxipyridine (giving 3u in 15% yield), pyridine-2-thiol (giving 3v in 38% yield),
quinoline (giving 3w in 72% yield) and quinoxaline (giving 3x in 71% yield). Overall, the
substitued pyridines with electron-withdrawing and donating groups yielded produtcs from
low to acceptable yields (12-41%). The pyridine-2-thiol yielded the product 3v (38%) with
the arylation in the thiol position and not in the aromatic ring. Both quinoline and
quinoxaldine yielded arylated poducts in good yields (71-72%) demonstrating additional
possibilities to apply this methodology.
Mechanistic Insights, and Counterpoints with Ru-photocatalyzed reactions
To gain some insights into the mechanism of this metal-free C–H photoarylation
reaction, we conducted several control experiments with the substrates 1a and 2a and
compared our results with the literature using Ru-photocatalysts (see Scheme 3). As
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observed in our experiments performed in the dark (Table 1, entries 1 and 17) only traces
of the 2-aryl-regioisomer 3a were detected by GC-MS after 48 h, showing that the reaction
is being promoted by blue LED visible-light. We also performed a reaction in the presence
of 2 equiv. of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and
only partial inhibition of the reaction was observed (Scheme 3, Eq. 1). The aryl radical
was trapped with TEMPO and was detected by GC-MS (see Figure S1, SI) and 3a
obtained in 70% yield (as against 96% yield, Table 1, entry 15, in the absence of TEMPO).
This result suggests that the reaction involves radical intermediates, but complete radical
trapping with full inhibition was not observed, probably due to the low solubility of TEMPO
in water.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Subsequently, we tried to reproduce in our setup and optimized substrate
proportions, the reaction between 1a and 2a reported by Xue and co-workers41 using
Ru(bpy) Cl (2.5 mol%) in the presence of 2 equiv. of TEMPO. However, in our hands,
3
2
the compound 3a was obtained in 66% yield and only traces of the radical trapped with
TEMPO was detected by CG-MS, against the 0% described by the before-mentioned
authors (Scheme 3, Eq. 2 and Figure S2, SI). Furthermore, we tried to reproduce the
same previous reaction without TEMPO (Scheme 3, Eq. 3) and obtained the compound
3a in 94% yield. This result is statistically the same as compared to that reported in the
mentioned literature (93%) by using the Ru-photocatalyst. However, this is also consistent
with the yield obtained by us without photocatalyst (96%, Table 1, entry 15), showing that
these photoarylation reactions work in 48 h (against the 60-80 h reported) independently
41
of Ru-catalysts. It is important to highlight that the literature background reaction use p-
CF -pyridine (1b) with 2a (Scheme 3, Eq. 4) mentions that only traces of the product 3s
3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
were formed. We obtained the product 3s in 41% yield after 48 h, as opposed to the
41
reported traces obtained by Xue and co-workers after 60 h.
These results show an inconsistency between our data and the above-mentioned
report, but these differences may be due to the different reagent proportions, as well as
their use of 45W white fluorescent light bulbs against the 30W blue LEDs used in this
study.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
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0
1
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Ar
O
N
4
Blue LED

(1)
HCl + Ar N BF + TEMPO
Ar +
2
4
2
N
1a
H O, O , r.t., 48 h
2
2
N
2a
1
mmol
3a (70%)
0.5 mmol
(GC-MS)
7
.5 mmol
(
2-aryl/4-aryl, 71:29)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ar
O
N
4

[Ru(bpy) Cl ] 6H O (2.5 mol %)
3
2
2

HCl + Ar N BF + TEMPO
Ar +
(2)
2
4
2
Blue LED, H O, O , r.t., 48 h
N
2
2
N
3
2a
1 mmol
1a
a (66%)
0.5 mmol
(GC-MS)
7
.5 mmol
(
2-aryl/4-aryl, 66:34)
4

[
Ru(bpy) Cl ] 6H O (2.5 mol %)
3 2 2

Ar
(3)
HCl + Ar N BF
2
4
2
Blue LED, H O, O , r.t., 48 h
N
2
2
N
2a
in all experiments
1a
3a (94%)
0.5 mmol
7.5 mmol
(
2-aryl/4-aryl, 59:41)
Ar =
CF3
CF3
N
OMe
Blue LED

(4)
HCl + Ar N BF
2
4
N
H O, O , r.t., 48 h
2
2
Ar
2a
1b
0.5 mmol
7
.5 mmol
3
s (41%)
4
Blue LED

HCl + Ar N BF
Ar
(5)
2
4
2
N
D O, O , r.t., 48 h
2
2
N
2a
1a
3
a (90%)
0.5 mmol
7
.5 mmol
(
2-aryl/4-aryl, 63:37)
Scheme 3. Mechanistic investigations.
An additional control experiment was performed with deuterated water as solvent
(Scheme 3, Eq. 5), obtaining 3a in a comparable 90% yield and with no incorporation of
deuterium, showing no hydrogen transfer.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In order to understand which intermediate is photoactive in this reaction (a
photochemical intermediate such as a diazopyridinium salt or an EDA complex) we
1
1
15
carried out several UV-Vis, H and H- N HMBC NMR studies. The literature indicates
that the formation of colored charge-transfer (CT) complexes between the electron-poor
aryldiazonium salts and aromatic hydrocarbons occurs spontaneously, presenting a
progressive bathochromic (red) shift with the decrease of the ionization potential of these
aromatic substrates.67,68 We have successfully detected a new UV-Vis band by mixing 1a
and 2a as demonstrated in Figure 2A, and confirmed a very close match between the
new band (black line) and the blue LED emission (blue line) (Figure 2A).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A)
B)
1
2a
a + 2a
1a' + 2a
2a
1a'
1
,0
,8
CT Band
1,0
0,8
0,6
0,4
0,2
0,0
1,0
0,5
CT Band
1,0
1a
0
0,5
0,6
0,4
0,0
LED emission
0,0
400
500
600
400
500
600
Wavelength (nm)
Wavelength (nm)
0
,2
,0
0
400
450
500
Wavelength (nm)
550
600
400
450
500
550
600
Wavelength (nm)
C)
D)
N BF
2
4
1a
2a 1a+2a 1a'+2a
HCl
N
N
OMe
1a'
1a
2a
Figure 2. (A) UV-Vis absorption spectra of 1a (3 mmol), 2a (0.2 mmol), and the mixture
of 1a and 2a at 2 and 0.13 mM in H O, respectively. Inset: charge transfer band (CT) of
2
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(
1a + 2a) EDA complex. (B) UV-Vis absorption spectra in NaCl solution (1M) for 1a’, 2a
and their mixture of 1a’ and 2a at 2 and 0.13 mM. Inset: the charge transfer band (CT) of
(1a’ + 2a) EDA complex. (C) Images of the solutions 1a, 2a, 1a + 2a and 1a’ +2a. D)
molecular structure of the species.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
These first studies by UV-Vis (Figure 2A) are consistent with the occurrence of an
EDA complex. However, it is well-known in the literature that EDA complexes are
69
supramolecular structures. In the case of mixtures of diazonium salts and pyridines the
70
literature describes the occurrence of diazopyridinium salts at low temperatures, which
are discrete structures and could not be considered as EDA complexes. In order to find
more data to confirm the real photochemical intermediate of this study, we performed one
experiment with the diazonium salt 2a in the presence of NaCl instead of pyridinium
chloride, obtaining exactly the same UV-Vis band of the diazonium salt 2a and showing
that the chloride ion is not able to form an EDA with 2a. In addition, an UV-Vis experiment
with the diazonium salt 2a and free pyridine (1a’) was carried out showing a very similar
new UV-Vis band with an evident more colored solution (Figure 2B and 2C). We were
able to conclude that there is an evident interaction between pyridine and the diazonium
salt moieties, which is present when mixing pyridine.HCl (1a) and the diazonium salt 2a.
Due to the acid-base equilibrium the concentration of free pyridine is low and the EDA
formed is more discrete (low concentration). However, in the presence of high
concentrations of free pyridine 1a’ the occurrence of the EDA complex is more evident
(
Figure 2B). It is important to highlight that our methodology deals with the formation of
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
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3
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5
6
an EDA, but also with a relative concentration of protonated pyridine or heterocycle in
order to have the radical acceptor activated.
1
We also performed H NMR experiments in D O analysing 1a and 2a individually and
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixtures of both in diferent proportions. First, aggregation studies at high concentrations
1
(
from 35-280 mM) of 1a and 2a were carried out by H NMR (Figure S3 – Supporting
Information), and no aggregation in solution was detected even at high concentrations
280 mM); it is well-known that aggregation on aromatic compounds in solutions can
(
dramatically change the chemical shifts.71
1
In the H NMR analysis of the mixture of both 1a and 2a (1:1 equiv.) in D O we
2
1
observed a slight protection of the H signals of the diazonium salt 2a and a slight
1
deprotection of the H signals in 1a (Figure 3). Similarly, the mixture of the diazonium salt
1
2
a and free pyridine (1a’) yielded H NMR analyses with protected signals for the
diazonium salt 2a and deprotected signals for the free pyridine (1a’) in both 1:1 and 1:5
molar proportions (Figure 4). This indicates an electron-donor effect by the pyridine
nucleus and an electron-acceptor effect by the diazonium salt moiety. It is important to
highlight that the protection/deprotection effects are more relevant in the 1:5 molar ratio
experiment, which is in aggrement with the supramolecular properties of the EDA
1
15
complexes. Additional experiments of H- N HMBC were performed (Figure S7 -
1
15
Supporting Information) and from the results only H- N correlations of individual 1a’ and
2a were found by mixing these starting materials in D O with no photochemically active
2
intermediate such as a diazopyridinium salt detected in these reaction conditions.
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MeO
1
1
equiv.
equiv.
N BF
2
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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0
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9
0
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3
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8
9
0
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0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N BF
2
4
MeO
HCl
N
9,0 8,8 8,6 8,4 8,2 8,0 7,8 7,6 7,4 7,2 7,0

(ppm)
1
Figure 3: H NMR spectrum for 1a (at 35 mM), 2a (at 35 mM) and their mixture 35 mM
(1:1 equiv.) in D O.
2
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9
1
1
1
1
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2
2
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N
0
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8
9
0
1
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0
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9
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9
0
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2
3
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7
8
9
0
N BF
2
4
MeO
-
0.008 ppm
-0.009 ppm
+0.040 ppm
MeO
1
1
equiv.
N BF
2
4
+
0.033 ppm
equiv.
+
0.040 ppm
N
+0.003 ppm
MeO
+0.001 ppm
1
equiv.
N BF
2
4
+
0.001 ppm
-0.051 ppm
5 equiv.
-0.040 ppm
N
9
,0 8,8 8,6 8,4 8,2 8,0 7,8 7,6 7,4 7,2 7,0

(ppm)
1
Figure 4: H NMR spectrum for 1a’ (at 35 mM), 2a (at 0.18 mM) and their mixture
(1:1equiv. at 35 mM and 1:5 equiv, 35: 175 mM) in D O.
2
Based on these results we propose a plausible mechanism for the visible-light-
induced direct C–H arylation of pyridines (Scheme 4). Initially, the aryldiazonium salt
reversibly combines with free pyridine/heterocycle generating the EDA complex which
absorbs blue light, and then the rupture in the excited state yields the aryl radical.72,73
Then, the aryl radical reacts with the pyridinium salt to form a new radical intermediate.
The latter is subsequently re-aromatized by reaction with oxygen gas. It is relevant to
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highlight that we have confirmed that the oxygen atmosphere has an important role in
improving the yields.45 Finally, aqueous work-up liberates the desired arylated
heterocycles.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
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5
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6
0
1
2
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9
0
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2
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9
0
1
2
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8
9
0
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2
3
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9
0
1
2
3
4
5
6
7
8
9
0
t
R
BF4
ligh
BF4
N
N
N2
visible
R
N
N2 + py + BF4
EDA Complex
H O
2
+
H O
3
N
N
H
N
TEMPO
R
O
(
GC-MS)
R
R
N
H
workup
O2
N
H
R
R
HOO
N
H
H
N
arylated N-heteroarenes
Scheme 4. Proposed mechanism for the visible-light induced direct C–H arylation of
pyridines.
Conclusion
We have developed a metal-free methodology for the photoarylation of pyridines and
other heterocycles in water, using a very simple photoreactor setup. The scope of the
diazonium salt is presented showing the relative strength of this methodology when both
electron-withdrawing and donating groups are attached to the diazonium salts (ortho,
meta and para positions). Mechanistic investigations were carried out giving support for
the proposed mechanism and the occurence of an EDA complex.
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6
EXPERIMENTAL SECTION
General Information
All commercial reagents were used without further purification. Aryldiazonium salts were
7
4
prepared according to the literature procedure. All the reactions were carried out under
an oxygen atmosphere. Reactions were monitored by thin layer chromatography (TLC)
carried out on 0.25 mm silica plates, using short-wave UV light (254 nm or 365 nm) for
visualization. Flash column chromatography was performed on silica gel (70 – 230 mesh).
NMR spectra were recorded on a Bruker Avance 400 MHz instrument, and chemical shifts
0
1
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7
8
9
0
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9
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
1
for H and C{ H} NMR are reported in ppm relative to TMS as internal reference. All
coupling constants (J values) are reported in Hertz (Hz). The following abbreviations were
used to describe NMR peak multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
and m = multiplet. High-resolution mass spectra (HRMS) were performed on Agilent LC-
6545, Q-TOF MS with Jet Stream ESI ionization. UV-Vis absorption spectra were
recorded on a Perkin Elmer Lambda 25 UV-visible absorption spectrophotometer.
General Procedures
Aryldiazonium salt preparation:
To a solution of aniline (10 mmol) in distilled H O (4 mL), aq. HBF 50 wt. % was added
2
4
o
(3.4 mL) and the mixture was stirred while cooled to 0 C. Subsequently, a solution of
NaNO (10 mmol, 690 mg) in H O (2 mL) was added dropwise. After addition, the reaction
2
2
mixture was stirred for 45 min and then the solid filtered off under vacuum. The precipitate
was re-dissolved in a minimum amount of acetone (ca 5-8 mL). Diethyl ether was added
until precipitation of the diazonium tetrafluoroborate. The solid was filtered off and washed
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with diethyl ether and dried under vacuum. The NMR data were consistent with those
previously reported.75
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
4
4
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5
5
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5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthetic methodology:
To a test tube (borosilicate, 10 mm internal diameter and 1 mm thick walls) N-heterocycle
hydrochloride salt (1a-g) (7.5 mmol, 15 equiv.) was added to 1.5 mL of H O. The test tube
2
was then sonicated to remove the solubilized air and after saturated with pure O by
2
bubbling this gas for 10 min. The aryldiazonium salt (2a-r) (0.5 mmol, 1 equiv.) was
quickly added, the tube was closed and sealed with Teflon tape. The reaction mixture
was stirred and irradiated using a homemade batch photoreactor (30W blue LEDs) under
an oxygen atmosphere (balloon) at r.t. for 48h. The reaction mixture was quenched with
saturated aqueous NaHCO (10 mL) and extracted with EtOAc (3 × 20 mL). The organic
3
extracts were washed with brine (1 × 10 mL), dried over MgSO , filtered, and the solution
4
concentrated under vacuum. The crude reaction product was chromatographed on silica
gel (70–230 mesh) using EtOAc/hexane mixtures of increasing polarity to afford 2-aryl/4-
aryl substituted pyridines (3a-v), 2-aryl/4-arylquinoline (3w) and 2-aryl-quinoxaline (3x) in
yields ranging from 12 to 96%.
Experimental Data
2-(4-methoxyphenyl)pyridine – 2-aryl (3a): The compound 2-aryl (3a) (known
76
compound) was obtained following the general procedure. It was obtained in 68% yield
(0.341 mmol, 63.2 mg) as a yellow solid after purification on silica gel column
23
chromatography (Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). Mp: 51–53 °C (lit. mp 53–
1
55 °C). H NMR (400 MHz, CDCl ):  8.65 (m, 1 H), 7.95 (d, J = 9.0 Hz, 2 H), 7.74−7.64
3
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(
m, 2 H), 7.17 (ddd, J = 7.1 ,4.9 ,1.4 Hz, 1 H), 7.00 (d, J = Hz, 9.0 Hz, 2 H), 3.86 (s, 3 H).
1
3
1
C{ H} NMR (100 MHz, CDCl ):  160.5, 157.1, 149.5, 136.7, 132.0, 128.2, 121.4, 119.8,
3
1
14.1, 55.4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
4
-(4-methoxyphenyl)pyridine – 4-aryl (3a): The compound 4-aryl (3a) (known
76
compound) was obtained following the general procedure. It was obtained in 28% yield
(0.138 mmol, 25.5 mg) as a yellow solid after purification over silica gel column
77
chromatography (Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). Mp: 91–94 °C (lit. mp 94–
1
96 °C). H NMR (400 MHz, CDCl ):  8.62 (d, J = 6.2 Hz, 2 H), 7.60 (d, J = 9.0 Hz, 2 H),
3
13
1
7
.47 (d, J = 6.2 Hz, 2 H), 7.01 (d, J = 9.0 Hz, 2 H), 3.87 (s, 3 H). C{ H} NMR (100 MHz,
CDCl ):  160.5, 150.2, 147.8, 130.4, 128.2, 121.1, 114.6, 55.4.
3
2-phenylpyridine – 2-aryl (3b): The compound 2-aryl (3b) (known compound)78 was
obtained following the general procedure. It was obtained in 44% yield (0.219 mmol, 34.0
mg) as a yellow oil after purification over silica gel column chromatography
1
(Hexane/EtOAc = from 9.5/0.5 (v/v) to 8/2 (v/v). H NMR (400 MHz, CDCl ):  8.71-8.68
3
(m, 1H), 7.99 (d, J = 7.0 Hz, 2H), 7.78-7.71 (m, 2H), 7.50-7.45 (m, 2H), 7.44-7.39 (m, 1H),
13
1
7
1
4
.23 (ddd, J = 6.8, 4.8, 2.0, 1H). C{ H} NMR (100 MHz, CDCl ):  157.5, 149.7, 139.4,
3
36.8, 129.0, 128.8, 126.9, 122.1, 120.6.
-phenylpyridine – 4-aryl (3b): The compound 4-aryl (3b) (known compound)79,80 was
obtained following the general procedure. It was obtained in 18% yield (0.090 mmol, 13.9
mg) as a yellow solid after purification over silica gel column chromatography
80
1
(Hexane/EtOAc = from 9.5/0.5 (v/v) to 8/2 (v/v)). Mp: 62–64 °C (lit. mp 67–68 °C). H
NMR (400 MHz, CDCl ):  8.59 (d, J = 5.6, Hz, 2H), 7.57 (d, J = 6.8 Hz, 2H), 7.46-7.34
3
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1
(
m, 5H). 13C{ H} NMR (100 MHz, CDCl ):  150.3, 148.4, 138.2, 129.1, 129.0, 127.0,
3
1
21.7.
2
-(4-chlorophenyl)pyridine – 2-aryl (3c): The compound 2-aryl (3c) (known compound)80
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was obtained following the general procedure. It was obtained in 54% yield (0.272 mmol,
1.6 mg) as a yellow solid after purification over silica gel column chromatography
5
80
1
(Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). )). Mp: 46 – 48 °C (lit. mp 44 – 45 °C). H
NMR (400 MHz, CDCl ):  8.69 (ddd, J = 4.8, 1.8, 1.1 Hz, 1H), 7.94 (d , J = 9.0 Hz, 2H),
3
7
.76 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.72-7.68 (m, 1H), 7.45 (d, J = 9.0 Hz, 2H), 7.25 (ddd,
13
1
J = 7.4, 4.8, 1.3 Hz, 1H). C{ H} NMR (100 MHz, CDCl ):  156.2, 149.8, 137.8, 136.9,
3
1
35.1, 129.0, 128.1, 122.4, 120.4.
4
-(4-chlorophenyl)pyridine – 4-aryl (3c): The compound 4-aryl (3c) (known compound)80
was obtained following the general procedure. It was obtained in 26% yield yield (0.128
mmol, 24.3 mg) as a yellow solid after purification over silica gel column chromatography
80
1
(
Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). Mp: 70 – 71 °C (lit. mp 70 – 71 °C). H
13
1
NMR (400 MHz, CDCl ):  8.68 (s, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.50-7.45 (m, 4H). C{ H}
3
NMR (100 MHz, CDCl ):  150.4, 147.1, 136.6, 135.4 129.4, 128.3, 121.5.
3
2-(4-fluorophenyl)pyridine – 2-aryl (3d): The compound 2-aryl (3d) (known
compound)23,81 was obtained following the general procedure. It was obtained in 31%
yield (0.156 mmol, 27.1 mg) as a white solid after purification over silica gel column
23
chromatography (Dichloromethane/EtOAc = 9.5/0.5 (v/v)). Mp: 35–37 °C (lit. mp 39–41
1
°
C). H NMR (400 MHz, CDCl ):  8.67 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.00-7.95 (m, 2H),
3
7
.75 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.70-7.66 (m, 1H), 7.22 (ddd, J = 7.4, 4.8, 1.2 Hz,
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2
2
2
2
2
2
2
2
3
3
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5
5
5
5
5
5
5
6
1
3
1
1
1
4
H). 7.19-7.12 (m, 2H). C{ H} NMR (100 MHz, CDCl ):  163.5 (d, J = 248 Hz), 156.5,
3
CF
49.7, 136.8, 135.5, 128.7, 122.1, 120.2, 115.8, 115.6.
-(4-fluorophenyl)pyridine – 4-aryl (3d): The compound 4-aryl (3d) (known
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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0
compound)82,83 was obtained following the general procedure. It was obtained in 22%
yield (0.109 mmol, 19.0 mg) as a white solid after purification over silica gel column
82
chromatography (Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). 112–114 °C (lit. mp 116–
1
1
18 °C). H NMR (400 MHz, CDCl ):  8.66 (d, J = 4.6 Hz, 2 H), 7.66 - 7.58 (m, 2 H),
3
.50-7.44 (m, 2 H), 7.22-7.14 (m, 2 H). 13C{ H} NMR (100 MHz, CDCl ):  163.5 (d,
1
7
3
JC-F = 248 Hz), 150.2, 147.4, 134.2, 134.1, 128.8, 128.7, 121.5, 116.3, 116.1.
-(3-fluorophenyl)pyridine – 2-aryl (3e): The compound 2-aryl (3e) (known compound)84
2
was obtained following the general procedure. It was obtained in 36% yield (0.178 mmol,
3
0.8 mg) as a yellow oil after purification over silica gel column chromatography
1
(
Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). H NMR (400 MHz, acetone-d6):  8.70 (ddd,
J = 4.8, 1.8, 1.0 Hz, 1H), 8.01 – 7.95 (m, 2H), 7.94-7.88 (m, 2H), 7.57-7.51 (m, 1H), 7.38
13
1
(
ddd, J = 7.4, 4.8, 1.1 Hz, 1H), 7.21 (dddd, J = 8.6, 8.2, 2.6, 0.9 Hz, 1H). C{ H} NMR
(
100 MHz, acetone-d6):  164.2 (d, JCF = 242 Hz), 156.1, 150.6, 142.7 (d, JCF = 7 Hz),
138.0, 131.4 (d, JCF = 8 Hz), 123.9, 123.3, 121.2, 116.4 (d, JCF = 21 Hz), 114.0 (d, JCF
=
23 Hz).
4
-(3-fluorophenyl)pyridine – 4-aryl (3e): The compound 4-aryl (3e) (known compound)85
was obtained following the general procedure. It was obtained in 22% yield (0.109 mmol,
18.9 mg) as a yellow oil after purification over silica gel column chromatography
1
(
Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). H NMR (400 MHz, CDCl ):  8.69 (d, J =
3
13
1
6
.0 Hz, 2H), 7.51 – 7.41 (m, 4H), 7.36 – 7.32 (m, 1H), 7.18 – 7.12 (m, 1H). C{ H} NMR
28
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Page 29 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
100 MHz, CDCl ):  164.4,162.0, 150.4, 147.1, 140.3 (d, J = 8.0 Hz), 130.7 (d, JCF = 8
3
CF
Hz), 122.7, 121.6, 115.9 (d, JCF = 21 Hz), 114.0 (d, JCF = 22 Hz).
2
-(2-fluorophenyl)pyridine – 2-aryl (3f): The compound 2-aryl (3f) (known compound)86
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was obtained following the general procedure. It was obtained in 20% yield (0.098 mmol,
1
6.9 mg) as a yellow oil after purification over silica gel column chromatography
1
(Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). H NMR (400 MHz, CDCl ):  8.70 (ddd, J =
3
4
8
1
1
1
4
.8, 1.8, 1.0 Hz, 1H), 7.92 (dt, J = 8.0, 1.8 Hz, 1H), 7.78-7.68 (m, 2H), 7.34 (dddd, J =
.3, 7.3, 5.0, 1.9, 1H), 7.24 (ddd, J = 7.3, 4.8, 1.4 Hz, 1H), 7.20 (ddd, J = 7.8, 7.3, 1.2 Hz,
13
1
H), 7.12 (dddd, J = 11.7, 8.2, 1.2, 0.3 Hz, 1H). C{ H} NMR (100 MHz, acetone-d6): 
61.4 (d, JCF = 251 Hz), 153.9, 150.7, 137.4, 132.0, 131.5 (d, JCF = 8 Hz), 128.3 (d, JCF
=
1 Hz), 125.4, 125.1 (d, JCF = 9 Hz), 123.6, 116.9 (d, JCF = 23 Hz).
-(2-fluorophenyl)pyridine – 4-aryl (3f): The compound 4-aryl (3f) (new compound) was
obtained following the general procedure. It was obtained in 11% yield (0.054 mmol, 9.4
mg) as a yellow solid after purification over silica gel column chromatography
1
(Hexane/EtOAc = from 9/1 (v/v) to 7/3 (v/v)). Mp: 62–64 °C. H NMR (400 MHz, acotone-
d6):  8.55 (d, J = 5.9 Hz, 2H), 7.50 (dt, J = 7.8, 0.3 Hz, 1H), 7.46-7.42 (m, 2H), 7.39
(
dddd, J = 8.2, 7.3, 5.1, 1.8, 1H), 7.23 (dt, J = 7.3, 1.2 Hz, 1H), 7.17 (dddd, J = 11.2, 8.3,
13
1
1
.2, 0.3 Hz, 1H). C{ H} NMR (100 MHz, acetone-d6):  160.6 (d, J = 248 Hz), 150.9,
CF
1
43.9, 131.8 (d, JCF = 9 Hz), 131.5, 127.0 (d, JCF = 13 Hz), 126.0 (d, JCF = 4 Hz), 124.4,
+
1
17.1 (d, JCF = 21 Hz). HRMS-ESI-TOF: m/z calcd for C H FN [M+H] 174.0714, found
11
8
174.0712.
2
-(3-(trifluoromethyl)phenyl)pyridine – 2-aryl (3g): The compound 2-aryl (3g) (known
87
compound) was obtained following the general procedure. It was obtained in 31% yield
29
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