Facile synthesis of aryl-substituted pyridines via Suzuki-Miyaura approach

Article abstract of DOI:10.1016/j.tet.2015.09.063

A facile and efficient synthetic route to arylpyridines is reported. When heated with boronic acids in the presence of 5 mol % PdCl₂(PPh₃)₂ and KHCO₃ in 4:1 DMF/H₂O solution at 110°C, 5-iodopyridines

Full text of DOI:10.1016/j.tet.2015.09.063

Accepted Manuscript
Facile synthesis of aryl-substituted pyridines via Suzuki-Miyaura approach
Eda Karadeniz, Metin Zora, Nihan Zülay Kılıçaslan
PII:
S0040-4020(15)30091-0
10.1016/j.tet.2015.09.063
TET 27160
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 July 2015
Revised Date: 17 September 2015
Accepted Date: 25 September 2015
Please cite this article as: Karadeniz E, Zora M, Kılıçaslan NZ, Facile synthesis of aryl-substituted
pyridines via Suzuki-Miyaura approach, Tetrahedron (2015), doi: 10.1016/j.tet.2015.09.063.
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Facile synthesis of aryl-substituted pyridines via
Suzuki-Miyaura approach
Leave this area blank for abstract info.
Eda Karadeniz, Metin Zora*, Nihan Zülay Kılıçaslan
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
4
R −B(OH)
2
3
3
O
R
O
R
PdCl (PPh )
2
3 2
4
R
I
2
2
R
R
KHCO
DMF/H O (4:1)
3
1
1
N
N
R
R
2
o
110
C
18 examples
up to 98% yield
1
2
4
R
R
R
= alkyl, aryl, heteroaryl
= aryl; R = aryl
= aryl, heteroaryl, ferrocenyl
3

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Facile synthesis of aryl-substituted pyridines via Suzuki-Miyaura approach
Eda Karadeniz, Metin Zora , Nihan Zülay Kılıçaslan
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile and efficient synthetic route to arylpyridines is reported. When heated with boronic
acids in the presence of 5 mol% PdCl2(PPh3)2 and KHCO3 in 4:1 DMF/H2O solution at 110 oC,
5-iodopyridines have undergone Suzuki-Miyaura coupling reactions to afford 5-aryl-substituted
pyridines in good to excellent yields. The coupling reaction has been found to be general for a
broad range of iodopyridines and boronic acids, and demonstrated good tolerance to a variety
of aliphatic, aromatic, heteroaromatic and ferrocenyl groups with electron-withdrawing and
electron-donating substituents. This coupling approach could accommodate various functional
groups and provide rapid access to a library of functionalized arylpyridines of pharmacological
interest. The starting 5-iodopyridines have been prepared from α,β-alkynic ketones, involving
conjugate addition of propargylamine to alkynones, followed by metal-catalyzed cross-
coupling of the resulting N-propargylic β-enaminones with aryl iodides and electrophilic
cyclization with molecular iodine.
Available online
Dedicated to the memory of Prof. Dr. Ayhan S. Demir
Keywords:
Pyridine
Arylpyridine
Iodopyridine
Coupling
Suzuki-Miyaura reaction
Ferrocene
2015 Elsevier Ltd. All rights reserved
.
methods have been developed for the synthesis of pyridines,21
and new variants continue to come out since pyridines are critical
molecules for the synthesis of various drugs and natural
products.22 Recently, electrophilic cyclizations of N-propargylic
β-enaminones have been recognized as an attractive way to
synthesize a variety of important heterocycles,23 including
pyridines24 and dihydropyridines.25 Cacchi and coworkers have
reported that when subjected to Cu(I)-catalyzed cyclization, N-
propargylic β-enaminones afford pyridines via 6-endo-dig
cyclization.24 Saito and Martins’ research groups have investi-
gated Au(I)-catalyzed amino-Claisen rearrangements of N-tosyl,
N-propargylic β-enaminones and Ag(I)-catalyzed cyclizations of
N-alkyl/aryl, N-propargylic β-enaminones, respectively, both of
which have yielded 1,2-dihydropyridines.25 N-Propargylic β-
enaminoesters have also been frequently used in the same manner
to synthesize pyridines and 1,2-dihydropyridines.26
1. Introduction
Pyridines represent
a privileged class of heterocyclic
compounds, and emerge in many naturally occurring bioactive
molecules and medicinal compounds.1 Indeed, pyridines have a
range of applications in many areas of chemistry, including
catalysis, drug design and synthesis, molecular recognition, and
material science.2 Pyridines are also important components of
structurally diverse natural products such as Diploclidine and
Nakinadine A.3 Moreover, many pyridine-based alkaloid natural
products are the derivatives of nicotinic acid (called also vitamin
B3 and Niacin).4 Pyridines are widely used as building blocks as
well for pharmaceutical research since they occur in the
structures of a diverse range of pioneering drugs, including
anticancer Imatinib,5 antidiabetic Pioglitazone,6 antihistaminic
Desloratadine,7 antineoplastic and HIV antiviral Atazanavir,8
bone calcium regulator Risedronate,9 hipnotic and sedative
Eszopiclone,10 cholesterol and triglyceride regulator Niacin,11 and
antiulcerants Esomeprazole,12 Pantoprazole,13 Dexlansoprazole,14
Lansoprazole,15 Omeprazole16 and Rapeprazole.17 Pyridines are
also employed in the preparation of conjugated polymers and
functional materials which are often utilized in the light-emitting
devices (LEDs).18
In particular, aryl-substituted pyridines have attracted
considerable interest since the properly substituted derivatives
show antibacterial,27 antifungal,28 anti-inflammatory,29 anti-
malarial,30 antitumor,31 selective cannabinoid CB2 receptor
agonist,32 high potency calcium-sensing receptor antagonist,33
allosteric Akt1 and Akt2 kinase dual inhibitory,34 dipeptidyl
peptidase 4 (DPP-4) inhibitory,35 and sodium channel inhibitory
activities.36 Pyridinitril is a well known arylpyridine-type
fungicide.28 Etoricoxib, a simple derivative of arylpyridines, is a
new class nonsteroidal anti-inflammatory drug, which have a
Typical methods for the synthesis of pyridines involve the
approaches based either on the condensation of carbonyl
compounds with amines,19 or the cycloaddition of azadienes and
nitriles with alkenes and alkynes.20 In fact, over the years, many
100-fold selectivity for cyclooxygenase
2 (COX-2) over
———
Corresponding author. Tel.: +90-312-210-3213; fax: +90-312-210-3200; e-mail: zora@metu.edu.tr

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and Discussion
cyclooxygenase 1 (COX-1), presumably preventing the long
term side effects such as gastric ulceration, common to non-
selective COX inhibitors.29 Arylpyridine-based DPP-4 inhibitors
are a class of oral hypoglycemics that block DPP-4, which can be
used to treat diabetes mellitus type 2.35 Some terpyridines and the
related aryl-substituted pyridines have displayed strong antitumor
cytotoxicities against several human cancer cell lines or strong
topoisomerase I or II inhibitory activities.31 However, from the
structure-activity relationships, it has been concluded that the
number of aryl groups attached to pyridine core plays an
important role for their biological activities. For instance, the
corresponding pyridines bearing three aryl groups have exhibited
stronger biological activity as compared to those containing two
aryl groups.31 Notably, an increase in the number of aryl
substituents on the pyridine ring could result in beneficial
biological properties. Thus, numerous studies have been focused
on the polyarylation of pyridines since properly functionalized
derivatives could be potential drug substances.37 In this respect,
Suzuki-Miyaura38 cross-coupling reactions of halogenopyridines
with arylboronic acids allow for regiocontrolled aryl substitutions
at the halide- or pseudohalide- (functionally equivalent group)
containing positions of the pyridine rings.39 Arylation of
pyridines by the Suzuki-Miyaura reaction can be realized
between pyridinylboronic acids and arylhalides as well.40 In
addition, transition metal catalyzed or uncatalyzed direct
arylation of pyridines with convenient substrates provides rapid
access to arylated pyridines via C–H activation.41
Initially, we prepared the necessary 5-iodopyridines 4 from
α,β-alkynic ketones 1 according to a recent report as depicted in
Scheme 1.42 First, conjugate addition of propargylamine to α,β-
alkynic ketones 1 in refluxing methanol produced N-propargylic
β-enaminones 2 in 94-99% yields. Then palladium-catalyzed
cross-coupling of β-enaminones 2 with aryl iodides was carried
out at room temperature to provide the arylated β-enaminones 3
in 77-88% yields. Lastly, β-enaminones 3 were exposed to
iodine-mediated electrophilic cyclization in refluxing acetonitrile
to afford iodopyridines 4 in 62-80% yields (Scheme 1). For the
identity of R groups and yields, see Supplementary data.
After synthesizing 5-iodopyridines 4, we investigated their
Suzuki-Miyaura reaction with boronic acids for the rapid access
to 5-arylpyridines 6. In order to optimize the reaction conditions,
we first examined the reaction between iodopyridine 4a and
phenylboronic acid (5a) under different conditions as illustrated
in Table 1. It is worth mentioning that Suzuki-Miyaura cross-
coupling reactions have been examined with a variety of
catalysts, bases and solvents by researchers.38 Our literature
search45 indicated that palladium catalysts with triphenyl-
phosphine ligands, particularly PdCl2(PPh3)2, and bases in
bicarbonate salt form work quite efficiently in such reactions.
Moreover, instead of a palladium salt such as PdCl2, the use of a
palladium catalyst with triphenylphosphine ligands such as
PdCl2(PPh3)2 could have an inhibiting effect on the homo-
coupling of arylboronic acids.46 Additionally, the experiments
were performed under an argon atmosphere, which prevents
oxidative homocoupling of boronic acids as well.46 Accordingly,
after adopting PdCl2(PPh3)2 as catalyst and KHCO3 as base for
our coupling reactions, we started optimization reactions by
employing 5 mol% PdCl2(PPh3)2 and 1.4 equiv. of both boronic
acid and KHCO3, relative to starting 5-iodopyridine. Initially, the
reaction was conducted in DMF, THF, CH3CN and dioxane at
We have recently synthesized N-propargylic β-enaminones 3
from α,β-alkynic ketones 1 and investigated their regioselective
cyclization to 5-iodo-substituted pyridines 4 (Scheme 1).42 We
have found that when reacted with molecular iodine in the
presence of sodium bicarbonate, N-propargylic β-enaminones 3
experiences electrophilic cyclization to furnish 5-iodopyridines 4
in good to high yields. Iodocyclization has been found to be
general for a range of N-propargylic β-enaminones and allowed
the presence of a variety of aromatic, heteroaromatic and
aliphatic groups with electron-withdrawing and electron-donating
substituents.42 Admittedly, iodine-containing pyridines are very
attractive building blocks for the synthesis of diverse natural
products and pharmaceuticals since they present a platform for
the metal-catalyzed cross-coupling strategies that can elaborate
the corresponding molecules to more complex structures.43 In this
regard, the coupling of 5-iodopyridines with boronic acids,
classified as a Suzuki-Miyaura reaction,38 may offer a rapid entry
to a diverse range of 5-arylpyridines. As noted before,31
increasing the number of aryl groups on a potentially bioactive
molecule may provide the derivatives with pronounced or distinct
biological activities. Our continued interest44 in the synthesis of
new compounds as potential pharmaceuticals and scaffolds has
prompted us to investigate the Suzuki-Miyaura reaction between
5-iodopyridines and boronic acids. We herein report the full
details of this study.
o
room temperature, 110 C and/or refluxing conditions (Table 1,
Entries 1-5). These reactions went to completion in 10-24 h and
produced the expected 5-arylpyridine 6a in 60-85% yields, where
the highest yield of 6a was obtained in DMF at 110 oC. It should
be mentioned that 4:1 solvent/H2O combination, particularly 4:1
DMF/H2O, is widely used in these reactions.45 Then the same
reaction was examined in 4:1 DMF/H2O, THF/H2O, CH3CN/H2O
and dioxane/H2O at 110 oC or refluxing conditions (Table 1,
Entries 6-9). The reaction in DMF/H2O (4:1) yielded arylpyridine
6a in 94% yield (Table 1, Entry 6), which was the highest yield
of 6a obtained from these reactions. Moreover, this reaction in
DMF/H2O (4:1) went to completion in 8 h, but others required
longer reaction times (15-18 h). After choosing DMF/H2O (4:1)
as the reaction solvent, we determined the effective number of
equivalents of boronic acid in the reaction. When the reaction
was performed in turn with 1.0 and 2.0 equiv. of boronic acid 5a,
it produced arylpyridine 6a in 88% and 94% yields, respectively
(Table 1, Entries 10 and 11). Clearly, the lower number of
equivalents (1.0 equiv.) of boronic acid decreased the yield of 6a
while a higher number of equivalents (2.0 equiv.) did not
improve the yield. Hence, in the reactions, 1.4 equiv. of boronic
acid was used. The reaction was conducted in the presence of
different catalysts as well. When the reaction was run with
Pd(OAc)2 and Pd(PPh3)4, arylpyridine 6a was obtained in 86%
and 89% yields, respectively (Table 1, Entries 12 and 13), the
yields of which were relatively lower as compared to that with
PdCl2(PPh3)2. When the equivalency of base, KHCO3, was
lowered to 1.0, arylpyridine 6a was produced in comparatively
low yield (87%) (Table 1, Entry 14). At last, different bases were
tested in the reaction. When the reaction was applied in the
presence of NaHCO3 and K2CO3, arylpyridine 6a was obtained in
2
R
H
NH
C
R I
2
3
o
O
O
CH OH, 65
PdCl (PPh )
3
2
3 2
2
1
R
R
NH
1
CuI, Et N
3
DMF, r.t.
R
1
H
2
2
R
3
R
O
1
O
I , NaHCO
2
3
I
2
1
R
R
NH
o
CH CN, 82
C
3
R
N
3
R
4
3
Scheme 1. Synthesis of iodopyridines from α,β-alkynic ketones.

3
Table 1. Optimization studies for Suzuki-Miyaura reaction of
iodopyridine 4a with phenylboronic acid (5a).a
derivatives of fluorine-containing pyridines, 6d and 6m, were
ACCEPTED MANUSCRIPT
synthesized in 72% and 98% yields, respectively (Table 2,
Entries 4 and 13). Since thiophenes are often used as building
blocks in a variety of pharmaceuticals, agrochemicals and
materials science,48 we synthesized two derivatives of 5-
(thiophen-3-yl)pyridines, 6h and 6o, in 84-87% yields (Table 2,
Entries 8 and 15). We also synthesized 5-ferrocenyl-substituted
pyridine derivative 6i in 88% yield (Table 1, Entry 9). Notably,
ferrocenyl-substituted pyridines may have great potential for
biological and medicinal studies since, according to previous
studies,49 the incorporation of a ferrocenyl group into potentially
bioactive molecules may improve the current biological activities
or generate new medicinal properties. In brief, by employing
Suzuki-Miyaura approach, we achieved the synthesis of eighteen
new derivatives of heavily substituted 5-arylpyridines 6 from the
corresponding iodopyridines 4 and boronic acids 5 in good to
excellent yields.
O
Ph
O
Ph
I
Ph
Catalyst, Base
Ph
Ph
Ph
Ph
Ph B(OH)2
+
Solvent
Temp., Time
N
N
5a
4a
6a
Entry Boronic Catalyst
Base
(equiv.)
Solvent
Temp. Time Yield
Acid
(5 mol%)
(oC)
(h)
24
10
18
18
12
8
(%)b
60
85
70
76
80
94
74
79
84
88
94
86
89
87
86
89
(equiv.)
1
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.0
2.0
1.4
1.4
1.4
1.4
1.4
PdCl2(PPh3)2 KHCO3 DMF
(1.4)
r.t.
2
PdCl2(PPh3)2 KHCO3 DMF
(1.4)
110
65
3
PdCl2(PPh3)2 KHCO3 THF
(1.4)
4
PdCl2(PPh3)2 KHCO3 CH3CN
(1.4)
82
3. Conclusion
5
PdCl2(PPh3)2 KHCO3 Dioxane 100
(1.4)
In summary, we have synthesized 5-iodopyridines and investi-
gated their Suzuki-Miyaura coupling with boronic acids. 5-Iodo-
pyridines were prepared by conjugate addition of propargylamine
to α,β-alkynic ketones, followed by metal-catalyzed cross-
coupling of the resulting N-propargylic β-enaminones with aryl
iodides, and then electrophilic cyclization with molecular iodine.
Afterwards, we have investigated the feasibility of Suzuki-
Miyaura cross-coupling reactions of 5-iodopyridines with
boronic acids. The reactions were accomplished by using 5 mol%
PdCl2(PPh3)2, and 1.4 equiv. of both boronic acids and KHCO3,
relative to starting 5-iodopyridine, in 4:1 DMF/H2O solution at
6
PdCl2(PPh3)2 KHCO3 DMF/H2O 110
(1.4)
(4:1)
7
PdCl2(PPh3)2 KHCO3 THF/H2O 65
18
18
15
8
(1.4) (4:1)
8
PdCl2(PPh3)2 KHCO3 CH3CN/
(1.4) H2O (4:1)
82
9
PdCl2(PPh3)2 KHCO3 Dioxane/ 100
(1.4) H2O (4:1)
o
10
11
12
13
14
15
16
PdCl2(PPh3)2 KHCO3 DMF/H2O 110
(1.4) (4:1)
110 C. Indeed, Suzuki-Miyaura coupling reactions between 5-
iodopyridines and boronic acids proceeded well and afforded 5-
arylpyridines in good to excellent yields. The reactions were
found to be general for a diverse range of iodopyridines and
boronic acids, and tolerated a variety of substituents with
electron-withdrawing and electron-donating groups. In
conclusion, the chemistry developed here is very versatile and
accommodates various functional groups, which can be used for
the generation of the corresponding pyridine libraries.
Furthermore, the synthesized arylpyridines have great potential to
act as new pharmacophores and scaffolds in medicinal chemistry.
PdCl2(PPh3)2 KHCO3 DMF/H2O 110
(1.4) (4:1)
8
Pd(OAc)2
KHCO3 DMF/H2O 110
(1.4) (4:1)
8
Pd(PPh3)4
KHCO3 DMF/H2O 110
(1.4) (4:1)
8
PdCl2(PPh3)2 KHCO3 DMF/H2O 110
(1.0) (4:1)
8
PdCl2(PPh3)2 NaHCO3 DMF/H2O 110
8
(1.4)
(4:1)
4. Experimental section
4.1. General information
PdCl2(PPh3)2 K2CO3
(1.4)
DMF/H2O 110
(4:1)
8
1H and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively. Chemical shifts are reported relative to CDCl3 (7.26
and 77.16 ppm in 1H and 13C NMR, respectively). Coupling
constants (J) are reported in Hertz (Hz), and spin multiplicities
are presented by the following symbols: s (singlet), br s (broad
singlet), d (doublet), t (triplet), q (quartet), m (multiplet). DEPT
13C NMR information is given in parentheses as C, CH, CH2 and
CH3. Infrared spectra (IR) were recorded by using attenuated
total reflection (ATR). Band positions are reported in reciprocal
centimeters (cm-1). Mass spectra (MS) and high resolution mass
spectra (HRMS) were obtained by using Electrospray Ionization
(ESI) with Micro-Tof; m/z values are reported (For each
measurement, the mass scale was recalibrated with sodium
formate clusters, and samples were dissolved and measured in
CH3CN or MeOH). Flash chromatography was performed using
thick-walled glass columns and “flash grade” silica (230-400
mesh). Thin layer chromatography (TLC) was performed by
using commercially prepared 0.25 mm silica gel plates and
visualization was effected with short wavelength UV lamp (254
nm). The relative proportions of solvents in chromatography
solvent mixtures refer to the volume:volume ratio. All
a The optimization reactions were carried out on a 0.25 mmol scale of
iodopyridine 4a under the indicated conditions.
b Isolated yield.
relatively lower yields (86-89%). (Table 1, Entries 15 and 16). In
brief, Suzuki-Miyaura coupling reactions of 5-iodopyridines 4
were carried out with 5 mol% PdCl2(PPh3)2 and 1.4 equiv. of both
boronic acid 5 and KHCO3, with respect to iodopyridine 4, in 4:1
DMF/H2O at 110 oC (i.e., with the conditions in Entry 6 of Table
1). The results from a systematic study are depicted in Table 2.
As shown in Table 2, a diverse range of arylpyridines 6 were
synthesized by employing a variety of iodopyridines 4 and
boronic acids 5. In nearly all, coupling reactions proceeded
effectively and furnished the corresponding arylpyridines 6 in
good to excellent yields (65-98%). Notably, coupling reactions
were general for a wide range of iodopyridines and boronic acids
and allowed the presence of a variety of groups with electron-
withdrawing and electron-donating substituents. The integration
of fluorine-bearing substituents into organic compounds could
result in beneficial biological properties.47 Accordingly, two

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 2. Synthesis of 5-arylpyridines from 5-iodopyridines via Suzuki-Miyaura reaction.
O
R3
O
R3
PdCl2(PPh3)2
KHCO3
R4
I
R2
R2
R4
+
B(OH)2
R1
R1
DMF/H2O (4:1)
110 oC
N
N
5
4
6
Entry
1
Iodopyridine
Boronic Acid
Arylpyridine
% Yielda
O
O
I
B(OH)
2
94
N
N
5a
6a
4a
Et
O
Et
B(OH)
2
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
98
87
72
75
80
83
87
88
N
5b
5c
6b
Cl
O
Cl
B(OH)
2
N
6c
OEt
F
F
O
EtO
B(OH)2
N
5d
5e
6d
OMe
O
N
N
MeO
B(OH)2
N
6e
O2N
O
NO2
B(OH)2
N
5f
6f
O
O
O
B(OH)2
O
O
N
5g
6g
S
B(OH)2
S
N
5h
6h
Fe
B(OH)
2
Fe
N
5i
6i

5
ACCEPTED MANUSCRIPT
Entry
10
Iodopyridine
Boronic Acid
Arylpyridine
% Yielda
O
O
I
5a
85
N
N
MeO
MeO
6j
4b
4b
Et
O
11
12
13
14
15
5b
5c
5d
5g
5h
82
65
98
75
84
N
MeO
6k
Cl
O
4b
4b
4b
4b
N
MeO
6l
OEt
F
O
N
MeO
6m
O
O
N
MeO
6n
O
S
N
MeO
6o
O
O
I
16
17
5a
5b
77
78
N
N
S
S
6p
4c
4c
Et
O
N
S
6q
O
O
I
18
5a
80
N
N
6r
4d
a Isolated yield.

6
Tetrahedron
commercially available reagents were used directly without
KHCO3 (24.2 mg, 0.242 mmol) and PdCl2(PPh3)2 (6.1 mg, 0.009
ACCEPTED MANUSCRIPT
purification unless otherwise stated. All the solvents used in
reactions and chromatography were distilled and/or dried
properly for purity. The inert atmosphere was created by slight
positive pressure (ca. 0.1 psi) of argon. All glassware was dried
in an oven prior to use.
mmol) were employed to afford 67.0 mg (87%) of the indicated
product as a yellowish white solid (Rf = 0.30 in 9:1 hexane/ethyl
o
1
acetate): mp 224–225 C. H NMR (400 MHz, CDCl3) δ 8.85 (s,
1H), 7.61–7.55 (m, 2H), 7.54 – 7.50 (m, 2H), 7.39–7.33 (m, 1H),
7.31–7.18 (m, 8H), 7.14–6.54 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 197.0 (CO), 155.9 (C), 150.6 (CH), 147.1 (C), 139.3
(C), 137.7 (CH), 135.7 (C), 135.6 (C), 134.6 (C), 134.1 (C),
133.9 (C), 133.3 (CH), 131.3 (CH), 129.4 (CH), 129.3 (CH),
128.8 (CH), 128.6 (CH), 128.4 (CH), 128.3 (CH), 128.1 (C),
128.0 (CH) (Note that two carbon peaks overlap with each other);
IR (neat) 3051, 1671, 1578, 1557, 1440, 1322, 1217, 1093, 1011,
947, 832, 807, 762, 697, 585, 527 cm-1; MS (ESI, m/z): 446.13
[M+H]+; HRMS (ESI) calcd. for C30H21ClNO: 446.1306 [M+H]+,
found: 446.1318.
4.2. General procedure for the synthesis of 5-arylpyridines 6
(Table 2)
To a stirred solution of the proper 5-iodopyridine 4 (0.25
mmol) and boronic acid 5 (0.35 mmol) in 4:1 DMF/H2O (5 mL)
under argon was added KHCO3 (0.35 mmol) and PdCl2(PPh3)2
(0.0125 mmol). Then the resulting reaction mixture was heated at
o
110 C for approximately 8 h. The reaction was followed by
frequent TLC analysis for the completion of the reaction. When
the reaction was over, the mixture was quenched with saturated
aqueous NaCl solution (30 mL), and extracted with ethyl acetate
(2 x 30 mL). The combined organic layers were dried over
MgSO4 and evaporated on a rotary evaporator. The resulting
crude product was purified by flash chromatography on silica gel
using hexane/ethyl acetate (9:1 followed by 4:1) as the eluent to
afford the corresponding 5-arylpyridine 6.
4.2.4.
(5-(4-Ethoxy-3-fluorophenyl)-2,4-diphenylpyridin-3-
yl)(phenyl)methanone (6d) (Table 2, Entry 4). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (73.0 mg, 0.158
mmol), 4-ethoxy-3-fluorophenylboronic acid (5d) (40.7 mg,
0.221 mmol), KHCO3 (22.1 mg, 0.221 mmol) and PdCl2(PPh3)2
(5.5 mg, 0.008 mmol) were employed to afford 53.0 mg (72%) of
the indicated product as a brown solid (Rf = 0.16 in 9:1
hexane/ethyl acetate): mp 117–119 oC. 1H NMR (400 MHz,
CDCl3) δ 8.74 (s, 1H), 7.50–7.45 (m, 2H), 7.44–7.39 (m, 2H),
7.25 (t, J = 7.4 Hz, 1H), 7.21–7.14 (m, 4H), 7.10 (t, J = 7.7 Hz,
3H), 6.98 (t, J = 7.1 Hz, 2H), 6.82–6.50 (m, 4H), 3.97 (q, J = 7.0
Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
4.2.1. Phenyl(2,4,5-triphenylpyridin-3-yl)methanone (6a) (Table
2, Entry 1). (5-Iodo-2,4-diphenylpyridin-3-yl)(phenyl)methanone
(4a) (141.0 mg, 0.305 mmol), phenylboronic acid (5a) (52.1 mg,
0.427 mmol), KHCO3 (42.7 mg, 0.427 mmol) and PdCl2(PPh3)2
(10.7 mg, 0.015 mmol) were employed to afford 117.5 mg (94%)
of the indicated product as a off-white solid (Rf = 0.24 in 9:1
1
197.1 (CO) , 155.5 (CH), 152.1 (d, JCF = 246.6 Hz, C) , 150.6
(CH) , 147.0 (CH) , 146.5 (d, 2JCF = 10.8 Hz, C), 139.2 (C), 137.7
(CH), 135.8 (CH), 134.6 (C), 133.9 (C), 133.2 (CH), 129.7 (d,
3JCF = 6.9 Hz, C), 129.4 (CH), 129.3 (CH), 128.8 (C), 128.4
hexane/ethyl acetate): mp 169–170 C. 1H NMR (400 MHz,
o
CDCl3) δ 8.78 (s, 1H), 7.51–7.46 (m, 2H), 7.44 (d, J = 7.9 Hz,
2H), 7.25 (t, J = 7.3 Hz, 1H), 7.21–7.04 (m, 13H), 6.99–6.92 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 197.2 (CO), 155.6 (C),
150.8 (CH), 147.1 (C), 139.4 (C), 137.8 (C), 137.1 (C), 136.0
(C), 135.3 (C), 134.5 (C), 133.2 (CH), 130.1 (CH), 129.4 (CH),
129.3 (CH), 128.7 (CH), 128.4 (CH), 128.3 (CH), 128.26 (CH),
127.9 (CH), 127.8 (CH), 127.5 (CH) (Note that two carbon peaks
overlap with each other); IR (neat) 3049, 1672, 1595, 1529,
1433, 1371, 1317, 1217, 1172, 1024, 948, 753, 722, 695, 578,
516 cm-1; MS (ESI, m/z): 412.17 [M+H]+; HRMS (ESI) calcd.
for C30H22NO: 412.1696 [M+H]+, found: 412.1707.
4
(CH), 128.3 (CH), 128.0 (C), 127.8 (CH), 125.9 (d, JCF = 3.4
Hz, CH), 117.8 (d, JCF = 19.5 Hz, CH), 114.3 (C), 114.2 (C),
64.9 (CH2), 14.8 (CH3); IR (neat) 2980, 1736, 1666, 1595, 1513,
1440, 1390, 1298, 1243, 1139, 1042, 976, 922, 754, 692, 606,
523 cm-1; MS (ESI, m/z): 474.19 [M+H]+; HRMS (ESI) calcd.
for C32H25FNO2: 474.1864 [M+H]+, found: 474.1874.
2
4.2.5.
(6'-Methoxy-4,6-diphenyl-[3,3'-bipyridin]-5-
yl)(phenyl)methanone (6e) (Table 2, Entry 5). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (73.0 mg, 0.157
mmol), 6-methoxy-3-pyridinylboronic acid (5e) (33.7 mg, 0.220
mmol), KHCO3 (22.0 mg, 0.220 mmol) and PdCl2(PPh3)2 (5.5
mg, 0.008 mmol) were employed to afford 52.0 mg (75%) of the
indicated product as a yellowish brown solid (Rf = 0.10 in 9:1
hexane/ethyl acetate): mp 152–154 oC. 1H NMR (400 MHz,
CDCl3) δ 8.85 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.60–7.55 (m,
2H), 7.55–7.50 (m, 2H), 7.38–7.32 (m, 1H), 7.29–7.25 (m, 3H),
7.24–7.17 (m, 4H), 7.14– 6.66 (m, 4H), 6.57 (d, J = 8.6 Hz, 1H),
3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.0 (CO), 163.5
(CH), 155.9 (C), 150.4 (CH), 147.4 (C), 147.2 (CH), 140.0 (CH),
139.2 (C), 139.1 (C), 137.6 (C), 135.6 (CH), 134.7 (C), 133.3
(CH), 131.8 (C), 129.4 (CH), 129.3 (CH), 128.9 (C), 128.4 (CH),
128.3 (CH), 128.1 (CH), 127.9 (C), 126.0 (CH), 110.4 (CH), 53.6
(CH3); IR (neat) 2979, 1666, 1602, 1580, 1490, 1439, 1382,
1356, 1249, 1213, 1160, 1024, 947, 816, 751, 691, 582, 524 cm-1;
MS (ESI, m/z): 443.18 [M+H]+; HRMS (ESI) calcd. for
C30H23N2O2: 443.1754 [M+H]+, found: 443.1769.
4.2.2.
(5-(4-Ethylphenyl)-2,4-diphenylpyridin-3-
yl)(phenyl)methanone (6b) (Table 2, Entry 2). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (83.0 mg, 0.180
mmol), 4-ethylphenylboronic acid (5b) (37.7 mg, 0.252 mmol),
KHCO3 (25.2 mg, 0.252 mmol) and PdCl2(PPh3)2 (6.3 mg, 0.009
mmol) were employed to afford 77.4 mg (98%) of the indicated
product as a yellowish white solid (Rf = 0.26 in 9:1 hexane/ethyl
acetate): mp 164–165 C. H NMR (400 MHz, CDCl3) δ 8.78 (s,
1H), 7.50–7.45 (m, 2H), 7.45–7.41 (m, 2H), 7.27–7.21 (m, 1H),
7.21–7.14 (m, 4H), 7.13–7.06 (m, 2H), 7.03–6.57 (m, 8H), 2.51
(q, J = 7.6 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.3 (CO), 155.3 (C), 150.9 (CH), 147.0 (C), 143.6
(CH), 139.5 (C), 137.8 (C), 136.2 (C), 135.2 (C), 134.5 (C),
134.2 (C), 133.1 (CH), 130.0 (CH), 129.4 (CH), 129.3 (CH),
128.6 (C), 128.3 (CH), 128.25 (CH), 127.8 (CH), 127.77 (CH),
127.7 (CH), 28.5 (CH2), 15.4 (CH3) (Note that two carbon peaks
overlap with each other); IR (neat) 3050, 1670, 1557, 1524,
1435, 1315, 1285, 1215, 1019, 949, 833, 807, 752, 688, 544, 520
cm-1; MS (ESI, m/z): 440.20 [M+H]+; HRMS (ESI) calcd. for
C32H26NO: 440.2009 [M+H]+, found: 440.2007.
o
1
4.2.6.
(5-(3-Nitrophenyl)-2,4-diphenylpyridin-3-
yl)(phenyl)methanone (6f) (Table 2, Entry 6). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (91.0 mg, 0.197
mmol), 3-nitrophenylboronic acid (5f) (46.1 mg, 0.276 mmol),
KHCO3 (27.6 mg, 0.276 mmol) and PdCl2(PPh3)2 (6.9 mg, 0.010
mmol) were employed to afford 72.0 mg (80%) of the indicated
product as a white solid (Rf = 0.13 in 9:1 hexane/ethyl acetate):
4.2.3.
(5-(4-Chlorophenyl)-2,4-diphenylpyridin-3-
yl)(phenyl)methanone (6c) (Table 2, Entry 3). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (80.0 mg, 0.173
mmol), 4-chlorophenylboronic acid (5c) (37.9 mg, 0.242 mmol),

7
o
1
mp 168–169 C. H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H),
8.03–7.99 (m, 2H), 7.52–7.47 (m, 2H), 7.45–7.40 (m, 2H), 7.37
(dt, J = 7.7 and 1.4 Hz, 1H), 7.34–7.30 (m, 1H), 7.29–7.24 (m,
1H), 7.23–7.16 (m, 4H), 7.14–7.09 (m, 2H), 6.99 (t, J = 7.2 Hz,
2H), 6.94–6.42 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 196.7
(CO), 156.7 (C), 150.3 (CH), 148.2 (C), 147.4 (C), 139.0 (C) ,
138.9 (CH), 137.49 (C), 135.92 (CH), 135.07 (C), 134.70 (CH),
133.40 (CH), 132.93 (C), 129.35 (CH), 129.30 (CH), 129.25
(CH), 129.01 (CH), 128.43 (CH), 128.37 (CH), 128.34 (CH),
128.21 (C), 128.20 (C), 124.80 (CH), 122.51 (CH); IR (neat)
3059, 1672, 1557, 1535, 1447, 1346, 1321, 1216, 1176, 968, 881,
758, 737, 694, 582, 518 cm-1; MS (ESI, m/z): 457.16 [M+H]+;
HRMS (ESI) calcd. for C30H21N2O3: 457.1547 [M+H]+, found:
457.1560.
134.0 (C), 133.1 (CH), 132.8 (C), 129.4 (CH), 129.2 (CH),
ACCEPTED MANUSCRIPT
128.7 (C), 128.6 (CH), 128.3 (CH), 128.2 (CH), 128.0 (C), 127.9
(CH), 81.2 (CH), 69.9 (CH), 68.9 (CH) (Note that two carbon
peaks overlap with each other); IR (neat) 2925, 1669, 1615,
1593, 1557, 1443, 1427, 1363, 1250, 1046, 988, 894, 857, 758,
698, 572, 524 cm-1; MS (ESI, m/z): 520.14 [M+H]+; HRMS
(ESI) calcd. for. C34H26NOFe: 520.1359 [M+H]+, found:
520.1370.
4.2.10.
(2-(4-Methoxyphenyl)-4,5-diphenylpyridin-3-
yl)(phenyl)methanone (6j) (Table 2, Entry 10). (5-Iodo-2-(4-
methoxyphenyl)-4-phenylpyridin-3-yl)(phenyl)methanone (4b)
(174.0 mg, 0.354 mmol), phenylboronic acid (5a) (60.5 mg,
0.496 mmol), KHCO3 (49.6 mg, 0.496 mmol) and PdCl2(PPh3)2
(12.4 mg, 0.018 mmol) were employed to afford 130.0 mg (85%)
of the indicated product as a beige solid (Rf = 0.24 in 9:1
4.2.7.
(5-(Furan-2-yl)-2,4-diphenylpyridin-3-
1
yl)(phenyl)methanone (6g) (Table 2, Entry 7). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (96.5 mg, 0.209
mmol), 2-furanylboronic acid (5g) (32.8 mg, 0.293 mmol),
KHCO3 (29.3 mg, 0.293 mmol) and PdCl2(PPh3)2 (7.3 mg, 0.010
mmol) were employed to afford 70.0 mg (83%) of the indicated
product as an orange solid (Rf = 0.31 in 9:1 hexane/ethyl acetate):
hexane/ethyl acetate): mp 178–179 oC. H NMR (400 MHz,
CDCl3) δ 8.75 (s, 1H), 7.51–7.38 (m, 4H), 7.28–7.21 (m, 1H),
7.20– 6.99 (m, 9H), 6.94 (t, J = 7.0 Hz, 2H), 6.76–6.38 (m, 3H),
3.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.5 (CO), 160.0
(C), 155.1 (CH), 150.7 (CH), 147.0 (C), 137.8 (C), 137.1 (C),
136.0 (C), 134.7 (CH), 134.1 (C), 133.2 (CH), 131.9 (C), 130.7
(CH), 130.0 (CH), 129.4 (CH), 128.3 (CH), 128.2 (CH), 127.9
(C), 127.8 (C), 127.7 (CH), 127.4 (CH), 113.8 (CH), 55.3 (CH3);
IR (neat) 2927, 1668, 1606, 1513, 1432, 1316, 1253, 1214, 1176,
1030, 947, 837, 760, 698, 578, 518 cm-1; MS (ESI, m/z): 442.18
[M+H]+; HRMS (ESI) calcd. for C31H24NO2: 442.1802 [M+H]+,
found: 442.1817.
o
1
mp 175–176 C. H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H),
7.64–7.58 (m, 2H), 7.52–7.47 (m, 2H), 7.46–7.44 (m, 1H), 7.36
(m, 2H), 7.31–6.75 (m, 9H), 6.24 (dd, J = 3.5 and 1.8 Hz, 1H),
5.36 (dd, J = 3.5 and 0.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
196.8 (CO), 154.3 (C), 149.5 (C), 147.8 (CH), 144.5 (C), 142.7
(CH), 139.2 (CH), 137.7 (C), 136.1 (CH), 134.5 (C), 133.3 (CH),
129.3 (CH), 129.27 (CH), 128.8 (CH), 128.6 (C), 128.5 (C),
128.4 (CH), 128.3 (CH), 128.28 (CH), 124.4 (C), 111.8 (CH),
111.4 (CH); IR (neat) 2914, 1668, 1558, 1540, 1436, 1385, 1315,
1229, 1161, 1027, 960, 900, 768, 743, 698, 585, 523 cm-1; MS
(ESI, m/z): 402.15 [M+H]+; HRMS (ESI) calcd. for C28H20NO2:
402.1489 [M+H]+, found: 402.1497.
4.2.11. (5-(4-Ethylphenyl)-2-(4-methoxyphenyl)-4-phenylpyridin-
3-yl)(phenyl)methanone (6k) (Table 2, Entry 11). (5-Iodo-2-(4-
methoxyphenyl)-4-phenylpyridin-3-yl)(phenyl)methanone (4b)
(154.5 mg, 0.315 mmol), 4-ethylphenylboronic acid (5b) (66.1
mg, 0.440 mmol), KHCO3 (44.0 mg, 0.440 mmol) and
PdCl2(PPh3)2 (11 mg, 0.016 mmol) were employed to afford
121.0 mg (82%) of the indicated product as a pale yellow solid
(Rf = 0.32 in 9:1 hexane/ethyl acetate): mp 179–180 oC. 1H NMR
(400 MHz, CDCl3) δ 8.86 (s, 1H), 7.58–7.52 (m, 4H), 7.38–7.32
(m, 1H), 7.21 (t, J = 7.7 Hz, 3H), 7.11–6.90 (m, 7H), 6.86–6.53
(m, 3H), 3.75 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.5 (CO), 160.0 (C),
154.8 (C), 150.8 (CH), 147.0 (C), 143.5 (CH), 137.8 (C), 136.2
(CH), 134.7 (CH), 134.3 (C), 134.1 (C), 133.1 (CH), 132.0 (C),
130.7 (CH), 129.9 (CH), 129.4 (CH), 128.3 (CH), 127.9 (C),
127.8 (C), 127.7 (CH), 127.6 (C), 113.8 (CH), 55.3 (CH3), 28.5
(CH2), 15.3 (CH3); IR (neat) 2961, 1662, 1606, 1576, 1511, 1437,
1308, 1248, 1215, 1174, 1045, 948, 832, 763, 698, 682, 536 cm-1;
MS (ESI, m/z): 470.21 [M+H]+; HRMS (ESI) calcd. for
C33H28NO2: 470.2115 [M+H]+, found: 470.2132.
4.2.8.
(2,4-Diphenyl-5-(thiophen-3-yl)pyridin-3-
yl)(phenyl)methanone (6h) (Table 2, Entry 8). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (94.0 mg, 0.203
mmol), 3-thienylboronic acid (5h) (36.4 mg, 0.284 mmol),
KHCO3 (28.4 mg, 0.284 mmol) and PdCl2(PPh3)2 (7.1 mg, 0.010
mmol) were employed to afford 74.0 mg (87%) of the indicated
product as an off-white solid (Rf = 0.26 in 9:1 hexane/ethyl
acetate): mp 191–192 C. H NMR (400 MHz, CDCl3) δ 8.87 (s,
1H), 7.48 (d, J = 3.9 Hz, 2H), 7.43 (d, J = 7.4 Hz, 2H), 7.26 (t, J
= 7.2 Hz, 1H), 7.21–6.83 (m, 12H), 6.65 (d, J = 4.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 197.1 (CO), 155.3 (C), 150.4 (CH),
146.7 (C), 139.4 (C), 137.8 (C), 137.3 (C), 136.2 (CH), 134.6
(C), 133.2 (CH), 130.2 (C), 129.4 (CH), 129.3 (CH), 128.7 (CH),
128.6 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 128.06 (C),
125.5 (CH), 124.6 (CH) (Note that two carbon peaks overlap
with each other); IR (neat) 2980, 1736, 1666, 1595, 1529, 1440,
1390, 1372, 1243, 1139, 1042, 976, 922, 754, 692, 637, 523 cm-1;
MS (ESI, m/z): 418.13 [M+H]+; HRMS (ESI) calcd. for
C28H20NOS: 418.1260 [M+H]+, found: 418.1264.
o
1
4.2.12.
(5-(4-Chlorophenyl)-2-(4-methoxyphenyl)-4-
phenylpyridin-3-yl)(phenyl)methanone (6l) (Table 2, Entry 12).
(5-Iodo-2-(4-methoxyphenyl)-4-phenylpyridin-3-
yl)(phenyl)methanone (4b) (119.0 mg, 0.242 mmol), 4-
chlorophenylboronic acid (5c) (53.0 mg, 0.339 mmol), KHCO3
(33.9 mg, 0.339 mmol) and PdCl2(PPh3)2 (8.5 mg, 0.012 mmol)
were employed to afford 74.0 mg (65%) of the indicated product
as a dark beige solid (Rf = 0.41 in 9:1 hexane/ethyl acetate): mp
213–214 C. H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.55–
7.48 (m, 4H), 7.34 (t, J = 7.4 Hz, 1H), 7.24–7.15 (m, 6H), 7.06
(d, J = 8.5 Hz, 4H), 6.79 (d, J = 8.8 Hz, 2H), 6.66 (br s, 1H), 3.73
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.3 (CO), 160.2 (CH) ,
155.4 (C), 150.5 (CH), 147.1 (C), 137.7 (C), 135.8 (CH), 135.7
(C), 134.2 (C), 133.7 (C), 133.6 (C), 133.3 (CH), 131.8 (C),
131.3 (CH), 130.8 (CH), 130.1 (C), 129.4 (CH), 128.6 (CH),
128.4 (CH), 128.0 (C), 127.9 (CH), 113.9 (CH), 55.3 (CH3); IR
(neat) 2928, 1670, 1605, 1514, 1436, 1371, 1250, 1213, 1175,
4.2.9.
(5-(Ferrocenyl)-2,4-diphenylpyridin-3-
yl)(phenyl)methanone (6i) (Table 2, Entry 9). (5-Iodo-2,4-
diphenylpyridin-3-yl)(phenyl)methanone (4a) (96.0 mg, 0.208
mmol), ferrocene boronic acid (5i) (66.9 mg, 0.291 mmol),
KHCO3 (29.1 mg, 0.291 mmol) and PdCl2(PPh3)2 (7.3 mg, 0.010
mmol) were employed to afford 71.0 mg (88%) of the indicated
product as an orange solid (Rf = 0.36 in 9:1 hexane/ethyl acetate):
o
1
o
1
mp 146–148 C. H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H),
7.68–7.52 (m, 2H), 7.50–7.41 (m, 2H), 7.38–7.08 (m, 9H), 6.95
(br s, 1H), 6.67 (br s, 1H), 4.35 (br s, 1H), 4.29–3.95 (m, 7H),
3.73 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 197.4 (CO), 153.0
(C), 151.8 (CH), 145.9 (C), 139.5 (C), 137.8 (CH), 136.5 (C),

8
Tetrahedron
1094, 1029, 947, 828, 763, 698, 576, 523 cm-1; MS (ESI, m/z):
563 cm-1; MS (ESI, m/z): 448.14 [M+H]+; HRMS (ESI) calcd.
ACCEPTED MANUSCRIPT
476.14 [M+H]+; HRMS (ESI) calcd. for C31H23ClNO2: 476.1412
[M+H]+, found: 476.1420.
for C29H22NO2S: 448.1366 [M+H]+, found: 448.1359.
4.2.16.
(4,5-Diphenyl-2-(thiophen-3-yl)pyridin-3-
4.2.13.
(5-(4-Ethoxy-3-fluorophenyl)-2-(4-methoxyphenyl)-4-
yl)(phenyl)methanone (6p) (Table 2, Entry 16). (5-Iodo-4-phenyl-
2-(thiophen-3-yl)pyridin-3-yl)(phenyl)methanone (4c) (108.7
mg, 0.233 mmol), phenylboronic acid (5a) (39.7 mg, 0.326
mmol), KHCO3 (32.6 mg, 0.326 mmol) and PdCl2(PPh3)2 (8.2
mg, 0.012 mmol) were employed to afford 74.0 mg (77%) of the
indicated product as a yellow solid (Rf = 0.37 in 9:1 hexane/ethyl
acetate): mp 172–174 C. H NMR (400 MHz, CDCl3) δ 8.74 (s,
1H), 7.50–7.46 (m, 2H), 7.45 (dd, J = 3.0 and 1.3 Hz, 1H), 7.34
(dd, J = 5.0 and 1.2 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.19–7.10
(m, 7H), 7.06 (m, 2H), 7.00–6.43 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 197.7 (CO), 150.8 (CH), 150.2 (C), 146.9 (C), 140.4
(C), 137.6 (C), 137.0 (C), 135.9 (CH), 135.0 (C), 133.8 (C),
133.4 (CH), 130.0 (CH), 129.4 (CH), 128.6 (CH), 128.5 (CH),
128.3 (CH), 127.9 (C), 127.8 (CH) 127.5 (CH), 126.5 (CH),
125.7 (CH) (Note that two carbon peaks overlap with each other);
IR (neat) 2920, 1672, 1594, 1556, 1528, 1438, 1316, 1220, 1174,
1023, 949, 813, 760, 698, 571, 520 cm-1; MS (ESI, m/z): 418.13
[M+H]+; HRMS (ESI) calcd. for C28H20NOS: 418.1260 [M+H]+,
found: 418.1262.
phenylpyridin-3-yl)(phenyl)methanone (6m) (Table 2, Entry 13).
(5-Iodo-2-(4-methoxyphenyl)-4-phenylpyridin-3-
yl)(phenyl)methanone (4b) (110.0 mg, 0.224 mmol), 4-ethoxy-3-
fluorophenylboronic acid (5d) (57.7 mg, 0.314 mmol), KHCO3
(31.4 mg, 0.314 mmol) and PdCl2(PPh3)2 (7.9 mg, 0.011 mmol)
were employed to afford 108.0 mg (98%) of the indicated
product as a pale yellow solid (Rf = 0.46 in 9:1 hexane/ethyl
o
1
acetate): mp 175–176 oC. H NMR (400 MHz, CDCl3) δ 8.82 (s,
1
1H), 7.61–7.48 (m, 4H), 7.42–7.29 (m, 1H), 7.26–7.15 (m, 3H),
7.13–6.96 (m, 2H), 6.95–6.54 (m, 7H), 4.05 (q, J = 7.0 Hz, 2H),
3.73 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.33 (CO), 160.0 (CH), 155.0 (CH), 153.3 (C), 152.1
(d, 1JCF = 245.9 Hz, C), 150.5 (CH), 146.9 (CH), 146.4 (d, 2JCF
=
10.0 Hz, C) , 137.7 (C) , 135.8 (C), 134.1 (C), 133.3 (C), 133.2
(CH), 131.8 (C), 130.7 (CH), 129.8 (d, 3JCF = 6.6 Hz, C) , 129.3
4
(CH) , 128.3 (CH), 127.9 (C), 127.85 (CH), 125.9 (d, JCF = 3.4
Hz, CH) , 117.7 (d, 2JC F = 19.5 Hz, CH), 114.2 (C), 113.8 (CH),
64.8 (CH2), 55.2 (CH3), 14.8 (CH3); IR (neat) 2933, 1666, 1528,
1518, 1426, 1395, 1267, 1219, 1179, 1029, 970, 884, 809, 765,
687, 543 cm-1; MS (ESI, m/z): 504.20 [M+H]+; HRMS (ESI)
calcd. for C33H27FNO3: 504.1970 [M+H]+, found: 504.1974.
4.2.17. (5-(4-Ethylphenyl)-4-phenyl-2-(thiophen-3-yl)pyridin-3-
yl)(phenyl)methanone (6q) (Table 2, Entry 17). (5-Iodo-4-phenyl-
2-(thiophen-3-yl)pyridin-3-yl)(phenyl)methanone (4c) (113.7
mg, 0.243 mmol), 4-ethylphenylboronic acid (5b) (51.0 mg,
0.340 mmol), KHCO3 (34.0 mg, 0.340 mmol) and PdCl2(PPh3)2
(8.5 mg, 0.012 mmol) were employed to afford 84.0 mg (78%) of
the indicated product as a yellow solid (Rf = 0.25 in 9:1
hexane/ethyl acetate): mp 145–147 oC. 1H NMR (400 MHz,
CDCl3) δ 8.84 (s, 1H), 7.60–7.56 (m, 2H), 7.55 (dd, J = 2.9 and
1.2 Hz, 1H), 7.43 (dd, J = 5.1 and 1.2 Hz, 1H), 7.39 (d, J = 7.4
Hz, 1H), 7.30–7.19 (m, 4H), 7.11–6.83 (m, 7H), 6.75 (d, J = 8.4
Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 197.8 (CO), 150.9 (CH), 149.9 (C),
146.8 (C) 143.6 (C), 140.4 (C), 137.6 (CH), 136.0 (CH), 135.0
(C), 134.2 (C), 133.8 (C), 133.4 (CH), 129.9 (CH), 129.4 (CH),
128.9 (C), 128.6 (CH), 128.4 (CH), 127.8 (CH), 127.76 (CH),
126.5 (CH), 125.7 (CH), 115.3 (C), 28.6 (CH2), 15.4 (CH3); IR
(neat) 2966, 1670, 1593, 1514, 1442, 1314, 1206, 1171, 1020,
930, 834, 808, 761, 701, 680, 606, 545 cm-1; MS (ESI, m/z):
446.16 [M+H]+; HRMS (ESI) calcd. for C30H24NOS: 446.1573
[M+H]+, found: 446.1567.
4.2.14. (5-(Furan-2-yl)-2-(4-methoxyphenyl)-4-phenylpyridin-3-
yl)(phenyl)methanone (6n) (Table 2, Entry 14). (5-Iodo-2-(4-
methoxyphenyl)-4-phenylpyridin-3-yl)(phenyl)methanone (4b)
(122.0 mg, 0.248 mmol), 2-furanylboronic acid (5g) (39.0 mg,
0.348 mmol), KHCO3 (34.8 mg, 0.348 mmol) and PdCl2(PPh3)2
(8.7 mg, 0.012 mmol) were employed to afford 80.0 mg (75%) of
the indicated product as a brownish red solid (Rf = 0.39 in 9:1
hexane/ethyl acetate): mp 150–151 oC. 1H NMR (400 MHz,
CDCl3) δ 9.32 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.5
Hz, 2H), 7.44 (d, J = 1.4 Hz, 1H), 7.37 (t, J = 7.3 Hz, 2H), 7.30–
7.16 (m, 4H), 7.07 (br s, 1H), 6.79 (d, J = 8.5 Hz, 3H), 6.22 (dd,
J = 3.4 and 1.7 Hz, 1H), 5.32 (d, J = 3.4 Hz, 1H), 3.74 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 197.0 (CO), 160.1 (CH), 153.7
(C), 149.5 (C), 147.6 (CH), 144.6 (C), 142.6 (CH), 137.7 (C),
136.1 (CH), 134.1 (C), 133.3 (CH), 131.6 (C), 130.7 (CH), 129.3
(CH), 128.5 (C), 128.48 (C), 128.4 (CH), 128.3 (CH), 124.0 (C),
113.9 (CH), 111.7 (CH), 111.2 (CH), 55.3 (CH3); IR (neat) 2918,
1662, 1607, 1579, 1513, 1489, 1437, 1306, 1249, 1226, 1174,
1026, 956, 898, 839, 747, 698, 688, 574 cm-1; MS (ESI, m/z):
432.16 [M+H]+; HRMS (ESI) calcd. for C29H22NO3: 432.1594
[M+H]+, found: 432.1596.
4.2.18.
(4'-(Cyclopentylmethyl)-[1,1':2',1''-terphenyl]-3'-
yl)(phenyl)methanone (6r) (Table 2, Entry 18). (3-
(Cyclopentylmethyl)-6-iodo-[1,1'-biphenyl]-2-
4.2.15. (2-(4-Methoxyphenyl)-4-phenyl-5-(thiophen-3-yl)pyridin-
3-yl)(phenyl)methanone (6o) (Table 2, Entry 15). (5-Iodo-2-(4-
methoxyphenyl)-4-phenylpyridin-3-yl)(phenyl)methanone (4b)
(148.0 mg, 0.301 mmol), 3-thienylboronic acid (5h) (54.0 mg,
0.422 mmol), KHCO3 (42.2 mg, 0.422 mmol) and PdCl2(PPh3)2
(10.5 mg, 0.015 mmol) were employed to afford 99.0 mg (84%)
of the indicated product as a beige solid (Rf = 0.35 in 9:1
yl)(phenyl)methanone (4d) (230.0 mg, 0.492 mmol), phenyl-
boronic acid (5a) (84.0 mg, 0.690 mmol), KHCO3 (69.0 mg,
0.690 mmol) and PdCl2(PPh3)2 (17.3 mg, 0.025 mmol) were
employed to afford 164.0 mg (80%) of the indicated product as a
brownish white solid (Rf = 0.34 in 9:1 hexane/ethyl acetate): mp
1
117–118oC. H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.59–
7.54 (m, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 7.7 Hz, 2H),
7.23–7.16 (m, 3H), 7.15–7.10 (m, 3H), 6.99 (t, J = 6.4 Hz, 2H),
6.94–6.52 (m, 3H), 2.88–2.53 (m, 2H), 2.45 (septet, J = 7.7 Hz,
1H), 1.82–1.35 (m, 6H), 1.33–1.02 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 197.9 (CO), 157.4 (CH), 150.3 (CH), 145.8 (C), 137.5
(C), 137.1 (C), 136.1 (CH), 134.6 (C), 133.8 (C), 133.4 (CH),
129.9 (CH), 129.3 (CH), 128.4 (CH), 128.2 (CH), 127.7 (C),
127.72 (C), 127.6 (CH), 127.2 (CH), 41.7 (CH2), 40.1 (CH), 32.6
(CH2), 24.9 (CH2); IR (neat) 2943, 1667, 1578, 1559, 1439, 1316,
1273, 1213, 1027, 951, 758, 699, 568 cm-1; MS (ESI, m/z):
418.22 [M+H]+; HRMS (ESI) calcd. for C30H28NO: 418.2165
[M+H]+, found: 418.2162.
1
hexane/ethyl acetate): mp 197–198 oC. H NMR (400 MHz,
CDCl3) δ 8.92 (s, 1H), 7.56–7.48 (m, 4H), 7.37–7.30 (m, 1H),
7.23–7.16 (m, 3H), 7.15–7.07 (m, 3H), 7.03 (dd, J = 3.0 and 1.3
Hz, 1H), 7.00–6.87 (m, 1H), 6.85–6.74 (m, 3H), 6.71 (dd, J = 5.0
and 1.3 Hz, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
197.3 (CO), 160.1 (C), 154.7 (C), 150.2 (CH), 146.8 (C), 137.8
(C), 137.3 (CH), 136.2 (CH), 134.2 (C), 133.2 (CH), 131.8 (C),
130.7 (CH), 129.7 (C), 129.4 (CH), 128.6 (CH), 128.3 (CH),
128.2 (C), 128.0 (CH), 127.9 (C), 125.4 (CH), 124.4 (CH), 113.9
(CH), 55.3 (CH3); IR (neat) 3050, 1667, 1605, 1575, 1511, 1438,
1375, 1294, 1250, 1227, 1177, 1028, 971, 895, 837, 771, 699,

9
Acknowledgments
ACCEPTED MANUSCRIPT
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We thank the Scientific and Technical Research Council of
Turkey (110T113) and the Research Board of Middle East
Technical University (METU) (BAP-2011-07-02-00-01) for
financial support of this research, and Research Assistant Yılmaz
Kelgökmen for technical support.
Supplementary data
Supplementary data (synthesis of iodopyridines 4, copies of
1H and 13C NMR spectra for aryl-substituted pyridines 6 and
copies of COSY, HSQC and HMBC NMR spectra for pyridines
6a and 6l) related to this article can be found at
http://dx.doi.org/xxx.
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4324.
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ACCEPTED MANUSCRIPT
SUPPLEMENTARY MATERIAL
for
Facile synthesis of aryl-substituted pyridines
via Suzuki-Miyaura approach
Eda Karadeniz, Metin Zora*, Nihan Zülay Kılıçaslan
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
Table of Contents
Synthesis of 5-iodopyridines 4 ……........................................................................................…… S2-S4
Synthesis of 5-iodopyridine 4d ……......................................................................................….… S5-S7
Copies of 1H and 13C NMR spectra ………………….........………….…………….............…… S8-S29
Copies of COSY, HSQC and HMBC NMR spectra ………………….........…..….............……S30-S35
*Corresponding author. Fax: +90-312-2103200; Tel: +90-312-2103213; E-mail: zora@metu.edu.tr
S1

ACCEPTED MANUSCRIPT
Synthesis of 5-iodopyridines 4.
5-Iodopyridines 4a-d used in this study were synthesized from α,β-alkynic ketones 1a-d
according to our recent report1 or in this study, as depicted in Tables 1, 2 and 3.
N-Propargylic β-enaminones 2a-c (Table 1, Entries 1-3), N-propargylic β-enaminones 3a-c (Table
2, Entries 1-3) and 5-iodopyridines 4a-c (Table 3, Entries 1-3) were prepared according to our previous
report.1 For their experimental procedures, spectral data, and 1H and 13C NMR spectra, see that report1
and its Supplementary Material.
Note that N-propargylic β-enaminone 2d (Table 1, Entry 4), N-propargylic β-enaminone 3d
(Table 1, Entry 4) and 5-iodopyridine 4d (Table 3, Entry 4) was synthesized in this study. For their
experimental procedures, spectral data and 1H and 13C NMR spectra, see this Supplementary Material.
Table 1. Synthesis of N-propargylic β-enaminones 2 from α,β-alkynic ketones 1 via conjugate
addition of propargylamine.
R2
O
O
H
NH2
R2
R1
NH
R1
CH3OH, 65 oC
1
2
H
Entry
Alkynone 1
β-Enaminone 2
%Yielda
Entry
Alkynone 1
β-Enaminone 2
%Yielda
O
O
O
O
1
98
3
4
94
NH
NH
S
S
1a
1c
H
H
2a
2c
O
O
O
O
2
98
99
NH
NH
H3CO
1d
H3CO
1b
H
H
2b
2d
aIsolated yield.
1. Karabiyikoglu, S.; Kelgokmen, Y.; Zora, M. Tetrahedron 2015, 71, 4324.
S2

ACCEPTED MANUSCRIPT
Table 2. Synthesis of N-propargylic β-enaminones 3 from β-enaminones 2 via Sonogashira reaction.
R2
R2
R3I
O
O
PdCl2(PPh3)2
R1
NH
R1
NH
CuI, Et3N
DMF, r.t.
H
R3
2
3
Entry β-Enaminone
Aryl
β-enaminone
%Yielda Entry
β-Enaminone
Aryl
β-Enaminone
%Yielda
iodide
iodide
2
3
2
3
O
I
O
O
O
I
NH
1
88
3
83
NH
NH
NH
S
S
H
H
2a
2c
3a
3c
O
I
I
O
O
O
NH
2
84
4
77
NH
NH
NH
H3CO
H3CO
H
H
2b
aIsolated yield.
2d
3d
3b
S3

ACCEPTED MANUSCRIPT
Table 3. Synthesis of 5-iodopyridines 4 from N-propargylic β-enaminones 3 via electrophilic
cyclization.
R2
O
R3
O
I2, NaHCO3
I
R2
R1
NH
CH3CN, 82 oC
R1
N
4
R3
3
Entry N-propargylic β-enaminone
5-Iodopyridine % Yielda
Entry N-propargylic β-enaminone 5-Iodopyridine % Yielda
3
4
3
4
O
O
O
O
I
I
NH
NH
1
80
3
75
N
N
S
S
4a
4c
3a
3c
O
O
O
O
I
I
NH
NH
2
62
4
66
N
N
H3CO
H3CO
4b
4d
3b
3d
aIsolated yield.
S4

ACCEPTED MANUSCRIPT
Synthesis of 5-iodopyridine 4d.
Synthesis of 4-cyclopentyl-1-phenylbut-2-yn-1-one (1d) (Table 1). A mixture of benzoyl chloride
(824.4 mg, 5.890 mmol), PdCl2(PPh3)2 (68.9 mg, 0.098 mmol) and Et3N (595.0 mg, 5.890 mmol) was
put in anhydrous THF (15 mL) and stirred for 10 min at room temperature under argon. Then CuI (18.6
mg, 0.098 mmol) was added and the resulting mixture was stirred for another 10 min. Afterward, 3-
cyclopentyl-1-propyne (530.0 mg, 4.910 mmol) was added over 15 min and the resulting mixture was
stirred at room temperature for approximately 6h (Note that the progress of the reaction was monitored
by routine TLC for the disappearance of 3-cyclopentyl-1-propyne). After the reaction was over, ethyl
acetate (50 mL) was added, and the resulting solution was washed with 0.1 N HCl (10 mL) and
subsequently with a saturated NH4Cl solution (10 mL) in a separatory funnel. After the layers were
separated, organic phase was dried over MgSO4 and evaporated on a rotary evaporator to give the
crude product, which was purified by flash chromatography on silica gel using hexane/ethyl acetate
1
(19:1) as the eluent to afford 787.0 mg (76%) of the indicated product as a yellow oil. H NMR (400
MHz, CDCl3) δ 8.13-8.08 (m, 2H), 7.56–7.51 (m, 1H), 7.45–7.39 (m, 2H), 2.45 (d, J = 6.9 Hz, 2H),
13
2.14 (septet, J = 7.5 Hz, 1H), 1.89–1.77 (m, 2H), 1.69–1.47 (m, 4H), 1.36–1.24 (m, 2H); C NMR
(100 MHz, CDCl3) δ 177.9 (CO), 136.8 (C), 133.7 (C), 129.3 (CH), 128.4 (CH), 96.2 (C), 79.6 (C),
38.3 (CH), 32.1 (CH2), 25.1 (CH2), 24.8 (CH2); IR (neat): 2948, 2865, 2232, 2197, 1640, 1596, 1579,
1448, 1261, 904, 698 cm-1; MS (ESI, m/z): 213.13 [M+H]+; HRMS (ESI) calcd. for C15H17O: 213.1274
[M+H]+, found 213.1278.
Synthesis of 4-cyclopentyl-1-phenyl-3-(prop-2-yn-1-ylamino)but-2-en-1-one (2d) (Table 1, Entry
4). To a stirred solution of 4-cyclopentyl-1-phenylbut-2-yn-1-one (1d) (637.0 mg, 3.000 mmol) in
absolute MeOH (10 mL) was added propargylamine (198.0 mg, 3.600 mmol) and the resulting mixture
o
was heated at 65 C for approximately 6 h (Note that the progress of the reaction was monitored by
routine TLC for the disappearance of 4-cyclopentyl-1-phenylbut-2-yn-1-one, 1d). After the reaction
was over, the solvent was removed on a rotary evaporator, and ethyl acetate (50 mL) and a saturated
NaCl solution (50 mL) were added. After the layers were separated, the aqueous layer was extracted
with ethyl acetate (3 x 50 mL). The combined organic layers were dried over MgSO4 and evaporated
on a rotary evaporator to give the crude product, which was purified by flash chromatography on silica
gel using hexane/ethyl acetate (9:1 followed by 4:1) as the eluent to afford 793.0 mg (99%) of the
S5

ACCEPTED MANUSCRIPT
indicated product as an orange oil. 1H NMR (400 MHz, CDCl3) δ 11.51 (d, J = 5.5 Hz, 1H), 7.95–7.79
(m, 2H), 7.52–7.29 (m, 3H), 5.76–5.68 (m, 1H), 4.12–3.98 (m, 2H), 2.43–2.27 (m, 3H), 2.19–2.01 (m,
1H), 1.94–1.74 (m, 2H), 1.72–1.45 (m, 4H), 1.36–1.00 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 187.9
(CO), 167.1 (C), 140.13 (C), 130.4 (CH), 127.9 (CH), 126.7 (CH), 92.5 (CH), 79.0 (C), 72.3 (C), 38.2
(CH2), 37.6 (CH), 32.4 (CH2), 32.1 (CH2), 24.6 (CH2). IR (neat): 3289, 2947, 2865, 1732, 1594, 1549,
1516, 1328, 1289, 1176, 1061, 1025, 742, 698, 661 cm-1; MS (ESI, m/z): 254.16 [M+H]+; HRMS (ESI)
calcd. for C18H22NO: 254.1540 [M+H]+, found: 254.1551.
Synthesis of 4-cyclopentyl-1-phenyl-3-((3-phenylprop-2-yn-1-yl)amino)but-2-en-1-one (3d) (Table
2, Entry 4). To a stirred solution of 4-cyclopentyl-1-phenyl-3-(prop-2-yn-1-ylamino)but-2-en-1-one
(2d) (323.0 mg, 1.200 mmol) in DMF (0.45 mL) at room temperature under argon was added (i-Pr)2NH
(2.4 mL), PdCl2(PPh3)2 (16.9 mg, 0.024 mmol) and CuI (4.6 mg, 0.024 mmol) in turn and the reaction
mixture was stirred for 10 min. The iodobenzene (382.0 mg, 1.870 mmol) was then added and the
resulting mixture was stirred at room temperature for approximately 3-5 h (Note that stirring was
continued until 4-cyclopentyl-1-phenyl-3-(prop-2-yn-1-ylamino)but-2-en-1-one (2d) was completely
consumed as monitored by routine TLC). After the reaction was over, ethyl acetate (50 mL) was added,
and the resulting solution was washed with 0.1 N HCl (10 mL) and subsequently with a saturated
NH4Cl solution (10 mL) in a separatory funnel. After the layers were separated, organic phase was
dried over MgSO4 and evaporated on a rotary evaporator to give the crude product, which was purified
by flash chromatography on silica gel using hexane/ethyl acetate (9:1 followed by 4:1) as the eluent to
afford 415.0 mg (77%) of the indicated product as a brownish orange oil. 1H NMR (400 MHz, CDCl3)
δ 11.65 (t, J = 5.6 Hz, 1H), 7.99–7.88 (m, 2H), 7.54–7.40 (m, 5H), 7.38–7.29 (m, 3H), 5.80 (s, 1H),
4.35 (d, J = 6.1 Hz, 2H), 2.48 (d, J = 7.4 Hz, 2H), 2.24 (septet, J = 7.7 Hz, 1H), 1.98–1.86 (m, 2H),
13
1.78–1.53 (m, 4H), 1.38–1.23 (m, 2H); C NMR (100 MHz, CDCl3) δ 188.4 (CO), 167.5 (C), 140.5
(C), 131.72 (CH), 130.6 (CH), 128.5 (CH), 128.3 (CH), 128.2 (CH), 127.0 (CH), 122.5 (C), 92.9 (CH),
84.6 (C), 84.1 (C), 38.6 (CH2), 38.0 (CH2), 33.2 (CH), 32.8 (CH2), 24.8 (CH2); IR (neat): 2948, 2865,
1734, 1594, 1578, 1551, 1238, 1175, 1061, 1025, 753, 690 cm-1; MS (ESI, m/z): 330.19 [M+H]+;
HRMS (ESI) calcd. for C24H26NO: 330.1852 [M+H]+, found: 330.1864.
S6

ACCEPTED MANUSCRIPT
Synthesis of (2-(cyclopentylmethyl)-5-iodo-4-phenylpyridin-3-yl)(phenyl)methanone (4d) (Table
3, Entry 4). To a stirred solution of 4-cyclopentyl-1-phenyl-3-((3-phenylprop-2-yn-1-yl)amino)but-2-
en-1-one (3d) (345.0 mg, 1.050 mmol) in acetonitrile (15 mL) were added iodine (799.1 mg, 3.100
o
mmol) and NaHCO3 (264.3 mg, 3.100 mmol). The resulting mixture was then refluxed at 82 C under
air for approximately 8-10 h (Note that stirring was continued until 4-cyclopentyl-1-phenyl-3-((3-
phenylprop-2-yn-1-yl)amino)but-2-en-1-one (3d) was completely consumed as monitored by routine
TLC). After the reaction was over, the solventwas removed on a rotary evaporator, and ethyl acetate
(30 mL) and a saturated aqueous solution of Na2S2O3 (30 mL) were added (Note that the treatment of
the reaction mixture with a saturated Na2S2O3 solution removes the unreacted and/or excess I2). After
the layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The
combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator to give the
crude product, which was purified by flash chromatography on silica gel using hexane/ethyl acetate
(9:1 followed by 4:1) as the eluent to afford 323.9 mg (66%) of the indicated product as an orange oil.
1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.48–7.41 (m, 1H), 7.29 (t, J =
7.6 Hz, 3H), 7.18 (t, J = 6.2 Hz, 2H), 7.14–6.81 (m, 2H), 2.65 (d, J = 6.8 Hz, 2H), 2.37 (septet, J = 7.7
Hz, 1H), 1.76–1.62 (m, 2H), 1.60–1.37 (m, 4H), 1.13 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 196.1
(CO), 158.0 (CH), 157.0 (CH), 150.9 (C), 139.1 (CH), 137.0 (C), 135.7 (C), 133.7 (CH), 129.3 (CH),
128.5 (CH), 128.5 (CH), 128.0 (C), 127.9 (C), 96.4 (C), 41.3 (CH2), 39.9 (CH), 32.4 (CH2), 24.9
(CH2); IR (neat): 2945, 2862, 1735, 1668, 1595, 1520, 1425, 1372, 1227, 1175, 880, 757, 696, 665, 546
cm-1; MS (ESI, m/z): 468.08 [M+H]+; HRMS (ESI) calcd. for C24H23INO: 468.0819 [M+H]+, found:
468.0826.
S7

ACCEPTED MANUSCRIPT
Copies of 1H and 13C NMR spectra
2.5
2.0
1.5
f1 (ppm)
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
f1 (ppm)
Figure S1. 1H NMR spectrum of compound 1d.
Figure S2. 13C NMR spectrum of compound 1d.
S8

ACCEPTED MANUSCRIPT
Figure S3. 1H NMR spectrum of compound 2d.
Figure S4. 13C NMR spectrum of compound 2d.
S9

ACCEPTED MANUSCRIPT
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
f1 (ppm)
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
f1 (ppm)
Figure S5. 1H NMR spectrum of compound 3d.
Figure S6. 13C NMR spectrum of compound 3d.
S10

ACCEPTED MANUSCRIPT
Figure S7. 1H NMR spectrum of compound 4d.
160
155
150
145
f1 (ppm)
140
135
210
200
190
180
170
160
150
140
130
120
110
100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
Figure S8. 13C NMR spectrum of compound 4d.
S11

ACCEPTED MANUSCRIPT
7.6
7.5
7.4
7.3 7.2
f1 (ppm)
7.1
7.0 6.9
6.8
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
f1 (ppm)
Figure S9. 1H NMR spectrum of compound 6a.
Figure S10. 13C NMR spectrum of compound 6a.
S12

ACCEPTED MANUSCRIPT
Figure S11. 1H NMR spectrum of compound 6b.
140
138
136
134
132
130
128
126
f1 (ppm)
210
200
190
180
170
160
150
140
130
120
110
100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
.
Figure S12. 13C NMR spectrum of compound 6b.
S13

ACCEPTED MANUSCRIPT
Figure S13. 1H NMR spectrum of compound 6c.
139
137
135
133
131
129
f1 (ppm)
210
200
190
180
170
160
150
140
130
120
110
100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
.
Figure S14. 13C NMR spectrum of compound 6c.
S14

ACCEPTED MANUSCRIPT
O
F
CH3
O
N
Figure S15. 1H NMR spectrum of compound 6d.
O
F
CH3
O
N
Figure S16. 13C NMR spectrum of compound 6d.
S15

ACCEPTED MANUSCRIPT
O
O
CH3
N
N
8.0
7.8
7.6
7.4
7.2
7.0
6.8
6.6
f1 (ppm)
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
f1 (ppm)
Figure S17. 1H NMR spectrum of compound 6e.
O
O
CH3
N
N
Figure S18. 13C NMR spectrum of compound 6e.
S16

ACCEPTED MANUSCRIPT
7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6
f1 (ppm)
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
f1 (ppm)
Figure S19. 1H NMR spectrum of compound 6f.
Figure S20. 13C NMR spectrum of compound 6f.
S17

ACCEPTED MANUSCRIPT
O
O
N
Figure S21. 1H NMR spectrum of compound 6g.
O
O
N
Figure S22. 13C NMR spectrum of compound 6g.
S18