Pd-Catalyzed Decarboxylation and Dual C(sp3)-H Functionalization Protocols for the Synthesis of 2,4-Diarylpyridines

Article abstract of DOI:10.1021/acs.joc.8b02971

The Pd-catalyzed decarboxylation and dual C(sp³)-H bond functionalization approaches have been described for the preparation of symmetrical and unsymmetrical 2,4-diarylpyridines. The developed transformations were realized using nonactivated aromatic ketones and amino acids as C-N sources. The efficacy of the catalyst and reagent combination drives the transformation toward the formation of desired products with high yields and selectivity. The described reaction conditions have seduced the self-reaction of phenylalanine via [2 + 2 + 2] cycloaddition and minimized the formation of 3,5-phenylpyridine as a side product, whereas using glycine as a C-N source, the corresponding 2,6-diarylpyridines were formed as minor products.

Full text of DOI:10.1021/acs.joc.8b02971

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Article
The Pd-Catalyzed Decarboxylation and Dual C(sp3)-H
Functionalization Protocols for the Synthesis of 2,4-Diarylpyridines
Raghuram Gujjarappa, Nagaraju Vodnala, MOHAN kumar, and Chandi Charan Malakar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02971 • Publication Date (Web): 22 Mar 2019
Downloaded from http://pubs.acs.org on March 22, 2019
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The Pd-Catalyzed Decarboxylation and Dual C(sp3)-H
Functionalization Protocols for the Synthesis of 2,4-Diarylpyridines
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Raghuram Gujjarappa, Nagaraju Vodnala, Mohan Kumar and Chandi C. Malakar*
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Department of Chemistry, National Institute of Technology Manipur, Langol, Imphal – 795004,
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Manipur, India
E-mail: chdeepm@gmail.com, cmalakar@nitmanipur.ac.in
ABSTRACT: The Pd-catalyzed decarboxylation and dual C(sp3)-H bond functionalization approaches
have been described for the preparation of symmetrical and unsymmetrical 2,4-diarylpyridines. The
developed transformations were realized using non-activated aromatic ketones and amino acids as C-N
source. The efficacy of the catalyst and reagent combination drives the transformation towards the
formation of desired products with high yields and selectivity. The described reaction conditions have
seduced the self-reaction of phenylalanine via [2+2+2] cycloaddition and minimized the formation of 3,5-
phenylpyridine as side product, whereas using glycine as C-N source the corresponding 2,6-
diarylpyridines were formed as minor products.
INTRODUCTION
Pyridines belong to the eminently crucial cast of biological important scaffolds among the heterocyclic
framework.1 Pyridine embedded molecules witnessed their occurrence in numerous natural products,2 in
the valued marketed drugs3 as well as in clinically approved pharmaceuticals.4 Medicinal impact of the
pyridines aroused from their naturally occurring congeners including niacin (vitamins B3), pyridoxine
(vitamin B6), nicotine and NADP.5 This is due to their decisive positions in the pivotal biological
mechanisms.5 Pyridine containing pharmaceuticals like isoniazide (anti-tuberculosis drug),6 amlodipine
(anti-hypertensive drug),7 loratadine (treating allergies)8 and crizotinib9 (treating lung cancer) are
associated to the treatment for several life-threatening diseases and biological disorders.10 In extension to
their prominent pharmacological properties, a number of pyridine analogues have been recognized as
agriculturally active agents.11 In recent years, pyridine scaffolds have received ample attention in material
science, especially towards the synthesis of functional materials.12 Moreover, the pyridine derivatives
could serve as unique ligands for the novel catalytic transformations;13 for example the first-row
transition-metals form distinct reactive complexes with pyridine derivatives and that drives to the
selective chemical transformations.14 Therefore, the renowned application of the pyridine scaffolds in
diverse field of research appeals their “easy-to-operate”, efficient and selective synthesis using simple
substrates.
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A broad spectrum of strategic methods have been described towards the synthesis of pyridine scaffolds
using diversely functionalized precursors. In the recent years, the field has gained noticeable attention in
the field of drug discovery research as well as in material chemistry. To serve this purpose, a number of
classical approaches rely on condensation of amines with carbonyl compounds have been reported. These
methods are well-recognized as Hantzsch pyridine synthesis,15 Chichibabin reaction,16 Vilsmeier-Haack
reaction17 and Bohlmann-Rahtz pyridine synthesis.18 In consideration with the modern synthetic tools, an
array of transition-metals such as Mn,19 Cu,20 Ti,21 Zr,22 Ni,23 Pd,24 Rh25 and Ru26 have been investigated
in varieties of transformations for the synthesis of functionalized pyridines. Among these methods, the
Ru-catalyzed cycloisomerization of 3-azadienynes,26a the Cu- or Pd-catalyzed reaction of oxime
carboxylates,20,24 Rh-catalyzed ring expansion,25a the metal catalyzed cycloaddition,27 and C−H
functionalization28 have gained remarkable attention to achieve the construction of pyridine derivatives.
In addition to the noticeable isolated yields associated to the previous reported protocols, some of the
methods suffer from the limitations such as, use of complex precursors for which the required synthetic
routes remains rather long with low isolated yields. In view of the structural diversification, investigation
of the chemical transformations with high selectivity towards specific regio-isomer is always of
significance especially in the method development. In this regards, a spectrum of synthetic strategies have
been established for the preparation of symmetrical and unsymmetrical pyridines using simple substrates
and various nitrogen source.15-28 Wu and co-workers recently described a novel method by the reaction
between carbonyl compounds and ammonium acetate using equivalent amounts of both Cu(NO3)2.3H2O
and molecular iodine as reagents in which DMSO acts as both solvent and C1-source (Scheme 1a).20d
Rychnovsky and co-workers reported a three steps method for the synthesis of functionalized pyridines
using enones from which 1,5-dicarbonyls are obtained via two step Hosomi-Sakurai allylation/oxidative
cleavage sequence. Finally, the cyclization reaction was carried out with hydroxylamine hydrochloride to
afford corresponding pyridines (Scheme 1b).21b Deng et al has demonstrated the chemoselective synthesis
of 2,4-disubstituted pyridines from the reaction between enones and oximes using I2/NEt3 as reagents
combination (Scheme 1c).29 The one-pot synthesis of 2,4-functionalized pyridines was demonstrated by
Deng and co-workers. The reaction was carried out using acetophenones, ammonium acetate and DMF as
substrates under the oxygen atmosphere (Scheme 1d).26d The 2,4-functionalized pyridines were also
obtained via inverse electron demand Diels–Alder/retro-Diels-Alder reactions of ketones with 1,2,4-
triazines using simple base as reagents (Scheme 1e).30 The previous reported methods or their modified
procedures are proved to be powerful and general for the synthesis of symmetrical and unsymmetrical
pyridines. However, using amino acids as C-N source the synthesis of pyridines is still remains rarely
explored.31 For the first time, Wang and coworkers have explored the synthesis of 2,3,5-trisubstituted
pyridines using amino acids as N-source by the reaction of amino acids with aryl/alkyl aldehydes in the
presence of I2/TBHP catalyzed reaction conditions (Scheme 1f).31a Recently, Chen et al has reported the
molecular iodine mediated synthesis of 3,5-diarylpyridines and 2,6-diarylpyridines using amino acids as
source of nitrogen (Scheme 1g).31b The present protocol represents the first Pd-catalyzed preparation of
symmetrical and unsymmetrical 2,4-diarylpyridines using the combination of aromatic ketones and amino
acids (Scheme 1).
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Scheme 1. Related approaches for the synthesis of pyridines
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RESULTS AND DISCUSSION
Having the objective of developing efficient method for the preparation of a diverse range of substituted
pyridines, we began with the screening experiments using phenylalanine (1a) as C-N source and
acetophenone (2a) as starting material. To check the feasibility, initially a reaction has been attempted
between phenylalanine (1a) and acetophenone (2a) using 10 mol% Pd(OAc)2, 40 mol% FeCl3 and 1.0
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equiv. Cu(OAc)2⸳H2O. Interestingly, the reaction proceeded in DMF/DMSO (3:1) as solvent at 120 °C for
40 h leading to the formation of the products 2,4-diphenylpyridine (3aa) and 3,5-diphenylpyridine (4) in
58% and 26% yield respectively (Table 1, Entry 1). Next, the control experiments revealed that the
combination of Cu(OAc)2⸳H2O and FeCl3 delivers higher yield of the major product 3aa (Table 1, Entries
1-3). It was also investigated that the addition of DavePhos as ligand increases the efficacy of the reaction
towards selective formation of the product 3aa, when the reaction was performed using 10 mol%
Pd(OAc)2 as catalyst only in combination with Cu(OAc)2⸳H2O as an oxidant and FeCl3 as an additive
(Table 1, Entries 4-7). Moreover, it should also be noted that the combination of catalyst, ligand, oxidant
and additive remains crucial for the formation of 3aa as major product (Table 1, Entries 8-12).
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Table 1. Initial Optimization for the reaction between amino acid 1a and ketone 2aa
3aa (%
Yield)b
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< 10
33
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< 10
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4 (%
Yield)b
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Entry
Catalyst
Ligand
Oxidant/Additive
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2
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5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
-
-
-
-
Cu(OAc)2⸳H2O/FeCl3
FeCl3
Cu(OAc)2⸳H2O
Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O
FeCl3
DavePhos
DavePhos
DavePhos
DavePhos
-
DavePhos
Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O
FeCl3
-
-
-
-
-
-
-
15
< 10
0
10
11
12
Pd(OAc)2
-
0
0
aUnless otherwise indicated: All reactions were performed using 2 mmol of 1a, 2.6 mmol
of 2a, 10 mol% Pd(OAc)2, 10 mol% Davephos, 1 equiv. Cu(OAc)2⸳H2O and 40 mol%
FeCl3 in 1.5 mL DMF/0.5 mL DMSO at 120 °C for 40 h. bIsolated yields.
After having an overview of the initial optimization, a wide range of additives (e.g. In(OTf)3, Sc(OTf)3),
palladium catalysts (e.g. Pd(TFA)2, PdCl2, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(PPh3)4,) and phosphine ligands
(e.g. PPh3, P(Cy)3, P(p-CF3-Ph)3, P(2-furyl)3, P(o-tolyl)3) were scrutinized carefully (Table 2, Entries 1-
12). It is noteworthy that the presence of In(OTf)3 and Sc(OTf)3 as additives were inefficient than FeCl3
for the formation of the desired major product 3aa (Table 2, Entries 1-2). On the other hand, among the
Pd-catalysts and ligands were tested, the combination of Pd(OAc)2 and DavePhos has shown highest
efficacy for the reaction between 1a and 2a (Table 2, Entries 3-12) to deliver the expected product 3aa.
Next, the scope of a wide range of oxidants has been investigated (Table 2, Entries 13-18). It was
observed that among the tested oxidants, the best yield of the product 3aa was obtained using
Cu(OAc)2⸳H2O (Table 1, Entry 4). Further, optimization studies revealed that decreasing the catalyst
loading, reaction temperature and time leading to the unsatisfactory yields of 2,4-diphenylpyridine (3aa)
(details of further optimization given in SI). Hence, from the screening of the reaction conditions, it was
concluded that a combination of Pd(OAc)2 (10 mol%) as catalyst, DavePhos (10 mol%) as ligand,
Cu(OAc)2⸳H2O (1 equiv.) as oxidant and FeCl3 (40 mol%) as additive in DMF/DMSO (3:1) at 120 °C for
40 h has shown maximum efficiency for the formation of the desired 2,4-diphenylpyridine (3aa) in 76%
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yield along with the formation of the side product 3,5-diphenylpyridine (4) in 16% yield (Table 1, Entry
4).
Table 2. Further screening of the reaction conditions between 1a and 2aa
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3aa (%
4 (%
Entry Catalyst
Ligand
Oxidant/Additive
Yield)b Yield)b
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2
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4
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
DavePhos
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DavePhos
Cu(OAc)2⸳H2O/In(OTf)3
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Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O/FeCl3
14
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21
26
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62
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41
53
49
17
25
9
43
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31
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32
29
21
30
19
15
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48
5
Pd(dppf)Cl2
6
Pd(PPh3)2Cl2 DavePhos
7
8
9
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DavePhos
PPh3
P(Cy)3
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13
14
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16
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18
P(p-CF3-Ph)3 Cu(OAc)2⸳H2O/FeCl3
P(2-furyl)3
P(o-tolyl)3
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
Cu(OAc)2⸳H2O/FeCl3
Cu(OAc)2⸳H2O/FeCl3
AgSbF6/FeCl3
Ag2CO3/FeCl3
AgOAc/FeCl3
K2S2O8/FeCl3
MnO2/FeCl3
KNO3/FeCl3
aUnless otherwise indicated: All reactions were performed using 2 mmol of 1a, 2.6 mmol of 2a,
10 mol% catalyst, 10 mol% ligands, 1 equiv. oxidant and 40 mol% additive in 1.5 mL DMF/0.5
mL DMSO at 120 °C for 40 h. bIsolated yields.
To have an overview for the reaction mechanism, a reaction has been conducted using only phenylalanine
(1a) as starting material under the optimal conditions for 16 h (Scheme 2). It was observed that the
reaction leading to the formation of exclusively 3,5-diphenylpyridine (4) as product. The formation of the
product 4 can be realized by the self-cyclization of phenylalanine (1a).31b It is assumed that in the
presence of Pd(II)-catalyst, the decarboxylation32 of amino acid 1a would result an imine intermediate E,
which followed by tautomerization gives an enamine intermediate F. Further, the [2+2+2] cycloaddition33
between two molecules of E and one molecule of F gives an unstable penta-substituted piperidine
intermediate G, which followed by deamination, debenzylation and aromatization delivers the 3,5-
diphenylpyridine (4).
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Scheme 2. Control experiment using phenylalanine (1a) as substrate
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On the other hand, we looked into the plausible pathways for the formation of the major product 2,4-
diphenylpyridine (3aa) (Scheme 3). It is assumed that the intermediate H could be formed by the
condensation between 1a and 2a. Simultaneously, the Pd(OAc)2 undergoes ligand exchange processes to
give the Pd(0) species B. Then, consecutive Pd-catalyzed decarboxylation of the intermediate H and
functionalization with substrate 2a via sp3 C-H activation leading to the formation of an intermediate J.
The migratory insertion of palladium34 followed by C-H functionalization of methylene group could result
the intermediate K. The reductive elimination delivers the Pd(0) species along with the formation of
cyclic intermediate L. The Pd(II) species is regenerated back to the catalytic cycle by Cu(II) in the
presence of aerial oxygen. Finally, the aromatization followed by the debenzylation of intermediate L
leading to the formation of the desired product 3aa.
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Scheme 3. Plausible mechanism for the formation of 2,4-diphenylpyridine (3aa) using
phenylalanine (1a).
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Having successfully realized the detailed optimization process and the plausible reaction mechanism, the
scope of this transformation was explored using phenylalanine (1a) and a series of acetophenone
derivatives 2 (Scheme 4). It was investigated that irrespective of the electronic nature of the substitution
pattern on acetophenones 2, all substrates were well tolerated under the standard conditions to deliver the
corresponding 2,4-diarylpyridines 3ab-as in yields ranging from 56 - 69%, along with the formation of
side product 3,5-diphenylpyridine (4) in yields ranging from 10 - 18%. In all investigated examples the
side product 4 was realized under the reaction conditions, which is due to the competitive self-cyclization
of phenylalanine (1a) via [2+2+2] cycloaddition reaction.
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Scheme 4. Pd-Catalyzed synthesis of 2,4-diarylpyridines 3 using phenylalanine (1a) as C-N source.
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After, the successful development of the first multicomponent process using phenylalanine (1a), the scope
of this method was investigated using glycine (1b) as C-N source. A series of acetophenones 2 with both
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electron-donating (Ar = 2-MeC6H4, 3-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, 4-EtC6H4 and 4-
EtOC6H4) and electron-withdrawing (4-FC6H4, 3-ClC6H4, 4-ClC6H4, 2-BrC6H4, 4-CF3C6H4 and 3,4-
OCH2OC6H4) substituents were then subjected to the reaction with glycine (1b) under the developed
conditions (Scheme 5). This investigation reveals that all substituents were efficient for the
transformation, which delivered the desired products in good yields ranging from 52-70%. Notably, the
electron-withdrawing groups present in aromatic ring have slight impact in the yield of final products.
Additionally, the reactivity of the propiophenone (2o) with glycine (1b) has been verified, which delivers
the corresponding tetra-substituted pyridine 3as in 61% yield. It is also noteworthy that in all examples
along with the major products 3aa-ae, ag-al, ao-ap, ar-as a considerable amounts of 2,6-diarylpyridines
5ba-bo have been observed as side products (Scheme 5), whereas in case of phenylalanine (1a) as
substrate the 3,5-diphenylpyridine (4) was recognized as by-product (Scheme 4).31b
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Scheme 5. Pd-Catalyzed Synthesis of 2,4-diarylpyridines 3, 2,6-diarylpyridines 5 using glycine (1b) as N-
and C1 source.
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According to the proposed mechanism, it appears that the intermediate M could be formed by the
condensation between 1b and 2a. The intermediate M then undergoes decarboxylation32 through an
intermediate N. The intermediate N undergo functionalization with one more molecule of 2a via sp3 C-H
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functionalization leading to the formation of an intermediate O. This intermediate further undergoes
migratory insertion of palladium34 and subsequent sp2 C-H functionalization of methylene group results in
the formation of intermediate P. The palladacycle then undergoes reductive elimination leading to the
formation of intermediate Q and leaving behind the Pd(0) species back to the catalytic cycle. Finally,
intermediate Q undergoes dehydration followed by Cu(II)-mediated aerial oxidation to obtain the 2,4-
diphenylpyridine (3aa) (Scheme 6a). On the other hand, the intermediate N undergoes decarboxylation32
and resulting in intermediate R. The hydrolysis of intermediate R would deliver formaldehyde (S) and an
enamine T, which after condensation with one more molecule of ketone 2a produces an enamine U.
Addition of formaldehyde (S) into enamine U gives an intermediate V. Next, the Pd-catalyzed intra-
molecular cross-dehydrogenative-coupling (CDC)35 of intermediate V, leading to the side product 2,6-
diphenylpyridine (5ba) via the formation of palladacycle W. Finally, the Pd(II) species is regenerated
back to catalytic cycle by Cu(II) in presence of aerial oxygen (Scheme 6b).
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Scheme 6. Plausible mechanism for the formation of 2,4-diphenylpyridines (3aa) and 2,6-diphenylpyridines (5ba)
using glycine (1b) as amino acid.
Scheme 6a
Scheme 6b
Finally, in order to confirm the proposed reaction mechanism, an experiment was performed using
glycine (1b) and acetophenone (2a) under the standard conditions, for which the course of reaction was
monitored and analyzed by LC-MS. The reaction mixture was analysed by using LC-MS after an interval
of every 10 h. From mass spectroscopy data it was identified that the proposed mechanism (Scheme 6)
has the involvement of intermediates M, N, Q and V (details of mass spectra is given in Figure 1, SI). It
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was observed that the intermediate M ([M+Na+H2O]+ = 214.05), along with the formation of
corresponding tetra-saturated pyridine intermediate ([M+H]+ = 236.07) can be identified after 10 h of the
reaction. When the reaction mixture was analysed after 20 h, the corresponding peaks of the products 3aa
and 5ba ([M+H]+ = 232.09) started appearing along with the intermediate N ([M+H]+ = 279.12) and M.
Interestingly, the scenario has been improved after 30 h as the product peak appears as major with
decreasing amounts of intermediates M, N, Q and V. Moreover, after 40 h of the reaction the product 3aa
and 5ba ([M+H]+ = 232.1132) were found exclusively. Hence, having observed the experimental results,
it was concluded that the reaction proceeds via the proposed mechanistic pathway. It was also assumed
that the investigated selectivity towards formation of 2,4-diarylpyridines 3 over 2,6-diarylpyridines 5 or
self-cyclized 3,5-diphenylpyridine (4) can be explained due to the electron-donating ability of DavePhos
to the metal ion, which is facilitating the formation of products 3. This electronic nature of the DavePhos
could drive the tendency of metal ion to accommodate the second molecule of aryl ketone 2 to generate
the intermediate J (Scheme 3) and intermediate O (Scheme 6a), rather than formation of a Pd(0) species
B (Scheme 6).36
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Moreover, to gain further insight into the potential of described method, it was extended towards
installation of two different aryl moieties on the pyridine ring (Scheme 7). Hence, the glycine (1b) was
subjected to a combination of two acetophenone derivatives 2 under the standard reaction conditions. It
was investigated that the developed protocol is not only restricted to the synthesis of symmetrically
functionalized 2,4-diarylpyridines 3, rather it can be extended to the preparation of unsymmetrically
functionalized 2,4-diarylpyridines 6 in moderate yields ranging from 50-55%, along with the formation of
unsymmetrically functionalized 2,6-diarylpyridines 7 as side products in yields ranging from 21-24%.
Additionally, it is noteworthy that the formation of the symmetrically functionalized 2,4-diarylpyridines
remains unnoticeable during the reaction.
Scheme 7. Scope of unsymmetrically functionalized 2,4-diarylpyridines 6 and 2,6-diarylpyridines 7.
To further explore the substrate scope the amino acids such as valine (1c) and leucine (1d) were
investigated in this transformation (Table 3). It was found that the reactions with valine (1c) and leucine
(1d) did not proceed in the similar way as phenylalanine (1a) and glycine (1b). When, valine (1c) or
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leucine (1d) were reacted with acetophenone (2a) or propiophenone (2s) under the optimized conditions,
the corresponding 2,6-diarylpyridines 5ba or 5bo were isolated in yields ranging from 33-45%. However,
in these reactions the corresponding 2,4-diarylpyridines 3 were not observed.
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Table 3. Pd-Catalyzed Synthesis of 2,6-diarylpyridines 5 using valine (1c) and leucine (1d) as nitrogen
source.a,b
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1c, R1 = iPr
1c, R1 = iPr
1d, R1 = iBu
1d, R1 = iBu
2a, R2 = H
2s, R2 = Me
2a, R2 = H
2s, R2 = Me
3ca (0%)
3cs (0%)
3da (0%)
3ds (0%)
R1 = H, 5ba (33%)c
R1 = H, 5bo (45%)c
R1 = H, 5ba (29%)c
R1 = H, 5bo (40%)c
aUnless otherwise indicated: All reactions were performed using 2 mmol of 1c-d, 2.6 mmol of 2a,s, 10 mol% catalyst, 10
b
mol% ligands, 1 equiv. oxidant and 40 mol% additive in 1.5 mL DMF/0.5 mL DMSO at 120 °C for 40 h. Isolated yields.
cComplex reaction mixture.
CONCLUSIONS
In summary, a rapid one-pot tandem process for the synthesis of di-substituted pyridines involving
condensation, decarboxylation, dual C-H functionalization and debenzylation has been described. The
transformation was realized using various amino acids as C-N source and aryl ketones as easy available
and cheap substrates. Under the influence of Pd-catalysis, the potential of the developed one-pot multi-
bond forming process delivered a diverse range of symmetrical and unsymmetrical 2,4-diarylpyridines in
high yields with good selectivity. The proposed mechanistic pathway was verified by several control
experiments and mass spectrometry. Further, the investigation on the applications of the described one-
pot multistep process is currently on-going in our laboratory.
EXPERIMENTAL SECTION
General methods: All starting materials (including 1a-b, 2a-t) were purchased from commercial suppliers (Sigma-
Aldrich, Alfa-Aesar, SD fine chemicals, Merck, HI Media) and were used without further purification unless
otherwise indicated. All reactions were carried out under an argon atmosphere in oven-dried glassware with
magnetic stirring. The reactions were performed in pressure tube purchased from Sigma-Aldrich glassware. Solvents
used in extraction and purification were distilled prior to use. Thin-layer chromatography (TLC) was performed on
TLC plates purchase from Merck. Compounds were visualized with UV light (λ = 254 nm) and/or by immersion in
KMnO4 staining solution followed by heating. Products were purified by column chromatography on silica gel, 100
- 200 mesh. 1H (13C) NMR spectra were recorded at 600 (150) MHz and 400 (100) MHz on a Brucker spectrometer
using CDCl3 as a solvent. The H and 13C chemical shifts were referenced to residual solvent signals at H/C 7.26
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/77.28 (CDCl3) relative to TMS as internal standards. Coupling constants J [Hz] were directly taken from the spectra
and are not averaged. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
overlapped and br (broad).
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General experimental procedure for the synthesis of 2,4-diarylpyridines (3aa-as) and 3,5-diphenylpyridine (4)
using phenylalanine (1a)
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A 10 mL reaction vial was charged with phenylalanine 1a (2.0 mmol), arylketones 2a-s (2.6 mmol), FeCl3
(0.4 mmol), Cu(OAc)2⸳H2O (2.0 mmol), DavePhos (0.2 mmol), Pd(OAc)2 (0.2 mmol) and DMF:DMSO (3:1)
(2 mL). The reaction vial was then closed and heated at 120 °C for 40 h. After completion of the reaction (progress
was monitored by TLC; SiO2, Hexane/EtOAc = 9:1), the mixture was diluted with ethyl acetate (15 mL) and water
(20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (3 ×
10 mL) and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the remaining residue
was purified by column chromatography over silica gel using hexane / ethyl acetate = 9:1 as an eluent to obtain the
desired 2,4-arylpyridines 3aa-as and 3,5-diphenylpyridine 4 in high yields.
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General experimental procedure for the synthesis of 2,4-diarylpyridines (3aa-ae, ag-al, ao-ap, ar-as) and 2,6-
diarylpyridines (5ba-bo) using glycine (1b)
A 10 mL reaction vial was charged with glycine 1b (2.0 mmol), arylketones 2a-e, g-l, o-p, r-s (2.6 mmol), FeCl3
(0.4 mmol), Cu(OAc)2⸳H2O (2.0 mmol), DavePhos (0.2 mmol), Pd(OAc)2 (0.2 mmol) and DMF:DMSO (3:1)
(2 mL). The reaction vial was then closed and heated at 120 °C for 40 h. After completion of the reaction (progress
was monitored by TLC; SiO2, Hexane/EtOAc = 9:1), the mixture was diluted with ethyl acetate (15 mL) and water
(20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (3 ×
10 mL) and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the remaining residue
was purified by column chromatography over silica gel using hexane / ethyl acetate = 9:1 as an eluent to obtain the
desired 2,4-arylpyridines 3aa-ae, ag-al, ao-ap, ar-as and 2,6-diarylpyridines 5ba-bo in high yields.
General experimental procedure for the synthesis of 2,4-diarylpyridines (6aa-ab) and 2,6-diarylpyridines
(7aa-ab) using glycine (1b)
A 10 mL reaction vial was charged with glycine 1b (2.0 mmol), arylketones 2k,t, (1.3 mmol), arylketones 2a,p
(1.3 mmol), FeCl3 (0.4 mmol), Cu(OAc)2⸳H2O (2.0 mmol), DavePhos (0.2 mmol), Pd(OAc)2 (0.2 mmol) and
DMF:DMSO (3:1) (2 mL). The reaction vial was then closed and heated at 120 °C for 40 h. After completion of the
reaction (progress was monitored by TLC; SiO2, Hexane/EtOAc = 9:1), the mixture was diluted with ethyl acetate
(15 mL) and water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed
with brine (3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the
remaining residue was purified by column chromatography over silica gel using hexane / ethyl acetate = 9:1 as an
eluent to obtain the desired 2,4-arylpyridines 6aa-ab and 2,6-diarylpyridines 7aa-ab in high yields.
Experimental procedures and analytical data of synthesized 2,4-diarylpyridines (3aa-as), 3,5-
diphenylpyridine (4) and 2,6-diarylpyridines (5ba-bo)
Preparation of 2,4-diphenylpyridine (3aa) and 3,5-diphenylpyridine (4)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) acetophenone 2a
(2.6 mmol, 312 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-diphenylpyridine 3aa in
76% (176 mg) and 3,5-diphenylpyridine 4 in 16% (37 mg) yield as yellow solid and black solid respectively
(Scheme 4).
2,4-diphenylpyridine (3aa)20d (Table 1-2, Scheme 3, 4, 5): Yellow solid, Rf = 0.50 (SiO2, Hexane/EtOAc = 9:1);
m.p = 58 - 59 °C (Lit20d 57 - 61 °C); 1H NMR (600 MHz, CDCl3): δ = 8.75 (d, 3J = 5.1 Hz, 1H; 6-H), 8.05 (d, 3J =
7.8 Hz, 2H; 8-H), 7.94 (s, 1H; 3-H), 7.70 (d, 3J = 7.6 Hz, 2H; 12-H), 7.53 – 7.44 (m, 7H; 5-H, 9-H, 10-H, 13-H and
14-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 158.1 (C-2), 150.0 (C-6), 149.4 (C-4), 139.4 (C-7), 138.5 (C-11),
129.1 (C-13), 129.05 (C-10), 129.04 (C-14), 128.8 (C-9), 127.1 (C-8), 127.0 (C-12), 120.3 (C-5), 118.8 (C-3) ppm;
HRMS (EI-QTOF, [M + H]+): calculated for C17H14N: 232.1125; found: 232.1128.
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3,5-diphenylpyridine (4)31b (Table 1-2, Scheme 2, 4): Black solid, Rf = 0.75 (SiO2, Hexane/EtOAc = 9:1); m.p =
133 - 134 °C (Lit31b 132 - 135 °C); 1H NMR (600 MHz, CDCl3): δ = 8.83 (s, 2H; 2-H and 6-H), 8.06 (s, 1H; 4-H),
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7.65 (dd, J = 7.7 Hz, 4H; 8-H), 7.51 (td, J = 8.0 Hz, 4H; 9-H), 7.44 (dt, J = 8.6 Hz, 2H; 10-H) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ = 146.9 (C-2 and C-6), 137.7 (C-7), 136.7 (C-3 and C-5), 132.9 (C-4), 129.1 (C-9),
128.2 (C-10), 127.2 (C-8) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H14N: 232.1125; found: 232.1121.
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Preparation of 2,4-diphenylpyridine (3aa) and 2,6-diphenylpyridine (5ba)
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According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) acetophenone 2a (2.6 mmol,
312 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos
(0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-diphenylpyridine 3aa in 63% (146
mg) and 2,6-diphenylpyridine 5ba in 19% (44 mg) yield as yellow solid and white solid respectively (Scheme 5).
2,6-diphenylpyridine (5ba)31b (Scheme 5): White solid, Rf = 0.45 (SiO2, Hexane/EtOAc = 9:1); m.p = 76 - 77 °C
(Lit31b 75 - 78 °C); 1H NMR (600 MHz, CDCl3): δ = 8.16 (dd, 3J = 7.6 Hz, 4H; 8-H), 7.82 (t, 3J = 7.8 Hz, 1H; 4-H),
7.70 (dd, 3J = 7.8 Hz, 2H; 3-H and 5-H), 7.50 (t, 3J = 7.6 Hz, 4H; 9-H), 7.43 (t, 3J = 7.8 Hz, 2H; 10-H) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ = 156.8 (C-2 and C-6), 139.5 (C-4), 137.4 (C-7), 128.9 (C-9), 128.6 (C-8), 127.0 (C-10),
118.6 (C-3 and C-5) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H14N: 232.1125; found: 232.1126.
Preparation of 2,4-di-p-tolylpyridine (3ab) and 2,6-di-p-tolylpyridine (5bb)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 4׳-
methylacetophenone 2b (2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-di-p-
tolylpyridine 3ab in 68% (176 mg) and 3,5-diphenylpyridine 4 in 11% (28.5 mg) yield as white solid and black solid
respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 4׳-methylacetophenone 2b
(2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-di-p-tolylpyridine 3ab in
70% (181 mg) and 2,6-di-p-tolylpyridine 5bb in 21% (54 mg) yield as white solid and pale white solid respectively
(Scheme 5).
2,4-di-p-tolylpyridine (3ab)20d (Scheme 4, 5): White solid, Rf = 0.50 (SiO2, Hexane/EtOAc = 9:1); m.p = 108 -
109 °C (Lit20d 107 - 110 °C); 1H NMR (600 MHz, CDCl3): δ = 8.69 (d, 3J = 5.2 Hz, 1H; 6-H), 8.08 (d, 3J = 7.8 Hz,
2H; 8-H), 7.89 (s, 1H; 3-H), 7.58 (d, 3J = 7.6 Hz, 2H; 12-H), 7.42 (dd, 3J = 7.8 Hz, 1H; 3-H), 7.31 – 7.29 (m, 4H; 9-
H and 13-H), 2.42 (s, 3H; 15-H), 2.41 (s, 3H; 16-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 158.1 (C-2), 150.0
(C-6), 149.2 (C-4), 139.2 (C-7), 139.1 (C-11), 136.8 (C-14), 135.7 (C-10), 129.9 (C-13), 129.6 (C-9), 129.5 (C-12),
127.0 (C-8), 119.9 (C-5), 118.4 (C-3), 21.4 (C-15), 21.3 (C-16) ppm; HRMS (EI-QTOF, [M + H]+): calculated for
C19H18N: 260.1434; found: 260.1431.
2,6-di-p-tolylpyridine (5bb)37g (Scheme 5): Pale white solid, Rf = 0.75 (SiO2, Hexane/EtOAc = 9:1); m.p = 162 -
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165 °C (Lit37g 163 - 165 °C); 1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.2 Hz, 4H; 8-H), 7.76 (t, 3J = 7.8 Hz,
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1H; 4-H), 7.63 (d, J = 7.8 Hz, 2H; 3-H and 5-H), 7.30 (d, J = 8.3 Hz, 4H; 9-H), 2.42 (s, 6H; 11-H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ = 156.8 (C-2 and C-6), 139.0 (C-4), 137.4 (C-7), 136.9 (C-10), 129.5 (C-9), 127.0 (C-8),
118.1 (C-3 and C-5), 21.4 (C-11) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H18N: 260.1434; found:
260.1429.
Preparation of 2,4-di-m-tolylpyridine (3ac) and 2,6-di-m-tolylpyridine (5bc)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 3׳-
methylacetophenone 2c (2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-di-m-
tolylpyridine 3ac in 60% (155 mg) and 3,5-diphenylpyridine 4 in 13% (30 mg) yield as yellow oil and black solid
respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 3׳-methylacetophenone 2c
(2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
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DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-di-m-tolylpyridine 3ac in
63% (163 mg) and 2,6-di-m-tolylpyridine 5bc in 18% (47 mg) yield as yellow oil and white solid respectively
(Scheme 5).
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2,4-di-m-tolylpyridine (3ac)37d (Scheme 4, 5): Orange yellow oil, Rf = 0.40 (SiO2, Hexane/EtOAc = 9:1); H
NMR (600 MHz, CDCl3): δ = 8.72 (d, J = 5.1 Hz, 1H; 6-H), 7.90 (d, J = 6.4 Hz, 2H; 8-H and 12-H), 7.82 (d, J = 7.8
Hz, 1H; 5-H), 7.50 (d, J = 7.9 Hz, 2H; 3-H and 14-H), 7.44 - 7.37 (m, 3H; 11-H, 17-H and 18-H), 7.28 - 7.25 (m,
2H; 10-H and 16-H), 2.46 (s, 6H; 19-H and 20-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 158.2 (C-2), 149.9
(C-6), 149.4 (C-4), 139.5 (C-13), 138.8 (C-9), 138.6 (C-15), 138.4 (C-7), 138.3 (C-8), 129.7 (C-16), 129.0 (C-11),
128.6 (C-17), 127.8 (C-14), 127.7 (C-10), 124.2 (C-12), 124.1 (C-18), 120.2 (C-5), 118.8 (C-3), 21.52 (C-19), 21.50
(C-20) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H18N: 260.1434; found: 260.1422.
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2,6-di-m-tolylpyridine (5bc)37c (Scheme 5): White solid, Rf = 0.65 (SiO2, Hexane/EtOAc = 9:1); m.p = 65 - 67 °C
(Lit37a 64 - 65 °C); 1H NMR (600 MHz, CDCl3): δ = 7.96 (s, 2H; 4-H), 7.91 (d, J = 7.7 Hz, 2H; 12-H), 7.79 (t, J =
7.8 Hz, 1H; 3-H), 7.66 (d, J = 7.8 Hz, 2H; 12-H), 7.38 (t, J = 7.6 Hz, 2H; 12-H), 7.24 (d, J = 7.6 Hz, 2H; 12-H), 2.47
(s, 6H; 13-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.8 (C-2), 139.51 (C-4), 139.44 (C-9), 139.39 (C-7),
129.3 (C-8), 128.6 (C-11), 126.9 (C-10), 123.4 (C-12), 118.7 (C-3 and C-5), 19.9 (C-13) ppm; HRMS (EI-QTOF,
[M + H]+): calculated for C19H18N: 260.1434; found: 260.1437.
Preparation of 2,4-di-o-tolylpyridine (3ad) and 2,6-di-o-tolylpyridine (5bd)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 2׳-
methylacetophenone 2d (2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-di-o-
tolylpyridine 3ad in 61% (158 mg) and 3,5-diphenylpyridine 4 in 16% (37 mg) yield as yellow oil and black solid
respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 2׳-methylacetophenone 2d
(2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-di-o-tolylpyridine 3ad in
68% (176 mg) and 2,6-di-o-tolylpyridine 5bd in 20% (52 mg) yield as yellow oil and white solid respectively
(Scheme 5).
2,4-di-o-tolylpyridine (3ad)20d (Scheme 4, 5): Yellow oil, Rf = 0.35 (SiO2, Hexane/EtOAc = 9:1); H NMR (400
1
MHz, CDCl3): δ = 8.72 (d, J = 5.0 Hz, 1H; 6-H), 7.43 (d, J = 7.6 Hz, 1H; 5-H), 7.37 (s, 1H; 3-H), 7.31 - 7.26 (m,
7H; 9-H, 10-H, 12-H, 15-H, 16-H, 17-H and 18-H), 7.22 (t, J = 6.6 Hz, 1H; 11-H), 2.41 (s, 3H; 19-H), 2.33 (s, 3H;
20-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 159.9 (C-2), 150.0 (C-6), 149.2 (C-4), 140.5 (C-7), 139.3 (C-13),
135.8 (C-8), 135.2 (C-14), 130.85 (C-9), 130.79 (C-15), 129.8 (C-16), 129.4 (C-10), 128.5 (C-11), 128.4 (C-17),
126.2 (C-18), 126.0 (C-12), 124.7 (C-3), 122.3 (C-5), 20.50 (C-19), 20.49 (C-20) ppm; HRMS (EI-QTOF, [M +
H]+): calculated for C19H18N: 260.1434; found: 260.1440.
2,6-di-o-tolylpyridine (5bd)37g (Scheme 5): White solid, Rf = 0.60 (SiO2, Hexane/EtOAc = 9:1); m.p = 65 - 67 °C
(Lit37g 66 - 68 °C); 1H NMR (600 MHz, CDCl3): δ = 7.81 (td, J = 7.7 Hz, 1H; 4-H), 7.45 (d, J = 6.2 Hz, 2H; 12-H),
7.36 (dd, J = 7.7 Hz, 2H; 3-H and 5-H), 7.29 - 7.26 (m, 6H; 9-H, 10-H, and 11-H), 2.43 (s, 6H; 13-H) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ = 159.5 (C-2), 140.6 (C-4), 136.2 (C-8), 135.8 (C-7), 130.6(C-9), 129.8 (C-10), 128.1
(C-11), 125.8 (C-12), 121.9 (C-3 and C-5), 20.5 (C-13) ppm; HRMS (EI-QTOF, [M + H]+): calculated for
C19H18N: 260.1434; found: 260.1426.
Preparation of 2,4-bis(4-methoxyphenyl)pyridine (3ae) and 2,6-bis(4-methoxyphenyl)pyridine (5be)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 4׳-
methoxyacetophenone 2e (2.6 mmol, 390 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
methoxyphenyl)pyridine 3ae in 67% (195 mg) and 3,5-diphenylpyridine 4 in 15% (35 mg) yield as light yellow
solid and black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 4׳-methoxyacetophenone 2e
(2.6 mmol, 390 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
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DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
methoxyphenyl)pyridine 3ae in 64% (186 mg) and 2,6-bis(4-methoxyphenyl)pyridine 5be in 19% (55 mg) yield as
light yellow solid and white solid respectively (Scheme 5).
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2,4-bis(4-methoxyphenyl)pyridine (3ae)20d (Scheme 4, 5): Light yellow solid, Rf = 0.40 (SiO2, Hexane/EtOAc =
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9:1); m.p = 152 - 154 °C (Lit20d 153 - 156 °C); H NMR (400 MHz, CDCl3): δ = 8.66 (d, J = 5.5 Hz, 1H; 6-H),
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7.99 (d, J = 7.9 Hz, 2H; 8-H), 7.83 (s, 1H; 3-H), 7.65 (d, J = 8.0 Hz, 2H; 12-H), 7.36 (d, J = 7.8 Hz, 1H; 5-H),
7.04 - 7.01 (m, 4H; 9-H and 13-H), 3.88 (s, 6H; 15-H and 16-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 160.5
(C-10), 157.7 (C-14), 150.0 (C-2), 148.7 (C-4 and C-6), 132.2 (C-7), 131.0 (C-11), 128.3 (C-12), 128.2 (C-8), 119.1
(C-5), 117.5 (C-3), 114.5 (C-9), 114.1 (C-13), 55.43 (C-15), 55.39 (C-16) ppm; HRMS (EI-QTOF, [M + H]+):
calculated for C19H18NO2: 292.1332; found: 292.1312.
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2,6-bis(4-methoxyphenyl)pyridine (5be)37g (Scheme 5): Pale white solid, Rf = 0.65 (SiO2, Hexane/EtOAc = 9:1);
m.p = 184 - 187 °C (Lit37g 185 - 188 °C); 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, 3J = 8.4 Hz, 4H; 8-H), 7.73 (t,
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3J = 7.8 Hz, 1H; 4-H), 7.56 (d, J = 7.8 Hz, 2H; 3-H and 5-H), 7.01 (d, J = 8.2 Hz, 4H; 9-H), 3.87 (s, 6H; 11-H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 160.4 (C-10), 156.3 (C-2 and C-6), 137.3 (C-4), 132.3 (C-7), 128.2 (C-
8), 117.1 (C-3 and C-5), 114.0 (C-9), 55.3 (C-11) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H18NO2:
292.1332; found: 292.1329.
Preparation of 2,4-bis(3-methoxyphenyl)pyridine (3af)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 3׳-
methoxyacetophenone 2f (2.6 mmol, 390 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(3-
methoxyphenyl)pyridine 3af in 62% (181 mg) and 3,5-diphenylpyridine 4 in 16% (37 mg) yield as yellow solid and
black solid respectively (Scheme 4).
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2,4-bis(3-methoxyphenyl)pyridine (3af) (Scheme 4): Yellow solid, Rf = 0.35 (SiO2, Hexane/EtOAc = 9:1); H
NMR (400 MHz, CDCl3): δ = 8.78 (d, 3J = 5.8 Hz, 1H; 6-H), 7.93 (s, 1H; 3-H), 7.65 - 7.61 (m, 2H; 8-H and 12-H),
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7.49 - 7.42 (m, 3H; 11-H, 17-H and 18-H), 7.30 (d, J = 7.9 Hz, 1H; 5-H), 7.23 (s, 1H. 14-H), 7.04 - 7.02
(overlapped, 2H; 10-H and 16-H), 3.94 (s, 3H; 15-H), 3.93 (s, 3H; 16-H)ppm; 13C{1H} NMR (100 MHz, CDCl3) δ =
160.2 (C-9), 160.1 (C-15), 157.9 (C-2), 149.9 (C-4), 149.3 (C-6), 140.9 (C-13), 139.9 (C-7), 130.2 (C-11), 129.8 (C-
17), 120.5 (C-5), 119.54 (C-12), 119.51 (C-18), 119.2 (C-3), 115.3 (C-16), 114.3 (C-8), 112.9 (C-14), 112.2 (C-10),
55.44 (C-19 and C-20) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H18NO2: 292.1332; found: 292.1312.
Preparation of 2,4-bis(2-methoxyphenyl)pyridine (3ag) and 2,6-bis(2-methoxyphenyl)pyridine (5bf)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 2׳-
methoxyacetophenone 2g (2.6 mmol, 390 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(2-
methoxyphenyl)pyridine 3ag in 59% (172 mg) and 3,5-diphenylpyridine 4 in 12% (28 mg) yield as yellow oil and
black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 2׳-methoxyacetophenone 2g
(2.6 mmol, 390 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(2-
methoxyphenyl)pyridine 3ag in 59% (172 mg) and 2,6-bis(2-methoxyphenyl)pyridine 5bf in 16% (47 mg) yield as
yellow oil and white solid respectively (Scheme 5).
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2,4-bis(2-methoxyphenyl)pyridine (3ag)20d (Scheme 4, 5): Yellow oil, Rf = 0.30 (SiO2, Hexane/EtOAc = 9:1); H
NMR (600 MHz, CDCl3): δ = 8.71 (d, J = 5.1 Hz, 1H; 6-H), 7.95 (s, 1H; 3-H), 7.78 (dd, J = 7.6 Hz, 1H; 5-H), 7.42
- 7.36 (m, 4H; 10-H, 12-H, 16-H and 18-H), 7.10 - 7.06 (m, 2H; 9-H and 15-H), 7.01 (t, J = 7.7 Hz, 2H; 11-H
and17-H), 3.86 (s, 3H; 19-H), 3.85 (s, 3H; 20-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 157.0 (C-8), 156.6 (C-
14), 156.0 (C-2), 148.94 (C-6), 148.93 (C-4), 145.9 (C-13), 131.3 (C-12), 130.6 (C-16), 129.8 (C-8), 129.7 (C-10),
129.6 (C-7), 128.3 (C-17), 125.6 (C-11), 122.5 (C-3), 121.0 (C-15), 120.98 (C-5), 111.4 (C-9), 55.7 (C-19), 55.6 (C-
20) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H18NO2: 292.1332; found: 292.1331
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2,6-bis(2-methoxyphenyl)pyridine (5bf)37g (Scheme 5): White solid, Rf = 0.65 (SiO2, Hexane/EtOAc = 9:1); m.p
= 121 - 123 °C (Lit37g 122 - 124 °C); 1H NMR (600 MHz, CDCl3): δ = 7.94 (dd, J = 7.5 Hz, 2H; 12-H), 7.77 (d, J =
7.7 Hz, 2H; 3-H and 5-H), 7.72 (dd, J = 8.6 Hz, 1H; 4-H), 7.36 (td, J = 7.9 Hz, 2H; 10-H), 7.09 (t, J = 7.5 Hz, 2H;
11-H), 7.01 (dd, J = 8.3 Hz, 2H; 9-H), 3.88 (s, 6H; 13-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 157.1 (C-8),
155.4 (C-2 and C-6), 135.1 (C-4), 131.5 (C-12), 129.62 (C-10), 129.58 (C-7), 123.0 (C-11), 121.0 (C-3 and C-5),
111.4 (C-9), 55.6 (C-13) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H18NO2: 292.1332; found:
292.1316.
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Preparation of 2,4-bis(4-ethylphenyl)pyridine (3ah) and 2,6-bis(4-ethylphenyl)pyridine (5bg)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 4׳-ethylacetophenone
2h (2.6 mmol, 384.8 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-ethylphenyl)pyridine
3ah in 61% (175 mg) and 3,5-diphenylpyridine 4 in 18% (42 mg) yield as yellow solid and black solid respectively
(Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 4׳-ethylacetophenone 2h
(2.6 mmol, 384.8 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-ethylphenyl)pyridine
3ah in 63% (181 mg) and 2,6-bis(4-ethylphenyl)pyridine 5bg in 19% (55 mg) yield as yellow solid and pale yellow
solid respectively (Scheme 5).
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2,4-bis(4-ethylphenyl)pyridine (3ah) (Scheme 4, 5): Yellow solid, Rf = 0.35 (SiO2, Hexane/EtOAc = 9:1); H
NMR (400 MHz, CDCl3): δ = 8.71 (d, 3J = 6.0 Hz, 1H; 6-H), 7.98 (d, 3J = 7.6 Hz, 2H; 8-H), 7.91 (s, 1H; 3-H), 7.63
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(d, J = 8.2 Hz, 2H; 12-H), 7.42 (dd, J = 5.2 Hz, 1H; 5-H), 7.36 - 7.33 (m, 4H; 9-H and 13-H), 2.73 (q, 4H; 15-H
and 17-H), 1.30 (t, 6H; 16-H and 18-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 158.1 (C-2), 150.0 (C-4), 149.1
(C-6), 145.4 (C-14), 145.3 (C-10), 137.0 (C-11), 135.9 (C-7), 128.7 (C-9), 128.3 (C-13), 127.3 (C-12), 127.0 (C-8),
119.8 (C-5), 118.3 (C-3), 28.71 (C-15), 28.66 (C-17), 15.58 (C-16 and C-18) ppm; HRMS (EI-QTOF, [M + H]+):
calculated for C21H22N: 288.1752; found: 288.1750.
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2,6-bis(4-ethylphenyl)pyridine (5bg) (Scheme 5): Pale yellow solid, Rf = 0.60 (SiO2, Hexane/EtOAc = 9:1); H
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NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 4H; 8-H), 7.78 (t, J = 8.0 Hz, 1H; 4-H), 7.65 (d, J = 8.0 Hz,
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2H; 3-H and 5-H), 7.34 (d, J = 8.0 Hz, 4H; 9-H), 2.74 (q, J = 8.0 Hz, 4H; 11-H), 1.31 (t, J = 7.0 Hz, 6H; 12-H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 158.6 (C-2 and C-6), 145.2 (C-10), 137.3 (C-4), 137.1 (C-7), 128.2 (C-
9), 127.0 (C-8), 118.1 (C-3 and C-5), 28.7 (C-11), 15.7 (C-12) ppm; HRMS (EI-QTOF, [M + H]+): calculated for
C21H22N: 288.1752; found: 288.1750.
Preparation of 2,4-bis(4-ethoxyphenyl)pyridine (3ai) and 2,6-bis(4-ethoxyphenyl)pyridine (5bh)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 4׳-ethoxyacetophenone
2i (2.6 mmol, 426.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
ethoxyphenyl)pyridine 3ai in 65% (207 mg) and 3,5-diphenylpyridine 4 in 14% (32 mg) yield as white solid and
black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 4׳-ethoxyacetophenone 2i
(2.6 mmol, 426.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
ethoxyphenyl)pyridine 3ai in 60% (191 mg) and 2,6-bis(4-ethoxyphenyl)pyridine 5bh in 22% (70 mg) yield as
white solid and pale white solid respectively (Scheme 5).
2,4-bis(4-ethoxyphenyl)pyridine (3ai)20d (Scheme 4, 5): White solid, Rf = 0.35 (SiO2, Hexane/EtOAc = 9:1); m.p
= 156 - 157 °C (Lit20d 155 - 158 °C); 1H NMR (600 MHz, CDCl3): δ = 8.64 (d, 3J = 5.1 Hz, 1H; 6-H), 7.98 (d, 3J =
7.6 Hz, 2H; 8-H), 7.83 (s, 1H; 3-H), 7.63 (d, 3J = 8.7 Hz, 2H; 12-H), 7.35 (dd, 3J = 5.2 Hz, 1H; 5-H), 7.02 – 6.99 (m,
4H; 9-H and 13-H), 4.10 (q, 4H; 15-H and 17-H), 1.45 (t, 6H; 16-H and 18-H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ = 159.8 (C-10), 157.7 (C-14), 149.8 (C-2 and C-6), 148.7 (C-4), 132.0 (C-7), 130.7 (C-11), 128.3 (C-12),
128.2 (C-8), 119.0 (C-5), 117.4 (C-3), 115.0 (C-9), 114.6 (C-13), 63.63 (C-15), 63.54 (C-17), 14.86 (C-16), 14.83
(C-18) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C21H22NO2: 320.1645; found: 320.1642.
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2,6-bis(4-ethoxyphenyl)pyridine (5bh)37f (Scheme 5): Pale white solid, Rf = 0.55 (SiO2, Hexane/EtOAc = 9:1);
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m.p = 85 - 88 °C (Lit37f 85 - 87 °C); 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, 3J = 8.0 Hz, 4H; 8-H), 7.73 (t, J =
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7.8 Hz, 1H; 4-H), 7.57 (d, J = 8.0 Hz, 2H; 3-H and 5-H), 7.00 (d, 3J = 8.0 Hz, 4H; 9-H), 4.11 (q, 3J = 8.0 Hz, 4H;
11-H), 1.45 (t, 3J = 7.0 Hz, 6H; 12-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 159.8 (C-10), 156.3 (C-2 and C-
6), 137.3 (C-4), 132.1 (C-7), 128.2 (C-8), 117.1 (C-3 and C-5), 114.5 (C-9), 63.5 (C-11), 14.9 (C-12) ppm; HRMS
(EI-QTOF, [M + H]+): calculated for C21H22NO2: 320.1645; found: 320.1636.
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Preparation of 2,4-Bis(4-fluorophenyl)pyridine (3aj) and 2,6-Bis(4-fluorophenyl)pyridine (5bi)
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According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 4׳-fluoroacetophenone
2j (2.6 mmol, 359 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
fluorophenyl)pyridine 3aj in 58% (155 mg) and 3,5-diphenylpyridine 4 in 17% (40 mg) yield as yellow solid and
black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 4׳-fluoroacetophenone 2j
(2.6 mmol, 359 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
fluorophenyl)pyridine 3aj in 60% (160 mg) and 2,6-bis(4-fluorophenyl)pyridine 5bi in 21% (56 mg) yield as yellow
solid and pale yellow solid respectively (Scheme 5).
2,4-Bis(4-fluorophenyl)pyridine (3aj)20d (Scheme 4, 5): Yellow solid, Rf = 0.40 (SiO2, Hexane/EtOAc = 9:1); m.p
= 77 - 79 °C (Lit20d 78 - 81 °C); 1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 4.7 Hz, 1H; 2-H), 8.03 (m, 2H; 8-H),
7.83 (s, 1H; 3-H), 7.66 (m, 2H; 12-H), 7.39 (d, J = 5.1 Hz, 1H; 5-H), 7.22 - 7.16 (m, 4H; 9-H and 13-H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ = 164.8 (d, J = 246.2 Hz, C-14), 162.3 (d, J = 247.9 Hz, C-10), 157.2 (C-2),
150.2 (C-4), 148.4 (C-6), 135.6 (d, J = 3.1 Hz, C-11), 134.6 (d, J = 3.4 Hz, C-7), 128.9 (d, J = 1.3 Hz, C-8), 128.8
(d, J = 1.3 Hz. C-12), 120.0 (C-5), 118.2 (C-3), 116.2 (d, J = 21.4 Hz, C-9), 115.7 (d, J = 21.5 Hz, C-13) ppm;
HRMS (EI-QTOF, [M + H]+): calculated for C17H12F2N: 268.0937; found: 268.0940.
2,6-Bis(4-fluorophenyl)pyridine (5bi)37g (Scheme 5): Pale yellow solid, Rf = 0.60 (SiO2, Hexane/EtOAc = 9:1);
m.p = 92 - 94 °C (Lit37g 93 - 95 °C); 1H NMR (600 MHz, CDCl3): δ = 8.12 (m, 4H; 8-H), 7.81 (t, J = 7.8 Hz, 1H; 4-
H), 7.64 (d, J = 7.7 Hz, 2H; 3-H and 5-H), 7.17 (m, 4H; 9-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 163.1 (d,
J =247.0 Hz, C-10), 155.8 (C-2 and C-6), 137.6 (C-4), 135.48 (d, J =3.0 Hz, C-7), 128.73 (d, J =8.3 Hz, C-8), 118.2
(C-5), 115.6 (d, J =21.7 Hz, C-9) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H12F2N: 268.0937; found:
268.0940.
Preparation of 2,4-Bis(4-chlorophenyl)pyridine (3ak) and 2,6-Bis(4-chlorophenyl)pyridine (5bj)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 4׳-chloroacetophenone
2k (2.6 mmol, 403 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
chlorophenyl)pyridine 3ak in 69% (207 mg) and 3,5-diphenylpyridine 4 in 12% (28 mg) yield as yellow solid and
black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 4׳-chloroacetophenone 2k
(2.6 mmol, 403 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
chlorophenyl)pyridine 3ak in 61% (183 mg) and 2,6-bis(4-chlorophenyl)pyridine 5bj in 17% (51 mg) yield as
yellow solid and white solid respectively (Scheme 5).
2,4-Bis(4-chlorophenyl)pyridine (3ak)20d (Scheme 4, 5): Yellow solid, Rf = 0.50 (SiO2, Hexane/EtOAc = 9:1);
m.p = 98 - 100 °C (Lit20d 99 - 102 °C); 1H NMR (600 MHz, CDCl3): δ = 8.73 (d, J = 4.7 Hz, 1H; 2-H), 7.99 (dd, J =
8.6 Hz, 2H; 8-H), 7.85 (s, 1H; 3-H), 7.62 (dd, J = 8.5 Hz, 2H; 12-H), 7.50 - 7.41 (m, 4H; 9-H and 13-H), 7.42 (d, J =
5.1 Hz, 1H; 5-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 157.0 (C-2), 150.3 (C-6), 148.2 (C-4), 137.7 (C-11),
136.8 (C-7), 135.4 (C-13), 135.3 (C-10), 129.4 (C-9), 129.0 (C-13), 128.33 (C-8), 128.27 (C-12), 120.2 (C-5), 118.2
(C-3) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H12Cl2N: 300.0341; found: 300.0312.
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2,6-Bis(4-chlorophenyl)pyridine (5bj)31b (Scheme 5): White solid, Rf = 0.60 (SiO2, Hexane/EtOAc = 9:1); m.p =
158 - 161 °C (Lit31b 157 - 160 °C); 1H NMR (600 MHz, CDCl3): δ = 8.07 (d, J = 8.2 Hz, 4H; 8-H), 7.83 (t, J = 7.8
Hz, 1H; 4-H), 7.67 (d, J = 7.7 Hz, 2H; 3-H and 5-H), 7.46 (d, J = 8.2 Hz, 4H; 9-H) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δ = 155.7 (C-2 and C-6), 137.7 (C-4), 137.6 (C-7), 135.2 (C-10), 128.9 (C-8), 128.2 (C-9), 118.6 (C-3 and
C-5) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H12Cl2N: 300.0341; found: 300.0345.
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Preparation of 2,4-Bis(3-chlorophenyl)pyridine (3al) and 2,6-Bis(3-chlorophenyl)pyridine (5bk)
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According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 3׳-chloroacetophenone
2l (2.6 mmol, 403 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(3-
chlorophenyl)pyridine 3al in 60% (180 mg) and 3,5-diphenylpyridine 4 in 17% (39 mg) yield as brown solid and
black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 3׳-chloroacetophenone 2l
(2.6 mmol, 403 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(3-
chlorophenyl)pyridine 3al in 55% (165 mg) and 2,6-bis(3-chlorophenyl)pyridine 5bk in 15% (45 mg) yield as
brown solid and yellow oil respectively (Scheme 5).
2,4-Bis(3-chlorophenyl)pyridine (3al)26d (Scheme 4, 5): Brown solid, Rf = 0.60 (SiO2, Hexane/EtOAc = 9:1); m.p
= 95 - 96 °C (Lit26d 95 - 97 °C); 1H NMR (400 MHz, CDCl3): δ = 8.75 (d, J = 5.1 Hz, 1H; 6-H), 8.06 (s, 1H; 8-H),
7.95 (d, J = 7.6 Hz, 1H; 12-H), 7.82 (s, 1H; 3-H), 7.66 (s, 1H; 14-H), 7.51 (d, J = 2.6 Hz, 1H; 5-H), 7.45 - 7.41 (m,
5H; 10-H, 11-H, 16-H, 17-H and 18-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 157.0 (C-2), 150.4 (C-6), 148.2
(C-4), 141.0 (C-13), 140.1 (C-7), 135.3 (C-9), 135.0 (C-15), 130.5 (C-8), 130.1 (C-11), 129.3 (C-16), 129.28 (C-17),
127.33 (C-10), 127.33 (C-14), 125.4 (C-12), 125.2 (C-18), 120.8 (C-5), 118.8 (C-3) ppm; HRMS (EI-QTOF, [M +
H]+): calculated for C17H12Cl2N: 300.0341; found: 300.0340.
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2,6-Bis(3-chlorophenyl)pyridine (5bk)37g (Scheme 5): Yellow oil, Rf = 0.70 (SiO2, Hexane/EtOAc = 9:1); H
NMR (400 MHz, CDCl3): δ = 8.12 (s, 2H; 8-H), 7.98 (t, J = 7.5 Hz, 2H; 11-H), 7.81 (t, J = 8.0 Hz, 1H; 4-H), 7.66
(d, J = 7.6 Hz, 2H; 3-H and 5-H), 7.42 - 7.36 (m, 4H; 10-H and 12-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ =
155.6 (C-2 and C-6), 141.0 (C-4), 137.9 (C-7), 134.9 (C-9), 130.0 (C-8), 129.2 (C-11), 127.2 (C-10), 125.1 (C-12),
119.3 (C-3 and C-5) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H12Cl2N: 300.0341; found: 300.0331.
Preparation of 2,4-bis(4-bromophenyl)pyridine (3am)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) and 4׳-
bromoacetophenone 2m (2.6 mmol, 517 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(4-
bromophenyl)pyridine 3am in 60% (233 mg) and 3,5-diphenylpyridine 4 in 12% (28 mg) yield as yellow solid and
black solid respectively (Scheme 4).
2,4-bis(4-bromophenyl)pyridine (3am)26d (Scheme 4): Yellow solid, Rf = 0.45 (SiO2, Hexane/EtOAc = 9:1); m.p
1
= 137 - 139 °C (Lit26d 136 - 138 °C); H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 4.6 Hz, 1H; 6-H), 7.97 (d, J =
8.0 Hz, 2H; 8-H), 7.84 (s, 1H; 3-H), 7.61 (d, J = 7.6 Hz, 2H; 12-H), 7.47 (d, J = 8.2 Hz, 4H; 9-H and 13-H), 7.40 (d,
J = 7.8 Hz, 1H, 5-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.7 (C-2), 150.3 (C-6), 148.2 (C-4), 137.7 (C-
11), 136.8 (C-7), 132.8, 132.0, 128.4, 128.3, 127.1, 124.9, 120.3 (C-5), 118.2 (C-3) ppm; HRMS (EI-QTOF, [M +
H]+): calculated for C17H12Br2N: 387.9336; found: 387.9301.
Preparation of 2,4-bis(3-bromophenyl)pyridine (3an)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) and 3׳-
bromoacetophenone 2n (2.6 mmol, 517 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O
(2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(3-
bromophenyl)pyridine 3an in 56% (218 mg) and 3,5-diphenylpyridine 4 in 16% (37 mg) yield as reddish brown
solid and black solid respectively (Scheme 4).
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2,4-bis(3-bromophenyl)pyridine (3an)26d (Scheme 4): Reddish brown solid, Rf = 0.40 (SiO2, Hexane/EtOAc =
9:1); m.p = 87 - 89 °C (Lit26d 89 - 91 °C); 1H NMR (400 MHz, CDCl3): δ = 8.74 (d, J = 4.7 Hz, 1H; 6-H), 8.05 (s,
1H; 8-H), 7.90 (d, J = 7.6 Hz, 1H; 12-H), 7.84 (s, 1H; 3-H), 7.65 (s, 1H; 14-H), 7.57 – 7.51 (m, 2H; 10-H and 16-H),
7.44 - 7.40 (m, 4H, 5-H, 11-H, 17-H and 18-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 158.3 (C-2), 150.3 (C-
6), 147.9 (C-4), 140.4 (C-7), 139.2 (C-13), 130.4 (C-14), 129.2 (C-17), 129.1 (C-11), 129.0 (C-8), 128.8 (C-16),
127.3 (C-10), 127.1 (C-12), 127.06 (C-18), 125.8 (C-9), 125.3 (C-15), 120.1 (C-5), 118.7 (C-3) ppm; HRMS (EI-
QTOF, [M + H]+): calculated for C17H12Br2N: 387.9336; found: 387.9322.
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Preparation of 2,4-bis(2-bromophenyl)pyridine (3ao) and 2,6-Bis(2-bromophenyl)pyridine (5bl)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 2׳-bromoacetophenone
2o (2.6 mmol, 517 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(2-
bromophenyl)pyridine 3ao in 57% (222 mg) and 3,5-diphenylpyridine 4 in 18% (42 mg) yield as brown solid and
black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 2׳-bromoacetophenone 2o
(2.6 mmol, 517 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2,4-bis(2-
bromophenyl)pyridine 3ao in 57% (222 mg) and 2,6-bis(2-bromophenyl)pyridine 5bl in 16% (62 mg) yield as
brown solid and yellow solid respectively (Scheme 5).
2,4-bis(2-bromophenyl)pyridine (3ao)26e (Scheme 4): Brown solid, Rf = 0.40 (SiO2, Hexane/EtOAc = 9:1); m.p =
125 - 128 °C (Lit26e 124 - 126 °C); 1H NMR (400 MHz, CDCl3): δ = 8.77 (d, J = 4.7 Hz, 1H; 6-H), 8.08 (d, J = 7.6
Hz, 2H; 9-H and 15-H), 7.96 (s, 1H; 3-H), 7.74 – 7.72 (d, J = 8.0 Hz, 2H; 12-H and 18-H), 7.45 – 7.46 (m, 5H; 5-H,
10-H, 11-H, 16-H and 17-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 158.1 (C-2), 150.1 (C-6), 149.3 (C-4),
139.5 (C-7), 138.6 (C-13), 130.9 (C-15), 130.3 (C-9), 130.0 (C-16), 129.7 (C-18), 129.15 (C-10), 129.1 (C-12),
129.07 (C-17), 128.8 (C-11), 127.1 (C-14), 127.0 (C-8), 120.3 (C-5), 118.8 (C-3) ppm; HRMS (EI-QTOF, [M +
H]+): calculated for C17H12Br2N: 387.9336; found: 387.9326.
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2,6-Bis(2-bromophenyl)pyridine (5bl) (Scheme 5): Yellow solid, Rf = 0.65 (SiO2, Hexane/EtOAc = 9:1); H
NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.8 Hz, 2H; 12-H), 7.82 (t, J = 7.5 Hz, 1H; 4-H), 7.62 (d, J = 7.2 Hz, 2H;
3-H and 5-H), 7.57 - 7.44 (m, 6H; 9-H, 10-H and 11-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.8 (C-2 and
C-6), 139.5 (C-13), 137.5 (C-4), 129.0 (C-9), 128.8 (C-12), 128.7 (C-10, 127.1 (C-11), 123.2 (C-8), 118.7 (C-3 and
C-5) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H12Br2N: 387.9336; found: 387.9337.
Preparation
of
2,4-bis(4-(trifluoromethyl)phenyl)pyridine
(3ap)
and
2,6-bis(4-
(trifluoromethyl)phenyl)pyridine (5bm)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 4׳-
(trifluoromethyl)acetophenone 2p (2.6 mmol, 489 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg),
Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the
desired 2,4-bis(4-(trifluoromethyl)phenyl)pyridine 3ap in 59% (217 mg) and 3,5-diphenylpyridine 4 in 14% (32 mg)
yield as yellow solid and black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 4׳-
(trifluoromethyl)acetophenone 2p (2.6 mmol, 489 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg),
Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the
desired
2,4-bis(4-(trifluoromethyl)phenyl)pyridine
3ap
in
52%
(191
mg)
and
2,6-bis(4-
(trifluoromethyl)phenyl)pyridine 5bm in 20% (73 mg) yield as yellow solid and pale yellow solid respectively
(Scheme 5).
2,4-bis(4-(trifluoromethyl)phenyl)pyridine (3ap)37i (Scheme 4, 5): Yellow solid, Rf = 0.55 (SiO2, Hexane/EtOAc
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= 9:1); m.p = 68 - 69 °C (Lit37i 69 - 70 °C); H NMR (600 MHz, CDCl3): δ = 8.81 (d, 3J = 5.1 Hz, 1H; 6-H), 8.17
(d, 3J = 8.0 Hz, 2H; 8-H), 7.95 (s, 1H; 3-H), 7.83 - 7.72 (m, 6H; 9-H, 13-H and 14-H), 7.51 (d, 3J = 7.8 Hz, 1H; 5-H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.8 (C-2), 150.6 (C-6), 148.2 (C-4), 142.4 (C-12), 141.8 (C-7), 131.2
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(q, J = 16.8 Hz, C-10 and C-15), 127.6 (C-13), 127.3 (C-8), 126.2 (q, J = 3.7 Hz, C-9), 125.8 (q, J = 3.7 Hz, C-14),
124.0 (q, J = 251.7 Hz, C-11 and C-16), 121.1 (C-5), 119.1 (C-3) ppm; HRMS (EI-QTOF, [M + H]+): calculated
for C19H12F6N: 368.0873; found: 368.0861.
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2,6-bis(4-(trifluoromethyl)phenyl)pyridine (5bm)37g (Scheme 5): Pale yellow solid, Rf = 0.65 (SiO2,
Hexane/EtOAc = 9:1); m.p = 144 - 146 °C (Lit37g 143 - 145 °C); 1H NMR (400 MHz, CDCl3): δ = 8.25 (d, 3J = 8.0
Hz, 4H; 8-H), 7.91 (t, 3J = 7.9 Hz, 1H; 4-H), 7.80 - 7.76 (m, 6H; 3-H, 5-H and 9-H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ = 155.65 (C-2 and C-6), 142.4 (C-4), 138.0 (C-7), 131.0 (q, J = 28.0 Hz, C-10), 127.3 (C-8), 125.7 (q, J =
240.6 Hz, C-11), 122.83 (C-9), 119.8 (C-3 and C-5) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H12F6N:
368.0873; found: 368.0871.
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Preparation of 2,4-bis(3-(trifluoromethyl)phenyl)pyridine (3aq)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 3׳-
(trifluoromethyl)acetophenone 2q (2.6 mmol, 489 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg),
Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the
desired 2,4-bis(3-(trifluoromethyl)phenyl)pyridine 3aq in 60% (220 mg) and 3,5-diphenylpyridine 4 in 16% (37 mg)
yield as yellow solid and black solid respectively (Scheme 4).
2,4-bis(3-(trifluoromethyl)phenyl)pyridine (3aq) (Scheme 4): Yellow solid, Rf = 0.40 (SiO2, Hexane/EtOAc =
1
3
3
9:1); H NMR (400 MHz, CDCl3): δ = 8.81 (d, J = 5.1 Hz, 1H; 6-H), 8.33 (s, 1H, 8-H), 8.23 (d, J = 8.0 Hz, 1H;
3
12-H), 7.94 (s, 2H; 3-H and 14-H), 7.87 (d, J = 8.0 Hz, 1H; 10-H), 7.76 - 7.63 (m, 4H; 11-H, 16-H, 17-H and 18-
H), 7.51 (d, J = 7.8 Hz, 1H; 5-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.8 (C-2), 150.5 (C-6), 148.3 (C-
3
4), 139.8 (C-13), 141.8 (C-7), 131.5 (q, J = 16.8 Hz, C-10 and C-15), 130.5, 130.3, 130.05, 129.8, 129.4, 125.8
124.0 (q, J = 251.7 Hz, C-19, C-20), 120.0 (C-5), 118.9 (C-3) ppm; HRMS (EI-QTOF, [M + H]+): calculated for
C19H12F6N: 368.0873; found: 368.0861.
Preparation of 2,4-bis(benzo[d][1,3]dioxol-5-yl)pyridine (3ar) and 2,6-bis(benzo[d][1,3]dioxol-5-yl)pyridine
(5bn)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) 3,4-
methylenedioxyacetophenone 2r (2.6 mmol, 426 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg),
Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the
desired 2,4-bis(benzo[d][1,3]dioxol-5-yl)pyridine 3ar in 66% (211 mg) and 3,5-diphenylpyridine 4 in 10% (23 mg)
yield as yellow solid and black solid respectively (Scheme 4).
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) 3,4-
methylenedioxyacetophenone 2r (2.6 mmol, 426 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg),
Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the
desired 2,4-bis(benzo[d][1,3]dioxol-5-yl)pyridine 3ar in 66% (211 mg) and 2,6-bis(benzo[d][1,3]dioxol-5-
yl)pyridine 5bn in 19% (61 mg) yield as yellow solid and pale yellow solid respectively (Scheme 5).
2,4-bis(benzo[d][1,3]dioxol-5-yl)pyridine (3ar)20d (Scheme 4, 5): Yellow solid, Rf = 0.45 (SiO2, Hexane/EtOAc =
1
3
9:1); m.p = 116 - 118 °C (Lit20d 115 - 117 °C); H NMR (600 MHz, CDCl3): δ = 8.63 (d, J = 5.1 Hz, 1H; 6-H),
7.75 (s, 1H; 8-H), 7.56 (s, 1H; 15-H), 7.54 (dd, 3J = 8.8 Hz, 1H; 13-H), 7.32 (dd, 3J = 5.2 Hz, 1H; 5-H), 7.18 (dd, 3J
= 8.2 Hz, 1H; 20-H), 7.15 (s, 1H; 3-H), 6.94 – 6.90 (m, 2H; 12-H and 19-H), 6.04 (s, 2H; 10-H), 6.03 (s, 2H; 17-H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 157.5 (C-2), 149.8 (C-4), 149.0 (C-6), 148.57 (C-9), 148.55 (C-16 and
C-18), 148.3 (C-11), 133.8 (C-14), 132.6 (C-7), 121.1 (C-13), 121.05 (C-20), 119.5 (C-5), 117.9 (C-3), 108.9 (C-8),
108.5 (C-12), 107.5 (C-19), 107.3 (C-15), 101.5 (C-10), 101.4 (C-17) ppm; HRMS (EI-QTOF, [M + H]+):
calculated for C19H14NO4: 320.0917; found: 320.0907.
2,6-bis(benzo[d][1,3]dioxol-5-yl)pyridine (5bn)37h (Scheme 5): Pale yellow solid, Rf = 0.60 (SiO2, Hexane/EtOAc
= 9:1); 1H NMR (600 MHz, CDCl3): δ = 7.72 (t, 3J = 7.8 Hz, 1H; 8-H), 7.69 (s, 2H; 8-H), 7.61 (dd, 3J = 8.1 Hz, 2H;
3
3
13-H), 7.54 (d, J = 7.8 Hz, 2H; 3-H and 5-H), 6.91 (d, J = 8.1 Hz, 2H; 12-H), 6.03 (s, 4H; 10-H) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ = 156.0 (C-2 and C-6), 148.4 (C-9), 148.2 (C-11), 137.4 (C-4), 134.0 (C-7), 120.9 (C-
13), 117.5 (C-3 and C-5), 108.3 (C-8), 107.4 (C-12), 101.2 (C-10) ppm; HRMS (EI-QTOF, [M + H]+): calculated
for C19H14NO4: 320.0917; found: 320.0910.
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Preparation of 3,5-dimethyl-2,4-diphenylpyridine (3as) and 3,5-dimethyl-2,6-diphenylpyridine (5bo)
According to the general procedure, reactions between phenylalanine 1a (2.0 mmol, 330 mg) and propiophenone 2s
(2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 3,5-dimethyl-2,4-
diphenylpyridine 3as in 64% (166 mg) and 3,5-diphenylpyridine 4 in 13% (30 mg) yield as white solid and black
solid respectively (Scheme 4).
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According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg) and propiophenone 2s
(2.6 mmol, 348.4 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg),
DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 3,5-dimethyl-2,4-
diphenylpyridine 3as in 61% (158 mg) and 3,5-dimethyl-2,6-diphenylpyridine 5bo in 17% (44 mg) yield as white
solid and pale yellow solid respectively (Scheme 5).
3,5-dimethyl-2,4-diphenylpyridine (3as)37b (Scheme 4, 5): White solid, Rf = 0.50 (SiO2, Hexane/EtOAc = 9:1);
m.p = 82 - 84 °C (Lit37b 84 - 85 °C); 1H NMR (600 MHz, CDCl3): δ = 8.52 (s, 1H; 6-H), 7.55 (d, 3J = 7.9 Hz, 2H; 8-
H), 7.51 – 7.46 (m, 4H), 7.42 (d, 3J = 4.8 Hz, 2H; 13-H), 7.15 (d, 3J = 4.8 Hz, 2H), 2.08 (s, 3H; 15-H), 2.03 (s, 3H;
16-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 156.3 (C-2), 149.3 (C-4), 146.2 (C-6), 143.1 (C-11), 137.3 (C-7),
130.0, 129.7, 129.2, 129.01, 128.4, 128.3, 128.0, 127.6, 17.9 (C-15), 17.6 (C-16) ppm; HRMS (EI-QTOF, [M +
H]+): calculated for C19H18N: 260.1439; found: 260.1428.
3,5-dimethyl-2,6-diphenylpyridine (5bo)20d (Scheme 5): Pale yellow solid, Rf = 0.75 (SiO2, Hexane/EtOAc = 9:1);
m.p = 128 - 129 °C (Lit20d 127 - 130 °C); 1H NMR (400 MHz, CDCl3): δ = 7.60 (d, 3J = 7.8 Hz, 4H; 8-H), 7.48 (s,
3
3
1H; 4-H), 7.44 (t, J = 8.2 Hz, 4H; 9-H), 7.36 (t, J = 8.4 Hz, 2H; 10-H), 2.39 (s, 6H; 11-H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ = 155.8 (C-2), 141.1 (C-4), 140.7 (C-7), 129.2 (C-9), 129.1 (C-3 and C-5), 128.0 (C-8), 127.7
(C-10), 19.6 (C-11) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C19H18N: 260.1439; found: 260.1431.
Experimental procedures and analytical data of synthesized 2,4-diarylpyridines (6aa-ab) and 2,6-
diarylpyridines (7aa-ab)
Preparation of 2-(4-Chlorophenyl)-4-phenylpyridine (6aa) and 2-(4-Chlorophenyl)-6-phenylpyridine (7aa)
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg), acetophenone 2a (1.3 mmol,
312 mg) and 4׳-chloroacetophenone 2k (1.3 mmol, 403 mg) were performed using FeCl3 (0.4 mmol, 64.8 mg),
Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg), Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the
desired 2-(4-Chlorophenyl)-4-phenylpyridine 6aa in 55% (146 mg) and 2-(4-Chlorophenyl)-6-phenylpyridine 7aa in
21% (56 mg) yield as off white solid and pale white solid respectively (Scheme 7).
2-(4-Chlorophenyl)-4-phenylpyridine (6aa)30 (Scheme 7): Off white solid, Rf = 0.40 (SiO2, Hexane/EtOAc =
9:1); m.p = 56 - 58 °C (Lit30 57 - 58 °C); 1H NMR (400 MHz, CDCl3): δ = 8.71 (d, 3J = 4.8 Hz, 1H; 6-H), 7.98 (d,
3
3J = 8.2 Hz, 2H; 8-H), 7.89 (s, 1H; 3-H), 7.68 (d, J = 7.6 Hz, 2H; 12-H), 7.53 – 7.44 (m, 6H; 5-H, 9-H, 13-H and
14-H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ = 156.9 (C-2), 150.3 (C-6), 149.6 (C-4), 138.4 (C-11), 138.0 (C-7),
135.3 (C-10), 129.3 (C-9), 129.0 (C-13), 128.9 (C-14), 128.4 (C-8), 127.2 (C-12), 120.6 (C-5), 118.6 (C-3) ppm;
HRMS (EI-QTOF, [M + H]+): calculated for C17H13ClN: 266.0737; found: 266.0732.
2-(4-Chlorophenyl)-6-phenylpyridine (7aa)37e (Scheme 7): Pale white solid, Rf = 0.65 (SiO2, Hexane/EtOAc =
1
3
9:1); m.p = 105 - 107 °C (Lit37e 104 - 105 °C); H NMR (600 MHz, CDCl3): δ = 8.16 (d, J = 8.0 Hz, 2H; 8-H),
8.10 (d, 3J = 7.6 Hz, 2H; 12-H), 7.82 (t, 3J = 7.5 Hz, 1H; 4-H), 7.70 (d, 3J = 7.8 Hz, 2H; 3-H and 5-H), 7.50 (t, 3J =
8.2 Hz, 4H; 9-H and 13-H), 7.43 (t, 3J = 7.9 Hz, 1H; 14-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 156.8 (C-2),
155.6 (C-6), 139.5 (C-4), 137.6 (C-11), 137.4 (C-7), 135.0 (C-10), 129.1 (C-9), 128.8 (C-12), 128.6 (C-8), 128.2 (C-
14), 127.0 (C-13), 118.9 (C-5), 118.6 (C-3) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C17H13ClN:
266.0737; found: 266.0715.
Preparation of 2-(4-nitrophenyl)-4-(4-(trifluoromethyl)phenyl)pyridine (6ab) and 2-(4-nitrophenyl)-6-(4-
(trifluoromethyl)phenyl)pyridine (7ab)
According to the general procedure, reactions between glycine 1b (2.0 mmol, 150 mg), 4׳-
(trifluoromethyl)acetophenone 2p (1.3 mmol, 244 mg) and 4׳-nitroacetophenone 2t (1.3 mmol, 215 mg) were
performed using FeCl3 (0.4 mmol, 64.8 mg), Cu(OAc)2⸳H2O (2.0 mmol, 398 mg), DavePhos (0.2 mmol, 78.6 mg),
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Pd(OAc)2 (0.2 mmol, 44.8 mg) to obtain the desired 2-(4-nitrophenyl)-4-(4-(trifluoromethyl)phenyl)pyridine 6ab in
50% (172 mg) and 2-(4-nitrophenyl)-6-(4-(trifluoromethyl)phenyl)pyridine 7ab in 24% (83 mg) yield as orange
solid and yellow solid respectively (Scheme 7).
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2-(4-nitrophenyl)-4-(4-(trifluoromethyl)phenyl)pyridine (6ab) (Scheme 7): Orange solid, Rf = 0.40 (SiO2,
Hexane/EtOAc = 9:1); m.p = 55 - 58 °C; 1H NMR (600 MHz, CDCl3): δ = 8.82 (d, 3J = 5.1 Hz, 1H; 6-H), 8.34 (dd,
3J = 7.8 Hz, 2H; 8-H), 8.17 (d, 3J = 8.1 Hz, 2H; 9-H), 7.95 (s, 1H; 3-H), 7.80 – 7.77 (m, 4H; 12-H and 13-H), 7.51
(dd, 3J = 5.1 Hz, 1H; 5-H) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ = 156.8 (C-2), 150.5 (C-6), 148.5 (C-4), 148.3
(C-10), 144.9 (C-11), 138.1 (C-7), 131.5 (q, J = 208.0 Hz, C-14), 127.5 (C-8), 127.3 (C-9), 126.2 (q, J = 28.0 Hz, C-
13), 125.8 (q, J = 256.0 Hz, C-15), 124.0 (C-9), 120.1 (C-5), 119.1 (C-3) ppm; HRMS (EI-QTOF, [M + H]+):
calculated for C18H12F3N2O2: 345.0851; found: 345.0841.
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2-(4-nitrophenyl)-6-(4-(trifluoromethyl)phenyl)pyridine (7ab) (Scheme 7): Yellow solid, Rf = 0.55 (SiO2,
Hexane/EtOAc = 9:1); 1H NMR (600 MHz, CDCl3): δ = 8.35 (dd, 3J = 8.8 Hz, 4H; 8-H), 8.25 (dd, 3J = 8.1 Hz, 2H;
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8-H), 7.95 (t, J = 7.9 Hz, 1H; 4-H), 7.84 (dd, J = 7.8 Hz, 2H; 3-H and 5-H), 7.78 (d, J = 8.2 Hz, 2H; 9-H) ppm;
13C{1H} NMR (150 MHz, CDCl3) δ = 155.9 (C-2), 154.6 (C-6), 144.9 (C-10), 142.1 (C-4), 138.1 (C-7 and C-11),
132.4 (q, J = 33.6 Hz, C-14), 127.7 (C-8), 127.6 (q, J = 15.73 Hz, C-13), 127.3 (C-12), 125.7 (q, J = 269.0 Hz, C-
15), 124.0 (C-9), 120.3 (C-5), 120.1 (C-3) ppm; HRMS (EI-QTOF, [M + H]+): calculated for C18H12F3N2O2:
345.0851; found: 345.0846.
ASSOCIATED CONTENT
Additional optimization tables, copies of LC-MS for investigation of the reaction mechanism, copies of
1H NMR and 13C NMR spectra for all synthesized compounds are available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cmalakar@nitmanipur.ac.in
ORCID ID
Raghuram Gujjarappa: 0000-0002-2586-3190
Nagaraju Vodnala: 0000-0001-9549-934X
Chandi C. Malakar: 0000-0002-9478-017X
Notes
The authors declare no competing financial interest
ACKNOWLEDGEMENTS
CCM appreciate Science and Engineering Research Board (SERB), New Delhi and NIT Manipur for
financial support in the form of research grant (ECR/2016/000337). We sincerely thank Prof. Anil
Kumar, Vikki N Shinde and Shiv Dhiman from BITS Pilani for sample analysis and research support. We
thank Dr. Chinmoy K. Hazra from King Abdullah University of Science and Technology, KAUST
Catalysis Center for sample analysis. We also thank Dodla Sivanageswara Rao from Department of
Chemistry, Malaviya National Institute of Technology, Jaipur for NMR and HR-MS analysis. RG and NV
grateful to Ministry of Human Resource and Development (MHRD), New Delhi for fellowship support.
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