Design, synthesis and application of triazole ligands in suzuki miyaura cross coupling reaction of aryl chlorides

Article abstract of DOI:10.1016/j.molstruc.2020.127753

DFT calculations have been demonstrated to be a valuable tool for the mechanistic study of reaction which is difficult to acquire from pure experimental techniques. Structural, electronic and coordination aspects of synthesized triazole ligands were investigated theoretically by structure optimization on Gaussian 09 package by DFT approach at B3LYP/6-31G (d, p). HOMO-LUMO energy gaps correlated to its chemical reactivity and this information applied to interpret the role of ligand in the formation of ligand-metal complex. Electron rich environment around the triazole core stabilized the HOMO orbital and made these electrons available to form complex with Pd centre. The DFT calculations provide a plausible mechanism for the reaction that is consistent with the available experimental facts. A series of triazole ligands have been synthesized via efficient 1,3-dipolar cycloaddition of readily available azide and alkynes for coordination to Pd centre. Characterization of all the synthesized compounds was done by FTIR, ¹H NMR, ¹³C NMR and HRMS. Their ligand-Pd complexes provided excellent yields in the Suzuki-Miyaura coupling reactions (up to 92% yield) of unactivated aryl chlorides. Ligand 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2) was found to be most effective ligand because of electron donating 2,6 dimethoxy phenyl moiety attached to triazole ring at 4-position that facilitated the formation of electron rich ligand-catalyst complex. The complex favoured the oxidative addition step of Pd across the aryl chloride substrate and thus allowed for the development of highly active ligand-catalyst system for Suzuki reaction. During computational analysis, 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2) also showed lowest band gap due to electron rich distribution pattern on the HOMO that are involve in ligand-Pd complex formation. Conclusively, these triazoles ligands were found to be more competent and attractive for palladium catalyst because of simplistic pathway for the synthesis of triazole motif and the ease of individual tuning of the substituents on triazole core or exocyclic to it.

Full text of DOI:10.1016/j.molstruc.2020.127753

Journal Pre-proof
Design, synthesis and application of triazole ligands in suzuki miyaura cross coupling
reaction of aryl chlorides
Sobia Jabeen, Rasheed Ahmad Khera, Javed Iqbal, Muhammad Asgher
PII:
S0022-2860(20)30077-6
DOI:
https://doi.org/10.1016/j.molstruc.2020.127753
MOLSTR 127753
Reference:
To appear in: Journal of Molecular Structure
Received Date: 27 July 2019
Revised Date: 19 November 2019
Accepted Date: 18 January 2020
Please cite this article as: S. Jabeen, R.A. Khera, J. Iqbal, M. Asgher, Design, synthesis and application
of triazole ligands in suzuki miyaura cross coupling reaction of aryl chlorides, Journal of Molecular
Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.127753.
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Graphical abstract

Design, synthesis and application of triazole ligands in Suzuki Miyaura cross coupling
reaction of aryl chlorides
Sobia Jabeena, Rasheed Ahmad Kheraa*, Javed Iqbala,b*, Muhammad Asgherc
a. Department of Chemistry, University of Agriculture, Faisalabad 38040-Pakistan.
b. Punjab Bioenergy Institute, University of Agriculture, Faisalabad, 38040, Pakistan
c. Department of Biochemistry, University of Agriculture, Faisalabad, 38040, Pakistan
Email: javedkhattak79@gmail.com, javed.iqbal@uaf.edu.pk, rasheedahmadkhera@yahoo.com
Abstract
DFT calculations have been demonstrated to be a valuable tool for the mechanistic study of
reaction which is difficult to acquire from pure experimental techniques. Structural, electronic
and coordination aspects of synthesized triazole ligands were investigated theoretically by
structure optimization on Gaussian 09 package by DFT approach at B3LYP/6-31G (d, p).
HOMO-LUMO energy gaps correlated to its chemical reactivity and this information applied to
interpret the role of ligand in the formation of ligand-metal complex. Electron rich environment
around the triazole core stabilized the HOMO orbital and made these electrons available to form
complex with Pd center. The DFT calculations provide a plausible mechanism for the reaction
that is consistent with the available experimental facts. A series of triazole ligands have been
synthesized via efficient 1,3-dipolar cycloaddition of readily available azide and alkynes for
coordination to Pd center. Characterization of all the synthesized compounds was done by FTIR,
1H NMR, 13C NMR and HRMS. Their ligand-Pd complexes provided excellent yields in the
Suzuki-Miyaura coupling reactions (up to 92% yield) of unactivated aryl chlorides. Ligand 4-
(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2) was found to be most effective ligand
because of electron donating 2,6 dimethoxy phenyl moiety attached to triazole ring at 4-position
that facilitated the formation of electron rich ligand-catalyst complex. The complex favoured the
oxidative addition step of Pd across the aryl chloride substrate and thus allowed for the
development of highly active ligand-catalyst system for Suzuki reaction. during computational
analysis, 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2) also showed lowest band gap
due to electron rich distribution pattern on the HOMO that are involve in ligand-Pd complex
formation. Conclusively, these triazoles ligands were found to be more competent and attractive
for palladium catalyst because of simplistic pathway for the synthesis of triazole motif and the
ease of individual tuning of the substituents on triazole core or exocyclic to it.

Key words: Triazole, Electronic properties, DFT analysis, Ligand, Pd catalyzed cross coupling
reaction, Suzuki-Miyaura cross coupling reaction, Aryl chlorides
Introduction
Designing of ligands with structural diversity and new strategies for ligand-catalyst system
development is crucial for dealing with challenging substrates like aryl chlorides [1, 2]. As
advancement in cross coupling reactions based upon two major thrusts: (1) Improved reactivity
and stability of catalytic system either by incorporating electron rich ligands (2) The application
of novel halides, pseudohalides or alternative organometallic nucleophiles [3]. Generally, in all
transition metal catalyzed reactions, the catalyst activity and selectivity depends upon the
characteristics and nature of the ligand bind to central metal atom, therefore selection of a
suitable ligand is critical for the successful operation of catalyst during reaction [4]. In fact,
ligand controls the kinetics of catalytic cycle by changing the activation energy barrier during
elementary steps of Pd catalyzed reaction. Besides this, ligand also strongly binds to Pd(0) that
extends the lifetime of catalyst in the solution and prevents its agglomeration as inactive Pd
black that is a major cause of catalyst deactivation [5]. Generally the first step of cross coupling
reaction is oxidative addition that is strongly affected by electronic factor of ligand; while the
second step is transmetallation and third step reductive elimination are affected by steric and
electronic factor of ligand [6, 7]. Therefore an ideal catalytic system of coupling reaction is one
in which ligand possess both steric as well as electronic factor. Thus the electronics of ligand and
its complex with metal is an imperative factor for successful catalytic application in cross
coupling reactions [8, 9]. The flexible environment of transition metal helps to design the
catalytic system in which metal center is surrounded by electron rich ligand. At present, the
phosphine based ligands are the most noteworthy class of ligand for cross coupling reactions
[10]. However, these organophosphine ligands are susceptible to oxidation, subsequently loss
their coordinating power to metals that decrease the catalytic power. Thus this is not favorable
for long term storage of phosphine ligands [11].

The designing new ligands with improved steric and electronic factors is a challenging task to
compete with unreactive substrate in the cross coupling field. Computational chemistry has made
significant contribution in understanding the mechanistic details of palladium catalyzed C-C
bond forming reactions prior to experimentation. As this reaction is complicated and laborious
involving multistep catalytic reaction, so the identification of reaction intermediates solely by
experimental method is tricky [12]. Therefore, computational studies give preliminary details
which can be used to predict the experimental data of entirely known molecule or to explore
reaction mechanisms and so forth. Different kinds of ligands play vital role in the progression of
transition metal catalyzed reactions [8, 9] however the quest to find more proficient and versatile
ligands has been a leading task for organic chemist [13]. Triazole based ligand system have
attained significant attention over few decades owing to their novelty in catalytic system [14-16].
Designing of triazole ligand to assess the effect of several substituents on reactivity, relative
stability, volatility and energetic of these triazole ligands through both theoretical and
experimental approaches is of great significance. Experimental and theoretical studies provide
complete description of vibrational harmonic spectra and molecular structure of triazoles. The
effective quantum mechanical approach DFT (Density functional theory) has established as
potent tool for analyzing molecular and vibrational ground state properties of compounds [17].
The theoretical calculations are important for giving reliable insight into electronic energies and
molecular characteristics. HOMO and LUMO investigation is imperative for the elucidation of
information with respect to charge transfer in molecule [18].
This research work aimed to design new class of triazole base ligand library and their application
in Suzuki cross coupling reaction of unreactive aryl chlorides. We focused on both
computational and experimental studies to provide a deeper insight into reaction mechanism.
Because it is always tedious to envisage experimentally which molecule could lead to new
system with desirable properties. Therefore in the first step, we carried theoretical calculations
by using density functional theory (DFT) method to investigate the electronic properties of
design molecules. Electronic properties such frontier molecular orbitals (HOMO-LUMO), band
gap energies and density of states were analyzed. Then Cu catalyzed azide-alkyne cycloaddition
reaction was carried out to synthesize the designed triazole ligand library that was used in Suzuki
coupling reaction of aryl chlorides. Synthesis of such substituted triazole core enabled handling
of electronic and steric properties of ligands and their metal complexes. Besides this, chelating

ligands could also be synthesized by substituting more electron donor moieties onto the triazole
ring or exocyclic to ring that would make it more powerful chelating ligand.
2. Methodology
2.1. Computational details
Gaussian 09 package was used to carry out all the theoretical calculations. In the search of
attaining accurate computational method for optimization of molecular geometries, DFT with
functional B3LYP [12] and 6-31G basic set was used. Initially, the 3D structures of all
compounds were drawn with the Gauss View 5. All computation calculations were carried out by
adding diffuse function (d) and polarization function (p) on heavy atoms. After conformational
study, geometry optimizations and energy calculations of triazoles in the ground state was
computed by performing DFT method with functional i.e. B3LYP by using the 6-31G(d,p) level
of theory [19]. Graphs were plotted by using Origin 6.0 program [20]. The density of states were
also carried out on B3lyp/6-31G(d,p) level of theory and the DOS were analyzed by PyMOlyze
software.
2.2. Experimental
2.2.1. Materials and instrumentation
All chemicals and commercial reagents were used as received without purification unless
otherwise noted. Reaction solvents were freshly distilled and degassed before use. All non-
aqueous reactions were carried out under inert atmosphere of nitrogen. Reactions were
1
monitored by using silica gel and F254 fluorescent coated glass TLC plates. H NMR and 13C
NMR spectra were recorded in CDCl3 on Bruker Advance 400 MHz NMR Spectrometer (Bruker
Ettlingen, Germany) using Tetramethylsilane as internal standard. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet of doublet, t = triplet, q =
quartet, m = multiplet) and coupling constants (J in hertz). IR spectra’s are recorded on Bruker-
IFS 48 Spectrometer and values are reported in cm-1. Column chromatography was performed
with silica gel (50-63 ꢀm mesh).

2.2.2. Synthesis of terminal alkynes
Three types of terminal alkynes i.e. 1-ethynyl-2-methoxybenzene (2a), 1-ethynyl-2,6-
dimethoxybenzene (2b) and phenyl acetylene (2c) were used for the synthesis of click triazole
ligands. Two derivatives of terminal alkynes i.e. 2a and 2b were synthesized in laboratory by
following literature procedure whereas 2c was used from commercial source.
2.2.3. General procedure (A) for the synthesis of terminal alkynes (2a-2b): In the 1st step,
benzaldehyde (2.00 mmol) was added to the solution of triphenyl phosphine (2.00 g, 8.00 mmol)
and tetrabromomethane ( 1.33 g, 4 mmol) in dichloromethan (20 mL) at 0 . (yellow to red)
stirred for 1h at 0 . After this, the resulting mixture was poured into the water and aq. layer
extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with
brine, dried with Na2SO4 and conc. in vacuo. Removal of solvent and chromatography (8:2,
hexane: EtOAc) afforded desired product 1a and 1b. In the 2nd step, n-BuLi (2.7M in hexane)
(3.20 mmol, 1.18 mL) was added drop wise to the stirring solution of 3a or 3b (129 mg, 0.40
mmol) in 8 mL of tetrahydrofuran at -78 and stirred for 1h under the inert atmosphere of Ar
gas at -78 . After that, 10% aq. HCl solution was added into the above mixture at room
temperature and extracted with DCM (3 X 30 mL). Washed with brine (30 mL), dried with
Na2SO4 and conc. in vacuo. Removal of solvent and chromatography (5:1, hexane: CH2Cl2)
afforded desired product 2a and 2b [21].
2.2.4. 1-(2,2-dibromovinyl)-2-methoxybenzene (1a): 1a was synthesized by following the general
procedure A using 2 methoxybenzaldehyde (0.68 g, 5.00 mmol), triphenyl phosphine (5.24 g,
20.00 mmol), tetrabromomethane (3.31 g, 10.00 mmol), DCM (50 mL). Removal of solvent and
1
chromatography afforded 1a as light yellow oil in 96% yield (1410 mg). H NMR (400 MHz,
CDCl3) δ 7.70 (dd, 1H; J = 7.6, 1.5 Hz), 7.60 (s, 1H), 7.34-7.31 (m, 1H); 6.97 (t, 1H; J = 7.6),
6.88 (d, 1H; J = 8.3Hz), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 156.8, 133.1, 130.2, 129.4,
124.62, 120.4, 110.7, 88.9; IR (neat) 1597, 1579, 1484, 1462, 1435, 1289, 1245, 1175, 1162,
1110, 1049, 1026 cm-1.
2.2.5. 2-(2,2-dibromovinyl)-1,3-dimethoxybenzene (1b): 1b was synthesized by following the
general procedure A using 2,6-dimethoxybenzaldehyde (0.33 g, 2.00 mmol), triphenyl phosphine
(2.00 g, 8.00 mmol), tetrabromomethane (1.33 g, 4mmol), DCM (20mL). Removal of solvent

and chromatography afforded 1b as white solid in 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.28
13
(t, 1H; J = 8.5 Hz), 7.25 (s, 1H), 6.55 (d, 2H; J = 8.4 Hz), 3.83 (s, 6H); C NMR (100 MHz,
CDCl3) δ 157.5, 131.3, 130.2, 114.1, 93.4, 56.0; IR (neat) 2959, 2935, 2836, 1585, 1469, 1430,
1305, 1288, 1249, 1197, 1106, 1034 cm-1.
2.2.6. 1-ethynyl-2-methoxybenzene (2a): 2a was synthesized by following the general procedure
A using 1a (0.12g, 0.40 mmol), n-BuLi (2.7 M in hexane, 3.20 mmol, 1.18 mL), THF (8 mL).
Removal of solvent and chromatography afforded 2a as light yellow oil in 87% yield (46mg). 1H
NMR (400 MHz, CDCl3) δ 7.47 (dd, 1H; J = 7.5, 1.7 Hz), 7.34-7.30 (m, 1H), 6.93-6.88 (m, 2H),
3.91 (s, 3H), 3.31 (s, 1H); 13CNMR (100 MHz, CDCl3) δ 160.8, 134.4, 130.5, 120.7, 111.4,
110.8, 81.3, 56.0; IR (neat) 3280, 1596, 1576, 1489, 1464, 1434, 1289, 1278, 1250, 1177, 1162,
1109, 1046, 1022 cm-1.
2.2.7. 1-ethynyl-2,6-dimethoxybenzene (2b): 2b was synthesized by following the general
procedure A using 1b (129 mg, 0.40 mmol), n-BuLi (2.7M in hexane) (3.20 mmol, 1.18 mL),
THF (8 mL). Removal of solvent and chromatography afforded 2b as white solid in 71% yield.
1H NMR (400 MHz, CDCl3) δ 7.26 (t, 2H; J = 7.5 Hz), 6.55 (d, 2H; J = 8.5 Hz), 3.90 (s, 6H);
3.56 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.4, 130.5, 103.6, 85.6, 56.4; IR (neat) 3271,
2927, 2840, 2103, 1584, 1474, 1432, 1296, 1254, 1109, 1030 cm-1
2.3. Synthesis of azides (3a-b)
Two types of azides i.e. 1-azido-4-methoxybenzene (3a) and phenyl azide (3b) were used for
azide-alkynes cycloaddition reaction. 3a was synthesized by following the literature procedure
[22].
2.3.1 1-azido-4-methoxybenzene (3a): To prepare 1-azido-4-methoxybenzene, 0.13 mL
concentrated HCl was added to the suspension of 4-methoxyaniline (62 mg, 0.50 mmol) in water
(0.65 mL) at 0 . Then aq. solution of NaNO2 (41 mg, 0.60 mmol) in water (0.15 mL) was added
and stirred for 10 min at 0-5 . Then the solution warmed to room temperature and sodium azide
(39 mg, 0.60 mmol) was added portion wise to the reaction mixture in about 15 min. and stirred
for 1h at room temperature. After this, the resulting solution was diluted with 15 mL of EtOAc,
washed successively with water and brine (20 mL), and dried with Na2SO4. Removal of solvent

afforded 3a as dark brown liquid in 87% yield (65 mg) [22].1H NMR (400 MHz, CDCl3)
(dd, 2H; J = 6.8, 2.3 Hz), 6.88 (dd, 2H; J = 6.7, 2.3 Hz), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) 157.2, 132.6, 120.2, 115.4, 55.8; IR (neat) 2098, 1608, 1586, 1501, 1464, 1441, 1284,
δ 6.95
δ
1240, 1180, 1173, 1131, 1108, 1032 cm-1.
2.4. General procedure (B) for the synthesis of 1,4-Disubstituted Triazole ligands (L1-L6)
1 ethynyl 2-methoxybenzene (2a) (265 mg, 2 mmol) and phenyl azide (238 mg, 2 mmol) were
added in 8 mL of a water and tert-butanol (1:1) mixture. Then 200 µL of freshly prepared 1 M
aq. solution of sodium ascorbate (0.2 mmol) was added, following the addition of 65 µL of aq.
CuSO4.5H20 (5 mg, 0.02 mmol) solution. The reaction mixture was stirred for approximately
14h at room temperature and reaction progress was monitored by TLC until its reactants were
completely consumed. Then 30 mL of ice cold water was poured into the reaction mixture and
flask put in ice bath for 15 min. following the filtration to get white precipitate that were
thoroughly rinsed with cold water (2×15mL). The collected solid was dried under vacuum to get
pure product [23, 24].
2.4.1. 4-(2-methoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L1): The representative procedure B was
followed for the synthesis of triazole using 1 ethyne 2-methoxybenzene (2a) (265 mg, 2 mmol),
phenyl azide (238 mg, 2 mmol), 8 mL of a water and tert-butanol mixture (1:1), CuSO4.5H2O
(0.02 mmol, 5 mg), Sodium ascorbate (0.2 mmol). Filtration and vaccum drying afforded L1 as
off white solid in 89% yield (474mg). 1H NMR (400 MHz, CDCl3) δ 8.11(s, 1H), 7.58 (d, 2H; J
= 7.4 Hz), 7.42 (t, 1H; J = 8.5 Hz), 7.34-7.28 (m, 3H), 7.16 (d, 1H; J = 7.1 Hz), 7.00-6.94 (m,
2H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5, 139.5, 136.7, 131.6, 129.2, 128.5,
128.1, 126.5, 120.3, 109.2, 104.1, 56.1. HRMS (ESI-TOF) m/z = 251.1059 calcd for C15H14N3O
[M+H]+ found 251.1057.
2.4.2. 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2):The representative procedure B
was followed for the synthesis of triazole using 1-ethynyl-2,6-dimethoxybenzene (2b) (325 mg,
2 mmol), phenyl azide (238 mg, 2 mmol), 8 mL of a water and tert-butanol mixture (1:1),
CuSO4.5H2O (0.02 mmol, 5 mg), Sodium ascorbate (0.2 mmol). Filtration and vaccum drying
1
afforded L2 as white solid in 91% yield (540mg). H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H),
7.54 (d, 2H; J = 7.1 Hz,), 7.38 (t, 1H; J = 7.6 Hz,), 7.34-7.28 (m, 3H), 6.61 (d, 2H; J = 7.1 Hz),
3.69 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 158.5, 141.9, 138.9, 135.6, 131.9, 128.6, 128.2,

127.6, 105.1, 103.6, 55.3, HRMS (ESI-TOF) m/z = 282.1160 calcd for C16H16N3O2 [M+H]+
found 282.1161.
2.4.3. 1,4-diphenyl-1H-1,2,3-triazole (L3): The representative procedure B was followed for the
synthesis of triazole using phenylacteylene (204 mg, 2 mmol), phenyl azide (238 mg, 2 mmol), 8
mL of water and tert-butanol mixture (1:1), CuSO4.5H2O (0.02 mmol, 5 mg), Sodium ascorbate
1
(0.2 mmol). Filtration and vaccum drying afforded L3 as white solid in 89% yield (420 mg). H
NMR (400 MHz, CDCl3) δ 8.14(s, 1H), 7.54 (d, 2H; J = 6.9 Hz), 7.46-7.41 (m, 3H), 7.36-7.29
(m, 5H), 13C NMR (100 MHz, CDCl3) δ 145.8, 137.0, 136.9, 135.2, 130.6, 130.1, 129.0, 128.5,
127.6, 126.0. HRMS (ESI-TOF) m/z = 222.0957 calcd for C14H12N3 [M+H]+ found 222.0953.
2.4.4. 4-(2-methoxyphenyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole (L4): The representative
procedure B was followed for the synthesis of triazole using 1 ethyne 2-methoxybenzene (2a)
(265 mg, 2 mmol), 1-azido-4-methoxybenzene (3a) (298 mg, 2 mmol), 8 mL of water and tert-
butanol mixture (1:1), CuSO4.5H2O (0.02 mmol, 5 mg), Sodium ascorbate (0.2 mmol). Filtration
1
and vaccum drying afforded L4 as white solid in 87 % yield (492 mg). H NMR (400 MHz,
CDCl3) δ 8.47 (s, 1H), 7.46 (t, 2H; J = 7.8 Hz), 7.43-7.29 (m, 3H), 7.13 (t, 1H; J = 6.8), 7.04-
6.97 (m, 2H), 3.74 (s, 6H), 13C NMR (100 MHz, CDCl3) δ 159.9, 139.4, 131.0, 130.7, 129.9,
129.3, 128.8, 126.5, 126.1, 122.0, 114.5, 111.1, 55.7. HRMS (ESI-TOF) m/z = 282.1169 calcd
for C16H16N3O2 [M+H]+ found 282.1166.
2.4.5. 4-(2,6-dimethoxyphenyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole (L5): The representative
procedure B was followed for the synthesis of triazole using 1-ethynyl-2,6-dimethoxybenzene
(2b) (325 mg, 2 mmol), 1-Azido-4-methoxybenzene (3a) (298 mg, 2 mmol), 8 mL of water and
tert-butanol mixture (1:1), CuSO4.5H2O (0.02 mmol, 5 mg), Sodium ascorbate (0.2 mmol).
1
Filtration and vaccum drying afforded L5 as white solid in 87% yield (546 mg). H NMR (400
MHz, CDCl3) δ 8.50 (s, 1H), 7.17-7.15 (m, 3H), 6.95 (d, 2H; J = 6.9 Hz), 6.48 (d, 2H; J = 8.4
Hz), 3.50 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 160.2, 157.0, 136.8, 131.0, 129.8, 129.3,
128.3, 126.8, 114.6, 108.1, 55.7. HRMS (ESI-TOF) m/z = 312.1265 calcd for C17H18N3O3
[M+H]+, found 312.1269.
2.4.6. 1-(4-methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (L6): The representative procedure B was
followed for the synthesis of triazole using phenylacteylene (204 mg, 2 mmol), 1-azido-4-
methoxybenzene (3a) (298 mg, 2 mmol), 8 mL of water and tert-butanol mixture (1:1),

CuSO4.5H2O (0.02 mmol, 5 mg), Sodium ascorbate (0.2 mmol). Filtration and vaccum drying
1
afforded L6 as white solid in 90% yield (456 mg). H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H),
7.37-7.33 (m, 3H), 7.26-7.21 (m, 4H), 6.88 (d, 2H; J = 7.7, 1.5 Hz), 3.81 (s, 3H) 13C NMR (100
MHz, CDCl3) δ 160.1, 132.6, 131.0, 129.8, 129.0, 128.9, 126.8, 119.3, 114.6, 56.7 HRMS (ESI-
TOF) m/z = 252.1066 calcd for C15H14N3O [M+H]+, found 252.1065
2.5. General Procedure (C) for Suzuki coupling reaction: In the inert atmosphere of glove box,
4-chlorotoluene (1.00 mmol, 127 mg), Pd(OAc)2 (2.5 mol%), PhB(OH)2 (1.00 mmol, 122 mg),
ligand (5 mol%), K3PO4 (2.00 mmol, 0.45 g), were weighed into oven dried micro-vial, fitted
with rubber septum and purged under argon outside the glove box. Freshly distilled toluene (3
mL) was added under argon to micro-vial via syringe. The septum was removed and micro-vial
was sealed with teflon screw cap. The mixture was stirred at 80 in oil bath for 12 h. Reaction
progress was monitored by TLC until substrate was completely consumed. After cooling to rt,
and diluting with EtOAc (20 mL), the mixture was washed with brine solution (20 mL). The aq.
layer was extracted with EtOAc (20 mL) and the combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated. The material was then purified by
chromatography on silica gel.
1
2.5.1. 4-methyl biphenyl (6a): White solid. H NMR (400 MHz, CDCl3) δ 7.61 (d, 2H; J = 7.9
Hz), 7.49 (d, 2H; J = 8.20), 7.40 (t, 2H; J = 8.20 Hz), 7.30 (t, 1H; J = 7.6 Hz), 7.23 (d, 2H; J =
8.17 Hz), 2.38 (s, 3H).
2.5.2. 4-Acetylbiphenyl (8a): white solid. 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, 2H; J = 1.4,
7.3 Hz), 7.70 (dd, 2H; J = 1.6, 7.1 Hz), 7.69-7.64 (m, 2H), 7.50-7.43 (m, 3H), 2.60 (s, 3H)
2.5.3. 4-Phenylbenzonitrile (8b): off white solid. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, 2H; J =
8.4 Hz), 7.70 (d, 2H; J = 8.2 Hz), 7.60 (t, 2H; J = 6.9 Hz), 7.49 (t, 2H; J = 6.7 Hz), 7.41(t, 1H; J
= 7.2 Hz).
2.5.4. 4-Carbomethoxybiphenyl (8d): white solid 1H NMR (400 MHz, CDCl3) δ 8.15 (d, 2H; J =
8.5 Hz, 2H), 7.71-7.60 (m, 4H), 7.53-7.46 (m, 2H), 7.42-7.37 (m, 1H), 3.93 (s, 3H)
1
2.5.5. 4-Trifluoromethylbiphenyl (8e): off white solid H NMR (400 MHz, CDCl3) δ 7.78-7.72
(m, 4H), 7.69-7.62 (m, 2H), 7.54-7.41 (m, 3H);

2.5.6. 4-nitrobiphenyl (8f): pale yellow solid 1H NMR (400 MHz, CDCl3) δ 8.31 (d, 2H; J = 8.8
Hz), 7.75 (d, 2H; J = 8.9 Hz), 7.67-7.60 (m, 2H), 7.55-7.43 (m, 3H)
2.5.7. 2-Phenyl-pyridine (8g): off white solid 1H NMR (400 MHz, CDCl3) δ 8.69 (d, 1H; J = 5.2
Hz, 1H), 8.03 (d, 2H; J = 7.5 Hz), 7.69 (d, 2H; J = 4.3 Hz), 7.50 (t, 2H; J = 7.4 Hz), 7.44 (t, 1H;
J = 7.3 Hz), 7.19 (dd, J = 4.3, 7.9 Hz, 1H)
2.5.8. 4-Tert-Butylbiphenyl (8h): white solid 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz,
2H), 7.53 (t, J = 8.5 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 6.9 Hz, 1H), 7.35 (d, J = 8.6
Hz, 2H), 1.37(s, 9H).
2.5.9. 2,5-Dimethylbiphenyl (8k): white solid 1H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H),
7.44-7.38 (m, 3H), 7.25 (d, 1H; J = 8.4 Hz,), 7.19-7.13 (m, 2H), 2.46 (s, 3H), 2.35 (s, 3H);
2.5.10. 4-Methoxybiphenyl (8l): white solid. 1H NMR (400 MHz, CDCl3): δ 7.65 (d, 2H; J = 7.6
Hz), 7.45 (t, 2H; J = 7.8 Hz), 7.35 (t, 1H; J = 7.6 Hz), 7.29 (t, 2H; J = 7.7 Hz), 6.98 (d, 2H; J =
8.7 Hz) 3.86 (s, 3H)

3. Results and Discussion:
3.1. Computational analysis
3.1.1. Frontier molecular orbitals
Frontier molecular orbital theory is a powerful approach for elucidating the chemical reactivity
of particular species in the reaction as this gives information about the electron density in
molecule. HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied
molecular orbital) analysis have great significance for the determination of excitation properties
i.e. electrical and optical properties of compounds. These electronic properties decide the way
wherein molecule interacts by other species [25]. Electrons density mostly localized on the
HOMO orbital of molecules that is available to participate in the reaction as nucleophile whereas
LUMO act as good electrophilic region. The difference of energy in HOMO and LUMO orbital
is identified as energy gap which enables to explain the chemical softness or hardness, kinetic
stability, chemical reactivity of compound. Lower energy gap shows that compound is soft and
chemically more reactive as the electrons pass to rich energy state easily while large energy gap
related to hardness and less reactive molecule. Soft compounds have low kinetic stability and
more polarizable than hard compounds and require less energy for excitation [26].
The molecular structures and optimized geometries of synthesized ligands (L1-L6) at the
B3LYP/6-31G(d,p) level of theory by using DFT are shown in Fig. 1 and 2. While the
distribution patterns of the highest occupied molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO) are shown by frontier molecule orbital diagram (FMOs) in Fig. 3.
FMO diagrams illustrate the distribution pattern of the electron density in the highest occupied
molecular orbital i.e. HOMO and LUMO. So it is important to investigate theoretical analysis of
reaction to envisage which side of molecule act as nucleophile and provide mechanistic details.
As it is obvious from the HOMO diagrams in fig. 3, electron density mostly reside on the central
triazole core that is more electron rich which has stabilized the HOMO orbital. Besides this
electronic cloud disperse over the molecule as more electron donor groups attached the triazole
core which further stabilized the HOMO orbital and thus made these electrons available to form
complex with Pd centre fig 3 (L2). All the LUMO orbital exhibit low electron density that
provides electrophilic region during catalytic cycle to the base for the tranmetallation step during
which base also activates the organoboron species.
Figure 1

Figure 2
Figure 3
The HOMO-LUMO energies along their energy gaps are shown in Table 1. The HOMO energies
of synthesized ligands (L1-L6) are -5.703, -5.533, -5.971, -5.604, -5.407 and -5.791 eV
respectively whereas LUMO energies are -0.942, -0.788, -1.141, -0.690, -0.550 and -0.910 eV
respectively. The HOMO-LUMO energy gaps of all the molecules are 4.761, 4.745, 4.829,
4.914, 4.857 and 4.881 respectively as shown in fig.4. Not surprisingly, a strong correlation is
found between the HOMO-LUMO gap and the charge transfer during transition structures [27].
Ligand L2 shows lowest energy gap (4.745 eV) due to donating effect of two methoxy moieties
on the benzene ring exocyclic to electron rich triazole core which stabilized the HOMO and
enhance electron density all over the molecule thus made it better ligand to coordinate to Pd
centre and facilitate the oxidative addition step of metal-ligand complex across the aryl chloride
bond. From mechanistic point of view, such donating moieties stabilized the transition state by
strong coordination to metal centre, improve reactivity and also lessen the transition state energy
by partial dissociation and thus enhance the catalyst efficiency during reaction. The use of strong
electron donating ligands may also lead the equilibrium to be shifted to the oxidative addition
(OA) product and improved the rate of reaction. When relatively inert aryl chlorides are used as
substrates, the C-C bond-forming reactions become more facile in the presence of bulky and
electron-rich phosphine ligands [12]. Then ligand L1 showed low energy gap (4.761) owing to
reduce electron density on triazole core due one methoxy group on the benzene ring attached to
triazole core. Whereas L3 showed 4.829 eV band gap because this molecule contained only
phenyl ring on the triazole core. Ligand L4 showed band gap energy 4.875 eV in which the
electron density of HOMO reside on triazole core and 2-methoxy phenyl ring which is shifted
toward the LUMO of 4-methoxy phenyl ring of triazole. L5 showed analogous behavior to L2
because of similar structural characteristic. The observed band gap energy increased in the
following order of L2 < L1 <L3 < L5 < L4 < L6.
Table 1
Figure 4

3.1.2. Density of electron states
Density of state (DOS) calculations were also carried out at the B3LYP/6-31G (d,p) level of
theory to find collaboration with FMO. The DOS diagrams of L1-L6 are shown in Fig. 5 which
supports the FMO diagrams. The DOS graphs showed overlapping population in the molecular
orbital. The DOS graphs represent bonding, antibonding and non bonding interactions between
the two electronic orbitals. The positive and negative values correspond to the bonding and
antibonding interactions respectively while zero values indicates the non bonding interactions
[26]. The electron density distribution patterns on molecule depend on the nature of substituent
attached to electron rich triazole central core. In L1 the electron density spread over the HOMO
whereas LUMO distributed over the entire molecule. While L2 was slightly difference than L1
because electron density become more saturated over the HOMO due to electron donor groups
on triazole core and this increased the interaction of HOMO and LUMO. In L3, the HOMO
resides on the triazole core while LUMO is homogenously distributed over the entire molecules.
L4 showed electron distribution pattern analogues to L1. However in L5, HOMO electron
density spread over the entire molecule due to donating effect of methoxy moieties on the
triazole core. DOS graph of L6 showed electronic distribution pattern over the HOMO surround
the triazole core while homogenous dispersal of LUMO over the molecule because of simple
phenyl groups.
Figure 5
3.2. Synthesis
The Cu-catalyzed 1,3 dipolar cycloaddition click reaction is a distinctive reaction for ligating
organic azide and alkyne and a practical approach to diversify triazole based ligand structure. In
the first step, terminal alkynes (2a,2b) were synthesized by following literature procedure [21].
These terminal alkynes and azides (3a,3b) were reacted through copper catalyzed click reaction
to afford 1,4 disubstituted triazole in good yield (scheme1). The success of this click reaction
lies in the fact that there is no need to protect functional groups, very robust reaction, insensitive
to water, pH and temperature and quantitative yield of product etc. Furthermore, there is no need
of flash column chromatography for product isolation as simple filtration and vaccum drying
gave desired product. All these characteristic have made this reaction ideal for the synthesis of
triazole base ligands. Click reaction was performed using CuSO4.5H2O and sodium ascorbate as

reducing to generate Cu(I) active catalytic species. The Cu(I) immediately coordinates with π
electrons of acetylene forming Cu-acetylides complex which coordinated with azide generating
copper-azide-acetylide complex followed by rearrangement into six member metallocycle.
Finally, this copper complex release 1,4 disubstituted triazole product.
Scheme 1: Synthesis of Click triazoles
3.3. Application of triazole ligands in Suzuki coupling reactions
The development of efficient ligand-catalyst system is essential for widespread
application of Suzuki cross coupling reaction of unreactive aryl chlorides. Aryl chlorides always
seem to be good coupling moieties in cross coupling reaction due to their low cost, availability
and diversity. However activation of benign aryl chloride is a difficult task due to strong C-Cl σ
bond. Therefore catalytic potential of synthesized ligands could be discern more effectively by
using arylchloride substrate instead of traditional arylbromides. To investigate the effectiveness
of synthesized ligands in Suzuki cross coupling reaction, we opted to carry the reaction between
4-chlorotoluene and phenyl boronic acid with ligands L1-L6 (Table 2, entries 1-6). The reaction
was carried out with Pd(OAc)2 (2-2.5mol %), 5 mol % of ligand using K3PO4 as base in dioxane
at 80 for 12h, which afforded good yield of 6a.
Table 2
Table 2 summarized the results of Suzuki coupling of 4 chlorotoluene by using synthesized
triazole ligands. The σ-donor electron of nitrogen of triazole core made more liable to oxidative
addition step of catalytic cycle. This triazole-Pd catalytic system showed good reactivity toward

Suzuki cross coupling reaction. Among all the synthesized ligands, 4-(2,6-dimethoxyphenyl)-1-
phenyl-1H-1,2,3-triazole ligand (L2) gave the best yield that was might be due to the bulky and
more electron donating substituent i.e. 2,6 dimethoxy benzene on triazole core at 4-position
which made the triazole core more electron rich (Table 2, entry 2). The results were consistent
as reported in literature that electronically rich and bulky ligand facilitated reductive elimination
of product during catalytic cycle [28]. As it has been reported in literature that electronic rich
environment of ligand made oxidative addition of palladium easier in aryl chloride substrate
while the steric factor promoted the ligand dissociation to provide active monophosphine Pd
complex. Thus 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole (L2) catalytically more
reactive than others due to its electronic and steric effect.
On the basis of above screen, 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole ligand (L2)
was selected to optimize the reaction condition of Suzuki cross coupling reaction. Several factors
that affect the efficacy of reaction such as palladium source, base, solvent, reaction time,
temperature had been investigated.
Table 3
.
The effect of various bases on yield was initially investigated and results are shown in table 3.
We found NaOtBu as best base to carry further Suzuki coupling reaction whereas all other bases
i.e. Cs2CO3, KOH, K3PO4, CsF, KF, K2CO3 and KOtBu gave comparatively low yield. Besides
basicity, nature of metal cation released from base could be another factor to increase the
reaction yield. The nature of base employed in cross coupling reaction influenced the slow
transmetallation step of catalytic cycle by generating more reactive boronate intermediate [29].
Base activated the boronic acid by increasing its nucleophilicity as boronic acid alone did not
favor the formation of transmetallation complex [29, 30]. Beside this, base also replaced halide
atom from metal coordination sphere and thus facilitated the intermolecular transmetallation [31,
32]. However, the selection of base in cross coupling reactions is empirical and no rule has been
established for base selection up till now. Therefore the exact role of base in catalysis remains
ambiguous and unpredictable.
Table 4

During optimization of above reaction conditions, it was observed that solvent and
temperature had a significant effect on the reaction yield. Product yield was lowered when
reaction carried out at low temperature. As activation of aryl chloride bond was difficult due to
its inert nature therefore high temperature 100 was found to be optimum as at 120 yield was
found to be lowered again because product started decomposing at higher temperature which
significantly decreased the reaction yield. The solubility of substrate and ligand-catalyst system
in a particular solvent greatly influenced the rate of reaction and product yield. The reaction yield
was surprisingly lowered in DMF, dioxane, THF and found to be highest in toluene (Table 4,
entry 6). Toluene facilitated the solubilization of reacting species that strongly affected the rate
of reaction, hence improved the product yield.
Table 5
Subsequently, effect of Pd source and time on reaction rate was examined. This Investigation
suggested that Pd(dba)2 was best Pd source with synthesized ligand as this ligand- catalyst
system gave the 81 % yield in 18 h (Table 5, entry 6). Whereas 2 mol% of Pd (OAc)2 gave only
43% yield when reaction was run for 12 h. Then reaction time was increased upto 24 h. But even
after prolong reaction time, yield was only 77% (Table 5, entry 5). Later Pd source was change
to Pd(dba)2 (Bis (dibenzylideneacetone) palladium) and PdCl2 along variation in reaction time.
Pd(dba)2 gave the highest yield in 18 h. Reaction yield was found to be lowered again when
reaction time was again increased to 24 h using Pd(dba)2 that was due to the decomposition of
product. Thus the reaction conditions were optimized as: 1.0 equiv. of aryl halide, Pd(dba)2 (2.5
mol%), ligands (L2) 5 mol%, 3 mL of toluene, 2 equiv. of NaOtBu and reaction time 18 h at
100 temperature.
After establishing optimal protocol for Suzuki coupling, investigation into numerous aryl
chloride substrates were performed to investigate the efficacy of the palladium-ligand catalytic
system (Table 6) [33]. For this purpose, we selected 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-
1,2,3-triazole (L2) for further investigation which gave good yield in preliminary experiment of
4 chlorotoluene. In this investigation, evaluation of activated, non-activated and deactivated aryl
chloride substrates was carried out. Activated aryl halides have electron withdrawing groups at
ortho/ para-positions respective to the halide (entries 1-6), while deactivated have electron
donating groups ortho/para to the halide (entries 9-13) [23].

Table 6
Good to excellent yields were achieved using selected triazole ligand L2. Aryl chlorides
with electron withdrawing groups gave desired biaryl product in 92-87% yield. Electron
withdrawing aptitude of substitute was linearly allied to their product yields as follow -NO2
(90%) > -CF3 (89%) > -CN (87%) > -COMe (86%) > -CO2Me (86%) (Table 6, entries 6, 5, 2,
4, 1 respectively). Whereas electron donating substituent on substrate afforded biaryl product in
comparatively low yield (84-80%). The electron donating effect of substituent made difficult to
break C-Cl bond of substrate that had subsequently reduced the product yield (Table 6, entries 9-
13). The electron neutral substituent i.e. chlorobenzene (Table 6, entry 8) gave moderate yields
(80%). Moreover, meta-, or ortho substituted boronic acid do not affect the efficiency of this
transformation (Table 6, entries 3,10,12 respectively) [24]. These results reveal the wide range of
unreactive aryl chloride substrate and good efficacy of Pd-L2 catalytic system for Suzuki cross
coupling reaction with comparable or better yield of products than those reported in literature
with other catalytic system. In general all of these triazole ligands offer a good and novel hint for
designing new ligand libraries.
Conclusion
Computational chemistry has made significant contributions to get clear picture on the
mechanism of the reaction. In this study, six new triazole based ligand were designed and
theoretical calculations were performed on Gaussian 09 by using DFT with functional B3LYP
and 6-31G (d, p) basic set. Electronic orbitals energies and density of electron states were
analyzed. These triazole ligands were synthesized by Cu catalyzed azide-alkyne cycloaddition
reaction. The synthesized ligands were employed in Suzuki cross coupling reaction. More
electronically rich and bulky ligand helps oxidative addition step of catalyst across the aryl
halide σ bond. Among all the ligands, 4-(2,6-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazole
ligand (L2) which has 2,6-dimethoxybenzene group on the triazole ring was most efficient in the
Suzuki coupling. This ligand-catalyst system was then employed for various aryl chloride
substrates. The theoretical results were then assessed via comparison with the experimental
results, which showed reliable agreement. This new catalytic system offered an exceptional level
of reactivities for Suzuki coupling of benign aryl chlorides. This investigation gives a hunt for
designing of more proficient and electron rich ligands for cross coupling reactions.

Acknowledgments
Financial support from the Higher Education Commission (HEC) of Pakistan in this project is
gratefully appreciated.
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Fig. 1: Molecular structures of ligands L1-L6

Fig 2: Optimized geometries of ligands (L1-L6) at the B3LYP/6-31G(d,p) level of theory.

Fig 3: Frontier molecular orbital diagram of L1-L6 at the B3LYP/ 6-31G (d,p) level of theory

Fig. 4. Energy of HOMO, LUMO and the HOMO-LUMO gap from B3LYP/ 6-31G (d,p)
calculations of L1-L6

Fig 5: Density of states (DOS) around HOMOs and LUMOs of L1-L6 at B3LYP/6-31G (d,p)
level of theory

List of Tables
Table 1: Energy of HOMO, LUMO and their HOMO–LUMO gap by using the B3LYP/6
31G(d,p) level of theory
Table 2: Screening triazole ligands for Suzuki cross coupling reaction of Aryl Chlorides
Table 3: The effect of different base on Suzuki reaction of Aryl Chlorides
Table 4: Effect of temperature and solvent on Suzuki reaction of Aryl Chlorides
Table 5: Effect of reaction time and catalyst source on Suzuki reaction of Aryl Chlorides
Table 6: Pd/Clicktriazole-Catalyzed Suzuki reaction of various Aryl Chloride
Table 1: Energy of HOMO, LUMO and their HOMO–LUMO gap by using the B3LYP/6-
31G(d,p) level of theory
Molecule
L1
EHOMO (eV)
-5.703
ELUMO (eV)
-0.942
Eg (eV)
4.761
4.745
4.829
4.875
4.857
4.881
L2
L3
L4
L5
-5.533
-5.971
-5.604
-5.407
-0.788
-1.142
-0.729
-0.550
L6
-5.791
-0.910
Table 2 Screening triazole ligands for Suzuki cross coupling reaction of Aryl Chloridesa
Entry
Ligand
Yield (%)b
L1
L2
L3
L4
L5
L6
57
69
61
55
64
54
1
2
3
4
5
6
a Reaction conditions: 1.0 equiv. of 4-chlorotoluene (4a), 1.5 equiv. of phenylboronic acid (5a), Pd(OAc)2
(2.5mol%), ligands 5 mol %, 3 mL of toluene, 2 equiv. of base, 12h, 80 °C. bisolated yield

Table 3 The effect of different base on Suzuki reaction of Aryl Chloridesa
Entry
Base
Cs2CO3
KOH
K3PO4
NaOtBu
CsF
Yield (%)b
60
45
69
74
59
55
58
49
1.
2.
3.
4.
5.
KF
6.
7.
8.
K2CO3
KOtBu
aReaction conditions 1.0 equiv. of 4-chlorotoluene 3a, 1.5 equiv. of phenylboronic acid 4a, Pd(OAc)2 (2.5 mol%),
ligands 5 mol%, 3 mL of dioxane, 2 equiv. of base, bisolated yield
Table 4: Effect of temperature and solvent on Suzuki reaction of Aryl Chloridesa
T
Solvent
Entry
Yield
(%)b
62
69
71
50
47
77
35
Dioxane
Dioxane
Toluene
DMF
60
80
60
80
80
100
120
80
1.
2.
3.
4.
5.
6.
7.
THF
Toluene
Toluene
Water
35
8.
Toluene/H2O
EtOH
80
80
43
9.
10.
48
aReaction conditions 1.0 equiv. of 4-chlorotoluene 3a, 1.5 equiv. of phenylboronic acid 4a, Pd(OAc)2 (2.5 mol%),
ligands 5 mol%, 2 equiv. of base, bisolated yield.

Table 5 Effect of reaction time and catalyst source on Suzuki reaction of Aryl Chloridesa
Pd (mol%)
Time (h)
Entry
Yield
(%)b
43
60
65
63
77
81
40
2.0 % Pd(OAc)2
2.0 % Pd(dba)2
2.5 % Pd(dba)2
2.5 % Pd(OAc)2
2.5 % Pd(OAc)2
2.5 % Pd(dba)2
2.5 % PdCl2
12
12
15
15
24
18
18
18
24
1.
2.
3.
4.
5.
6.
7.
2.5 % Pd(OAc)2
2.5 % PdCl2
45
36
8.
9.
aReaction conditions 1.0 equiv. of 4-chlorotoluene 4a, 1.5 equiv. of phenylboronic acid 5a, ligands 5 mol%, 3 mL
of toluene, 2 equiv. of base, bisolated yield.
Table 6: Pd/Clicktriazole-Catalyzed Suzuki reaction of various Aryl Chloridea
R
Entry
1.
Yield (%)a
p-COMe
p-CN
o-CN
86
90
87
2.
3.
p-CO2Me
p-CF3
p-NO2
86
89
90
4.
5.
6.
2-pyridinyl
H
tert-Butyl
o-Me
2,5 di-Me
o-OMe
p-OMe
82
80
80
80
84
83
82
7.
8.
9.
10.
11.
12.
13.
aReaction conditions 1.0 equiv. of aryl chloride (7a-m), 1.5 equiv. of phenylboronic acid 5a, Pd(dba)2 (2.5 mol%),
ligands 5 mol %, 3 mL of toluene, 2 equiv. of NaOBut, bisolated yield.