Synthesis of Triazole Click Ligands for Suzuki-Miyaura Cross-Coupling of Aryl Chlorides

Article abstract of DOI:10.1134/S1070428019090239

A series of new triazole ligands has been synthesized via copper-catalyzed cycloaddition reaction of readily available azides and alkynes. The synthesized compounds were characterized by FTIR, ¹H and ¹³C NMR, and high-resolution mass spectra. The ligands provided excellent yields (up to 92%) in the palladium-catalyzed Suzuki-Miyaura cross coupling of unactivated aryl chlorides with phenylboronic acid. 1-Benzyl-4-(2,6-dimethoxyphenyl)-lH-1,2,3-triazole was found to be the most effective ligand due to the presence of electron-donating 2,6-dimethoxyphenyl substituent, which made it possible to develop a highly active ligand-catalyst system for the Suzuki reaction of aryl chlorides.

Full text of DOI:10.1134/S1070428019090239

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 9, pp. 1416–1422. © Pleiades Publishing, Ltd., 2019.
Synthesis of Triazole Click Ligands for Suzuki–Miyaura
Cross-Coupling of Aryl Chlorides
S. Jabeena, R. A. Kheraa,* J. Iqbala, and M. Asgherb
a Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
*e-mail: rasheedahmaduaf@yahoo.com
b Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan
Received April 24, 2019; revised June 26, 2019; accepted July 2, 2019
Abstract—A series of new triazole ligands has been synthesized via copper-catalyzed cycloaddition reaction of
1
readily available azides and alkynes. The synthesized compounds were characterized by FTIR, H and 13C
NMR, and high-resolution mass spectra. The ligands provided excellent yields (up to 92%) in the palladium-
catalyzed Suzuki–Miyaura cross coupling of unactivated aryl chlorides with phenylboronic acid. 1-Benzyl-
4-(2,6-dimethoxyphenyl)-1H-1,2,3-triazole was found to be the most effective ligand due to the presence of
electron-donating 2,6-dimethoxyphenyl substituent, which made it possible to develop a highly active ligand–
catalyst system for the Suzuki reaction of aryl chlorides.
Keywords: triazoles, palladium-catalyzed reaction, Suzuki–Miyaura cross coupling, aryl chlorides, azide–
alkyne cycloaddition, click reaction.
DOI: 10.1134/S1070428019090239
Despite the availability of diverse ligands, rapid
development of structurally modifiable ligands by
efficient synthetic route is still imperative for coupling
reactions of relatively inert substrates such as aryl
chlorides. Click reaction is an indispensable and
versatile methodology which facilitates the practices of
organic strategies and provides joining of two building
moieties in a facile and energetically favored selective
pathway with excellent yield under moderate reaction
conditions [1, 2]. Huisgen reaction is an exergonic
C–N bond-forming 1,3-dipolar cycloaddition reaction
between terminal acetylene and organic azide
affording five-membered 1,2,3-triazole derivatives [3].
Sharpless referred this reaction as the cream of the
crop in click chemistry and the premier model of
a click reaction [4]. However, a drawback of this
reaction is that a mixture of regioisomeric 1,4- and
1,5-disubstituted triazoles is always formed. In 2005,
Sharpless–Fokin [5–7] and Meldal research groups
[8, 9] independently proposed copper-catalyzed ad-
dition reaction between organic azides and terminal
alkynes producing exclusively 1,4-disubstituted tri-
azoles under mild conditions.
transition metal catalyzed cross-coupling reactions
remains unexplored. Therefore, triazole-based ligand
systems have attained significant attention over the
past few years owing to their novelty in catalytic
systems [12] with distinctive application as directing
moiety in C–H bond activation [13, 14] in organo-
metallic chemistry [15–18] and versatile building
blocks in organic synthesis [19]. Triazole ring has
shown attractive features in terms of most basic donor
atom, which made it monodentate ligand [20]. Depro-
tonated triazole ring via C3 coordination can also act as
monodentate carbanionic ligand [21, 22]. Thus we
were interested in exploiting the coordination chem-
istry of 1,2,3-triazoles toward transition metals since
we anticipated that electron-donating substituents at
the 1- and 4-positions of the triazole ring would in-
fluence their steric and electronic properties that are
decisive factors for the coordination with transition
metals. The electronic structure of a ligand and its
metal complex is an imperative factor for successful
catalytic application in cross-coupling reactions. It has
also been admitted that ligand plays a significant role
in the catalysis because the key factors of catalysis
such as reactivity, stability, and selectivity of reaction
could be changed by varying electronic and steric
properties of the ligand according to reaction condi-
tions or desirability of catalyst [23, 24]. The activation
Triazole is a privileged functional group found in
several areas of chemistry (bioactive ingredients in
drugs) [10, 11], materials science, polymer chemistry,
etc. Surprisingly, the role of triazoles as ligands in
1416

SYNTHESIS OF TRIAZOLE CLICK LIGANDS
1417
Scheme 1.
CBr4, PPh3
CH2Cl2, 0°C
BuLi, THF
–78°C, 1 h
Br
R1 CHO
R1
CH
2a, 2b
R1
Br
1a, 1b
CuSO4·5H2O (1 mol %)
sodium ascorbate (10 mol %)
H2O/n-BuOH (1:1), room temp., 14 h
N
N
R1
CH
+
R2N3
N
R1
R2
2a–2c
3a, 3b
L1–L6
1, 2, R1 = 2-MeOC6H4 (a), 2,6-(MeO)2C6H3 (b); 3, R2 = C8H15 (a), PhCH2 (b); L1, R1 = 2-MeOC6H4, R2 = PhCH2;
L2, R1 = 2,6-(MeO)2C6H3, R2 = PhCH2; L3, R1 = Ph, R2 = PhCH2; L4, R1 = 2-MeOC6H4, R2 = C8H15; L5, R1 = 2,6-(MeO)2C6H3,
R2 = C8H15; L6, R1 = Ph, R2 = C8H15.
of specific bond in a substrate (C–Cl, C–O, C–I, C–H,
C–N, C–Br, etc.) mainly depends upon the nature of
metal–ligand complex formed during the catalytic
cycle. Therefore, the synthesis of novel ligand is
considered the driving force in the success of transition
metal-catalyzed cross coupling reactions to improve
reaction selectivity under mild reaction conditions.
However, some challenges in cross-coupling reactions,
e.g., activation of inert substrates, are at the forefront
of the search for appropriate ligands in order to carry
out the reaction under moderate reaction conditions
[25]. Aryl chlorides seem to be good coupling moieties
in cross coupling reaction due to their low cost, avail-
ability, and diversity [26].
there was no need of chromatographic isolation since
simple filtration and vacuum drying gave pure prod-
ucts in good yield.
The Suzuki–Miyaura cross-coupling reaction is the
most efficient route to access biaryls and substituted
aromatics. During the last decade, the application of
ligands radically improved the efficacy and selectivity
in cross-coupling reactions. Most of the Suzuki cou-
pling reactions catalyzed by Pd–phosphine complexes
required excess ligand. However, these phosphine
ligands lose their coordinating power to soft metals
due to oxidation, and are therefore unsuitable for long-
term storage. The synthesized triazole ligands were
tested to substitute phosphine ligands in the Suzuki–
Miyaura reaction.
The copper-catalyzed cycloaddition reaction also
termed “click reaction” was used to synthesize triazole
ligands L1–L6 (Scheme 1). Initial terminal alkynes 2a
and 2b were prepared by the two-step Corey–Fuchs
reaction. Phenylacetylene (2c) is a commercially avail-
able product. In the first step, 1,1-dibromoolefins 1a
and 1b were obtained from the corresponding alde-
hydes, and in the second step, dibromides 1a and 1b
were treated with n-butyllithium in THF [27]. Copper-
catalyzed click reaction of terminal alkynes 2a–2c with
azides 3a and 3b afforded 1,4-disubstituted triazoles
L1–L6 in good yields. Several key features, such as no
need to protect functional groups, insensitivity to
water, and the possibility of working in a broad range
of solvent systems, pH, and temperature made this
reaction ideal for the synthesis of substituted triazoles
as compared to other catalytic reaction. Moreover,
Initially, Suzuki cross-coupling of 4-chlorotoluene
(4a) with phenylboronic acid (5) was studied as
a model reaction (Scheme 2, Table 1). The reaction
was carried out in the presence of 2.5 mol % of
Pd(OAc)2, 5 mol % of ligand L1–L6, and 2 equiv of
K3PO4 as a base in dioxane at 80°C for 24 h. In all
cases, 4-methylbiphenyl (6a) was obtained in good
yields, and the best yield was achieved using 2,6-di-
methoxyphenyl-substituted triazole L2 (Table 1, entry
no. 2). Thus, 1-benzyl-4-(2,6-dimethoxyphenyl)-1H-
1,2,3-triazole (L2) was selected to investigate the
effects of the base, solvent, reaction time, temperature,
and Pd source on the Suzuki cross-coupling reaction
of 4a and 5.
Further optimization showed that the base had
significant effect on the reaction yield (Table 2).
Scheme 2.
Pd(OAc)2 (2.5 mol %), L1–L6 (5 mol %)
K3PO4 (2 equiv), dioxane, 80°C, 24 h
Cl
Ph
+ PhB(OH)2
Me
Me
4a
5
6a
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

JABEEN et al.
1418
Table 1. Suzuki cross-coupling of 1-chloro-4-methylben-
zene (4a) with phenylboronic acid (5) in the presence of
triazole ligands L1–L6a
Sodium tert-butoxide proved to the best one (yield
75%; Table 2, entry no. 4), though K3PO4 also gave
a comparable result (71%, entry no. 3). Actually, the
base employed in the cross-coupling reaction in-
fluences the slow transmetalation step of the catalytic
cycle by generating more reactive boronate interme-
diate [28, 29] and replacing halide ion from the metal
coordination sphere [30]. However, the selection of
base for cross-coupling reactions is empirical, and no
rule has been established for base selection until now.
Entry no.
Ligand
Yield of 6a,b %
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
68
71
61
60
66
59
Temperature optimization experiments showed that
the product yield decreased as the temperature was
lowered (Table 3). Due to low reactivity of aryl
chloride 4a, the optimal temperature was relatively
high (100°C). Further raising the temperature to 120°C
reduced the yield because of decomposition of the
ligand or product. The reaction yield was surprisingly
low in DMF, EtOH, and THF, and toluene was found
to ensure the best results (Table 3, entry no. 6), pre-
sumably due to solubilization of the reacting species.
a
Reaction conditions: 4a, 1.0 mmol; 5, 1.5 mmol; Pd(OAc)2,
2.5 mol %; ligand L1–L6, 5 mol %; dioxane, 3 mL; K3PO4,
2 mmol; 24 h, 80 °C.
b
Hereinafter, isolated yield is given.
Table 2. Suzuki cross-coupling of 1-chloro-4-methylben-
zene (4a) with phenylboronic acid (5) in the presence of
different basesa
Entry no.
Base
Yield of 6a, %
1
2
3
4
5
6
7
8
Cs2CO3
KOH
60
45
71
75
59
55
68
49
Different palladium sources were tested in com-
bination with different reaction times. The reaction
with 2 mol % of Pd(OAc)2 afforded only 46% yield of
6a in 12 h. NMR monitoring of the reaction progress
showed the presence of unreacted substrate 4a. When
the reaction time was prolonged to 24 h, the yield
increased only to 69% (Table 4, entry no. 5). The
palladium source was then changed to Pd(dba)2 and
PdCl2 along variation of the reaction time. A good
yield of 6a (81%) was achieved in the presence of
Pd(dba)2 in 18 h (Table 4, entry no. 6), whereas
increase of the reaction time to 24 h reduced the yield,
which may be due to decomposition of the product.
Thus the optimum conditions were as follows:
Pd(dba)2, 2.5 mol %, as palladium source; 1-benzyl-4-
(2,6-dimethoxyphenyl)-1H-1,2,3-triazole (L2),
5 mol %, as ligand; toluene, 3 mL, as solvent; sodium
tert-butoxide, 2 equiv, as base; reaction time 18 h;
temperature 100°C.
K3PO4
NaOBu-t
CsF
KF
K2CO3
KOBu-t
a
Reaction conditions: 4a, 1.0 mmol; 5, 1.5 mmol; Pd(OAc)2,
2.5 mol %; ligand L2, 5 mol %; dioxane, 3 mL; base, 2 mmol;
24 h, 80 °C.
Table 3. Temperature and solvent effects on the Suzuki
cross-coupling of 1-chloro-4-methylbenzene (4a) with
phenylboronic acid (5)a
Entry no. Temperature, °C
Solvent
Dioxane
Yield of 6a, %
01
02
03
04
05
06
07
08
09
10
060
080
060
080
080
100
120
080
080
080
56
75
59
51
50
79
35
35
48
43
Dioxane
Toluene
DMF
After establishing the optimal conditions, the
Suzuki coupling was carried out with a number of aryl
chlorides 4b–4n to examine the efficacy of the palla-
dium–ligand catalytic system (Scheme 3, Table 5). The
substrate series included activated (Table 5, entry
nos. 1–7) non-activated (entry no. 8), and deactivated
aryl chlorides (entry nos. 8–13). Aryl chlorides with
electron-withdrawing groups give the desired biaryl
coupling product in 92–87% yield, and the electron-
withdrawing power of the substituent was related to
the product yield: NO2 (92%) > CF3 (91%) >
THF
Toluene
Toluene
Water
Toluene/H2O
EtOH
a
Reaction conditions: 4a, 1.0 mmol; 5, 1.5 mmol; Pd(OAc)2,
2.5 mol %; ligand L2, 5 mol %; solvent, 3 mL; NaOBu-t,
2 mmol; 24 h.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SYNTHESIS OF TRIAZOLE CLICK LIGANDS
1419
Scheme 3.
Pd(dba)2 (2.5 mol %), L2 (5 mol %)
NaOBu-t (2 equiv), PhMe, 100°C, 18 h
+ PhB(OH)2
X
Cl
X
Ph
R
R
4b–4n
6b–6n
For R and X, see Table 5.
CN (90%) > COMe (87%) > CO2Me (86%) (Table 5,
entry nos. 6, 5, 2, 4, and 1, respectively). Substrates
with electron-donating groups afforded the corre-
sponding biaryl in a lower yield (84–80%; entry
nos. 9–13). Good yields were also obtained with
2-chloropyridine (4h) and chlorobenzene (85 and 83%;
entry nos. 7 and 8, respectively).
8.00 mmol) and carbon tetrabromide (1.33 g, 4 mmol)
in methylene chloride (20 mL), cooled to 0°C, and the
mixture was stirred for 1 h at 0°C. The mixture was
poured into water, the organic phase was separated,
and the aqueous layer was extracted with methylene
Table 4. Effect of the reaction time and palladium catalyst
on the Suzuki cross-coupling of 1-chloro-4-methylbenzene
(4a) with phenylboronic acid (5)a
In summary, an effective synthetic route has been
developed for the synthesis of a series of 1,4-disub-
stituted 1,2,3-triazole ligands by copper-catalyzed
cycloaddition reaction of azides and terminal acety-
lenes. The obtained ligands were used in the Pd-cata-
lyzed Suzuki–Miyaura cross-coupling reaction with
a series of monohalogenated substrates. More electron-
rich and bulkier ligands proved to be more efficient,
and up to 92% yield of the coupling product was
achieved. 1-Benzyl-4-(2,6-dimethoxyphenyl)-1H-
1,2,3-triazole (L2) was the most efficient in the Suzuki
coupling. This new catalytic system offer an excep-
tional level of reactivity in the Suzuki coupling of
unactivated aryl chlorides, which was attributed to the
σ-donor nitrogen atom in the ligand.
Entry no.
[Pd], mol %
Time, h Yield of 6a, %
1
2
3
4
5
6
7
8
Pd(OAc)2, 2.0
Pd(dba)2, 2.0
Pd(dba)2, 2.5
Pd(OAc)2, 2.5
Pd(OAc)2, 2.5
Pd(dba)2, 2.5
PdCl2, 2.5
12
12
15
15
24
18
18
24
46
61
67
56
69
81
42
38
PdCl2, 2.5
a
Reaction conditions: 4a, 1.0 mmol; 5, 1.5 mmol; ligand L2,
5 mol %; toluene, 3 mL; NaOBu-t, 2 mmol; 100°C.
Table 5. Suzuki cross-coupling reaction of various aryl
chlorides 4b–4n with phenylboronic acid (5)a
EXPERIMENTAL
All chemicals and reagents were commercial prod-
ucts which were used as received without purification
unless otherwise noted. The solvents were dried,
degassed, and distilled before use. All non-aqueous
reactions were carried out in a nitrogen atmosphere.
The progress of reactions was monitored by TLC on
Entry no. Substrate no.
X
R
Yield of 6, %
01
02
03
04
05
06
07
08
09
10
11
12
13
4b
4c
4d
4e
4f
CH
CH
CH
CH
CH
CH
N
4-Ac
87
90
89
86
91
92
85
83
80
80
84
83
82
4-CN
2-CN
4-CO2Me
4-CF3
4-NO2
H
1
glass plates coated with silica gel F254. The H and
13C NMR spectra were recorded in CDCl3 on a Bruker
Avance 400 MHz Spectrometer (Germany) using TMS
as internal standard. The high-resolution mass spectra
(ESI-TOF) were run using an Agilent Technologies
MS-TOF 6224 instrument. The IR spectra were re-
corded on a Bruker IFS 48 spectrometer equipped with
a ZnSe ATR accessory. Column chromatography was
performed using silica gel (grain size 50–63 μm).
4g
4h
4i
CH
CH
CH
CH
CH
CH
H
4j
4-t-Bu
2-Me
2,5-Me2
2-OMe
4-OMe
4k
4l
4m
4n
Terminal alkynes 2a and 2b (general procedure).
The corresponding aromatic aldehyde (2.00 mmol)
was added to a solution of triphenylphosphine (2.00 g,
a
Reaction conditions: 4b–4n, 1.0 mmol; 5, 1.5 mmol; ligand L2,
5 mol %; toluene, 3 mL; NaOBu-t, 2 mmol; 100°C, 18 h.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

JABEEN et al.
1420
chloride (3×20 mL). The extracts were combined with
the organic phase, washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was subjected to chromatography (hexane–
EtOAc, 8 : 2) to isolate 1a or 1b. The product
(0.40 mmol) was dissolved in 8 mL of THF, the
solution was cooled to –78°C, and a 2.7 M solution of
n-butyllithium in hexane (3.20 mmol, 1.18 mL) was
added dropwise with stirring. The mixture was stirred
for 1 h under argon at –78°C and allowed to warm up
to room temperature, and 10% aqueous HCl was
added. The mixture was extracted with methylene
chloride (3 ×30 mL), the combined extracts were
washed with brine (30 mL), dried with Na2SO4, and
evaporated under reduced pressure, and the residue
was purified by chromatography (hexane–CH2Cl2,
5:1) to obtain alkyne 2a or 2b.
2927, 2840, 2103, 1584, 1474, 1432, 1296, 1254,
1109, 1030. 1H NMR spectrum, δ, ppm: 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 spectrum, δC, ppm: 162.4, 130.5,
103.6, 85.6, 56.4.
1-Azidooctane (3a) was synthesized according to
procedure reported in [31, 32]. Sodium azide (488 mg,
7.50 mmol) was added to a solution of 1-bromooctane
(966 mg, 5.00 mmol) in DMF (2 mL), and the mixture
was stirred for 4 h at room temperature (25°C). The
mixture was then diluted with water (20 mL) and
extracted with ethyl acetate (3×20 mL). The combined
extracts were washed with brine (20 mL) and dried
over Na2SO4, and the solvent was removed to leave 3a
as colorless oil. Yield 760 mg (98%). IR spectrum
(neat), ν, cm–1: 2927, 2857, 2091, 1466, 1349, 1259,
1
1124. H NMR spectrum, δ, ppm: 3.25 t (2H, J =
7.0 Hz), 1.62–1.57 m (2H), 1.39–1.27 m (10H), 0.88 t
(3H, J = 7.1 Hz). 13C NMR spectrum, δC, ppm: 51.7,
31.9, 29.3, 29.0, 26.9, 28.8, 22.8, 14.2.
1-(2,2-Dibromoethenyl)-2-methoxybenzene (1a)
was synthesized by reaction of 2-methoxybenzalde-
hyde (0.68 g, 5.00 mmol) with triphenylphosphine
(5.24 g, 20.00 mmol) and carbon tetrabromide (3.31 g,
10.00 mmol) in methylene chloride (50 mL). Yield
1.41 mg (96%), light yellow oil. IR spectrum (neat), ν,
cm–1: 1597, 1579, 1484, 1462, 1435, 1289, 1245, 1175,
Benzyl azide (3b) was commercial product.
1-Benzyl-4-(2-methoxyphenyl)-1H-1,2,3-triazole
(L1). 1-Ethynyl-2-methoxybenzene (2a, 265 mg,
2 mmol) and benzyl azide (266 mg, 2 mmol) were
added to a 1:1 water–tert-butyl alcohol mixture
(8 mL). A freshly prepared 1 M aqueous solution of
sodium ascorbate (200 µL, 0.2 mmol) and an aqueous
solution of CuSO4·5H2O (65 µL, 5 mg, 0.02 mmol)
were then added in succession, and the mixture was
stirred for ~14 h at room temperature (TLC). The
mixture was diluted with 30 mL of ice water and kept
for 15 min in an ice bath, and the white precipitate was
filtered off, thoroughly rinsed with cold water (2×
15 mL), and dried under reduced pressure. Yield
1
1162, 1110, 1049, 1026. H NMR spectrum, δ, ppm:
7.70 d.d (1H, J = 7.6, 1.5 Hz), 7.60 s (1H), 7.34–
7.31 m (1H), 6.97 t (1H, J = 7.6 Hz), 6.88 d (1H, J =
8.3 Hz), 3.84 s (3H). 13C NMR spectrum, δC, ppm:
156.8, 133.1, 130.2, 129.4, 124.62, 120.4, 110.7, 88.9.
2-(2,2-Dibromoethenyl)-1,3-dimethoxybenzene
(1b) was synthesized by reaction of 2,6-dimethoxy-
benzaldehyde (0.33 g, 2.00 mmol) with triphenylphos-
phine (2.00 g, 8.00 mmol) and carbon tetrabromide
(1.33 g, 4 mmol) in methylene chloride (20 mL). Yield
86%, white solid. IR spectrum (neat), ν, cm–1: 2959,
2935, 2836, 1585, 1469, 1430, 1305, 1288, 1249,
1
474 mg (89%), off-white solid. H NMR spectrum, δ,
ppm: 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), 6.13 s (2H), 3.70 s (3H).
13C NMR spectrum, δC, ppm: 159.5, 139.5, 136.7,
131.6, 129.2, 128.5, 128.1, 126.5, 120.3, 109.2, 104.1,
56.1, 54.0. Mass spectrum: m/z 266.1214 [M + H]+.
Calculated for C16H16N3O: 266.1217.
1
1197, 1106, 1034. H NMR spectrum, δ, ppm: 7.28 t
(1H, J = 8.5 Hz), 7.25 s (1H), 6.55 d (2H, J = 8.4 Hz),
3.83 s (6H). 13C NMR spectrum, δC, ppm: 157.5,
131.3, 130.2, 114.1, 93.4, 56.0.
1-Ethynyl-2-methoxybenzene (2a). Yield 46 mg
(87%), light yellow oil. IR spectrum (neat), ν, cm–1:
3280, 1596, 1576, 1489, 1464, 1434, 1289, 1278,
Ligands L2–L6 were synthesized in a similar way.
1
1250, 1177, 1162, 1109, 1046, 1022. H NMR spec-
1-Benzyl-4-(2,6-dimethoxyphenyl)-1H-1,2,3-tri-
azole (L2). Yield 540 mg (91%), white solid. 1H NMR
spectrum, δ, ppm: 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), 6.10 s (2H), 3.69 s (6H). 13C NMR spec-
trum, δC, ppm: 158.5, 141.9, 138.9, 135.6, 131.9,
128.6, 128.2, 127.6, 105.1, 103.6, 55.3, 52.3. Mass
trum, δ, ppm: 7.47 d.d (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). 13C NMR spectrum, δC, ppm: 160.8, 134.4,
130.5, 120.7, 111.4, 110.8, 81.3, 56.0.
1-Ethynyl-2,6-dimethoxybenzene (2b). Yield
71%, white solid. IR spectrum (neat), ν, cm–1: 3271,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

SYNTHESIS OF TRIAZOLE CLICK LIGANDS
1421
spectrum: m/z 296.1317 [M + H]+. Calculated for
C17H18N3O2: 296.1315.
added under argon via a syringe, the rubber septum
was replaced with a Teflon cap, and the mixture was
stirred in an oil bath at 100°C for 18 h. The progress of
the reaction was monitored by TLC until the substrate
was completely consumed. After cooling to room tem-
perature, 20 mL of ethyl acetate and 20 mL of brine
were added, and the mixture was vigorously stirred in
a separatory funnel. The organic phase was separated,
and the aqueous layer was extracted with ethyl acetate
(2 ×10 mL). The extracts were combined with the
organic phase, dried over Na2SO4, filtered, and con-
centrated, and the residue was purified by column
chromatography on silica gel.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (L3). Yield
1
420 mg (89%), white solid. H NMR spectrum, δ,
ppm: 8.14 s (1H), 7.54 d (2H, J = 6.9 Hz), 7.46–
7.41 m (3H), 7.36–7.29 m (5H), 6.14 s (2H). 13C NMR
spectrum, δC, ppm: 145.8, 137.0, 136.9, 135.2, 130.6,
130.1, 129.0, 128.5, 127.6, 126.0, 52.1. Mass spec-
trum: m/z 236.1109 [M + H]+. Calculated for C15H14N3:
236.1110.
4-(2-Methoxyphenyl)-1-octyl-1H-1,2,3-triazole
(L4). Yield 527 mg (92%), white solid. 1H NMR spec-
trum, δ, ppm: 8.19 s (1H), 7.46 d (1H, J = 6.6 Hz),
7.34–7.11 m (1H), 6.91 d.d (2H, J = 6.7, 15 Hz), 4.22 t
(2H, J = 7.6 Hz), 3.91 s (1H), 2.43–2.38 m (2H),
2.37 d (2H, J = 7.1 Hz), 2.02–1.83 m (2H), 1.49–
1.20 m (8H), 0.83 t (3H, J = 6.7 Hz). 13C NMR spec-
trum, δC, ppm: 159.5, 142.8, 142.5, 131.5, 127.1,
120.2, 109.4, 104.1, 56.1, 51.5, 31.9, 29.4, 26.9, 25.6,
22.9, 14.3. Mass spectrum: m/z 287.4075 [M + H]+.
Calculated for C17H26N3O: 287.4073.
1
4-Methylbiphenyl (6a). Colorless liquid. H NMR
spectrum, δ, ppm: 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).
1-(Biphenyl-4-yl)ethanone (6b). White solid.
1H NMR spectrum, δ, ppm: 8.07 d.d (2H, J = 1.4,
7.3 Hz), 7.70 d.d (2H, J = 1.6, 7.1 Hz), 7.69–7.64 m
(2H), 7.50–7.43 m (3H), 2.60 s (3H).
Biphenyl-4-carbonitrile (6c). Off-white solid.
1H NMR spectrum, δ, ppm: 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).
4-(2,6-Dimethoxyphenyl)-1-octyl-1H-1,2,3-tri-
azole (L5). Yield 589 mg (93%), white solid. 1H NMR
spectrum, δ, ppm: 8.21 s (1H), 7.38 t (1H, J = 7.6 Hz),
6.61 d (2H, J = 7.4 Hz), 4.01 t (2H, J = 7.3 Hz), 3.69 s
(6H), 1.95–1.91 m (2H), 1.73–1.58 m (2H), 1.30–
1.15 m (8H), 0.81 t (3H, J = 6.9 Hz). 13C NMR spec-
trum, δC, ppm: 159.5, 143.0, 132.5, 127.09, 111.8,
104.1, 56.3, 51.4, 31.9, 29.4, 26.6, 25.7, 22.7, 14.2.
Mass spectrum: m/z 318.2107 [M + H]+. Calculated for
C18H28N3O2: 318.2105.
Methyl biphenyl-4-carboxylate (6e). White solid.
1H NMR spectrum, δ, ppm: 8.15 d (2H, J = 8.5 Hz),
7.71–7.60 m (4H), 7.53–7.46 m (2H), 7.42–7.37 m
(1H), 3.93 s (3H).
4-(Trifluoromethyl)biphenyl (6f). Off-white solid.
1H NMR spectrum, δ, ppm: 7.78–7.72 m (4H), 7.69–
7.62 m (2H), 7.54–7.41 m (3H).
1-Octyl-4-phenyl-1H-1,2,3-triazole (L6). Yield
1
469 mg (91%), white solid. H NMR spectrum, δ,
1
4-Nitrobiphenyl (6g). Pale yellow solid. H NMR
ppm: 8.24 s (1H), 7.50 d.d (2H, J = 6.8, 2.3 Hz), 7.41–
7.37 m (3H), 4.55 t (2H, J = 7.8 Hz), 2.16–2.09 m
(2H), 2.01–1.93 m (2H), 1.36–1.24 m (8H), 0.79 t (3H,
J = 7.1 Hz). 13C NMR spectrum, δC, ppm: 150.1,
131.9, 129.7, 129.5, 128.7, 124.6, 51.7, 31.9, 31.8,
29.3, 28.7, 26.8, 22.8, 14.2. Mass spectrum:
m/z 258.1892 [M + H]+. Calculated for C16H24N3:
258.1895.
spectrum, δ, ppm: 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).
1
2-Phenylpyridine (6h). Off-white solid. H NMR
spectrum, δ, ppm: 8.69 d (1H, J = 5.2 Hz), 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 d.d (1H, J =
4.3, 7.9 Hz).
1
4-tert-Butylbiphenyl (6i). White solid. H NMR
General procedure for the Suzuki coupling
reaction of aryl chlorides 4a–4n with phenylboronic
acid (5). A Schlenk tube fitted with a rubber septum
was charged with aryl chloride 4a–4n (1.00 mmol),
Pd(dba)2 (2.5 mol %), PhB(OH)2 (1.5 mmol, 122 mg),
ligand L2 (5 mol %), and sodium tert-butoxide
(2.00 mmol, 0.45 g). The mixture was purged three
times with argon, freshly distilled toluene (3 mL) was
spectrum, δ, ppm: 7.60 d (2H, J = 8.3 Hz), 7.53 t (2H,
J = 8.5 Hz), 7.46 d (2H, J = 7.2 Hz), 7.41 t (1H, J =
6.9 Hz), 7.35 d (2H, J = 8.6 Hz,), 1.37 s (9H).
1
2,5-Dimethylbiphenyl (6l). White solid. H NMR
spectrum, δ, ppm: 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).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 9 2019

JABEEN et al.
1422
1
13. Ye, X., He, Z., Ahmed, T., Weise, K., Akhmedov, N.G.,
and Petersen, J.L., Chem. Sci., 2013, vol. 4, p. 3712. doi
10.1039/C3SC51211H
14. Gu, Q., Al Mamari, H. H., Graczyk, K., Diers, E., and
Ackermann, L., Angew. Chem., Int. Ed., 2014, vol. 53,
p. 3868. doi 10.1002/anie.201311024
4-Methoxybiphenyl (6n). White solid. H NMR
spectrum, δ, ppm: 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).
ACKNOWLEDGMENTS
15. Best, M.D., Biochemistry, 2009, vol. 48, p. 6571. doi
10.1021/bi9007726
Financial support from the Higher Education
Commission (HEC) of Pakistan to this project is
gratefully appreciated.
16. Chow, H.F., Lau, K.N., Ke, Z., Liang, Y., and Lo, C.M.,
Chem. Commun., 2010, vol. 46, p. 3437. doi 10.1039/
C0CC00083C
17. Hua, Y. and Flood, A.H., Chem. Soc. Rev., 2010,
vol. 39, p. 1262. doi 10.1039/B818033B
18. Hein, J.E., and Fokin, V.V., Chem. Soc. Rev., 2010,
vol. 39, p. 1302. doi:10.1039/B904091A
19. Gulevich, A.V. and Gevorgyan, V., Angew. Chem., Int.
Ed., 2013, vol. 52, p. 1371. doi 10.1002/anie.201209338
CONFLICT OF INTERESTS
The authors declare no conflict of interests.
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