Di(1H-benzo[d][1,2,3]triazol-1-yl)methane: An efficient ligand for copper and amine-free palladium-catalysed Sonogashira coupling reaction

Article abstract of DOI:10.1007/s12039-011-0174-4

An efficient Pd-catalysed Sonogashira coupling reaction was achieved in the absence of copper and amine with inorganic base using phosphene-free, air stable di(1H-benzo[d][1,2,3]triazol-1-yl)methane as ligand. The cross coupling of electron-rich, electron-defficient and hindered aryl halides with terminal alkynes afforded the internal alkynes in good to excellent yields. Indian Academy of Sciences.

Full text of DOI:10.1007/s12039-011-0174-4

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J. Chem. Sci. Vol. 123, No. 6, November 2011, pp. 937–942. ꢀ Indian Academy of Sciences.
Di(1H-benzo[d][1,2,3]triazol-1-yl)methane: An efficient ligand for copper
and amine-free palladium-catalysed Sonogashira coupling reaction
JASPAL SINGH and AKHILESH KUMAR VERMA∗
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi,
Delhi 110007, India
e-mail: averma@acbr.du.ac.in
Abstract. An efficient Pd-catalysed Sonogashira coupling reaction was achieved in the absence of copper
and amine with inorganic base using phosphene-free, air stable di(1H-benzo[d][1,2,3]triazol-1-yl)methane as
ligand. The cross coupling of electron-rich, electron-defficient and hindered aryl halides with terminal alkynes
afforded the internal alkynes in good to excellent yields.
Keywords. Palladium; terminal alkynes; benzotriazole; amine-free; copper-free.
1. Introduction
homocoupling reaction of acetylenes.10 To overcome
these drawbacks, many phosphine and copper-free
palladium-catalysed Sonogashira coupling protocols
have been developed.11 Recently a copper-free Sono-
gashira cross-coupling reaction was reported using
combination of phosphine and amine along with large
amount of tetra-n-butyl ammonium salt as an activa-
tor.12a,c Recently, Mino et al. described hydrazone li-
gands for such cross-coupling.12b Development of an
efficient, inexpensive, copper-, phosphine- and amine-
free catalytic system is considerable. In continua-
tion of our efforts on the designing of benzotriazole
based ligands for the coupling reactions, and syn-
thetic elaboration of heterocycles by using palladium-
catalysed coupling reactions,13a−h here we are report-
ing Di(1H-benzo[d][1,2,3]triazol-1-yl)methane (L4)
as new air-stable and phosphine-free ligand for
palladium-catalysed Sonogashira cross-coupling reac-
tion without using copper and amine (scheme 1).
Transition metal-catalysed reactions play an important
role in the synthesis of various organic substrates, natu-
ral products and pharmaceutically viable molecules.1
Among all the metals, palladium has emerged as a power-
ful tool2 for the cross coupling reaction like Heck,
Negishi, Suzuki and Sonogashira coupling reactions.3
The conjugated π systems resulting from alkynylation
reactions are building blocks often encountered within
natural products, pharmaceutical molecules, synthetic
agrochemicals, and molecular materials.4,5 During last
decade Sonogashira reaction has become one of the most
widely used method for the synthesis of aryl or vinyl ace-
tylenes from aryl or vinyl halides and terminal alkynes.
Many applications of Sonogashira coupling of aryl
halides with terminal alkynes have been reported in
the literature since 1975.5,6 A large number of efforts
have been directed to explore new catalytic systems.
The most common catalytic system for this reac-
tion is the combination of palladium and phosphines
such as PdCl2(PPh3)2, PdCl2/PPh3, and Pd(PPh3)4
with CuI as the co-catalyst and amines as the sol-
vents under degassed condition.7 Successful exam-
ples include replacement of triphenylphosphine with
some special phosphines to enhance the catalytic effi-
ciency.8 However, many phosphine ligands are air-
sensitive and expensive, resulting in significant limits
on their synthetic applications.9 Furthermore, the pres-
ence of CuI can result in the formation of some Cu(I)
acetylides in situ that can readily undergo oxidative
2. Experimental
2.1 General procedure for Sonogashira
cross-coupling reaction of terminal alkynes
with aryl halides
A flask was charged with Pd(OAc)2 (3 mol%), L4
(6 mol%) and 1.0 mmol of aryl halide in 1.5 mL of
DMSO. After stirring at room temperature for 15 min,
terminal alkyne (1.5 equiv.) and K2CO3 (2.5 equiv.)
were added to the flask, and the reaction mixture
was stirred at 80◦C for 10–12 h. After completion of
∗For correspondence
937

938
Jaspal Singh and Akhilesh Kumar Verma
Scheme 1. Sonogashira coupling reaction using di(1H-benzo[d][1,2,3]triazol-1-yl)methane (L4).
reaction as indicated by thin-layer chromatography (TLC), 3. Results and discussion
water (10 mL) was added to the reaction mixture. It
was then extracted with ethyl acetate (2 × 10 mL). Firstly, with the above precedents in mind, in order to
The combined organic layer was dried over anhydrous optimize the reaction conditions we undertook an inten-
Na2SO4 and was concentrated under reduced pressure. sive screening of variety of ligands and reaction vari-
The crude was then purified by column chromatog- ables. We first chose electron-rich p-bromoanisole (2a)
raphy on silica gel (100–200 mesh) using petroleum and penylacetylene (1a) as model reaction to screen
ether/ethyl acetate (98:2) as eluent to afford the desired the catalyst systems to optimize the reaction condi-
pure products.
tions. Initially, a series of ligands, benzotriazole and its
Table 1. Optization of Sonogashira reaction conditions.a
Entry
Solvent
Temp
(◦C)
Ligand
(L)
Base
Yield
(%)b
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
80
80
80
80
60
80
80
80
80
80
80
80
80
80
80
80
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
pyridine
Et3N
38
45
20
85
62
45
trace
65
9
Cs2CO3
KOH
78
10
11
12
13
14
15
16
DMF
DMF
trace
trace
68
38
60
75
90
KOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH3CN
Dioxane
DME
DMA
DMSO
aReaction conditions: 1.0 mmol of 1-bromo-4-methoxy-
benzene 2a, 1.5 mmol of phenylacetylene 1a, 2.5 equiv. of
base, 3 mol% of Pd(OAc)2, 6 mol% of ligand and 1.5 mL of
solvents. bIsolated yield

Metal-catalyzed C–C coupling reaction
939
derivatives (L1–L4) were examined (table 1, entries 1–4). lene. The addition of benzotriazole (L1) enhanced the
It was found that without ligand less than 10% of the yield of the coupling product 3a up to 38% (table 1,
desired cross-coupling product 3a was obtained, along entry 1). In order to achieve the best results in cross-
with 40% homo-coupling product of the phenylacety- coupling reaction, three derivatives of benzotriazole,
Table 2. Pd/L4 catalysed cross-coupling reaction of alkynes with aryl halides.a
Entry
Aryl halide
Product
Yield (%)b
1
2
3
4
5
2a
2b
2c
2d
2e
3a
90c
88
3a
3b
3b
3c
86c
82
84
6
7
8
9
2f
2g
2h
2i
3d
3e
3f
81c
87
92
80
3g
10
2j
3h
80
11
12
13
14
2k
2l
3i
3j
3k
3l
86
84
82
81
2a
2c
15
16
2l
3m
3b
81
2m
45d
aReaction conditions: 1.0 mmol of aryl halides, 1.5 mmol of terminal alkyne, 2.5 equiv. of
K2CO3, 3 mol% of Pd(OAc)2, 6 mol% of Ligand L4, and 1.5 mL of DMF at 80◦C, 10–12 h.
c
d
bIsolated yield. Reaction was carried out at 80◦C for 2–4 h. Reaction was carried out at
110◦C for 15 h.
1a
1b
1c
1d

940
Jaspal Singh and Akhilesh Kumar Verma
having more electron density and probable binding site, product was obtained (table 1, entries 10 and 11). It
1-H-benzotriazolylmethanol L2, 1-((1H-imidazol-1- can be observed from the table 1 that amongst the
yl)methyl)-1H-benzo[d][1,2,3]triazole L3, and di(1H- bases tested (table 1, entries 4, 6–11), K2CO3 was found
benzo[d][1,2,3]triazol-1-yl)methane L4, were tested as most suitable and amongst various solvents DMSO was
ligands and were found more effective than ligand L1 proved to be the best solvent (table 1, entries 4, 12–16).
in the cross-coupling reaction (table 1, entries 2, 3, and
Subsequently, selected terminal alkynes 1a–d, were
4). It was observed that in a series of reactions with reacted with various aryl iodides and bromides 2a–l
3 mol% of Pd(OAc)2 and 6 mol% of ligand L2, L3 under the optimized reaction conditions (table 2). All
and L4 in DMF at 80◦C using 2.5 equiv K2CO3, coup- the aryl halides with electron-releasing and electron-
ling product 3a was obtained in 45, 20 and 85% yields withdrawing groups were successfully coupled with ter-
respectively (table 1, entries 2, 3 and 4). Product 3a minal alkynes and afforded the corresponding cross-
was obtained in 62% yield at 60◦C (table 1, entry 5). coupling products in 80–92% yields. It is noteworthy
It is evident from the table 1 that ligand L4 was found that a variety of functional groups (nitro, keto, bromo,
more effective than ligand L1, L2 and L3. A signifi- and aldehydic) substituted aryl halides tolerate the reac-
cant effect of bases was found in the reaction. When tion condition, and afforded the coupling products in
Na2CO3 was used as a base 3a was obtained only in good yields in short reaction time using low catalyst
45% yield (table 1, entry 6). Pyridine was found in- loading (3 mol%).
effective; however Et3N afforded the coupling product
It is interesting to note that the reaction of aryl
in 65% yield under these reaction conditions (table 1, iodides with 2a, were very rapid at high temperature
entries 7 and 8). Cs2CO3 afforded the coupling prod- (80◦C) and gave excellent yields of the desired prod-
uct in 78% yield (table 1, entry 9). With strong bases ucts in 2–4 h (table 2, entries 1, 3, and 6), while
such as KOH and KOtBu, trace amount of the coupling the substituted alkynes 1b–d, having electron releasing
Table 3. Pd/L4 catalysed selective cross-coupling reaction of alkynes with o-iodo-
bromobenzene.a
Entry
1
Alkynes
Product
Yield (%)b
79
1e
1a
5a
5b
2
3
82
80
1b
1f
5c
5d
5e
4
5
60
65
1g
aReaction conditions: 1.0 mmol of 1-bromo-2-iodobenzene, 1.5 mmol of terminal alkyne,
2.5 equiv. of K2CO3, 4 mol% of Pd(OAc)2, 8 mol% of Ligand L4, and 1.5 mL of DMSO at
80◦C for 8 h. bIsolated yield.

Metal-catalyzed C–C coupling reaction
941
Scheme 2. Sonogashira coupling reaction of 1-(2-iodophenyl)-1H-indole 6a–b.
substituent, afforded the desired coupling products in Supporting information
longer duration (table 2, entries 12–16). The efficacy of
Characterization data and copies of 1H and 13C NMR spec-
tra of all the synthesized compounds are given as electro-
nic supporting information (see www.ias.ac.in/chemsci).
the catalyst system was also tested on aryl chloride 2m,
and it was found that the reaction of aryl chloride with
1a gave the desired product 3a in 45% yield at 110◦C
after 15 h.
Acknowledgements
Furthermore, the optimized combination of
Pd(OAc)2 and L4 was further tested with 1-bromo-2-
iodobenzene 4 and terminal alkynes 1a–b, 1e–g. It is
evident from the table 3 that the reaction outcome was
not much affected by the steric hindrance derived from
the ortho-substituents (table 3, entries 4 and 5).
Having the results on coupling of aryl halides and
1-bromo-2-iodobenzene benzenes in our hand, we fur-
ther investigated the coupling of more difficult and
large molecules 1-(2-iodophenyl)-1H-indoles 6a–b as
shown in scheme 2. Fortunately, the results indicated
that the present catalyst system also displayed the high
catalytic activity to catalyse the cross-coupling of ter-
minal alkynes 1a–c with 1-(2-iodophenyl)-1H-indole
6a–b using 5 mol% of Pd(OAc)2, 10 mol% of L4 and
afforded the coupling products 7a–e in 76–80% yields
at 110◦C.
We gratefully acknowledge the Department of Science
and Technology (DST), Council of Scientific and Indus-
trial Research (CSIR), New Delhi, and University of
Delhi, Delhi for the financial support. JS is thankful to
CSIR, for the SRF.
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