Efficient copper-catalyzed Sonogashira coupling reactions and simulation studies

Article abstract of DOI:10.1080/00397911.2017.1319488

A practical copper-catalyzed I-substitutions of alkyl-2-iodobenzoates with alkynes have been developed using Cu powder as a catalyst under solvent, cocatalyst, and base-free conditions. This reaction system is new, facile, efficient, and economical that g

Full text of DOI:10.1080/00397911.2017.1319488

Synthetic Communications
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An Efficient Copper Catalyzed Sonogashira
Coupling Reactions and Simulation Studies
Imran Ali, Dnyaneshwar Nighot, Mohammad Nadeem Lone & Arvind Jain
To cite this article: Imran Ali, Dnyaneshwar Nighot, Mohammad Nadeem Lone & Arvind Jain
(2017): An Efficient Copper Catalyzed Sonogashira Coupling Reactions and Simulation Studies,
Synthetic Communications, DOI: 10.1080/00397911.2017.1319488
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Date: 20 April 2017, At: 21:50

An Efficient Copper Catalyzed Sonogashira Coupling Reactions and Simulation
Studies
Imran Ali1,, Dnyaneshwar Nighot2, Mohammad Nadeem Lone1, Arvind Jain2
1Department of Chemistry, Jamia Millia Islamia, (Central University) New Delhi, India
2Department of Chemistry, School of Basic and Applied Sciences, Galgotias University
UP, India
Address Correspondence Dr. Imran Ali Department of Chemistry, Jamia Millia Islamia,
(Central University) Jamia Nagar, New Delhi, India. Email: drimranchiral@gmail.com;
drimran_ali@yahoo.com
Abstract
A practical copper catalyzed I-substitutions of alkyl-2-iodobenzoates with 1-octynes have
been developed using Cu powder as a catalyst under solvent, co-catalyst, and base free
conditions. This reaction system is new, facile, efficient, and economical that gives
Sonogashira coupling products in excellent yields (up to 97%). The coupled products (A-
1
13
J) were characterized by CHNS, H NMR and C NMR and are found soluble in ethyl
acetate and dichloromethane. In addition, simulation studies of A-J were carried out with
aspulvinone dimethylallyltransferase enzyme and observe good binding affinity. The
reported compounds may be future anti-cizmatics, anti-fobic disorder and inhibition of
aspulvinone dimethylallyltransferase properties to control Alzheimer's, Schizophrenia
etc. diseases.
Graphical Abstract
1

KEYWORDS: I-substitution; alkyl-2-iodobenzoates; Sonogashira coupling; Copper
metal powder; Solvent free; Co-Catalyst free; Simulation studies
1. INTRODUCTION
Sonogashira coupling reactions have wide range of applications in the synthetic field
such as material science, [1] pharmaceutical intermediates like isocoumarin derivatives, α-
pyrons and indole derivatives, [2-4], preparation of fluorescent molecules1 and
arylbenzofurans [5]. The specialty of the reaction is that it takes place under mild
conditions in the presence of a costly palladium catalyst. Besides, the functional groups
like -CHO, -CN, -OCH3 and -Cl remains unaffected. Due to these features several
modifications have been reported in Sonogashira coupling reaction [6]. But, the important
drawback of this reaction is the involvement of costly palladium catalyst. To avoid costly
palladium catalyst, many authors developed sonogashira coupling reactions by using
copper salts with phosphine ligands instead of palladium catalyst [7-10]. Moreover, the
reaction conditions have been modified using iron salts along with copper salts [10,11]
,
DABCO in solvent free conditions [12], iron salt nanoparticles [11, 13, 14]. However, the
2

reactions have some advantages in copper conditions over palladium. But, copper salts
with phosphines are also associated with certain drawbacks like copper salt being used
with phosphine ligand is poisonous in nature, longer reaction times and poor yields.
Furthermore, the usage of two moles of base with dodecane is also one of major
disadvantages. Recently, some reports on recent advances in copper catalyzed
sonogashira coupling reactions have highlighted the beneficial effects of copper catalyzed
reactions [15-16]. Keeping in view of these drawbacks, the efforts were made to carry out
Sonogashira cross coupling reactions of alkyl-2-iodobenzoates with terminal alkynes
using copper powder as a catalyst under solvent, co-catalyst, and base free conditions.
Additionally, simulation studies have been carried out to find out the interactions with
aspulvinone dimethylallyltransferase enzyme for the potential of inhibition property. The
results are given herein.
2. RESULTS AND DISCUSSION
A simple and successful protocol have been developed for Sonogashira coupling
reactions. In this protocol, initially we synthesized derivatives of iodobenzoic acid (I-V)
by the reaction of iodobenzoic acid with different alcohols (methanol, ethanol, n-butanol,
iso-butanol and sec-butanol). Then copper powder instead of palladium has been used as
a catalyst in the absence of co-catalyst under mild solvent free conditions for the
successful coupling reactions of alkyl-2- iodobenzoates with terminal alkynes (A-J)
Scheme 1. Besides, a reasonable mechanism for formation of Sonogashira coupled
products is shown in scheme 2. The yield of the coupled products (A-J) was founded
quite good in the range of 84-97%. The analytical and spectroscopic data of the coupled
3

products (A-J), supported their proposed structures. The chemical structures of initial and
final coupled products are given in in Table 1. The structures of synthesized compounds
(A-J) were determined by CHNS, 1H NMR and 13C NMR spectroscopy. The formations
of products (A-J) were confirmed by the presence of the characteristic 1H NMR signal of
alkyl protons in the range of 0.91-4.41 ppm, while aromatic protons appeared in the range
of 7.12-8.37 ppm. In addition to it the coupled products were found fully soluble in ethyl
acetate and dichloromethane and partially soluble in n-hexane, n-heptane. For ready
reference, the 1H NMR of compounds I and J are shown in Fig. 1, While the 1H NMR
and 13C NMR of compounds (A-H) are shown in Fig. FS1 a–n (Supplementary
Information).
The main advantages of our new protocol for the development of sonogashira coupling
products are as; high yields of products, nonpoisonous nature of catalyst and mild
reaction conditions.
3. OPTIMIZATION
The reaction conditions were optimized using various catalysts (Table 2). The yields
ranged from 22-97%. A perusal of this table indicates that the copper metal powder was
the best one; resulting in 98% yield. During the optimization of catalyst, reaction
completed within 12 hrs using 2.5 mole % of copper metal. Furthermore, with increment
of mole % of copper metal powder, the rate of reaction increased and became constant
after 20 mole % (Fig. 2).
4

4. IN SILICO STUDIES
Combinatorial chemistry and virtual screening are well reputed, possibly due to their
reduction of the extremely time consuming steps of organic and inorganic synthesis and
biological screening. Molecular docking is a very valuable tool for the prediction of the
interactions of drugs with various biological macromolecules at a supra molecular level
[17]. In biochemistry, transferase is the general name for the class of enzymes that enact
the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one
molecule to another [18]. In enzymology, an aspulvinone dimethylallyltransferase enzyme
catalyzes the chemical reaction of 2-dimethylallyl diphosphate and aspulvinone E in 2-
diphosphate + aspulvinone H. The systematic name of this enzyme class is dimethylallyl-
diphosphate: aspulvinone-E dimethylallyltransferase. This enzyme is also called
dimethylallyl pyrophosphate: aspulvinone dimethylallyltransferase. These results showed
the possible inhibitor for the aspulvinone dimethylallyltransferase enzyme to control
various diseases including Alzheimer's, Schizophrenia etc.
The rigid molecular of tRNA dimethylallyltransferase docking of the ligands has been
carried out using AutoDock 4.2 to find out the possible sites of the interactions of
aspulvinone dimethylallyltransferase with the ligands. The docking studies of ligands
were performed with aspulvinone dimethylallyltransferase (PDB ID: 2CRM). The order
of binding affinity of the synthesized compounds was F > G > J > B= C >H > E > I > A
= D. The docked models of A, B and C are shown in (Fig. 3a-c). While the docking
models of the other reported compounds are shown in Fig. FS2 a-g (supplementary
data). It is clear from the docked models that all the compounds interacted with tRNA
5

dimethylallyltransferase enzyme via different sites. The number of H- bonds formed by
the compounds A–J is given in Table 3. The number of hydrogen bonds were zero (F-J),
one (A, B and E), two (D), three (C). The common moities of ligands involved in
hydrogen bonding were carbonyl and ether groups and residues of receptor involved were
ALA-215H01, ARG-219H01, ASP-20H01, GLY-17H01, SER-303H01, GLU-229H01,
ARG-225H01 and ALA-218H01. In addition to hydrogen bondings, hydrophobic
interactions were also observed (Table 3). In addition, hydrophobic interactions were
also observed. The common residues involved Arg282, Ala221, Glu222, Arg225, Ser303,
Val215, Leu21, Leu304, Ser303 and Tyr270. The different simulation parameters of the
final compounds (A-J) are given in Table 3.
5. IMPORTANCE OF WORK
The iodoarenes are higher reactive than chloro, bromo ones for the synthesis of
substituted arynes/alkynes. As per the literature, the iodoarenes used in coupling
reactions by a palladium catalyst resulted poor yields because of poisonous palladium
catalyst [19-21]. But in this research article, the coupling reactions were performed with
iodoarenes by copper catalyst. The copper catalyst is not poisoned by iodoarenes; leading
to good yields of substituted arynes/alkynes. In addition to it, our method is found to be
eco-friendly involving no use of ligands, co-catalyst, base and solvent that is the main
speciality of our work. Furthermore, the prediction of the activities of the synthesized
compounds was carried out by online software (pass prediction). It was observed that the
compounds have anti-cizmatics, anti-fobic disorder and inhibition of aspulvinone
dimethylallyltransferase properties. Besides, in silico studies also indicated the prepared
6

compounds may act as inhibitor for aspulvinone dimethylallyltransferase enzyme to
control Alzheimer's, Schizophrenia etc. diseases.
6. CONCLUSIONS
In summary, we have reported a mild and efficient method for copper-catalyzed I-
substitution of alkyl-2-iodobenzoates with alkynes under solvent free conditions
(Sonogashira coupling reactions). The reactions were performed smoothly to generate the
desired products (A-J) in moderate to excellent yields (84-97%). This method offers one
of the important motifs for the synthesis of Sonogashira coupled products. Furthermore,
A-J compounds were soluble in ethyl acetate and dichloromethane. The docking
affinities varied from 3.3 to 4.6 kcal/mol, and the compounds formed 1-3 hydrogen bonds
with the amino acid residues of aspulvinone dimethylallyltransferase enzyme. The
reported compounds may be future anti-cizmatics, anti-fobic disorder and inhibition of
aspulvinone dimethylallyltransferase properties to control Alzheimer's, Schizophrenia
etc. diseases.
7. EXPERIMENTAL
2.3. Synthesis Of Alkyl 2-Benzoates (I-V)
Iodobenzoic acid (10 g) was added to 60 mL of alcohol derivatives (methanol, ethanol, n-
butanol, iso-butanol and sec-butanol) in 5 mL conc. H2SO4, separately. The reaction
mixtures were stirred electromagnetically in an oil bath at 65, 78, 100, 105 and 95°C for
24, 5, 2, 4 and 4 hrs, respectively. Then excess alcohol derivatives were removed under
vacuum rotary evaporator. Then water and ethyl acetate were added to final residues and
7

organic layer was separated and washed three times with water and with a saturated
bicarbonate solution. Finally, the mixtures were dried over Na2SO4 and excess solvent
was removed by distillation that resulted 97% yield of methyl-2-iodobenzoate, 99% yield
of ethyl 2-iodobenzoate, 95% yield of n-butyl 2-iodobenzoate, 96% yield of 2-
methylpropyl-2-iodobenzoate and 98% yield of butan-2-yl- 2-iodobenzoate, respectively.
(Scheme 1, Table 1).
2.4. Synthesis Of Final Coupled Products (A-J)
Reaction mixtures of 1-V (10 mL, 10 mM) separately, 1-octyne (12 mL, 12 mM), copper
powder (7.8mM, 0.5 g) in dichloromethane (DCM) were stirred electromagnetically at
120°C for 12 hrs. Filtration removed the catalyst. The crude products were purified over
silica gel column chromatography in 0.25% ethyl acetate with n- hexane solvent system
and resulted A-E products.
Reaction mixtures of 1-V (10 mL, 10 mM) separately, 1-chloro-3-ethynylbenzene, 1-
chloro-3-ethynylbenzene, phenylacetylene, phenylacetylene, phenylacetylene (12 mL, 12
mM), respectively, copper powder (0.5 g) in dichloromethane (DCM) were stirred
electromagnetically at 120°C for 12 hrs. Filtration removed the catalyst. The crude
products were purified over silica gel column chromatography in 0.25% ethyl acetate
with n- hexane solvent system and resulted F-J products (Scheme 1, Table 1).
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8

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11

Table 1: Chemical structures and percentage yields of I-V and A-J.
Iodobenzoates Alkynes Coupled products
Yields
(%)
97
95
93
86
89
90
94
91
12

92
84
13

Table 2: Catalytic screening during optimization.
Sl. Catalysts
No.
%
Yields
77
1
2
3
4
5
6
7
8
CuI/Orthophenylenediamine
CuI /Binap complex
Vanillin Cu Complexes
CuBr2(PPh3)3
Fe Powder
89
83
91
Traces
55
CuI
Copper metal powder
CuBr2
97
22
The reaction was conducted at110° C in presence of DMF, Idobenzene and 1-Octyne
used as reactant.
14

Table 3: The different simulation parameters of A-J with aspulvinone
dimethylallyltransferase.
Compounds Binding
affinity
Number of Residues involved in
Residues involved in
hydrogen
H-bonding (Bond
length)
hydrophobic attractions
(kcal/mol) bonds
-3.3
1
A: ALA-215H01:: O
of carbonyl group
(3.4)
Arg282:: C1&C2, Ala218::C10
Ala221:: C1,C7,C9,C12&C14
Glu222::C3,C4,C8&C11
Arg225::C4, C5,C9
A
-3.8
1
A: ARG-219H01:: O
of ester group (3.5)
Ser303::C1,C5,C9&C14
Arg219::C4,C7,C10,c16,C17&O
2
B
Val215::C4,C7, Asp20::C2,C9
Leu304::C8,C11&C12
Arg219::C1, Leu21::C8
Asp20::C4,C5,C8,C9,C13&C19
-3.8
3
A: ASP-20H01::O of
carbonyl group (3.5)
C
B: GLY-17H01:: O of Ala16::C11, Leu304::C11
carbonyl group (3.5)
C: SER-303H01:: O
of ester group (3.2)
A: GLU-229H01:: O
of carbonyl group
(3.5)
Ser303::C11,C17&C19
Ala304::C12, Ala305::C12,C18
-3.3
2
Tyr270::C2,C3,C5
D
Glu226::C4&C9, Glu222::C6
Arg225::C5,C6,C10,C13&C14
15

B: ARG-225H01:: O
of carbonyl group
(3.3)
Glu229::C18,C19,01&O2
-3.6
1
A: ALA-218H01:: O
of carbonyl group
(3.4)
Ser303::C1&C2 Val215::C16
Ala15&Pro210::C1
E
Ala16::C3,Ala15::C5
Glu222::C4,C6,C8,C9,
Ala218::O1Ala219::C5,C10,C10
,C16C17,O1
-4.6
-4.4
0
0
-
-
Ala218::C2,C5,Ala15::C3
Arg219::C5,C6,C10,C11&C14
Ser303::C7,Cl,Leu304::C13&Cl,
Val215::C11,C15&O2
F
Ala16::C1,Ala15::C1
G
Pro210::C1,C2,Arg219::C5,C11,
C16,Ala218::C3,C7
Ala215::C2,C5,C6, Leu304::O1
Ser303::C1,Leu216::C2,
Val215::C6,C10,C11C15
Arg225::C2,C6,C7,C9C10C13,C
15&C17,Glu229::C2,C3,C15
Glu222::C4,C10,C14
-3.7
0
-
H
Glu226::C6&C9
16

-3.5
-3.9
0
0
-
-
Arg225::C10,C15,C13,C9,C5&
O1,Gln226::C2&C5
I
Glu222::C14,C17,C9&C5
Ala218::C1&C4, Gln226::C5
Ala221::C10,Arg225::C15,C13,
C5&O1
J
Gln222::C10,C9,C17,C15,C8,
17

Scheme 1. Syntheses of alkyl 2-iodobenzoates and their coupling products.
18

Scheme 2. A reasonable proposed mechanism for formation of coupling products.
19

Fig. 1. 1H NMR spectra of compounds I and J
20

Fig. 2. Effect of mole percentage catalyst on rate of reaction.
21

Fig. 3. a. 2D and 3D docking poses of A with aspulvinone dimethylallyltransferase.; b.
2D and 3D docking poses of B with aspulvinone dimethylallyltransferase; c: 2D and 3D
docking poses of C with aspulvinone dimethylallyltransferase.
22