GREENER SYNTHESIS OF DIPHENYL ETHER BY NICKEL CATALYSED
CROSS COUPLING REACTION OF PHENOL WITH IODOBENZENE
Project report Submitted to
MAHATMA GANDHI UNIVERSITY
For the partial fulfillment of the requirements for the award of the degree of
MASTER OF SCIENCE IN CHEMISTRY
(2020-2022)
Submitted by
ASHAR NIZAR
Register No:200011009576
Under the guidance of
Dr. SARANYA T.V
Assistant Professor
Research and Post graduate department of chemistry
Government college kattappana
Kattappana, Idukki District, Kerala – 685508
Accredited by NAAC with 'A' Grade
RESEARCH AND POST GRADUATE DEPARTMENT OF CHEMISTRY
GOVERNMENT COLLEGE KATTAPPANA
CERTIFICATE
This is to certify that the project work entitled ‘Greener synthesis of diphenyl ether by nickel
catalysed cross coupling reaction of phenol with iodobenzene'is submitted for the
requirementof the fulfillment of the degree of master of science in chemistry is arecord of
original project work carried by ASHAR NIZAR (200011009576)under my guidance in the
institution,Research and Post Graduate Department of Chemistry Government College
Kattappana and it hasnot been submitted for the award of any degree in any otheruniversity or
institution.
Kattappana
Date
Dr . Saranya T. V
Assistant Professor
DECLARATION
I hereby declare that the work entitled „Greener synthesis of diphenyl ether by nickel
catalyzed cross coupling reaction of phenol with iodobenzene' submitted to Mahatma
Gandhi University of the requirement for the partial fulfillment of the degree of Master of
Science in Chemistry is a record of original project work done by me during the period of
studies (2020- 2022) under the guidance of Dr.Saranya T.V, Assistant Professor, Research and
Post Graduate Departmentof Chemistry, Government College, Kattappana. It has not been
submitted for the award of any degree in any other university or institution.
Kattappana
Date
Ashar Nizar
ACKNOWLEDGEMENT
My boundless appreciation and heartfelt indebtedness to Dr.Sarnaya T.V, Assistant Professor,
Research and Post Graduate Department of Chemistry, Government College Kattappana is
beyond expression for her regular guidance, valuable suggestion, correction, encouragement,
sacrificing her valuable time and energy giving educative and informative feedbacks to
improve the content, pain and patience you took to go through the content submitted for
correction.
Sentiments of gratitude and thankfulness to Principal, Dr V Kannan, Government College
Kattappana for permitting us to do the work in this institution utilizing all the facilities
available. Sincere thanks to Ms. Sreelakshmi S (HOD, Department of Chemistry) Government
College Kattappana for all the corporation and help in suggesting and finding the apt books and
materials for reference and for the timely clarification and doubt and meticulous explanations.
Infinite love and appreciation to all my teachers, friends, parents for directing me to my destiny
with timely guidance and blessings. Above all, my wholehearted gratitude and heartfelt
gratefulness to God Almighty for the divine prudence and the blessings showered on me.
Ashar Nizar
CONTENTS
Chapter1: Introduction
1.1. Diaryl ether
1.2. Importance of Diaryl ether
1.3. Methods of synthesis of Diaryl ether
1.4. Objectives
Chapter 2: Materials and methods
2.1. Materials
2.2 Experimental
2.2.1. Instrumentation
2.2.2. Synthesis of Diaryl ether
Chapter 3. Result and Discussion
3.1. Optimization studies
Conclusion
Reference
CHAPTER 1
INTRODUCTION
6
1.1 Diaryl Ether
Diaryl ether (DE) is a functional scaffold existing widely both in natural products (NPs) and
syntheticorganiccompounds. Statistically, diaryl ether is the second most popular and enduring
scaffold within thenumerous medicinal chemistry andagrochemical reports. Given its unique
physicochemical properties and potential biological activities, diaryl ether nucleus is
recognized as a fundamental element of medicinal[1] and agrochemical[2] agents aimed at
different biological targets. Its drug-like derivatives have been extensivelysynthesized with
interesting features including anticancer,anti-inflammatory,antiviral, antibacterial,antimalarial,
herbicidal, fungicidal, insecticidal, and so on. In this review, we highlight the medicinal and
agrochemical versatility of the diaryl ether motif according to the published information in the
past decade and comprehensively give a summary of the target recognition,structure−activity
relationship (SAR), and mechanism of action of its analogues. It is expected that this profile
may provide valuable guidance for the discovery of new active ingredients both in drug and
pesticide research.
1.1.1 Properties of Diaryl ether
Diaryl ether delegates a class of compounds with two aromatic ring systems and a flexible
oxygen bridge (Figure1), which is identified as an essential subunit encountered in numerous
synthetic pharmaceutical molecules.The diaryl ether scaffold possesses universal but unique
molecular characteristics like double aromaticity and conformational flexibility. Based on this,
the double aromatic ring of diaryl ether is capable of offering a decent π-system in the binding
of the corresponding ligand with targets or engaging in hydrophobic contact with some key
residues, and the oxygen atom in diaryl ether is a favorable flexible linker which can allow
molecules to form a multidimensional conformation in the active pockets of potential targets
for increasing the binding affinity, which offers sufficient evidence for the importance of the
diaryl ether motif in molecular drug design.
7
Molecular Properties of Diaryl ether

Sufficient molecular flexibility

Cell membrane penetration

Excellent lipid solubility

Strong hydrophobicity

Metabolic stability
1.1.2. Conformations of diaryl ether
Four distinct types of rigid conformations have been considered, viz. A, B, C, and D :
A is the all-planar structure In B the Ph ring planes are perpendicular to the C-X-C
p1ane. In the “skewed” form C. referred to as the “Morino structure”,‟ the Ph ring
planes are orthogonal. Finally, in the “butterfly” conformation DB the Ph groups are
rotated about their C-X bonds by angles a and /I out of coplanarity with the C-X-C
triangle.
8
1.1.3.Biologically impotant Diaryl Ethers
Most diaryl ethers in nature originate from the aromatic amino acids (l-tyrosine, lphenylalanine, l-tryptophan) or their biosynthetic precursors, joined together through oxidative
phenol coupling. A naturally occurring diaryl ether therefore usually bears an ortho-hydroxy or
–alkoxy substituent and a meta-alkyl chain on one of the aryl rings and a para-alkyl substituent
on the other. It can be acyclic or cyclic, and further oxygenation or halogenation of the
aromatic rings is commonly observed.

Amino Acids and Peptides
Thyroxin , or 3,5,3,5-tetraiodothyronine is the major hormone secreted, along with 3,5,3triiodothyronine was among the first diaryl ethers detected in nature and prepared in the
laboratory.
Figure 1. Thyroxin (T4) and triiodothyronine (T3).
9

Isodityrosines
The oxidative coupling of two l-tyrosine molecules to form dityrosine, isodityrosine, and
pulcherosine(. Figure 2).
(Figure 2. isodityrosine and pulcherosine.)

Glycopeptide
Antibiotics Vancomycin (Figure 3) is perhaps the most widely known member of this
class of natural diaryl ethers, being a powerful antibiotic.
(Figure 3. Vancomycin)
10

Cyclic Diaryl Heptanoids
Cyclic diaryl ether heptanoids, such as the acerogenins , galeon , pterocarine , and
ovalifoliolatin are a subclass of a family of natural products related to curcumin.

Benzylisoquinoline Alkaloids
Benzylisoquinoline alkaloids represent an ever-growing family of natural products with over
400 mem Tejed- Diaryl Ether Formation in the Synthesis of Natural Products Figure 4. Cyclic
diaryl ether heptanoids.( cularine and sarcocapnine aristoyagonine and o-methylthalibrine are
illustrative examples of members containing diaryl ether systems.
Figure 4. Cyclic diaryl ether heptanoids
11
1.1.4.Diphenyl ether
Diphenyl ether is an aromatic ether in which the oxygen is attached to two phenyl
substituents.Diphenyl ether is a starting material in the production of phenoxathiin via the
Ferrario reaction. Phenoxathiin is used in polyamide and polyimide production. Because of its
odor reminiscent of scented geranium, as well as its stability and low price, diphenyl ether is
used widely in soap perfumes.
Properties
Chemical formula : C12H10O
Molar mass : 170.211 g·mol−1
Appearance : Colorless solid or liquid
Odor : geranium-like
Density : 1.08 g/cm3 (20°C)[2]
Melting point : 25 to 26 °C (77 to 79 °F; 298 to 299 K)
Boiling point : 121 °C (250 °F; 394 K)[3] at 1.34 kPa (10.05 mm Hg), 258.55 °C at 100 kPa
(1bar)
Solubility in water : Insoluble
Vapor pressure : 0.02 mmHg (25°C)[2]
Magnetic susceptibility (χ) : 108.1·10−6 cm3/mol
1.2 .Importance of Diaryl ether
Diaryl ether moiety play important role in medicinal and agrochemical chemistry, being
present in awide range of natural products and biologically active compounds. Diaryl ether
containing drugs and pesticidesthat are available for the treatment of human diseases and pest
management in the agriculturalmarket.Several commercially available drugs, including
12
levothyroxine, vancomycin, and teicoplanin, are derived from this structural motif. Diaryl
ether derivatives have attracted interest as they are a common structural motif encountered
innumerous natural and synthetic pharmaceutically important compounds such as the
antithyroid levothyroxine ,the antibacterial vancomycin ,the antibiotic teicoplanin ,the antifungal piperazinomycin ,the antitumor riccardin C , the anti-HIV chloropeptin II ,and the
antineoplastic combretastatin . This motif is also found in many pesticides (e.g.,cypermethrin
and deltamethrin), polymers,and ligands.Due to their immense biological properties, the
synthesis of diaryl ethers received tremendous attention from synthetic organic chemists.
Diaryl ethers constitute an important class of organic compounds that are of paramount
importancethroughout the polymer and life-sciences industries. Indeed, many natural
cyclopeptides bearing a diaryl ether bridge, such as the antibiotic vancomycin and the antiHIV agents chloropeptins ,exhibit remarkable physiological activities. Consequently, the
development of any new and practical method for assembling the target compounds can be of
great synthetic significance.
The structural motif of diaryl ether also widely exists in an army of commercial agrochemicals. For instance, difenoconazole and famoxadone areutilized as fungicides to protect a
wide range of plants like rice, cotton, cereals, and F&V (fruit and vegetable) from
diseases.The benzoylurea insecticide named flufenoxuron is aninsect growth regulator with
acaricidal activity against abroadrange of mites. The main application of diphenyl ether is as
a eutectic mixture with biphenyl,used as a heat transfer fluid. Such a mixture is well-suited
for heat transfer applications because of the relatively large temperature range of its liquid
state.
Diphenyl ether is a starting material in the production of phenoxathiin via the Ferrario
reaction. Phenoxathiin is used in polyamide and polyimide production..Because of its odor
reminiscent of scented geranium, as well as its stability and low price, diphenyl ether is used
widely in soap perfumes. Diphenyl ether is alsoused as a processing aid in the production of
polyesters.The Diaryl ether is astarting material used in the production of phenoxathiin.
Phenoxanthin is used in polyamide and polyimide production. Comprehensively considering
theirpotential pharmaceutical value, good druggability, and diversity, diaryl ether and its
derivatives will unquestionably continue to occupy a prominent position in the development
of new medicines and agrochemicals.
13
1.3. Transition metal catalyzed synthesis of diaryl ether
Diaryl ethers are primarily synthesized using transition metal-catalyzed cross-coupling
reactions. Transition metal-catalysed cross-coupling reactions are among the most powerful
and versatile tools for the construction of various carbon – hetero atom bonds and have
experienced considerable growth over the past decades. In this domain, C–O cross-coupling
reactions have been considered as the most popular routes to diaryl ethers. Among the various
C–O cross coupling reactions for the construction of this biologically and synthetically
important structural motif ,Ullmann coupling reaction between easily available and low-cost
phenols and aryl halide find maximum application in industrial processes.
1.3.1. Iron catalyzed C-O Cross coupling of phenol with aryl Iodides
Iron, a practically ideal transition metal because of its low price and environmentally benign
features, has been extensively investigated as an alternative catalyst in the field of crosscoupling reaction. The establishment of new catalytic methods using iron is attractive due to
low cost, abundance, ready availability and very low toxicity of iron.Furthermore, due to
availability of several catalytic cycles iron-catalysis offers a potential for orthogonal
selectivity when compared to other metals, which allows for streamlined construction of
complex molecules by modern cross-coupling chemistry. Most notably, however, iron is one
of the very few metals that have been successfully field tested as highly effective base-metal
catalysts in practical, kilogram-scale industrial cross-couplings, thus validating the potential
and promise of iron-catalysis to address the challenge of sustainability for chemical synthesis.
In 2008, Bolm‟s group successfully developed an iron-catalyzed CAO cross-coupling
of phenols with aryl iodides which uses anhydrous FeCl 3/TMHD (2,2,6,6-tetra methyl-3,5heptanedione) catalyst, DMEDA,N,N-dimethylglycine as ligand and Cs2CO3 base in DMF
under argon atmosphere . Under these conditions, a wide range of phenol and idobenzene
could be readily converted to corresponding diphenyl ether in 85% yields at 135 0C within 20
hours.
14
In fact, over the last decade metal-catalyzed processes in green media have been an area
ofincreasing interest both from economical perspective and in terms of environmental
impacts.Thus,water has been the ideal choice of solvent due to its non-toxicity,low cost, and
availability compared with organic solvents.
S. Sindhu and coworkers in 2017 reported the first iron catalysed O-arylation of phenols
usingaryl halides in the presence of water under aerobic conditions. Here 5-iodoacetophenone
reacted with phenol using N,N-Dimethylethylene diamine (DMEDA)as ligand, Tetra butyl
ammonium bromide (TBAB) catalyst and K2CO3 base in water at 1300C for 36 hours.
1.3.2. Zinc catalyzed C-O Cross coupling of phenol with aryl Iodides
Zinc has been used in many important reactions such as Reformatsky, Simmon-Smith etc, the
exclusive use of zinc as a catalyst in cross-coupling reactions has not been extensively
studied so far.The catalytic and bio-catalytic ability of zinc are well ascertained and there
exist a large number of reports in which zinc is used as a catalyst. This prompted us the idea
of using zinc as a catalyst in C-O cross-coupling reactions and eventually resulted a method
of ether formation from aryl halide and phenol.
K.Keerthi Krishnan and co- workers in 2018 reported reaction using iodoacetophenone and
phenol
as the model substrates using Et 2Zn as the catalytic source, L-proline as the
ligand,Cs2CO3 as the base in acetonitrile medium at 145 0C for a period of 65 h under N2
atmosphere, which gave the desired cross-coupled product in 70% yield.
15
1.3.3. Copper catalyzed C-O Cross coupling of phenol with aryl Iodides
Copper catalyst, provide an alternative pathway by which the reaction can proceed, in which
the activation energy is lower. It thus increases the rate at which the reaction comes to
equilibrium. The catalyst itself takes part in the reaction without undergoing any permanent
chemical change, although it may undergo a physical one.
Fritz Ullmann and Bielecki in 1901 by adding copper particles to a solution
containing bromine derivatives of benzene, the Ullmann reaction is undergoing a
considerable revival in the past decade. Its application allowing the reliable synthesis of
extended polymers has opened a fruitful path in surface chemistry, leading to the formation of
polyphenyls, graphene structures of well-defined shape.
The Ullmann reaction is the metal-catalyzed coupling of halogene - benzene derivatives
leading to biaryls (an aryl group is a group obtained by removing a hydrogen atom from and
aromatic compound; if the aromatic compound is benzene, the aryl is the phenyl group) and
larger carbon-based structures. This reaction offers an unprecedented opportunity to access
the molecular functionality by improving the mechanical stability and electron conductance,
which are essential to advance in the realization of organic-based electronics.
In 2004 Henri-Jean Cristau et al introduced an efficient method for the synthesis of diaryl
ethers under particularly mild conditions is described. Inexpensive ligands were found to
greatly accelerate the Ullmann-type coupling of aryl bromides or iodides with phenols. A
series of diaryl ethers were obtained with excellent yields in acetonitrile in the presence of
16
Cs2CO3 and catalytic copper(I) oxide. The reaction tolerates substrates with unfavorable
substitution patterns, such as sterically hindered coupling partners or electron-rich aryl
halides.
DongFang and coworkers in 2014 designed copper-catalyzed Ullmann-type synthesis of
diaryl ethers using a series of salicylaldimine ligands promote the copper-catalyzed Ullmann
crosscoupling reaction. After a screening process, 2-((2 isopropylphenylimino)methyl)phenol
was found to serve as a good supporting ligand for this reaction. Employing this Schiff- base
ligand as a new supporting ligand, the copper-catalyzed coupling reactions of aryl bromides
and aryl iodides with various phenols successfully proceeded in good yields under mild
conditions. Various diaryl ethers were obtained with excellent yields in dioxane in the
presence of K3PO4 and catalytic amount of copper(I) salt.
In 2004 Henri-Jean Cristau et al introduced an efficient method for the synthesis of diaryl
ethers under particularly mild conditions is described. Inexpensive ligands were found to
greatly accelerate the Ullmann-type coupling of aryl bromides or iodides with phenols. A
series of diaryl ethers were obtained with excellent yields in acetonitrile in the presence of
Cs2CO3 and catalytic copper(I) oxide. The reaction tolerates substrates with unfavorable
substitution patterns, such as sterically hindered coupling partners or electron-rich aryl
halides.
1.3.4.Palladium catalyzed C-O Cross coupling of phenol with aryl Iodides
Efficient,experimentally simple, and air-stable Pd (0)-phosphine sulfide catalysts involved in
the formation of diaryl ethers by Ullmann-type cross coupling reactions. Phosphine sulfide
ligands can stabilize Pd(0) assulfide is good p-acceptor and it facilitates the oxidative
additionsince it is not a strong s-donor to Pd(II) .The cross coupling processes operate under
extremely mild reaction conditions under open atmosphere to form the products ingood to
excellent yields.
17
The catalytic system not only is capable ofcoupling hindered substrates but also tolerates a
broad range of aseries of functional groups. Less reactive aryl bromides can also beused for
such coupling reactions under the same reaction conditions without increasing the reaction
temperature and catalystloading. Recyclability studies indicate that our catalyst system
hasrecyclable properties up to 5 cycles.
A.Majumder et al. reported the synthesis of aryl ether using Pd(pp 3S4) as catalyst in the
presence of Cs2CO3 base in isopropanol medium.
1.3.5. Nickel catalyzed C-O Cross coupling of phenol with aryl Iodides
In the recent times, Yamaguchi et al. have developed a Ni or Pd catalyzed decarbonalative
strategy for the synthesis of these important scaffolds. Certain reports on the metal-free
synthesis of 2- aryloxypyridines are also available via nucleophilic aromatic substitution
reactions of activated halopyridines; however, large amounts of alkoxides or phenoxides and
harsh reaction conditions limit the applicability.
Nickel-catalyzed cross-coupling of arylboronic acids and (hetero)naphthyl alcohols has been
developed. A Nickel complex showed the highest efficiency and broadest substrate scope.
High functional group tolerance has been achieved where 35 compounds could be generated
in good to excellent yields, including both primary and secondary benzylic alcohols.
In 2014, Ghatak and co-workers reported the applicability of nickel catalyst as an efficient
catalysts for the coupling of phenols with aryl halides. This etherification reaction afforded
the optimum yield in aqueous solution of potassium carbonate, while the addition of 8 mol%
of SDS as a surfactant to the reaction mixture gave excellent results. Various phenols and
(het)aryl halides were used to establish the general applicability of the method. The results
showed that all the three kinds of aryl halides were applicable to this reaction .The separated
catalyst could be reused seven times with almost no loss of activity.
18
By considering the following reports our aim is to develop novel nickel catalyzed O-arylation
reaction, which features the synthesis of diaryl ether using readily available aryl halides and
green solvents. In this case, the success of the process relies on the employment of
environmental friendly reaction conditions. Temperature is retained in between 120-130°C.
Previous coupling reactions are of high temperature conditions.Use of water as solvent is the
key feature of this reaction .The use of green solvent than the high boiling toxic solvents like
DMS,DMF,and pyridine make the reaction more relevent.
1.4 Objectives
 To synthesise diphenyl ether using a novel reaction condition using nickel nanoparticle
 To carry out the reaction using green solvents so that the reaction is environmental friendly.
 To carry out the detailed optimisation studies.
 To isolate and characterise the synthesised product using spectrometrical tools.
19
CHAPTER 11
MATERIALS AND METHODS
20
2.1. Materials
The chemicals used in this project work were supplied by various suppliers around the world.
These materials are very close to hundred percentage purity and used without any
purification.
Table 1 : Detailed list of chemicals and supplier and purity
Chemicals
Purity
Supplier
Iodobenzene
99%
Lobal Chemicals
Phenol
99%
Nice Chemicals
Potassium carbonate
99%
Medilise Chemicals
Ethylenediamine
99%
Merck Life Science
Ptd
Dimethyl Glyoxime
98%
Kanton Laboratories
Nickel Chloride
98%
Rea Chemicals
21
2.2 Experimental
2.2.1 Instrumentation
The product obtained was isolated and characterized using the following instruments.

Reaction mixture is refluxed with Magnetic Stirrer

The TLC examined with UV ray instrument
2.2.2. Synthesis of Diaryl ether
A round bottam flask equipped with a magnetic stir bar was charged with phenol
(0.13g,1.47mmolanhydrous
NiCl2(0.0238g,0.098mmol),
K2CO3(0.41g,2.94mmol),
and
SDS(0.1413g,0.49mmol) were added under air atmosphere. Idobenzene (0.2g, 0.98 mmol),
and Ethylenediammine (0.029g,0.49mmol) were added by syringe, followed by adding
water(5ml). The reaction vessel provided with a condenser was stirred in an oil bath at 130 0C
under air atmosphere. After being stirred at this temperature for 24 hours, the heterogeneous
mixture was cooled to room temperature and diluted with ethyl acetate. The progression of
the reaction was monitored by TLC. The resulting suspension was directly filtered, and
organic layer is separated by using separating column and concentrated. The obtained crude
product was purified by column chromatography using hexane.
22
CHAPTER III
RESULT AND DISCUSSION
23
3.1. Optimization Studies
3.1.1 optimizationof reaction conditions using different ligand ,base, solvents and
temperature
Table 2:Result of optimization studies
Catal
Ligand
Additive
Base
yst
NiCl2
Dimethyl
-
K2CO3
Dimethyl
-
K2CO3
DMS
Desired
O
product
DMF
Desired
Glyoxime
NiCl2
Yield
nt
Glyoxime
NiCl2
Solve
Dimethyl
product
SDS
K2CO3
H2O
30% yield
SDS
K2CO3
H2O
Greater
Glyoxime
NiCl2
Ethylene
Diamene
than10%
yield
NiCl2
Dimethyl
-
K2CO3
H2O
No reaction
Glyoxime
(Reaction conditions :idobenzene(1 equiv), phenol (1.5equiv), Catalyst (0.1 equiv), Base (3
equiv),24 h,1300C}
Based on the above optimizations the reaction worked well in the presence of NiCl₂ (0.1eq),
,Dimethyl glyoxime (.2eq), K2CO3 (0.3eq) in water. The reaction did not work in the absence
of additive indicates the crucial role of additive.
24
CONCLUSION
We have developed environmental friendly reaction condition comprised of NiCl2 and
dimethyl glyoxime ligand serves as an efficient catalyst ligand system towards the coupling
reaction of iodobenzene and phenol in water under aerobic condition.The present protocol
provides economical and environmental advantages over other traditional methods due to the
low cost, and ecofriendly nature of the catalyst. Most importantly, the greenest solvent
available, water alone is used as the solvent.
25
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