Novel cobalt-valine catalyzed O-arylation of phenols with electron deficient aryl iodides

Article abstract of DOI:10.1007/s00706-018-2324-6

Abstract: A Novel cobalt-catalyzed O-arylation of phenols with electron deficient aryl iodides is described. The reaction employs cheap and easy-to-handle cobalt acetate tetrahydrate as the catalyst precursor and naturally occurring l-valine as the ligand without the use of any transmetallating or reducing agents. The new protocol offers a wide scope for a variety of phenols towards O-arylation with moderate to excellent yields with electron deficient aryl iodides.

Full text of DOI:10.1007/s00706-018-2324-6

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-018-2324-6
ORIGINAL PAPER
Novel cobalt‑valine catalyzed O‑arylation of phenols with electron
defcient aryl iodides
Sankuviruthiyil M. Ujwaldev1 · Salim Saranya1 · Nissy Ann Harry1 · Gopinathan Anilkumar1
Received: 26 July 2018 / Accepted: 15 October 2018
© Springer-Verlag GmbH Austria, part of Springer Nature 2019
Abstract
A Novel cobalt-catalyzed O-arylation of phenols with electron defcient aryl iodides is described. The reaction employs
cheap and easy-to-handle cobalt acetate tetrahydrate as the catalyst precursor and naturally occurring l-valine as the ligand
without the use of any transmetallating or reducing agents. The new protocol ofers a wide scope for a variety of phenols
towards O-arylation with moderate to excellent yields with electron defcient aryl iodides.
Graphical abstract
Keywords Cobalt catalysis · C–O coupling · Etherifcation · Valine · Reducing agent
Introduction
iron [6], or nickel [7] was also interesting and sometimes
more inventive. Another break through was the Chan–Lam
coupling, which couples boronic acids with phenols, has also
witnessed decent development [8]. In order to improve the
efciency of catalytic reactions, chemists in catalysis always
showed urge in fnding alternative metals or ligands in spite
of the efcacy of the prevailing protocols which always led
to the development of new catalysts and protocols. Cobalt-
catalyzed cross-coupling chemistry is also a well-developed
area having a history of more than 70 years with the ini-
tial report of homo-coupling of aromatic magnesium rea-
gents by Kharash [9]. Although initial focus of this area
was mainly on the development of carbon–carbon bonds,
worthy developments also ensued in carbon–sulfur [10] and
carbon–nitrogen [11] coupling reactions. However, cobalt-
catalyzed carbon–oxygen coupling reactions are sparsely
reported in literature and to the best of our knowledge the
only report available is by Kundu et al. in 2015 [12]. The
protocol was highly efcient for the coupling between phe-
nols and aryl/styrenyl halides; but required equal amounts
of copper iodide as the transmetallating agent along with
cobalt catalyst making the catalytic system more complex
and expensive (Scheme 1). As the catalytic activity of the
cobalt in other carbon–heteroatom bond forming reactions
Exploration of transition metal catalyzed methodologies for
the development of carbon–heteroatom single bonds, espe-
cially carbon–oxygen bonds, has been a persistent efort in
synthetic organic chemistry for the past few decades [1]. The
natural abundance and biological potencies of many pharma-
ceutical derivatives containing ether cores easily substantiate
their importance in synthetic organic chemistry [2].
After being frst reported in 1904 through a stoichiometric
amount of copper-mediated coupling between aryl halides
with phenols [3], the advances made in the feld had been
very fascinating [4]. Along with the development of catalytic
versions of the pioneering copper salt mediated C–O cou-
pling protocols, use of alternate metals like palladium [5],
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-018-2324-6) contains
supplementary material, which is available to authorized users.
* Gopinathan Anilkumar
anilgi1@yahoo.com
1
School of Chemical Sciences, Mahatma Gandhi University,
P D Hills P O, Kottayam, Kerala 686560, India
Vol.:(0123456789)
1 3

S. M. Ujwaldev et al.
Scheme 1
O
O
is well established without the use of any co-catalyst [10,
11] we decided to develop a protocol for carbon–oxygen
coupling between aryl halides and phenols using cobalt as
the sole catalyst based on our experience in transition metal
catalyzed cross-coupling reactions [13].
agent. Our previous experience in similar transformations
with other metals helped us to add a ligand and a base
to the formulation. Choosing Co(OAc)2·4H2O (10 mol%)
as the catalyst precursor, we performed the preliminary
reaction between 1a (1 equiv.) and 2a (1.2 equiv.) in the
presence of DMEDA (20 mol%), Zn dust (40 mol%), and
2 equiv. of K3PO4 in acetonitrile at 130 °C under nitrogen
atmosphere (Scheme 2). The progress of the reaction was
monitored by TLC. The reaction was quenched after 36 h
and an appropriate work up procedure was carried out fol-
lowed by purifcation of the crude reaction mixture by col-
umn chromatography using silica gel (1% hexane–EtOAc)
to aford the desired product 3a in 20% yield.
Herein, we report a copper-free cobalt-catalyzed coupling
between electron-defcient aryl halides and phenols using the
naturally occurring amino acid l-valine as the ligand in the
absence of any reducing agent.
Results and discussion
1
Initially, commercially available 4-iodonitrobenzene (1a)
and phenol (2a) were chosen as the model substrates to
develop an optimum condition. Expecting a CoI/CoII
catalytic process to cause the desired coupling, we also
decided to include a reducing agent. As we are interested
to develop an economic and eco-friendly protocol, cheap
and non-toxic zinc dust was chosen as a suitable reducing
The product 3a was characterized using H NMR, 13C
NMR, and HRMS studies. Duplication of the reaction
at 110 °C by using 2 equiv. of KOH instead of K3PO4
maintaining all other parameters the same resulted in the
enhancement of yield to 42%. Hence we decided to con-
tinue further optimization studies at 110 °C using KOH
as the base.
Scheme 2
1 3

Novel cobalt-valine catalyzed O-arylation of phenols with electron defcient aryl iodides
Since ligands hold a prominent role in metal catalyzed
coupling reactions by either stabilization of the active oxi-
dation state or that of possible organometallic intermediates
and thereby afecting the desired conversion, we decided
to perform ligand optimization studies frst. We have cho-
sen L1–L10 which includes N–N, N–O and O–O class of
ligands as well as a phosphine ligand (Table 1). The N–N
ligands such as L1 and L4 gave lower yields of 42% and
38%, respectively. Yields for both phosphine (L3) and
O–O ligands (L10) were in the range of 49–53%. The N–O
ligands were more promising as the picolinic acid (L2) gave
76% yield of the product. In order to make the ligand selec-
tion more environmentally friendly, amino acids were also
monitored. Proline (L5) and alanine (L6) gave identical
yields of 50% and 47%, respectively. We were pleased to
observe that l-valine (L7) gave a favourable yield of 75%.
But structurally resembling isoleucine (L9) aforded only
52% of the product while its structural isomer l-leucine (L8)
gave 68% yield. Although ligands L2 and L7 gave similar
yields, we decided to proceed further with the more envi-
ronmentally benign and cheap l-valine. The inevitability of
maintaining a 1:2 ratio of metal: ligand was clearly visible
from the lowering of yields in the case of L8 as ligand at a
lower concentration of 15 mol% (Table 1, entries 8 and 9).
Although the ligand optimization studies gave a good
yield of 75% with L7 as the ligand, quest for a quantitative
yield made us look for the possibility of a more ftting sol-
vent and base (Table 2). We performed a range of reactions
by altering the solvent/base while maintaining all the other
parameters intact with L7 as the ligand.
Apart from acetonitrile, all the remaining solvents failed
to give any promising yield. Both toluene and DME did not
aford any detectable conversion. The protic solvent etha-
nol also showed a poor conversion. Therefore, further base
optimization studies were done choosing acetonitrile as the
solvent. Thus the activity of hydroxide, carbonate, butox-
ide, bicarbonate, as well as phosphate-containing bases,
was monitored. Sodium bicarbonate, sodium carbonate,
and potassium carbonate only aforded traces of the desired
product. K3PO4 gave a yield of 39% while NaOH aforded
46%. KOtBu and NaOtBu gave moderate yields of 63% and
58%, respectively, while Cs2CO3 aforded, to our delight,
a good yield of 80%. We then decided to proceed further
with Cs2CO3 as the base despite the fact that almost similar
yield was given by KOH (75%). After fnding a successful
ligand, solvent and base, we decided to study the efect of
the catalyst loading and reaction time in the reaction in order
to make the protocol more efcient (Table 3).
From Table 3, we came to the conclusion that the reac-
tion is complete by 24 h using a loading of 15 mol% of
Co(OAc)2·4H2O and 30 mol% of valine afording 95%
of the coupling product. It is surprising that the reaction
Table 1 Ligand optimization studies for cobalt-catalyzed O-arylation of phenol with 4-nitroiodobenzene
a
Reaction c onditions: 4 -nitroiodobenzene (0.65 mmol), p henol (0.78 mmol), Co(OAc)2·4H2O (10 mol%),
b
ligand (20 mol%), Zn dust (40 mol%), KOH (2 equiv.), 2.5 cm3 CH3CN, 110 °C, 48 h, N2 atm; Isolated yield;
c ligand 15 mol%.
1 3

S. M. Ujwaldev et al.
Table 2 Solvent and base optimization studies for cobalt-catalyzed
the product was decreased to 28% attesting the inevitable
role of the catalytic system developed (Table 3, entry 6) in
the desired conversion. Thus having an optimized reaction
condition (Co(OAc)2·4H2O (15 mol%), l-Valine(30 mol%),
Cs2CO3 (2 equiv.), 2.5 cm3 CH3CN, 110 °C, 24 h, N2 atm)
afording excellent yield in hand, we decided to investigate
the scope of the reaction on a variety of aryl halides and
phenols.
O-arylation of phenol with 4-nitroiodobenzene
Entry
Solvent
Base
Yield/%a, b
1
CH3CN
CH3CN
Ethanol
Toluene
DME
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
KOH
KOH
KOH
KOH
75
50
23
nd
Traces
39
Traces
Traces
46
Traces
63
58
2c
3
4
5
6
7
8
9
10
11
12
13
KOH
When the optimized reaction conditions were attempted
in the case of neutral or electron rich aryl iodides towards
the coupling with phenols, the results were disappointing
as the desired coupling did not occur. We then decided
to continue with aryl iodides bearing electron withdraw-
ing groups. In the case of 4-nitroiodobenzene moderate
to excellent yields were observed except with 2-naphthol
(Table 4). Here, the yields were found to be decreasing
with the increase of electron density in the phenolic part-
ner (entries 3a, 3b, and 3c); Steric factors in the phenols
are also found to have remarkable efect as yields were
decreased for 2-substituted phenols compared to their
4-substituted analogues. Among chlorophenols 4-substi-
tuted analogue gave 90% of yield while it was reduced to
71% with 2-chlorophenol. Similarly, yields were 81% and
71%, respectively, for 4-cresol and 2-cresol. The lower
yield for the reaction of 2-naphthol was surprising despite
having any remarkable electronic or steric features. The
reaction was also applicable in the case of heterocyclic
phenol as 3-pyridinol gave 3h in a yield of 40%. The reac-
tivities of 4-bromo and 4-chloronitrobenzene were also
examined which furnished 3a in lower yields of 42% and
18%, respectively, in contrast to normal SNAr reactions.
K3PO4
Na2CO3·H2O
K2CO3
NaOH
NaHCO3
KOtBu
NaOtBu
Cs2CO3
80
nd not detected
aReaction conditions: 4-nitroiodobenzene (0.65 mmol), phenol
(0.78 mmol), Co(OAc)2·4H2O (10 mol%), l-valine (20 mol%), Zn
dust (40 mol%), base (2 equiv.), 2.5 cm3 solvent, 110 °C, 48 h, N2 atm
bIsolated yield
cCo(OAc)2·4H2O (15 mol%), l-valine (30 mol%), Zinc dust
(60 mol%)
worked without a reducing agent which prompted us a
diferent mechanistic proposal for the reaction as the reac-
tion gave 96% yield of the product in the absence of zinc
dust (Table 3, entry 5). When the reaction was performed
in the absence of cobalt catalyst and ligand the yield of
Table 3 Catalyst loading
studies for Cobalt-catalyzed
O-etherifcation
Entry
Co(OAc)2·4H2O (x mol%)
l-Valine (y mol%)
Zinc dust (z mol%)
Time/h
Yield/%a, b
1
2
3
4
5
6
7c
5
10
20
20
30
30
–
20
40
40
40
No zinc
–
–
48
24
48
24
24
24
24
67
78
80
95
96
28
77
10
10
15
15
–
15
30
aReaction conditions: 4-nitroiodobenzene (0.65 mmol), phenol (0.78 mmol), Cs2CO3 (2 equiv.), 2.5 cm3
CH3CN, 110 °C, N2 atm
bIsolated yield
cTEMPO (4 equiv.)
1 3

Novel cobalt-valine catalyzed O-arylation of phenols with electron defcient aryl iodides
R2
R2
Co(OAc)2. 4H2O (15 mol%)
L-Valine (30 mol%)
Table 4 Cobalt-catalyzed
X
O
HO
O-arylation of phenols using
Cs2CO3 (2 equiv.)
O2N
O2N
Y
R1
4-halonitrobenzene
Y
CH3CN, 110 o
N2, 24 h
C
R1 = H, 2-Me; X = I Y = C, N
1
2
3
Entry
1
Product
Yield (%) a, b
95
MP oC
MP: 58-60 oC
(lit.[15] 58-59
O
°C)
O2N
X = Br; 42
X = Cl; 18
3a
O
2
3
60
MP: 110-112
oC; (lit.[16] 110-111 °C)
N
O2
O
3b
81
MP: 69-71 oC
O
O2N
3c
4
71
O
O2N
3d
MP: 76-78 oC
O
5
6
90
76
N
l
C
O2
(lit.[17] 75-78
°C)
3e
MP: 76-78 oC
Cl
O
(lit.[18] 76.8-77 o
MP: 138-139
C)
O2N
3f
O
7
24
oC (lit.[17] 137-139 °C)
O2N
3g
O
8
9
40
17
110-112 oC
(lit.[19] 106-108 °C).
N
O2N
3h
O
O2N
O2N
O2N
O
C
3i
O
10
11
traces
ndc
N
3j
O
NO2
3k
nd not detected
aReaction conditions: 4-iodobenzonitrile (0.65 mmol), phenol (0.78 mmol), Co(OAc)2·4H2O
(15 mol%), l-valine (30 mol%), Cs2CO3 (2 equiv.), 2.5 cm3 CH3CN, 135 °C, 48 h, N2 atm
bIsolated yield
1 3

S. M. Ujwaldev et al.
Table 5 Cobalt-catalyzed
O-arylation of phenols
Entry
1
Product
Yield/%a, b
55
M.p./°C
Ref.
5a, R1 =4-OMe
109–111
(109–110 [19])
2
3
4
5
5b, R1 =4-Me
5c, R1 =2-Me
5d, R1 =H
45
43
36
35
72–73
5e, R1 =4-Cl
80–82
(80–83 [19])
6
5f, R1 =2-Cl
31
nd not detected
aReaction conditions: 4-iodobenzonitrile (0.65 mmol), phenol (0.78 mmol), Co(OAc)2·4H2O (15 mol%),
l-valine (30 mol%), Cs2CO3 (2 equiv.), 2.5 cm3 CH3CN, 135 °C, 48 h, N2 atm
bIsolated yield
The reaction failed in the case of 4-cyano- and 4-nitrophe-
nols as only traces of the product was formed in the former
while the latter did not aford the product at all.
Conclusions
In summary, we have developed a novel cobalt-valine cata-
lyzed O-arylation of phenols using electron defcient aryl
iodides without the use of any transmetallating or reducing
agents. The methodology uses cheap and easy-to-handle
Co(OAc)2·4H2O as the catalyst and naturally occurring
l-valine as the ligand. The reaction provided excellent
yields in the case of 4-nitroiodobenzene and also worked
well in the case of 4-iodobenzonitrile, but the latter case
required a slightly elevated temperature and slightly more
reaction time. At this stage the protocol is only limited to
electron-defcient aryl halides. But eforts are still going
on in our laboratories to include electron-rich aryl halides
and to widen the substrate scope with more phenols and
more electron-defcient aryl iodides. A plausible mecha-
nism was proposed which involves a halogen atom transfer
step and needs further studies to ascertain.
The reaction also worked in the case of cyano substituted
iodobenzene 4 but required some elevated temperature and
increased reaction span (Table 5). In the case of 4 more
electron-rich phenols were found to give the highest yields.
Moreover, steric factors have not found much impact. Even
under this elevated reaction temperature, other aryl iodides
including 4-iodoanisole, iodobenzene, methyl-4-iodobenzo-
ate, etc. did not give any conversion while 4-iodoacetophe-
none and 3-(trifuoromethyl)iodobenzene furnished traces
of the products.
A plausible mechanism (Scheme 3) can involve an
initial complexation of the phenol with the Co(II)-metal
ion forming a complex A. Complex A then reacts with
iodoarene leading to a four-membered transition state B.
The etherifcation can involve an intermolecular halogen
exchange at this stage (C) releasing catalytically active
Co(II) species. The involvement of radical species at any
stage in this process was ruled out as the yield remained
good even after performing the reaction in the presence
of four equivalents of TEMPO as the radical scavenger
(Table 3, entry 7). Although this kind of halogen exchange
mechanism has been theoretically proposed for copper-
catalyzed etherifcation reactions [14] the feasibly of this
in the current cobalt-catalyzed protocol needed further
studies including computational calculations which are
still going on in our laboratories.
Experimental
Co(OAc)2·4H2O was purchased from Merck Spe-
cialities Pvt. Ltd, India. Ligands such as DMEDA,
trans-cyclohexane-1,2-diol, picolinic acid, triphenyl
phosphine, and phenanthroline were purchased from
Sigma-Aldrich, USA. Amino acids including l-alanine,
l-valine, l-leucine, and l-isoleucine as well as zinc dust
were purchased from SRL, India. The bases used were
1 3

Novel cobalt-valine catalyzed O-arylation of phenols with electron defcient aryl iodides
Scheme 3
potassium phosphate (Alfa Aesar), cesium carbonate,
KOtBu, NaOtBu (Spectrochem, India), KOH, NaOH
(Merck), NaHCO3, and K2CO3 (Nice Chemicals, India).
Aryl iodides and phenols were purchased from Alfa
Aesar and Sigma-Aldrich. All the solvents used for the
purification of the products were purchased from Nice
Chemicals and distilled prior to use. NMR spectra were
recorded on 500 (1H) and 125 (13C) MHz, respectively,
on a Bruker-500 MHz NMR spectrometer instrument.
The chemical shift values were reported relative to TMS
(1H) and CDCl3 (13C) as internal standards. Coupling
constants (J) were stated in Hertz (Hz). The HRMS were
recorded on XEVO G2 Q-TOF (Waters) mass spectrom-
eter. Column chromatography was performed using silica
gel 100–200 mesh purchased from Merck Specialities
Pvt. Ltd. India and mixtures of hexane–ethylacetate were
used for elution. TLC was carried out using Merck Sili-
caGel 60/UV254 either by UV fluorescence or by iodine
chamber.
bath for 24–48 h. After the completion of the reaction, the
reaction mixture was extracted with 15 cm3 of EtOAc and
the EtOAc layer was separated and washed with water.
The aqueous layer was collected and further extracted
two more times with EtOAc (2 × 15 cm3). The combined
organic layers were dried over anhydrous Na2SO4 and
evaporated using a rotatory evaporator. The residue was
later purifed by column chromatography (silica 100–200
mesh) using hexane–EtOAc mixture as the eluent.
1‑(4‑Methoxyphenoxy)‑2‑methyl‑4‑nitrobenzene (3i,
C14H13NO4) Pale yellow liquid; yield: 29 mg (17%);
1
Rf = 0.70 (hexane); H NMR (500 MHz, CDCl3): δ = 8.13
(s, 1H), 7.96 (dd, J=9.0, 3.5 Hz, 1H), 6.99 (d, J=9.0 Hz,
2H), 6.94 (d, J=9.0 Hz, 2H), 6.67 (d, J=9.0 Hz, 1H), 3.83
(s, 3H), 2.96 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3):
δ=162.29, 156.92, 148.38, 142.10, 128.66, 126.64, 123.15,
121.51, 115.26, 55.69, 16.36 ppm; HRMS (QToF): m/z
calculated for C14H13NO4 ([M+H]+) 260.0923, found
260.0931.
General procedure for O‑arylation of phenol
Acknowledgements SMU thanks the University Grants Commis-
sion (UGC-New Delhi), India for a research fellowship. SS and NAH
thank the Council of Scientifc and Industrial Research (CSIR-New
Delhi), India for their research fellowships. GA thanks the Kerala State
Council for Science Technology and Environment (KSCSTE), Trivan-
drum, India for a research grant (Order no. 341/2013/KSCSTE dated
15.03.2013). We greatly acknowledge the support from Department
of Science and Technology (DST-New Delhi) under the DST-PURSE
programme.
An oven-dried sealed tube equipped with a magnetic
stirring bar was charged with aryl iodide (0.65 mmol),
Co(OAc)2·4H2O (15 mol%), l-valine (30 mol%), cesium
carbonate (2 equiv.), and phenol (0.78 mmol). Acetoni-
trile solvent (2.5 cm3) was added and the sealed tube was
evacuated using a vacuum pump, flled with nitrogen,
and tightly sealed. It was then stirred in a pre-heated oil
1 3

S. M. Ujwaldev et al.
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