Co(II)-catalyzed regioselective clean and smooth synthesis of 2-(aryl/alkyl-thio)phenols via sp2 C-H bond activation

Article abstract of DOI:10.1016/j.mcat.2018.04.020

The first example of a smooth, practical and useful strategy for the preparation of ortho-aryl/alkyl sulfenyl phenols by using the reaction of aryl/alkyl thiols with phenols in the presence cobalt as catalyst, and with the assistance of acetic anhydride as directing group via C-H bond activation, was developed. Described method enables to form selectively C-S bond without any ligand, oxidant, and aryl/alkyl halide under mild conditions.

Full text of DOI:10.1016/j.mcat.2018.04.020

MolecularCatalysis452(2018)260–263
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Co(II)-catalyzed regioselective clean and smooth synthesis of 2-(aryl/alkyl-
thio)phenols via sp2 CeH bond activation
Abed Rostamia,b, Vahid Khakyzadehc,⁎, Mohammad Ali Zolfigola,⁎, Amin Rostamid
a
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65167, Iran
Kurdistan University of Medical Science, Sanandaj, Iran
Faculty of Science, Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
Department of Chemistry, Faculty of Science, University of Kurdistan, 66177-15175, Sanandaj, Iran
b
c
d
A R T I C L E I N F O
A B S T R A C T
Keywords:
Cobalt catalyst
Homogeneous catalyst
CeH bond activation
2-(aryl/alkyl-thio) phenol
The first example of a smooth, practical and useful strategy for the preparation of ortho-aryl/alkyl sulfenyl
phenols by using the reaction of aryl/alkyl thiols with phenols in the presence cobalt as catalyst, and with the
assistance of acetic anhydride as directing group via CeH bond activation, was developed. Described method
enables to form selectively CeS bond without any ligand, oxidant, and aryl/alkyl halide under mild conditions.
Introduction
boronic acid [10], triphenyl tin chloride [11] and nitro arenes [12] with
S-containing nucleophiles in the presence of transition metal catalysts.
Discovering novel organic methodologies are always an important
and main concern for chemists over the world [1]. In recent years, a
selective ‘inert' CeH bond activation/subsequent functionalization, is a
challenging theme in many laboratories to furnish more versatile syn-
thetic compounds and consider as a potent strategy for integrating
small molecules to reach complex structures [2]. However, such CeH
bond activations usually, suffer from critical challenges such as intrinsic
reactivity and selectivity as well as a big part of them is conducted
under harsh conditions [3]. In this regard, the directing groups perform
a significant task because they can guide the specific “inert” CeH bond
toward activation [4]. Owing to the unique place of sulfur, as a vital
element, in living cells, decoration of new sulfur-containing compounds
is a noted importance in organic synthesis, particularly, because of their
extensive presence in medicines and natural products [5].
Among sulfur-containing compounds, 2-(aryl/alkyl-thio) phenols
consider as notable skeletal motifs because of their therapeutic value in
the treatment of cancer, HIV, heart disease, allergies, and obesity (Chart
1) [6a–c]. They have been broadly used in the creation of natural
products and also drugs, such as flavonoid derivative F1, and essential
intermediate F2 as potent inhibitor for aldosterone synthase inhibitor
(ASI) [6d–f]. On this matter, regioselective and direct CeS bond for-
mation via CeH bond activation, as one of the most powerful protocols,
has attracted considerable attention [7].
Another method involves the cross-coupling diary disulfides with aryl
halides or coupling partners in the presence of rhodium [13], copper
[14] and nickel [15] metals.
To the best of our knowledge, CeH bond activation of aromatic
compounds by transition metal catalyst under mild conditions is still
the research target especially in halide-free processes [16] and litera-
ture survey shows that not only a few reports are available for sulfe-
nylation of aryl 2-naphthols [17] but also direct synthesizing of 2-(aryl/
alkyl-thio)phenol via sp2 CeH bond activation and then subsequent
CeS bond formation is rare and highly desirable. Through documented
methods, up-to-date, (Scheme 1), in 2010, Pan and coworkers described
a copper (I)-catalyzed tandem transformation of CeS coupling/CeH
functionalization method through reaction of thiophenol derivatives
with aryl halides for the preparation of 2-(aryl)thiophenols (path I)
[18]. After that, Deng et al. introduced coupling of thiols and cyclo-
hexanones via a dehydrogenation and tautomerization reaction by
employing of Iodine as a catalyst (path II) [19] and, very recently Wang
and Shi presented a copper-catalyzed tandem thiophenol hydroxylation
subsequent S-arylation using aryl boronic acids (path III) [20]. Ac-
cordingly, it is urgent to recognize new synthetic methods in this case.
As the part of our continuing efforts for the CeS bond formation and
the synthesis of aryl sulfides [21], as well as considering that employing
directing groups could be simply used in such directed CeH bond ac-
tivation we postulated that free-phenols could be feasible as a starting
material and by connecting directing group on its hydroxy group, the
As a glance to the typical preparation of the aryl sulfides, they have
synthesized by the reaction of aryl halides [8], phenolic esters [9], aryl
⁎
Corresponding authors.
E-mail addresses: v.khakyzadeh@kntu.ac.ir (V. Khakyzadeh), zolfi@basu.ac.ir (M.A. Zolfigol).
https://doi.org/10.1016/j.mcat.2018.04.020
Received 24 February 2018; Received in revised form 16 April 2018; Accepted 19 April 2018
2468-8231/©2018ElsevierB.V.Allrightsreserved.

A. Rostami et al.
MolecularCatalysis452(2018)260–263
Table 1
Catalyst, base, additive and solvent screening table.[a]
Entry
Catalyst
Solvent[b]
Base
Additive
Yield[c] (%)
1
2
3
4
5
6
7
8
Cu(OAc)2
Pd(OAc)2
Ru(Cl)3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NaOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
–
–
–
–
–
–
–
40
15
45
47
55
9
Chart 1. Selected examples of 2-(aryl/alkyl-thio) phenol derivatives in natural
products and medicines.
Fe(Cl)3
Fe(Cl)3
[d]
Ni(Cl)2
Co(Cl)2
Co(Cl)2
Co(Cl)2
Co(Cl)2
Co(Cl)2
Co(Cl)2
–-
75
70
72
94
38
9
–
10
11
12
13
14
TBAC
TBAC
TBAC
TBAC
TBAC
[e]
DMSO
DMSO
DMSO
0
0
[f]
[g]
Co(Cl)2
19
[a]
Condition: At first; 1a (1 mmol), (CH3CO)2O (1.2 mmol), base (2 mmol),
additive (0.5 mL) and solvent (2.0 mL) mixed together for 20 min at room
temperature then, 2a (1.2 mmol) and catalyst (10 mol%) added to the flask at
90 °C for15 h, under air atmosphere. Finally, product was obtained by acidic
[b]
[c]
[d]
[e]
hydrolysis.
all solvents were dried.
GC yield.
Fe(Cl)3 × 6H2O.
[f]
[g]
Without acetic anhydride.
Without catalyst.
Under argon.
TBAC = Tributylmethylammonium chloride. More details are in supporting
information.
was performed in the absence either one (entries 12 and 13) also the
desired product did not obtain when the reaction was carried out under
an argon atmosphere (entry 14).
To demonstrate the utility of this method, with the optimized con-
ditions in hand, various aryl thiols and phenols were chosen to establish
the scope, limitations, and generality of this protocol (Table 2).
Initial investigations were performed on the coupling of 2-Naphthol
with free/substituted thiophenol derivatives. Electron-donating and
halogen substituted thiophenol were suitable substrates (3a-d) and
coupled smoothly in good to excellent yields. The moderate yield (60%)
Scheme 1. Possible approach for ortho-functionalization of phenols, our hy-
pothesis, and work.
desired CeH activation could take place and let to selective CeS bond
formation (hypothesis). Herein we disclose the successful and selective
synthesis of alkyl/aryl sulfenyl-phenols through cobalt catalyzed CeH
bond activation/functionalization of phenols with thiols in the presence
of acetic anhydride as directing group under ligand and additive-free
conditions (Scheme 1, this work).
Table 2
Substrate scope of ortho- sulfenylation of phenols.[a]
Our initial efforts were focused on finding an efficient catalytic
system using 1-naphthol (1a), thiophenol (2a), and acetic anhydride as
model substrates (Table 1). Using 10 mol% Cu(OAc)2 as a catalyst and
K2CO3 in dimethyl sulfoxide (DMSO) solvent gave the desired product
in 40% yield (entry 1). Surprisingly, no improvement was observed
with employing Pd(OAc)2 and Ru(Cl)3 as catalysts and desired products
produced in only 15 and 45% yields, respectively (entries 2 and 3). Fe
and Ni were also examined as other metal catalysts in this reaction, and
moderate yields were detected for iron and trace yield in case of the Ni
catalyst (entries 4–6). A sharp progress was seen by switching the
catalyst to Co(Cl)2 (entries 7–9) and the best efficiency for reaching to
the corresponding product 3a was viewed in the presence of K2CO3,
75% yield. Almost same yields were obtained by other base sources
(entries 8 and 9). To our delight, a series of ionic liquids were in-
vestigated as phase transfer materials and led to a better result (entry
10, 94%). Dimethylformamide (DMF), was also utilized in the present
of TBAC; the desired product was obtained in poor, 38%, yield (entry
11). Cobalt chloride as the catalyst and acetic anhydride as directing
group is both necessary, and no yields were observed when the reaction
[a] Reaction Condition: ROH (1 mmol), (CH3CO)2O (1.2 mmol), ArSH
(1.2 mmol), K2CO3 (2 mmol), DMSO (2.0 mL), TBAC (0.5 mL), Catalyst (10 mol
%), under air. [b] Isolated Yield.
261

A. Rostami et al.
MolecularCatalysis452(2018)260–263
was obtained when benzene-1,3,5-triol was employed, probably be-
cause of multiple reaction sites (3e). Next, the coupling of para sub-
stituted phenols (para methyl and para ethyl) with different mono-
substituted thiophenols were tested (3f-m) and well tolerated in this
study. A strong electron withdrawing group (–NO2) on para position of
phenol suppressed coupling reaction (3n, 10%). Interestingly, good to
excellent yields (80–92%) and selectivity were obtained by using of
ortho or meta-substituted phenols, and only CeH activation on 2-po-
sition of the hydroxy group was observed, in contrary to steric effects
(3o-p, 3u). Moreover, dimethyl substituted phenols smoothly partici-
pated in coupling with several thiophenols and furnished corresponding
products in excellent yields (3q-t).
Generally, phenols with electron-rich groups were efficiently pro-
duced the desired product in high yields, but we found that phenols
containing electron withdrawing groups (eNO2, eCN, eCHO) are not
fit for this transformation.
To show the more synthetic applicability of defined system and also
ability to discriminate between CeH bonds, the sulfunylation of 2-
naphthol, benzene rings fused to phenol, were investigated and the
possibility of synthesis of aryl/alkyl sulfenylphenols using the reaction
of aryl/alkyl thiols with 2-naphthol was examined under optimized
reaction conditions (Table 3).
Scheme 2. Chemoselective control experiments.
[a] All yields are GC yields. [b] In the precence of butylated hydroxytoluene
(BHT). [c] In the precence of Iodine.
reaction, desired product (3a) obtained in 94% yield (Scheme 2II).
Employing disulfide (4a) instead of thiophenol (2a), the product 3a was
formed in only 15% yield under the standard reaction conditions
(Scheme 2III). The model reaction was also studied in the presence of
Iodine and Butylated Hydroxytoluene (BHT) as the common radical
scavengers. From the taken results, trace yield for BTH and 20% in case
of I2, it can, therefore, be concluded that reaction pathway is sensitive
to radical scavengers (Scheme 2IV). Additionally, in a control experi-
ment in the absence of phenol substrates, thiophenol (2a) underwent
dimerization to afford disulfide (4a) in 15% yield (V).
Based on the above experimental results, a plausible reaction
pathway for the reaction of thiols with phenols in the presence of acetic
anhydride as directing group and cobalt catalyst has been presented in
Scheme 3. It is hypothesized that phenol reacts with acetic anhydride to
produce phenolic ester C1. Then, cobalt is coordinated to oxygenate
atom leading to a directed ortho-metalation by a radical pathway and
provide the key intermediate C2 which is cobalt (III) intermediate.
Since cobalt (III) complexes are very kinetically inert [22], we imagine
that oxygen molecule can be responsible for re-aromatization of ring
and reactivating cobalt by reducing of cobalt (III) to cobalt (II) in an
internal cyclic pathway to produce C3. In continue, the intermediate C4
generate by reaction of sulfur source with cobalt (II), then C5 form by
an internal immigration. Finally, protected desired product results from
regeneration of CoCl2 and can easily deprotected by an acidic hydro-
lysis strategy.
The results in Table 3 demonstrate that most of the thiols tested
underwent smooth transformations to afford the corresponding 1-aryl/
alky sulfenyl naphthol in good to excellent yields (83–93%) with high
selectivity (> 80% in position 1 and < 10% in positon 3 of 2-naphthol).
Not only free thiophenol but also electron-donating (–CH3) and halogen
(–F, –Cl, –Br) substituted thiophenols were well tolerated and known as
suitable substrates by smoothly coupling in the reaction and giving
good to excellent yields (4ba-4be). After that desired product was ob-
tained in 90% yield when naphthalene-1-thiol employed as another
partner in coupling reaction (4bf). Aliphatic thiols including benzyl
mercaptan, 1-octanethiol, and cyclohexzanthiol as sulfenylating agents
were also performed successfully under present reaction conditions
(4bg-4bi), showing the high potential of the system for further in-
vestigations. Our experimentations on scope indicated that the presence
of an electron donating/withdrawing groups on the benzene ring of
thiols did not prevent the smooth formation of the expected products.
To gain an understanding the reaction mechanism, we conducted a
good range of experiments to explore the roles of directing group,
catalyst and other aspects of the reaction (Scheme 2). Under the stan-
dard condition without the addition of acetic anhydride, 1-naphthol
(1a) not converted to the corresponding product (3a), leaving the
starting material intact and disulfide (4a) obtained in 25% yield
(Scheme 2I). The reaction of naphthalen-1-yl acetate, 5a, (instead of the
1-naphthol/acetic anhydride system) with thiophenol (2a) in the
Table 3
Scope of sulfenylation of 4a.[a]
[a] Reaction Condition: ROH (1 mmol), (CH3CO)2O (1.2 mmol), ArSH
(1.2 mmol), K2CO3 (2 mmol), DMSO (2.0 mL), TBAC (0.5 mL), Catalyst (10 mol
%), under air. [b] Isolated Yield.
Scheme 3. Proposed mechanism for the sulfunylation of phenols.
262

A. Rostami et al.
MolecularCatalysis452(2018)260–263
Conclusions
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We thank Bu-Ali Sina University, University of Kurdistan, K. N.
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(INSF). This research was supported under Iran national science foun-
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