Iodine catalysed synthesis of unsymmetrical benzylic ethers by direct cross-coupling of alcohols

Article abstract of DOI:10.1016/j.tetlet.2021.153370

Although symmetrical ethers can be synthesized easily from alcohols, synthesis of unsymmetrical ethers by dehydrative cross-coupling of alcohols is still a challenge. While dehydrative cross-coupling is environmentally appealing due to formation of water as the only byproduct, the chances for formation of symmetrical ethers always exist. The existing transition metal based methods give good selectivity, but the catalyst are costly and not readily available. Here, we present a simple, readily available, and cost-effective catalyst in the form of molecular iodine which catalyzes a highly selective cross-coupling of benzylic alcohols with benzyl, alkyl, and aryl alcohols to give their corresponding unsymmetrical ethers in good to excellent yield.

Full text of DOI:10.1016/j.tetlet.2021.153370

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iodine catalysed synthesis of unsymmetrical benzylic ethers by direct
cross-coupling of alcohols
⇑
Balamphrang Kharrngi, Grace Basumatary, Ghanashyam Bez
Department of Chemistry, North Eastern Hill University, Shillong 793022, Meghalaya, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Although symmetrical ethers can be synthesized easily from alcohols, synthesis of unsymmetrical ethers
by dehydrative cross-coupling of alcohols is still a challenge. While dehydrative cross-coupling is envi-
ronmentally appealing due to formation of water as the only byproduct, the chances for formation of
symmetrical ethers always exist. The existing transition metal based methods give good selectivity,
but the catalyst are costly and not readily available. Here, we present a simple, readily available, and
cost-effective catalyst in the form of molecular iodine which catalyzes a highly selective cross-coupling
of benzylic alcohols with benzyl, alkyl, and aryl alcohols to give their corresponding unsymmetrical
ethers in good to excellent yield.
Received 16 May 2021
Revised 10 August 2021
Accepted 23 August 2021
Available online xxxx
Keywords:
Iodine
Benzyl alcohol
Cross-coupling
Unsymmetrical ether
Metal-free
Ó 2021 Elsevier Ltd. All rights reserved.
Introduction
enhance its ability to act as a leaving group in the presence of
another to facilitate nucleophilic addition reaction. Most of the
Ethers have widespread applications as solvents, plasticizers,
disinfectants, herbicides, fragrances, and precursors for polymers
and drugs [1–3]. Although the synthesis of symmetrical ethers
are easy, synthetic chemists rely on the Williamson ether synthesis
for the preparation of unsymmetrical ethers [4] where alkyl/benzyl
halides are treated with alcohol under strongly basic conditions. It
may be noted that the preparation of alkyl/benzyl halides also
requires the treatment of alcohols with environmentally harmful
phosphorous halides leading to generation of undesired waste.
Transition-metal-catalyzed methods, such as Pd- and Cu-catalyzed
Ullmann-type synthesis, are also developed for the synthesis of
ethers [5–7], but they have their own shortcomings. Synthesis of
ethers by oxidative etherification of aryl CAH bonds [8–13],
hydroetherification of alkenes using alcohols [14–16], Mit-
sunobu-type etherification reactions [17–20], and reductive
deoxygenation of esters [15], are also reported, despite their lim-
ited scope and poor atom economy in some cases. In contrast,
dehydrative cross-coupling of alcohol offers the best way to syn-
thesize unsymmetrical ethers due to formation of water as the only
by-product. But the use of dehydrative methods for selective cross-
coupling of alcohols to synthesize unsymmetrical ethers are diffi-
cult, as they lead to formation of the symmetrical counterpart also.
This is due to poor selective activation of one hydroxy group to
reported methods for dehydrative ether synthesis maneuvers the
acid catalyst, viz. heterogeneous acid, strong Brønsted and Lewis
acid, to achieve optimum chemoselectivity and yield. Firouzabadi
et al. [21] employed AlPW12O40, a highly water tolerant Lewis acid,
as catalyst for cross-coupling of alcohols with simple alcoholic sol-
vents such as methanol, ethanol, propanol and butanol, while in
dichloromethane medium homocoupling took place. Kaneda
et al. [22] developed titanium-exchanged montmorillonite (Ti4+
-
mont) and studied its catalytic application for dehydrative cross-
coupling of a host of alcohols for synthesis of unsymmetrical
ethers. Lingaiah et al. [23] employed zirconia supported cesium
exchanged 12-tungstophosphoric acid catalysts for synthesis of
wide range of unsymmetrical ethers from primary and secondary
alcohols. Corma et al. [24] also employed Sn- and Zr-containing sil-
icate molecular sieves for selective synthesis of unsymmetrical
ethers. Despite the efficacy of these methods, requirement of
presynthesis of the catalyst, high catalyst loading, and poor recov-
ery of the catalysts were the common deterrents against general
applicability of these methods. Recently Gunanathan et al. [25]
employed Fe(III) triflate for direct coupling of benzylic alcohols,
but use of costly catalyst and longer reaction time were the major
drawbacks. Likewise, many homogeneous catalysts showed poor
reactivity, low selectivity, require continuous removal of water to
avoid deactivation of the reaction, and most importantly give poor
yields of cross coupling product [26–29].
⇑
Corresponding author.
E-mail address: bez@nehu.ac.in (G. Bez).
https://doi.org/10.1016/j.tetlet.2021.153370
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: B. Kharrngi, G. Basumatary and G. Bez, Iodine catalysed synthesis of unsymmetrical benzylic ethers by direct cross-coupling of
alcohols, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153370

B. Kharrngi, G. Basumatary and G. Bez
Tetrahedron Letters xxx (xxxx) xxx
Iodine [30–32] has proven to be a wonder catalyst in organic
synthesis that mainly act as acid catalyst by generating strongly
acidic hydroiodic acid. Given our interest [33–36] in catalytic
application of iodine due to its simple handling, cost-effectiveness,
simpler termination of the reaction by adding aqueous sodium
thiosulfate, effectiveness as dehydrating agent without needing
any periodic elimination of water as demonstrated by dehydrative
acetalization of aldehyde and ketones [37], we planned to employ
molecular iodine as a catalyst for dehydrative cross-coupling of
alcohol for direct synthesis of unsymmetrical ethers. Here, we pre-
sent our findings on direct cross-coupling of alcohols using molec-
ular iodine as environmentally benign and efficient catalyst
(Scheme 1). Literature survey revealed that Stavber et al. [38] con-
ducted some preliminary studies on solvent-free reaction of iodine
with benzylic alcohols to achieve a mixture of products such as
symmetrical ethers, alkene and rearrangement products
(Scheme 1), but no attempts to synthesize unsymmetrical ethers
were made. Recently, we reported trans-esterification of ethyl acet-
ate with alcohol upon heating at reflux temperature [34]. We
observed that the method is excellent for acetylation of primary
benzylic alcohol and aliphatic 1° and 2° alcohols (Fig. 1).
We planned to extend the protocol for acylation of secondary
benzylic alcohols by refluxing in ethyl acetate in the presence of
iodine as catalyst. To our surprise, 1-phenyl ethanol upon heating
under reflux in ethyl acetate in the presence of 30 mol% iodine gen-
erated a symmetrical dibenzyl ethers (90% yield) (Table 1, entry 1).
Interestingly, the reduction of catalyst loading to 10 mol% also gave
similar results. Since the methods for synthesis of unsymmetrical
ethers are mostly metal based, we wanted to explore if unsymmet-
rical ethers can be synthesized by mixing two alcohols employing
the same method. To our pleasure, when a stoichiometric amount
of benzyl alcohol was added to a mixture of 1-phenyl ethanol in
ethyl acetate in the presence of 10 mol% iodine, formation of 1-
benzyloxy-1-phenylethane was observed to obtain 65% yield
(Scheme 1). In contrast, stoichiometric amount of benzyl alcohol
with 1-phenyl ethanol in the absence of any solvent showed the
formation of the symmetrical ether in higher ratio (Entry 4). We
assumed that the solvent-free reaction conditions did not allow
proper mixing of the reactants and resulted in formation of the
mixture. Therefore, we employed 1,2-dichloroethane as solvent
for the said reaction and obtained an improved yield (85%) upon
heating under reflux. Surprisingly though, the heating the reaction
mixture at reflux temperature in chloroform improved the reaction
further to give 89% isolated yield of the cross-coupling product (C)
with no formation of the symmetrical ethers (B and D). Some other
solvents such as dichloromethane, diethyl ether, acetonitrile, and
THF were also screened, but the yields were comparatively inferior.
The catalyst loading was also varied from 5 to 15 mol% to
observe that 10 mol% gives optimum efficacy. The optimum reac-
Fig. 1. Iodine catalyzed CAO bond-forming reactions.
tion conditions allowed direct dehydrative coupling between two
alcohols in the presence of 10 mol% iodine as catalyst upon heating
under reflux. It may be noted that the formation of dibenzyl ether
(D) was not observed at all. Since reaction was extremely selective
towards the formation of unsymmetrical ether, it gives a simple
catalytic approach for cross-coupling of alcohols without using
any metal-based catalyst.
After getting optimum reaction conditions for the synthesis of
unsymmetrical ethers, we extended the reaction of 1-phenyl etha-
nol with various benzylic primary alcohols under the optimized
conditions (Table 2). Incidentally, all the reaction gave excellent
yields of unsymmetrical ethers irrespective of the substitutions
on the phenyl ring. Reactions of ring-substituted 1-phenyl ethanols
with benzylic alcohols gave excellent yields of unsymmetrical
ethers. Cross-coupling of 1-phenyl ethanol with long chain alipha-
tic alcohol such as 1-dodecanol were also equally effective. Reac-
tion of a few primary benzylic alcohols with p-methylbenzyl
alcohol, and 1-naphthyl methanol were also found to be effective
and gave very good yield of the cross-coupling products (1t-v),
but the reactions took longer time for complete conversion. Ironi-
cally, the reaction of benzyl alcohol with 1-butanol, 1-octanol, and
cyclohexanol did not give any product under our reaction condi-
tions (Scheme 2a). This may be due to relatively lower stability
of primary benzyl carbocation in comparison to secondary benzyl,
p-methylbenzyl, 1-naphthylmethyl carbocations. These observa-
tions also explain the non-formation of dibenzyl ether (D) under
our screening conditions (Table 1). Moreover, the method failed
to give cross-coupling products in the reaction of 2-phenyl ethanol
with cyclohexanol (Scheme 2b) suggesting that having one ben-
zylic alcohol is a necessary condition to facilitate the reaction
and the reactivity is largely dependent on the nature of benzyl
alcohol.
The scope of the reaction extended to the reaction of 1-phenyl
ethanol with phenolic alcohols (Scheme 3). Despite having possi-
bilities to form symmetric ether in the presence of poorly nucle-
ophilic phenols, 1-phenyl ethanol gave exclusively the cross-
coupling product in excellent yields. The general reluctance of
the catalytic system in the chloroform medium to facilitate homo-
coupling is very interesting and deserves extensive investigation.
Attempts were also made to study the reaction of benzyl alco-
hols with nucleophiles such as thiols and amines. To test the for-
mation of thioether, 1-phenyl ethanol in chloroform was stirred
with a stoichiometric amount of thiophenol in the presence of a
catalytic amount of iodine (10 mol%). The colour of iodine immedi-
ately disappeared. The reaction mixture was heated under reflux
with stirring for 3 h, but the starting materials largely remained
intact. Careful scrutiny of the TLC plate revealed formation of a less
polar product in trace amount which was later confirmed to be
diphenyl disulphide. When the same reaction was carried out with
2-mercaptoethanol, formation of neither thioether nor ether were
detected (Scheme 4b). This information confirmed that the thiol
group might have consumed the catalyst iodine by forming corre-
sponding disulphide derivatives. In fact, coupling of thiols in the
Scheme 1. Iodine catalyzed coupling of alcohols.
2

B. Kharrngi, G. Basumatary and G. Bez
Tetrahedron Letters xxx (xxxx) xxx
Table 1
Screening of cross-coupling reaction between benzylic alcohols.a
Entry
Iodine (mol%)
Solvent
Time/h
Yield (%)b,c
A
B
C
1
2
3
4
5
6
7
8
30
10
10
10
10
10
10
10
10
10
10
15
5
EtOAc
EtOAc
EtOAc
–
ClCH2CH2Cl
CHCl3
CH2Cl2
Et2O
1,4-dioxane
THF
CHCl3
CHCl3
CHCl3
2
2
2
2
1.5
1.5
3
3
3
1.5
8e
1.5
1.5
–
90d
71d
5
23
–
–
–
–
–
–
–
–
–
–
–
27
25
10
–
65
58
85
89
55
52
37
69
50
90
62
–
42
38
12
27
34
–
9
10
11
12
13
27
a
b
c
Equimolar mixture of 1-phenylethanol and benzyl alcohol was taken.
Yield of the purified product.
Formation of the product (D) was not observed.
Only 1-phenyl ethanol was treated with iodine.
At room temperature.
d
e
Table 2
Synthesis of unsymmetrical ethers by cross-coupling with benzylic alcohols.a,b
Scheme 3. Synthesis of unsymmetrical ethers by cross-coupling of benzylic alcohol
with phenols.
Scheme 4. Cross-coupling of benzylic alcohol with amine and thiol nucleophile.
presence of iodine with DMSO as iodine regenerating additive has
already been reported by AL Braga and coworkers [39].
a
The reaction was conducted in 1 mmol scale in 4 mL solvent.
Yields are calculated after purification by column chromatography.
b
Cross-coupling of 1-phenylethanol with diethylamine was also
studied under similar reaction conditions, but the reaction did
not proceed at all. Here too, iodine might have reacted with amine
faster than the alcohol to form corresponding hydrazine and
ammonium salts [40].
Since the reaction of 1-phenyl ethanol in ethyl acetate medium
in the presence of a catalytic amount of iodine gave corresponding
symmetrical ether, we assumed that the reaction might have pro-
ceeded through formation of a carbocation from the reaction of
reaction iodine with 1-phenyl ethanol. If the reactions indeed pro-
ceeds through a carbocation, an optically active 1-phenyl ethanol
Scheme 2. Study on coupling with aliphatic alcohol.
3

B. Kharrngi, G. Basumatary and G. Bez
Tetrahedron Letters xxx (xxxx) xxx
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgment
Sophisticated Analytical Instruments Facility, NEHU is acknowl-
edged for analytical support.
Scheme 5. Proof of carbocation formation.
Appendix A. Supplementary data
Typical procedure, data and 1HNMR and 13CNMR spectra for
selected compounds). Supplementary data to this article can be
found online at https://doi.org/10.1016/j.tetlet.2021.153370.
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mixture of (S)-1-phenyl ethanol and benzyl alcohol in chloroform
was carried out in the presence of 10 mol% of iodine under the
optimized reaction conditions (Scheme 5). The HPLC chro-
matogram using chiralcel ADH column showed the formation of
( )-1-benzyloxy-1-phenylethane to suggest that the preferentially
formed secondary benzylic carbocation reacted with benzyl alco-
hol to give the unsymmetrical ether. Although there was every
chance of formation of symmetrical ether from 1-phenyl ethanol,
it was not observed in the product. In order to see if the reaction
might proceed through a symmetrical ether intermediate, we
reacted an equimolar mixture of 1,10-diphenylethyl ether and ben-
zyl alcohol under our reaction conditions and observed 18% con-
version to the corresponding unsymmetrical ether, 1-benzyloxy-
1-phenylethane after heating under reflux for 5 h. Although the
observation (b) does not ascertain the formation of the symmetri-
cal ether during the reaction, it does not rule out formation of
unsymmetrical ethers from symmetrical ethers as one of the plau-
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In conclusion, we have developed a simple, yet efficient method
for the synthesis of unsymmetrical benzylic ethers from different
alcohols using molecular iodine as an efficient and environmen-
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formed in chloroform. The protocol also gives excellent yield of
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4