Bismuth(III)-catalyzed dehydrative etherification and thioetherification of phenolic hydroxy groups

Article abstract of DOI:10.1021/ol501744g

Use of a bismuth catalyst allowed efficient dehydrative substitution of phenolic hydroxy groups with alcohols and thiols to form C-O and C-S bonds. The reaction required equimolar amounts of two readily available substrates that generated H₂O as the only byproduct. The relatively mild reaction conditions were compatible with the functional groups selected, and provided excellent chemoselectivity.

Full text of DOI:10.1021/ol501744g

Letter
pubs.acs.org/OrgLett
Bismuth(III)-Catalyzed Dehydrative Etherification and
Thioetherification of Phenolic Hydroxy Groups
Masahito Murai,*,† Kazuki Origuchi,† and Kazuhiko Takai*,†,‡
‡
†Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology and Research Center of New
Functional Materials for Energy Production, Storage and Transport, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama,
Okayama Prefecture 700-8530, Japan
S
* Supporting Information
ABSTRACT: Use of a bismuth catalyst allowed efficient dehydrative
substitution of phenolic hydroxy groups with alcohols and thiols to form
C−O and C−S bonds. The reaction required equimolar amounts of two
readily available substrates that generated H2O as the only byproduct. The
relatively mild reaction conditions were compatible with the functional
groups selected, and provided excellent chemoselectivity.
lkyl naphthyl ethers constitute important structural units
naphthols with alcohols occurred selectively to form new C−O
Ain perfumes, cosmetics, and flavoring compounds, such as bonds in the presence of a catalytic amount of a bismuth
complex. This observation prompted a detailed examination of
this unique reaction because (1) the reaction proceeded
efficiently with phenols and alcohols, even at a 1:1 ratio, and
(2) bismuth salts are readily available, possess low toxicity
despite being the heavy metal, and have been used as
environmentally benign reagents and catalysts during the past
few years.7 The present study describes a highly selective,
operationally simple catalytic substitution reaction enabling the
direct use of phenols and alcohols as substrates and the
production of water as the only byproduct.
Conditions were optimized for the reaction of 2-naphthol 1a
with a stoichiometric amount of 1-hexanol 2a. After a screening
of reaction conditions, we found the 2-(hexyloxy)naphthalene
3a was obtained quantitatively in the presence of 5 mol % of
Bi(OTf)3 in 1,2-dichloroethane at 80 °C (eq 1). It is worth
yara yara (Nerolin I), bromelia (Nerolin II), and fragrol
(Nerolin Fragnol).1 They also serve as versatile synthetic
building blocks of drug candidates. For example, 2-methox-
ynaphthalene is an important intermediate for the production
of naproxen and nabumetone, widely used as nonsteroidal anti-
inflammatory drugs.2 Because of their usefulness in fine
chemical synthesis, alkyl aryl ethers have been investigated as
synthetic targets. The most common approach for their
preparation known as Williamson’s synthesis, involves the
treatment of preactivated phenol derivatives with alkylating
reagents containing good leaving groups such as halides,
tosylates (OTs), or triflates (OTf) under basic conditions.3
Unfortunately, these organic halides and pseudohalides result in
the formation of undesirable acidic byproducts and are usually
more expensive compared with the corresponding alcohols.4
Representative alternative preparative methods include SNAr
reactions with electron-deficient aromatics, and reactions with
Mitsunobu type reagents or benzyne intermediates.5 Although
these methods are widely used, they require multiple steps to
prepare the starting materials and generate stoichiometric
byproducts. Therefore, effort has been devoted to the
development of highly efficient dehydrative etherification of
phenols with alcohols as an environmentally benign process.
Classical reactions require stoichiometric amounts of strong
Brønsted acids, such as hydrochloric acid, sulfuric acid, or
fluorosulfonic acid, to activate the hydroxy groups because they
are inherently poor leaving groups.6 These methods are very
useful, but possess drawbacks such as limited substrate scope
and low functional group compatibility (i.e., they tend to
produce undesirable products when hydroxy and halide
functional groups exist in their backbones). In addition, the
use of strong acid or harsh conditions limits their application in
the syntheses of complex molecules.
mentioning that the reaction occurred as well on a 5 mmol
scale (0.72 g of 1a with 0.51 g of 2a) as on a 0.5 mmol scale
under these reaction conditions (eq 1). Several other transition
metal complexes, such as Sc(OTf)3, FeCl3, Fe(OTf)3, Cu-
(OTf)2, Zn(OTf)2, and In(OTf)3, showed catalytic activity,
although none of which were superior to Bi(OTf)3.8,9 Other
bismuth complexes, including Bi(OAc)3, BiCl3, and BiBr3, were
ineffective and resulted in recovery of most of the 1a and 2a
used.8 When TfOH was used as a catalyst, the yield decreased
During a study designed to develop new and efficient
Received: June 17, 2014
catalytic processes, unexpected dehydrative coupling of 2-
© XXXX American Chemical Society
A
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Letter
to 66% and the undefined byproducts, such as di(2-naphthyl)
ether and BINOL, were formed.10
Table 2. Bismuth(III)-Catalyzed Dehydrative Etherification
and Thioetherification of 2-Naphthol 1a
Using the optimized reaction conditions, the scope of
phenols was investigated for dehydrative etherification with 1-
hexanol 2a as a model reaction (Table 1). 2-Naphthols 1b, 1c,
Table 1. Bismuth(III)-Catalyzed Dehydrative Etherification
of Phenols 1 with 1-Hexanol 2a
a
b
Isolated yields. 2f (2 equiv).
a
b
Isolated yields. At 115 °C.
obtained selectively without forming 2-(hexyloxy)naphthalene
3a, clearly indicating that substitution of the phenolic hydroxy
group occurred with the current catalyst system.11 Although the
reaction did not proceed using sterically hindered secondary
alcohols, such as 2-propanol and cyclohexanol, the substrate
cyclohexanethiol 2i furnished the cyclohexyl naphthyl thioether
4i in 95% yield (entry 8). Thiophenol 2j was also applicable to
give the corresponding thioether 4j in 94% yield (entry 9).
To obtain insight into the reaction mechanism, the effect of
the leaving group of the naphthalene derivatives was
investigated (Scheme 1). Interestingly, other oxygen-based
and 1d possessing electron-neutral, -donating, and -with-
drawing substituents on the naphthyl ring all reacted to form
the corresponding 2-(hexyloxy)naphthalenes 3b, 3c, and 3d in
good-to-excellent yields (entries 1−3). 1-Naphthol 1e was also
a suitable substrate and afforded 1-(hexyloxy)naphthalene 3e
albeit in slightly lower yield compared with the reaction of 1a
(entry 4 vs eq 1). In contrast, the use of phenol derivatives,
such as 1f as substrates resulted in a decrease in yield to less
than 30% (entry 5). Notably, dehydrative etherification was not
restricted to naphthols but could be achieved using 2-
anthracenol 1g and 5-hydroxybenzothiophene 1h as substrates,
although slight excess of 1-hexanol 2a was required to obtain
the adducts in high yields (entries 6 and 7).
Scheme 1. Effect of the Leaving Group
Next, several nucleophiles were subjected to the optimized
reaction conditions (Table 2). Reaction with alcohols
containing a linear alkyl chain 2b gave the corresponding
ether 4b in quantitative yield (entry 1). A chloro group was
well-tolerated under the present reaction conditions (entry 2).
A perfluorinated alkyl chain was also introduced to furnish the
corresponding ether 4d in excellent yield (entry 3). In addition,
the branched alcohol 2e derived from (−)-β-citronellol could
be employed as a substrate to furnish 4e with complete
retention of stereochemistry (entry 4). Unfortunately, phenol
derivatives were less reactive and afforded the corresponding
naphthyl ethers 4f and 4g in moderate-to-low yields (entries 5
and 6). The reaction occurred at the alcoholic oxygen not on
the aromatic ring probably due to the steric hindrance. Thiols
could be applied to the present dehydrative carbon-hetero bond
formation to furnish the corresponding naphthyl thioether 4h
in 94% yield (entry 7). Note that naphthyl thioether 4h was
leaving groups, including acetate (OAc) and trifluoromethane-
sulfonate (OTf), which often act as good leaving groups in
various transition metal-catalyzed cross-coupling reactions, did
not work.12 In addition, halides and cyano groups did not afford
the corresponding substituted product 3a, even though they are
better leaving groups compared with hydroxy groups. This
unique chemoselectivity enables selective substitution of the
phenolic hydroxy group in the presence of other “good” leaving
groups. For example, treatment of 2-naphthol 1b with 1-
hexanol 2a in the presence of the corresponding triflate 5 gave
3b quantitatively along with the recovery of intact 5 (Scheme
B
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2). This result confirms that leaving group ability is in the order
OH > OTf with the current bismuth catalyst system.
Scheme 2. Selective Substitution of the Phenolic Hydroxy
Group
To gain understanding into the reaction mechanism, 2-
naphthol 1a was treated with 3 equiv of D2O in the presence of
the bismuth catalyst (Scheme 3). A total of 66% of the
Figure 1. Proposed reaction mechanism.
hydroxy group assisted by the bismuth complex furnished the
corresponding coupling product followed by regeneration of
the bismuth catalyst.16
Scheme 3. Control Experiment
Because Bi(OTf)3 is known to serve as both an σ- and π-acid
catalyst,7,16,17 the cascade reaction was likely initiated by the
dehydroetherification that takes advantage of the dual activation
mode. Treatment of 2-naphthol 1a with allyl thiol in the
presence of Bi(OTf)3 provided 1,2-dihydro-2-methylnaphtho-
[2,1-b]thiophene 6 in 65% yield (Scheme 4). The reaction
deuterium atoms was incorporated exclusively into the 1-
position to afford the deuterium incorporated naphthol 1a-d
quantitatively.13 Incorporation of deuterium was not observed
when 1a was reacted with D2O in the absence of Bi(OTf)3.
Since Bi(OTf)3 is known to generate TfOH in the presence of
H2O, this result indicated that the present reaction proceeded
via selective protonation by TfOD at the 1-position.10,14
Among the results obtained above, we focused on the
following three observations to discuss the reaction mechanism.
(1) Selective C−S bond formation occurred without
production of a C−O bond in the reaction of 2-naphthol 1a
with thiols (Table 2, entries 7 and 8), indicating that alcohols
and thiols acted as nucleophiles and cleaved the phenolic
hydroxy group in the presence of the bismuth catalyst. (2)
Substituted 2-naphthols underwent selective etherifications
exclusively at the ipso carbon of the phenolic hydroxy group,
irrespective of the electronic nature of the substituent (Table 1,
entries 1−3). (3) Common leaving groups, including halide
and cyano groups,15 remained intact, and only naphthalene
derivatives with hydroxy groups were suitable substrates
(Scheme 1). This observation ruled out the possibility of the
present reaction proceeding via an SNAr reaction mechanism.
Since the phenolic anions are good σ-donor ligands, they could
bind to the bismuth catalyst and induce bismuth-assisted
cleavage of the hydroxy group. The lack of homocoupling of
alcohols under the current reaction conditions also supports
bismuth-assisted selective elimination of the phenolic hydroxy
group.
Scheme 4. Bismuth(III)-Catalyzed Cascade Reaction
Initiated by Dehydrative Thioetherification of 1a
sequence involves not only the dehydrative etherification of 1a
to generate allyl 2-naphthyl ether D, but also subsequent thio-
Claisen rearrangement followed by the cycloisomerization
leading to 6. A catalytic amount of Bi(OTf)3 was also
confirmed to promote thio-Claisen rearrangement and
cyclization of allyl 2-naphthyl thioether D, which was prepared
by the Williamson ether method, probably as a π-acid.18,19
In conclusion, a novel straightforward bismuth-catalyzed
dehydrative substitution of phenolic hydroxy groups with
alcohols and thiols has been developed. Neither severe reaction
conditions nor an excess of substrates are required in the
current catalytic system, which offer a practical and environ-
mentally friendly route to a wide variety of aryl ethers.
Although catalytic cleavage of C(aryl)−OH bonds has been
reported recently using a late transition metal catalyst,11 its
replacement by an inexpensive, air-stable, and environmentally
friendly bismuth catalyst that offers practical production
possibilities is an important development. Thus, we believe
the present system opens up new perspectives for advances in
the dehydrative nucleophilic substitution system. Further
investigation on the highly efficient bismuth-catalyzed trans-
Taking these observation into consideration, a possible
mechanism is depicted in Figure 1, which exemplifies the
reaction of 2-naphthol. Initially, ligand exchange of Bi(OTf)3
with 2-naphthol generated intermediate A along with
elimination of TfOH. Subsequent protonation of A with
TfOH formed the oxocarbenium ion intermediate B,10 which
was trapped by nucleophiles leading to C. At this stage,
nucleophiles selectively attacked the most electronically
deficient oxocarbenium carbon. Finally, the elimination of the
C
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Letter
Roux, C. Trends Org. Chem. 2006, 11, 65−80. (g) Hua, R. Curr. Org.
Synth. 2008, 5, 1−27. (h) Salvador, J. A. R.; Pinto, R. M. A.; Silvestre,
S. M. Curr. Org. Synth. 2009, 6, 426−470. (i) Salvador, J. A. R.; Pinto,
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2755.
(8) Investigation of several transition-metal catalysts (5 mol%):
Sc(OTf)3, 40%; [ReBr(CO)3(thf)]3 (2.5 mol%), 12%; FeCl3, 37%;
Cu(OTf)2, 72%; AuCl3, 15%; In(OTf)3, 36%; BiCl3, 6%. The
following catalysts did not afford 3a: Re2(CO)10, Sm(OTf)3,
Yb(OTf)3, Fe(OTf)3, RhCl(PPh3)3, Ir4(CO)12, BiBr3.
formations as well as applications of the resulting aryl ethers are
currently in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data for all new
1
compounds, and copies of H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
(9) Investigation of solvents: toluene, quant; n-octane, quant; 1,4-
dioxane, 54%; MeCN, 0%; DMF, 0%; neat 90%.
(10) In the Bi(OTf)3-catalyzed reaction, the catalytic role of the
bismuth ion vs activity of TfOH formed by hydrolysis from residual
water is still under debate. See: (a) Lambert, R. F.; Hinkle, R. J.;
Ammann, S. E.; Lian, Y.; Liu, J.; Lewis, S. E.; Pike, R. D. J. Org. Chem.
2011, 76, 9269−9277. (b) Godeau, J.; Olivero, S.; Antoniotti, S.;
*E-mail: masahito.murai@cc.okayama-u.ac.jp.
*E-mail: ktakai@cc.okayama-u.ac.jp.
Notes
The authors declare no competing financial interest.
́
Dunach, E. Org. Lett. 2011, 13, 3320−3323. (c) Ollevier, T.; Nadeau,
E. Org. Biomol. Chem. 2007, 5, 3126−3134. When 5 mol% and 15 mol
% of TfOH was used, 3a was obtained in 66% and 68% yield,
respectively, indicating a difference in behavior between TfOH and
Bi(OTf)3 for this transformation.
(11) Cross-coupling reactions involving the cleavage of C(aryl)−OH
bonds in the presence of a nickel catalyst have been reported. See:
(a) Yu, D.-G.; Li, B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi, Z.-
J. Angew. Chem., Int. Ed. 2010, 49, 4566−4570. (b) Yu, D.-G.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2011, 50, 7097−7100.
(12) For reviews on cross-coupling reactions via C−O bond cleavage,
see: (a) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.;
Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2010, 111, 1346−
1416. (b) Yu, D.-G.; Li, B.-J.; Shi, Z.-J. Acc. Chem. Res. 2010, 43,
1486−1495. (c) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem.Eur.
J. 2011, 17, 1728−1759. (d) Tobisu, M.; Chatani, N. Top. Organomet.
Chem. 2013, 44, 35−54.
(13) Theoretical percentage of deuterium incorporation would be
75%, when 3 equiv of D2O was employed because one equiv of H2O
should be eliminated upon substitution of the hydroxy group of 1a
with D2O.
ACKNOWLEDGMENTS
■
This work was financially supported by a Grant-in-Aid (No.
26248030) from MEXT, Japan, and MEXT program for
promoting the enhancement of research universities. The
authors gratefully thank Mr. Ryo Okada and Masahiro
Nakamura (Okayama University) for HRMS measurements.
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