Lanthanide(III) triflate-catalyzed thermal- and microwave-assisted synthesis of benzyl ethers from benzyl alcohols

Article abstract of DOI:10.1055/s-2004-836063

The lanthanide(III) trifluoromethanesulfonate-catalyzed condensation of benzyl alcohols with primary and secondary alcohols is described. This reaction proceeds readily with benzyl alcohols that have an alkyl or aryl substituent at the α-, ortho-, or para-position using microwave radiation or heating. The intra-molecular variant of this reaction leads to cyclic benzofurans.

Full text of DOI:10.1055/s-2004-836063

LETTER
111
Lanthanide(III) Triflate-Catalyzed Thermal- and Microwave-Assisted
Synthesis of Benzyl Ethers from Benzyl Alcohols
L
anthanide(III) Tr
n
iflate-Catalyz
t
edSyn
h
thesisof Be
o
Department of Medicinal Chemistry, GlaxoSmithKline, PO Box 13398, Research Triangle Park, NC 27709-3398, USA
Fax +1(919)3150430; E-mail: tony.l.handlon@gsk.com
Received 2 September 2004
Table 1 Effect of Catalyst
Abstract: The lanthanide(III) trifluoromethanesulfonate-catalyzed
condensation of benzyl alcohols with primary and secondary
alcohols is described. This reaction proceeds readily with benzyl
alcohols that have an alkyl or aryl substituent at the a-, ortho-, or
para-position using microwave radiation or heating. The intra-
molecular variant of this reaction leads to cyclic benzofurans.
Key words: condensation, ethers, lanthanides, Lewis acids, micro-
wave
Entry
Catalyst
Yield of Product 3 Yield of Product 4
(%)a
(%)b
The allyl group has proved to be one of the most valuable
protecting groups due to its high stability under a range of
1
2
3
4
5
6
Gd(OTf)3
Ce(OTf)3·H2O
Er(OTf)3
62
6
0
6
0
0
7
1
conditions and its ease of deprotection with PdCl2 or
87
2
SmI2 under neutral or near-neutral conditions. Unfortu-
89
nately, the allyl group is often installed under strongly
basic conditions (allyl bromide with sodium hydride or
sodium carbonate) that may limit the range of substrates
that can be used. We wished to avoid strongly basic con-
ditions and turned our attention to other methods for allyl-
ation. Several researchers have demonstrated that
lanthanide(III) triflates3 catalyze the condensation of
benzyl alcohols with aliphatic alcohols,4 but the reported
methods have been limited to strongly activated benzyl
alcohols such as 4-hydroxy- and 4-methoxybenzyl
alcohol4a,b or diphenylmethanol.4c We set out to expand
the scope of the lanthanide(III) triflate-catalyzed allyl-
ation and etherification of benzyl alcohols by taking
advantage of commonly available microwave and heat
block reactors.
Yb(OTf)3
Sc(OTf)3
94
91
Y(OTf)3
84
a Yields were determined by HPLC analysis using authentic samples
for reference.
b The remainder is unreacted starting material or trace side products.
with simple heating the reaction required seven hours for
completion. The 2-methyl and 4-methyl benzyl alcohols
(entries 3 and 5) gave the corresponding allyl ether in ex-
cellent yield. In contrast, 3-methylbenzyl alcohol (entry 4)
gave back only starting material. Likewise, unsubstituted
benzyl alcohol (entry 1) and 3-hydroxybenzyl alcohol
(entry 2) failed to yield the desired product. With benzyl
or isopropyl at the 4-position (entries 6 and 9) the product
readily formed. In the case of the 3-hydroxy-4-benzyl-
substituted derivative (entry 7) formation of insoluble ma-
terial was observed that may indicate polymerization and
may be responsible for the lowered yield. The 2- and 4-
phenyl substituted benzyl alcohols (entries 10, 11) gave
the appropriate product in excellent yields. Furthermore,
a-substituted benzyl alcohols (entries 12–14) gave prod-
uct in good to excellent yields. These data suggest that
either an alkyl group at the a-position or an alkyl/aryl sub-
stituent at the ortho- or para-position is required for the
allylation reaction to proceed. The observed structure–
reactivity relationships are consistent with a reaction
mechanism involving the generation of a benzyl cation
intermediate in which the positive charge is delocalized
into the phenyl ring and stabilized by the substituents.
Initially, we explored a series lanthanide(III) triflates for
their ability to serve as catalysts for the thermal etherifica-
tion of 1 (Table 1). Gadolinium triflate was the least effec-
tive catalyst leaving a substantial amount of unreacted
starting material. Cerium triflate gave the desired propyl
ether 3 cleanly and in good yield. Scandium and ytterbium
triflate gave the highest yields of 3. In the cases of
Y(OTf)3, Er(OTf)3 and Gd(OTf)3 small amounts of self-
coupled product 4 were detected.
Next, we wished to explore the structure–reactivity rela-
tionships of several benzyl alcohols in the Yb(OTf)3-cat-
alyzed allylation reaction under thermal and microwave
conditions (Table 2). In the microwave reactor the allyl-
ation reaction was complete in two hours or less, whereas
SYNLETT 2005, No. 1, pp 0111–0114
0
5.
0
1.
2
0
0
5
Advanced online publication: 07.12.2004
DOI: 10.1055/s-2004-836063; Art ID: S08204ST
© Georg Thieme Verlag Stuttgart · New York

112
A. L. Handlon, Y. Guo
LETTER
Table 2 Allylation of Substituted Benzyl Alcohols
Next, we investigated the generality of the etherification
reaction with regards to various alcohols under thermal
and microwave conditions (Table 3). Primary alcohols
(entries 1–7) and secondary alcohols (entries 8–11) gave
the expected ether products in good to excellent yields.
With tertiary butyl alcohol as the acceptor, 4-methyl-
benzyl alcohol gave the self-coupled product 4. We ob-
served that the reaction mixture became biphasic and
released hydrocarbon gas, which is consistent with de-
composition of t-butanol to isobutylene and water, al-
though these products were not characterized further. For
both the thermal- and microwave-mediated reactions the
rate of ether formation was fastest with propargyl and
allyl alcohol and substantially slower with the other pri-
mary and secondary alcohols. In the case of aromatic
alcohol 9, the Friedel–Crafts product 10 was isolated in
93% yield as a mixture of regioisomers (Equation 1). The
lanthanide(III) triflate-catalyzed Friedel–Crafts alkylation
of benzyl alcohols with aromatics has been reported
previously.5
Yield of Product 6 (%)
Thermala Microwaveb
NRc
NR
Entry
1
Benzyl alcohol 5
2
NR
NR
3
4
91
97d
NR
NR
Table 3 Etherification of 4-Methylbenzyl Alcohol
5
6
94
84
94
86
Yield of Product 8 (%)
7
8
51
93
68
88
Entry
ROH, 7
Thermala
Microwaveb
1
2
3
91
92
98
97c
97d
93d
9
10
11
79
91
96
79
94
93
4
5
6
7
8
72
80
90
71
88
96e
77f
89d
83g
86d
12
13
14
62
77
94
78
68e
92
9
73
81d
10
11
97
88
93d
64d
a Conditions: 140 °C, 7 h. Yields were determined by isolation of pure
product.
a Conditions: 140 °C, 20 h. Yields were determined by isolation of
pure product.
b Conditions: 150 °C, 2 h. Yields were determined by HPLC area
under the curve using authentic product as standard.
c NR: no reaction.
b Yields were determined by HPLC area under the curve using
authentic product as reference.
c Conditions: 135 °C, 2 h.
d Conditions:135 °C, 2 h.
d Conditions: 150 °C, 5 h.
e Conditions: 130 °C, 20 min.
e Conditions: 145 °C, 3 h.
f Conditions: 120 °C, 30 min.
g Conditions: 150 °C, 2 h.
Synlett 2005, No. 1, 111–114 © Thieme Stuttgart · New York

LETTER
Equation 1
Lanthanide(III) Triflate-Catalyzed Synthesis of Benzyl Ethers
113
trile for 13b) and treated with Yb(OTf)3 in a microwave
reactor for two hours. The corresponding 1,3-dihydro-
isobenzofuran products 14a and 14b were isolated in 77%
and 81% yields, respectively. To the best of our knowl-
edge, this represents the first reported example of a
lanthanide(III) triflate-catalyzed intramolecular conden-
sation of a benzyl alcohol to an isobenzofuran.
To further investigate differences in reactivity between
primary and secondary alcohols we investigated the ther-
mal etherification of various benzyl alcohols with n-pro-
pyl alcohol and isopropyl alcohol (Table 4). The 4-
methyl-, 4-benzyl- and 4-phenylbenzyl alcohols (entries
1–3) reacted equally well with the primary and secondary
alcohols giving the corresponding ethers in high yield.
The 2-methylbenzyl alcohol (entry 4) gave the expected
product with only a slight attenuation of yield for isopro-
pyl alcohol. Consistent with the previous structure–reac-
tivity observations, 3-methylbenzyl alcohol (entry 5) did
not react with either alcohol. In the case of the a-substitut-
ed benzyl alcohol (entry 6), there was a lowering of
product yield with isopropyl alcohol that may result from
the increased steric crowding in the product.
Equation 2
In conclusion, a variety of 2-substituted, 4-substituted or
a-substituted benzyl alcohols can be conveniently reacted
with primary and secondary alcohols to give benzyl ethers
in good to excellent yields. By taking advantage of micro-
wave or thermal energy inputs, the scope of the lan-
thanide(III) triflate-catalyzed etherification reaction has
been expanded beyond highly activated systems such as
4-hydroxy- and 4-methoxy-substituted benzyl alcohols
and diphenylmethanols. The product yields for the micro-
wave and thermal reactions were similar, but the micro-
wave has the advantage of significantly shorter reaction
times. We hope to further investigate microwave-assisted
ring-closure reactions in the near future.
The intramolecular version of the etherification reaction
(Equation 2) was investigated under microwave radiation
conditions. The benzhydrol derivatives 13a and 13b were
dissolved in solvent (DMF in the case of 13a and acetoni-
Table 4 Thermal Condensation of Substituted Benzyl Alcohols
with n-Propyl- and Isopropyl Alcohol
Typical Procedure for Etherification (Thermal)
To a solution of 4-methylbenzyl alcohol (61 mg, 0.5 mmol) in n-
propanol (1 mL) was added Yb(OTf)3 (31 mg, 0.05 mmol). The re-
action mixture was sealed in a pressure reaction tube and heated to
140 °C for 20 h. The solvent was removed by rotary evaporation.
The product was purified by silica gel column chromatography with
5% EtOAc–hexane as the mobile phase. 4-Methylbenzyl propyl
ether was isolated as a colorless oil (75 mg, 92% yield). 1H NMR
(300 MHz, CDCl3): d = 7.23 (d, 2 H, J = 7.9 Hz), 7.15 (d, 2 H,
J = 7.8 Hz), 4.47 (s, 2 H), 3.41 (t, 2 H, J = 6.7 Hz), 2.34 (s, 3 H),
1.61 (m, 2 H), 0.93 (t, 3 H, J = 7.3 Hz).
Yield of Product 12 (%)
Entry Benzyl alcohol 11
ROH = n-propyl ROH = isopropyl
alcohol
alcohol
1
92
88
Anal. Calcd for C11H16O: C, 80.44; H, 9.82. Found: C, 80.23; H,
9.83.
2
3
4
5
82
95
90
NR
81
87
Typical Procedure for Etherification (Microwave)
A solution of 4-methylbenzyl alcohol (61 mg, 0.5 mmol) and
Yb(OTf)3 (31 mg, 0.05 mmol) in n-propanol (1 mL) was sealed in a
microwave reaction vial and placed in a microwave reactor (Person-
al Chemistry Emrys Optimizer, 300 W maximum power) at 150 °C
for 5 h. The reaction was monitored by HPLC. 4-Methylbenzyl
propyl ether was identified as the product by referencing with an
authentic sample. The yield was determined by integrating the area
under the curve.
82
NRa
6
88
67
Acknowledgment
We wish to thank William Zuercher and Stephen Thomson for
reviewing the manuscript.
a NR: no reaction.
Synlett 2005, No. 1, 111–114 © Thieme Stuttgart · New York

114
A. L. Handlon, Y. Guo
LETTER
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Synlett 2005, No. 1, 111–114 © Thieme Stuttgart · New York