Regioselective ring-opening of epoxides with ortho-lithioanisoles catalyzed by BF3·OEt2

Article abstract of DOI:10.1016/j.tet.2012.05.116

It is presented that a number of o-2-hydroxyalkylanisoles could be efficiently synthesized through the regioselective ring-opening reaction of epoxides with o-lithioanisoles in the presence of BF₃·OEt ₂ Lewis-acid catalyst. Sterically demanding o-lithioanisoles had to be generated by exploiting the combination of ⁿBuLi and a catalytic amount of TMEDA (0.20 equiv) in Et₂O as the lithiator whereas 'normal' anisole could be lithiated at ortho-position by treatment with ⁿBuLi in THF as usual. Surprisingly, the availability of THF and a catalytic amount of TMEDA (0.20 equiv) in the reaction mixture was found to enhance the reaction yields dramatically. A complex aggregate formation by the co-operative ligation of THF and TMEDA to ortho-lithioanisole(s) was proposed to rationalize the high reactivity achieved in the ring-opening reaction of epoxides.

Full text of DOI:10.1016/j.tet.2012.05.116

Tetrahedron 68 (2012) 6463e6471
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Regioselective ring-opening of epoxides with ortho-lithioanisoles catalyzed
by BF3$OEt2
a
,
a
,
,
Erkan Erturk , Mustafa A. Tezeren b, Taner Atalar a, Tahir Tilki b
*
*
€
a Chemistry Institute, TUBITAK Marmara Research Center, 41470 Gebze, Kocaeli, Turkey
Department of Chemistry, Suleyman Demirel University, 32260 Isparta, Turkey
b
€
a r t i c l e i n f o
a b s t r a c t
Article history:
It is presented that a number of o-2-hydroxyalkylanisoles could be efficiently synthesized through the
regioselective ring-opening reaction of epoxides with o-lithioanisoles in the presence of BF3$OEt2 Lewis-
acid catalyst. Sterically demanding o-lithioanisoles had to be generated by exploiting the combination of
nBuLi and a catalytic amount of TMEDA (0.20 equiv) in Et2O as the lithiator whereas ‘normal’ anisole
could be lithiated at ortho-position by treatment with nBuLi in THF as usual. Surprisingly, the availability
of THF and a catalytic amount of TMEDA (0.20 equiv) in the reaction mixture was found to enhance the
reaction yields dramatically. A complex aggregate formation by the co-operative ligation of THF and
TMEDA to ortho-lithioanisole(s) was proposed to rationalize the high reactivity achieved in the ring-
opening reaction of epoxides.
Received 22 February 2012
Received in revised form 9 May 2012
Accepted 28 May 2012
Available online 2 June 2012
Dedicated to Professor Ender Erdik
Keywords:
Ortho-lithiation
DoM
Ó 2012 Elsevier Ltd. All rights reserved.
Catalytic TMEDA
Epoxide opening
BF3$OEt2
1. Introduction
nucleophiles or bases depending on their nature, the structure of
epoxide ring as well as experimental conditions.16 In 1984, Ganem
Epoxides are among the most versatile intermediates in organic
synthesis because they can be subjected to diverse stereoselective
transformations for the synthesis of higly valuable products.1 For
example, the regio- and stereoselective ring-opening reaction of
epoxides with carbon based nucleophiles is a well suited technique
for the generation of new carbonecarbon bonds in a very simple
and stereodefined manner.2 Consequently, a number of catalytic
methods for the ring-opening of epoxides with carbon nucleophiles
ranging from cyanide3,4 to organometallic compounds, such as
Grignard reagents,5 organocuprates,6 organolithiums7 as well as
organoaluminums8 have been developed in recent years.9,10 Addi-
tionally, FriedeleCrafts type alkylation of electron-rich aromatic
compounds with epoxides by using SnCl4 as a Lewis-acid catalyst,11
ring-opening of epoxides with indoles in 2,2,2-tifluoroethanol and
in the presence of certain Lewis-acids12 as well as ring-opening of
epoxides with boron esters of electron-rich phenols as carbon nu-
cleophiles13 were also reported as CeC bond forming reactions.14
Organolithium compounds are one of the most useful nucleo-
philes in organic synthesis regarding their easy availability as well
as their well established reactivity.15 Organolithiums can act as
and co-workers showed that the epoxide ring can be efficiently
opened with simple organolithiums bearing no functional group by
using BF3$OEt2 as the Lewis-acid catalyst (Scheme 1).7a Only one
((ꢀ)-3) of the possible regioisomers was obtained in high yields as
.
R2
R2
R2
BF3 OEt2
R1Li
+
+
HO
R1
O
THF
R1
( )-4
OH
( )-3
-78 oC, 5 min
1 (3 eq)
( )-2
(1 eq)
R1= Ph,
up to 99% y not formed
n
Bu,
vinyl
Scheme 1. BF3$OEt2 catalyzed epoxide opening with organolithium compounds.7a
the sole product formed through the fully regioselective attack of
organolithium to the less substituted carbon atom of the epoxide
ring. Inspired by the contribution from Ganem and co-workers and
considering the easy preparation of o-metalated anisoles as well,
we reasoned that ortho-lithioanisoles could be suitable nucleo-
philes for the regioselective ring-opening of epoxides. Herein, we
are presenting that a variety of epoxides can be regioselectively
opened with a number of o-lithioanisole nucleophiles in the pres-
ence of BF3$OEt2 catalyst.
* Corresponding authors. Tel.: þ90 262 677 2993; fax: þ90 262 641 2309; e-mail
€
address: erkan.erturk@mam.gov.tr (E. Erturk).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.116

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E. Erturk et al. / Tetrahedron 68 (2012) 6463e6471
6464
2. Results and discussion
reasoned that the TMEDA-free aryllithium compound is necessary
for the high yielding ring-opening reaction of epoxide. Additionally,
Slocum and co-workers had shown that lithiation of anisole (5a)
with nBuLi in the presence of catalytic TMEDA (20 mol %) in Et2O at
prolonged reaction times proceeds as efficiently as in the presence
of equimolar amount of TMEDA.20 Thus, we considered that the
generation of o-lithioanisole (6a) by lithiation with nBuLi and cat-
alytic TMEDA20 in Et2O and its subsequent treatment with rac-7 in
the presence of BF3$OEt2 could be a suitable procedure for the ring-
opening of the epoxide rac-7. This approach was then proven to be
successful so that the ring-opened products rac-8a and rac-9a were
obtained in 42% overall yield by employing nBuLi and catalytic
TMEDA as the lithiator (entry 6). Despite the fact that simple ani-
soles can be lithiated at ortho-position with nBuLi in THF without
the extra necessity for TMEDA, we prepared o-lithioanisole by
lithiating anisole with the equimolar amount of nBuLi and catalytic
TMEDA (20 mol % compared to anisole) in THF and the resulting o-
lithioanisole was subjected to the BF3$OEt2 catalyzed ring-opening
of styrene oxide. Delightfully, the ring-opening reaction took place
in almost quantitative yield (97% total yield, rac-8a/rac-9a¼85:15,
entry 7). Decrease in the amount of o-lithioanisole (6a, from 3.00 to
2.50 equiv) and TMEDA (from 0.60 to 0.30 equiv compared to ani-
sole) resulted in lower yield (entries 7, 8, and 1).
Next, we turned our attention to studying the ring-opening of
racemic styrene oxide (rac-7) with the sterically more demanding
o-lithioanisoles 6b and 6c (Table 2). When lithiation of 2,4-di-tert-
butylanisole (5b) was tried out at different temperatures in THF and
subsequent addition of rac-7 in the presence of BF3$OEt2 was per-
formed as described, almost no conversion of rac-7 observed, even
at prolonged lithiation times up to 16 h (Table 2, entries 1e3). This
might be due to the fact that the deprotonation of THF with nBuLi is
kinetically more favorable than the sterically hindered anisole 5b.21
On the other hand, the ring-opening products rac-8b and rac-9b
were obtained in 52% total yield by employing Et2O as the solvent
The chemo- and regioselective metalation of aromatic substrates
and treatment of the intermediate organometallics with electro-
philes is a powerful methodology for introducing new functional-
ities to an aromatic ring.17 In particular, the directed ortho-lithiation
of aromatic compounds bearing a directing metalation group (DMG)
is a widely used synthetic approach in this sense.18,19
Our approach toward the ring-opening of epoxides with o-
lithioanisoles was simply designed as a one-pot two-step pro-
cedure: in the first step, an anisole could be lithiated at the ortho-
position as usual and in the second step, the generated o-lith-
ioanisole would be allowed to react with an epoxide in the presence
of BF3$OEt2 at ꢁ78 ꢂC for 1 h. Racemic styrene oxide (rac-7) was
first subjected to the ring-opening with o-lithioanisole (6a) (Table
1). When o-lithioanisole (6a) that was generated by employing
equimolar amounts of anisole (5a) and nBuLi in THF was treated
with rac-7 in the presence of BF3$OEt2 at ꢁ78 ꢂC for 1 h the ring-
opened products rac-8a and rac-9a were obtained in good yield
(75%) with good regioselectivity (rac-8a/rac-9a¼88:12, entry 1).
This result was evaluated unsatisfactory in terms of the reaction
yield and regioselectivity by us, in view of the results on the ring-
opening of rac-7 with phenyllithium in the presence of BF3$OEt2
that were achieved by Ganem and co-workers (84% yield, >99%
regioselectivity, Scheme 1).7a On the other hand, o-lithiation by
n
using equimolar amounts of BuLi and TMEDA (N,N,N0,N0-tetrame-
thylethylenediamine) in THF and treating the resulting o-lith-
ioanisole (6a) with rac-7 in the presence of BF3$OEt2 did not lead to
formation of the desired products (entry 2). Employment of equi-
molar amounts of nBuLi and TMEDA as the lithiation mediator in
Et2O instead of THF did not afford the desired products rac-8a and
rac-9a, even in the presence of up-to 6.00 equiv of BF3$OEt2 (entries
3e5). At this point, we concluded that TMEDA inhibits the nucle-
ophilicity of o-lithioanisole(s) toward epoxide ring and adequately
Table 1
a
Ring-opening of racemic styrene oxide (rac-7) with o-lithioanisole (6a) in the presence of BF3$OEt2
Ph
(rac-7)
BF3 OEt2
n
O
BuLi
OMe
OMe
OMe Ph
OMe
.
TMEDA
Ph
Li
+
Solvent, N2
T (oC)
Solvent, N2
OH
OH
T (oC)
t11 (h)
t2 (h)
2
5a
6a
( )-8a
( )-9a
Entry
5a and
nBuLi
(equiv)
TMEDA
(equiv)
Solvent
T1 (ꢂC)
t1 (h)
BF3$OEt2
(equiv)
T2 (ꢂC)
t2 (h)
Yieldb
(%)
Regioisomeric ratio
((ꢀ)-8a/(ꢀ)-9a)c
1
2
3
4
5
6
7
8
3.00
3.00
3.00
3.00
3.00
3.00
3.00
2.50
d
THF
THF
Et2O
Et2O
Et2O
Et2O
THF
THF
0/rt
3
0/rt
3
0/rt
3
0/rt
3
0/rt
3
0/rt
3
0/rt
3
0/rt
3
2.50
2.50
2.50
4.50
6.00
2.50
2.50
2.50
ꢁ78
1
75
88:12
3.00
3.00
3.00
3.00
0.60
0.60
0.30
ꢁ78
dd
dd
dd
<10
42
1
ꢁ78
1
ꢁ78
1
ꢁ78
1
n.d.
ꢁ78
87:13
85:15
86:14
1
ꢁ78
1
97
ꢁ78
85
1
a
The reactions were carried out by employing 1.0 mmol (1.00 equiv) rac-7 and 8 mL of solvent.
Isolated yields.
b
c
Determined by the integration of the 1H NMR spectra of the crude product.
No conversion of rac-7 was observed.
d

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6465
Table 2
a
Ring-opening of racemic styrene oxide (rac-7) with the sterically demanding o-lithioanisole 6bec in the presence of BF3$OEt2
Ph
(rac-7)
BF3 OEt2
n
O
BuLi
OMe
OMe
OMe Ph
OMe
.
R3
R3
Ph
R3
R3
Li
TMEDA
+
Solvent, N2
T (oC)
Co-solvent, N2
OH
OH
T (oC)
t11 (h)
t2 (h)
2
R4
5b-c
R4
R4
R4
6b-c
( )-8b-c
( )-9b-c
t
b: R3 = R4 = Bu; c: R3 = Ph, R4 = H
Entry Anisole nBuLi (equiv) TMEDA (equiv) Solvent (Co-solvent) T1 (ꢂC) t1 (h) BF3$OEt2 (equiv) T2 (ꢂC) t2 (h) Yieldb (%) Regioisomeric ratio ((ꢀ)-8bec/(ꢀ)-9bec)c
1
2
3
4
5
6
7
8
9
5b
3.00
0.60
THF
(d)
0/rt
3/16
2.50
2.50
2.50
2.50
2.50
3.30
4.20
4.20
4.20
4.20
ꢁ78
dd
dd
dd
52
d
1
5b
3.00
d
THF
(d)
0/rt
3/16
ꢁ78
d
1
5b
3.00
0.60
0.60
0.60
0.80
1.00
1.00
1.00
1.00
THF
(d)
ꢁ78/0
ꢁ78
d
5
1
5b
3.00
Et2O
(d)
0/rt
16
ꢁ78
91 : 9
90:10
86:14
86:14
83:17
86:14
n.d.
1
5b
3.00
c-Hexane
(THF)
0/rt
16
ꢁ78
<10
58
1
5b
4.00
Et2O
(THF)
0/rt
16
ꢁ78
1
5b
5.00
Et2O
(THF)
0/rt
16
ꢁ78
77
1
5c
5.00
Et2O
(d)
0/rt
16
ꢁ78
46
1
5c
5.00
Et2O
(THF)
0/rt
16
ꢁ78
79
1
10
5c
5.00
THF
(d)
0/rt
16
ꢁ78
<10
1
a
The reactions were carried out by employing 1.0 mmol (1.00 equiv) rac-7 and 8 mL of solvent and 2 mL of co-solvent.
Isolated yields.
b
c
Determined by the integration of the 1H NMR spectra of the crude product.
No conversion of rac-7 was observed.
d
instead of THF and in the presence of catalytic TMEDA (rac-8b/rac-
cyclopentene oxide (12) gave the corresponding o-2-hydrox-
yalkylanisoles rac-11 and rac-13 nearly in quantitative yields, re-
spectively (entries 1 and 2). It should be noted that the ring-openingof
cyclohexene oxide (10) and cyclopentene oxide (12) with o-lith-
ioanisole (6a) that was generated by lithiation of anisole (5a) with
nBuLi and stoichiometric amount of TMEDA in Et2O proceeded in high
yields as well. The high reactivity of the bicyclic symmetrical epoxides
10 and 12 in the ring-opening with o-lithioanisole can be attributed to
their high ring-strain. Vrancken and co-workers reported similar be-
havior of bicyclic symmetrical epoxides toward organolithium com-
pounds in which the presence of the stoichiometric amounts of
TMEDA or (ꢁ)-sparteine with regard to organolithiums did not
hamper the BF3$OEt2 catalyzed ring-opening of cyclohexene oxide
(10) and cyclopentene oxide (12).10d 1,2-Epoxyoctane (rac-14), meth-
ylenecyclohexane oxide (16), and epichlorohydrin (rac-18) could be
opened in moderate to good yields with o-lithioanisole (6a) under the
standard reaction conditions, by employing the combination of cata-
lytic TMEDA (0.60 equiv)/nBuLi (3.00 equiv)/anisole (3.00 equiv)/
BF3$OEt2 (2.50 equiv) in THF and by stirring at ꢁ78 ꢂC for 1 h (entries
3e5). Careful analysis of the crude reaction mixtures by 1H NMR
spectroscopy as well as GCeMS revealed no formation of the other
possible regioisomers from the ring-opening of the terminal epoxides
rac-14, 16 and rac-18 with o-lithioanisole. It should be further noted
that no conversion of the terminal epoxides rac-14,16 and rac-18 was
observed when we used the stoichiometric amount of TMEDA in Et2O
9b¼91:9, entry 4). Using c-hexane as the solvent led to the for-
mation of the regioisomers rac-8b and rac-9b in lower yield (<%10,
entry 5). By adding THF as the ‘co-solvent’ to the reaction mixture in
Et2O, the yield could be dramatically increased and the desired
regioisomers rac-8b and rac-9b could be isolated in 77% yield
starting from 5.00 equiv of 2,4-di-tert-butylanisole (rac-8b/
rac-9b¼86:14, entry 7). The suitability of our method was also
examined for the regioselective ring-opening of rac-7 with 6-
phenyl-2-lithioanisole (6c) as another sterically demanding
o-lithioanisole compound that was formed from 2-phenylanisole
(5c) through lithiation with nBuLi and catalytic TMEDA in Et2O
and the o-2-hydroxyalkylanisoles rac-8c and rac-9c could be
obtained in high yields via incorporation of THF as the co-solvent
(entries
8 and 9). It is noteworthy that lithiation of 2-
phenylanisole (5c) with nBuLi in THF at different temperatures in
the presence or in the absence of catalytic TMEDA and subsequent
addition of rac-7 and BF3$OEt2 to the reaction mixture at ꢁ78 ꢂC did
not result in conversion of rac-7 (entry 10). The preferential re-
action of nBuLi as a base with THF instead of 2-phenylanisole (5c)
can account for this unsuccessful attempt, as in the case of 2,4-di-
tert-butylanisole (5b, entries 1e3).
To find out the substrate scope of the ring-opening procedure of
epoxides with o-lithioanisole (6a) further, we employed a number of
representative epoxides (Table 3). Cyclohexene oxide (10) and

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E. Erturk et al. / Tetrahedron 68 (2012) 6463e6471
6466
Table 3
20 (entry 6). Therefore, the epoxide 20 was then allowed to react with
o-lithioanisole between ꢁ78 ꢂC and 0 ꢂC. However, we isolated
the o-2-hydroxyalkylanisolerac-21 asthesolereactionproduct, which
can form via BF3$OEt2 catalyzed rearrangement of 20 to
2,2-diphenylacetaldehyde (hydride-migration, wH) and the sub-
sequent addition of o-lithioanisole (6a) to 2,2-diphenylacetaldehyde
instead of the expected nucleophilic addition of o-lithioanisole (6a)
to 2,2-diphenyloxirane (entry 7). Also trans-stilbene oxide (rac-22)
was found to be sluggish in the BF3$OEt2 catalyzed nucleophilic ad-
dition of o-lithioanisole (6a) at ꢁ78 ꢂC (entry 8). By allowing to react
trans-stilbene oxide (rac-22) with o-lithioanisole (6a) in the presence
Ring-opening of epoxides with o-lithioanisole (6a) in the presence of BF3$OEt2 as the
Lewis-acid catalysta
n
BuLi
Epoxide
OMe
OMe
.
TMEDA
BF3 OEt2
Li
Product
THF, N2
THF, N2
-78 oC
1 h
0 oC
rt
3 h
6a
5a
Entry
Epoxide
Product
Yieldb (%)
of BF3$OEt2 at elevated temperature up to
0
ꢂC, the o-2-
OMe
hydroxyalkylanisole rac-21 was obtained as the sole product
through BF3$OEt2 catalyzed epoxide rearrangement (phenyl-migra-
tion, wPh) and the subsequent addition of o-lithioanisole (6a) to the
corresponding carbonyl compound, 2,2,-diphenylacetaldehyde (entry
1
2
3
4
5
99
O
OH
OH
10
( )-11
OMe
9). 1-Phenyl-1,2-epoxycyclohexane and trans-b-methylstyrene oxide
as unsymmetrical epoxides could not give any ring-opened products
with o-lithioanisole (6a) at ꢁ78 ꢂC. We additionally attempted the
ring-opening reaction of trans-stilbene oxide (rac-22) with phenyl-
lithium (PhLi) instead of o-lithioanisole (6a) in the presence of
BF3$OEt2 at ꢁ78 ꢂC for 1 h, but no conversion of trans-stilbene oxide
was detected by GCeMS. Based on all these observations, it can be
concluded that the ring-opening reactivity of epoxides with aryl-
lithiums catalyzed by BF3$OEt2 is significantly affected by the sub-
stitution patterns around epoxide ring.
The BF3$OEt2 catalyzed stereospecific ring-opening of epoxides
with o-lithioanisoles was tested by reacting enantiomerically pure
(R)-(þ)-styrene oxide (7, >99% ee) with o-lithioanisole (6b) that was
generated by lithiation of anisole (5a) as described above (Scheme 2).
We are pleased to report that the corresponding o-2-
hydroxyalkylanisoles 8a and 9a were obtained in enantiopure form
with high yields and under high regioselectivity. The absolute con-
figuration of 8a ((R)-(ꢁ)-2-methoxyphenyl-1-phenylethanol) was
determined by comparison of its sign of optical rotation with ent-8a,
a known compound in the literature (see, Experimental section).
Given the ready availability of enantiopure epoxides from racemic
epoxides by the hydrolytic kinetic resolution,22 this technique could
be rather useful for the synthesis of enantiopure o-2-
hydroxyalkylanisoles. This result also indicates that the BF3$OEt2
catalyzed ring-opening of epoxides with o-lithioanisoles is an SN2-
type process.
99
77
75
53
O
12
( )-13
OMe
n
n
C6H13
C6H13
O
( )-14
OH
( )-15
OMe
O
OH
OH
16
17
OMe
Cl
Cl
O
( )-18
( )-19
Ph
Ph
6
d
dc
O
20
OMe
OMe Ph
OMe
.
BF3 OEt2
Li
OMe OH
Ph
Ph
+
+
O
Ph
THF, N2
-78 oC
1 h
OH
7d
20
45
OH
7
8a
9a
Ph
( )-21
6a
>99% ee
79%, >99% ee
18%, >99% ee
Scheme 2. BF3$OEt2 catalyzed stereospecific ring-opening of (R)-(þ)-styrene oxide (7)
with o-lithioanisole (6a).
Ph
8
d
dc
Ph
( )-22
Aggregation properties of any organolithium compound mark-
edly vary in its solid-state, in solution, and in the gas phase.18d,23
Additionally, the degree of aggregation as well as the distribution
of aggregates in solution are strongly dependent on temperature,
concentration as well as the presence of donor ligands. On the other
hand, aggregationproperties of organolithiums havedecisive effects
on the reaction yields and selectivities. However, it is often not easy
to find out the reactivity of any organolithium compound because
hetero-aggregates, besides homo-aggregates, can arise during the
course of a reaction and this can add another complexity to ratio-
nalize a reaction mechanism.23i,24 As for our catalytic system, the
effect of lithiation yield of anisole on the conversion of styrene oxide
(rac-7) can be ruled out since all the ortho-directed lithiation pro-
cedures employed are well established and recognized techniques
O
9d
(ꢀ)-22
(ꢀ)-21
35
a
The reactions were carried out by employing 3.00 mmol of anisole (5a),
3.00 mmol of nBuLi, 0.60 mmol of TMEDA, 1.0 mmol of epoxide, and 2.50 mmol of
BF3$OEt2 in 8 mL THF.
b
Isolated yields.
c
No conversion of epoxide was observed.
Epoxide was treated with o-lithioanisole (6a) at ꢁ78 ꢂC in the presence of
d
BF3$OEt2 and the reaction temperature was allowed to reach to 0 ꢂC.
instead of catalytic TMEDA in THF. However, treatment of 2,2-
diphenyloxirane (20) with o-lithioanisole (6b) at ꢁ78 ꢂC for 1 h
or for prolonged reaction times in the presence of BF3$OEt2 in
THF neither gave any expected product nor conversion of the epoxide

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E. Erturk et al. / Tetrahedron 68 (2012) 6463e6471
6467
O
N
O
N
N
O
THF
O
N
O
O
THF
O
N
N
O
Li Li
N
O
Li Li
Li Li
Li Li
Li Li
N
THF
O
THF
n
I
III
II
Fig. 1. Proposed aggregation types of o-lithioanisole (6a) in solution depending on the reaction conditions.
and should principally give similar lithiation yields. It was reported
by Boersma and co-workers that o-lithioanisole (ArLi, 6a) with
1.00 equiv TMEDA in Et2O solution forms a [(ArLi)2$(TMEDA)] type
polymeric aggregate structure (I, Fig. 1).25,23c This type highly or-
dered polymeric aggregate structure can account for the inefficiency
of o-lithioanisole in the ring-opening of rac-7 (Table 1, entry 3). On
the other hand, o-lithioanisole with 0.20 equiv TMEDA in Et2O so-
lution can form diverse aggregates, however, we are expecting for-
mation of (ArLi)4 type tetrameric aggregate besides the polymeric
aggregate I. Thus, the ring-opening of rac-7 could take place in
mediocre yield (42%, Table 1, entry 6). Based on NMR studies in so-
lution, Boersma and co-workers also suggested that o-lithioanisole
in pure THF is arranged as [(ArLi)2$(THF)2] type dimeric aggregate
(II, Fig.1).25 So, the higher reactivity of the dimeric aggregate II in the
ring-opening of rac-7 can be attributed to the formation lower ag-
gregate structure (Table 1, entry 1).18d It was really curious that no
ring-opening took place when o-lithioanisole was formed by
employing equimolar amounts of nBuLi and TMEDA in THF, even in
the presence of excessive BF3$OEt2, up to 6.00 equiv (Table 1, entry
2). It has been often observed that THF is the stronger donor ligand
than TMEDA when organolithium compounds come into consid-
eration.18d In o-lithioanisole case, however, TMEDA seems to be
competitive with THF and o-lithioanisole should predominantly
have the polymeric aggregate structure I. Furthermore, the highest
reactivity of o-lithioanisole in the ring-opening of rac-7 that was
achieved in the presence of catalytic TMEDA (0.20 equiv) in THF
(Table 1, entry 7) might be explained by the formation of the com-
plex tetrameric aggregate III in which two dimeric o-lithioanisole-
subunits are bridged by the competitive coordination of one TMEDA
molecule and one THF molecule is coordinated to each of dimeric
subunits, [(ArLi)4$(TMEDA)$(THF)2] (Fig. 1). Because the complex
aggregate III is co-operatively coordinated by TMEDA and THF, it
should be less stable and more reactive than the homo dimeric ag-
gregate II. Thus, this finding suggests one of the rare examples on the
competitive ligation of organolithium compounds by TMEDA
against THF and related reactivity enhancement thereof.18d,23a,26
Additionally, Mulliken population analysis at PM3 level of theory
for the aggregate II and III was performed. Based on the computed
Mulliken population analysis inwhich the structure of the aggregate
III was simplified (see, Supplementary data), the charge distribution
of the aggregate II is more uniform than that of the aggregate III. By
comparing the computed Mulliken atomic charges of Li and Cipso, the
ionic character of CeLi bond in the aggregate III was found to be
lower than that of the aggregate II. The lower ionic character of
LieCipso bond in the aggregate III can account for reduced stability.
These computational results also support observed higher reactivity
of the aggregate III than that of the aggregate II in the ring-opening
of epoxides.
BF3$OEt2 as the Lewis-acid catalyst. Two one-pot protocols for the
preparation of o-2-hydroxyalkylanisoles in high yields and regio-
selectivities were described: (i) Generation of simple o-lithioanisole
(6a) by ortho-directed lithiation of anisole (5a) with nBuLi and cat-
alytic TMEDA (0.20 equiv compared to nBuLi) in THF and subsequent
treatment of the resulting o-lithioanisole (6a) with an epoxide at
ꢁ78 ꢂC in the presence of BF3$OEt2 Lewis-acid catalyst; (ii) lithiation
of the sterically demanding anisoles such as 5b and 5c with nBuLi
and catalytic TMEDA (0.20 equiv compared to nBuLi) in Et2O and
subsequent treatment of the resulting o-lithioanisole 6b and 6c with
an epoxide at ꢁ78 ꢂC in the presence of BF3$OEt2 Lewis-acid catalyst
and THF as a co-ligand. Thus, the lithiation technique, which was
originally developed by Slocum and co-workers20 and includes the
use of nBuLi and catalytic TMEDA (20 mol % of nBuLi) in Et2O, was
properly exploited for the ortho-lithiation of the sterically de-
manding anisoles 5b and 5c. The presence of THF and the catalytic
TMEDA (0.20 equiv compared to nBuLi) was definitely found to be
beneficial in terms of the reaction yields. The synergistic combina-
tion of THF and catalytic TMEDA for achieving high yields could be
attributed to the formation of the complex aggregate III that rep-
resents one of the rare examples of the competitive coordination of
TMEDA to organolithium compounds in the presence of THF. Con-
sidering that o-2-hydroxyalkylanisoles are the protected forms of
the parent o-2-hydroxyalkylphenols,27 epoxide ring-opening pro-
tocol described herein can serve as an efficient method for the
synthesis of o-2-hydroxyalkylphenols.
4. Experimental section
4.1. General remarks
All reactions were carried out under an inert atmosphere of dry
nitrogen (N2) using oven-dried glassware. All reagents and solvents
were transferred using gas-tight syringe and cannula techniques
under N2. Tetrahydrofuran (THF), diethyl ether (Et2O), and c-hexane
was freshly distilled under N2 from sodium/benzophenone imme-
diately prior to use. TMEDA was distilled under N2 from calcium
hydride (CaH2). nBuLi (1.6 M solution in hexane), BF3$OEt2 as well
as the epoxides rac-7, 7, 10, 12, rac-14, rac-18, 20, rac-22 were
purchased from commercial suppliers and used as received.
Methylenecyclohexane oxide (16) was prepared by the Cor-
eyeChaykovsky epoxidation of cyclohexanone with trime-
thylsulfoxonium iodide. Anisole (5a) was provided by commercial
suppliers. 2,4-Di-tert-butylanisole (5b) and 2-phenylanisole (5c)
were prepared by methylation of the corresponding phenols with
dimethyl sulfate (Me2SO4) in the presence of potassium carbonate
(K2CO3) as the base in acetone. Thin layer chromatography (TLC)
was conducted on aluminum sheets that were pre-coated with
silica gel SIL G/UV254 from MN GmbH & Co., in which the spots were
3. Conclusion
visualized in UV-light (
l
¼254 nm) and/or by staining with phos-
phomolybdic acid. Chromatographic separations were performed
using silica gel (MN-silica gel 60, 230e400 mesh). All melting
points were determined in open glass capillary tube by means of
In conclusion, we have investigated the regioselective ring-
opening of epoxides with ortho-lithioanisoles in the presence of

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E. Erturk et al. / Tetrahedron 68 (2012) 6463e6471
6468
€
a BUCHI Melting Point B-540 apparatus. Infrared (FT-IR) spectra
were recorded on a PerkinElmer Spectrum One FT-IR spectrometer,
nmax in cmꢁ1. Bands are characterized as broad (br), strong (s),
medium (m), and weak (w). 1H and 13C NMR spectra were recorded
found 251.1045. rac-9a: Rf¼0.08 (silica gel; hexanes/EtOAc, 9:1); FT-
IR (KBr): nmax (cmꢁ1) 3354 (m), 3289 (m), 3064 (m), 2836 (m), 2057
(w), 1928 (w), 1798 (w), 1602 (m), 1587 (m), 1497 (s), 1466 (s), 1454
(s), 1245 (s), 1180 (m),765 (m), 745 (s), 699 (s); 1H NMR (500 MHz,
on a 500 MHz NMR spectrometer. Chemical shifts
parts per million (ppm) relative to the residual protons in the NMR
solvent (CHCl3: 7.26) and carbon resonance of the solvent (CDCl3:
d
are reported in
CDCl3):
d
3.79 (s, 3H), 4.15 (m, 2H), 4.67 (t, J¼7.2 Hz, 1H), 6.87 (d,
J¼8.1 Hz, 1H), 6.92 (dt, J¼7.5, 1.1 Hz, 1H), 7.18 (dd, J¼7.6, 1.5 Hz, 1H),
d
7.20e7.23 (m, 2H), 7.30 (m, 4H); 13C NMR (APT, 125 MHz, CDCl3):
d
77.00). NMR peak multiplicities were given as follows: s¼singlet,
d 46.4 (CH), 55.5 (CH3), 65.4 (CH2), 110.8 (CH), 120.6 (CH), 126.5
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad. Mass
spectra were recorded on a gas chromatography with mass sensi-
tive detector from Agilent Technologies 6890 N Network GC System
(EI, 70 eV) using Standard Method (column: HP-5MSI, 30 m,
(CH), 127.8 (CH), 128.2 (CH), 128.5 (CH), 128.5 (CH), 129.7 (C), 141.4
(C), 157.3 (C); GCeMS: tR¼28.59 min (rac-9a), m/z (%)¼228 ([M]þ,
5), 213 ([Mꢁ15]þ, 100), 195 ([Mꢁ33]þ, 26), 181 (6), 165 (27), 151
(32), 135 (57), 121 (7), 105 (32), 91 (19), 77 (23); HRMS (ESIþ): calcd
for C15H16O2Na ([MþNa]þ) 251.1048, found 251.1056.
0.25 mm ID, 0.25
300 ꢂC; He, 1 mL/min (constant flow modus); oven: 40 ꢂC (5 min),
ꢂC/min, 280 ꢂC (5 min)). High resolution electrospray ionization
mass spectra (HR-ESI-MS) were obtained with MeOH on a Bruker
micrOTOF-Q. The specific rotations ([ ]) were measured on an
m
m film tickness; inlet: 300 ꢂC (split modus); det:
5
4.3. (R)-(L)-2-(2-Methoxyphenyl)-1-phenylethanol (8a)28
and (R)-(D)-2-(2-methoxyphenyl)-2-phenylethanol (9a)
(Scheme 2)
a
Optical Activity Ltd. AA-55 polarimeter using 2 mL cell with
a 0.5 dm path length and the sample concentrations are given in g/
100 mL unit.
Compound 8a: ½a 2D0
ꢁ8.4 (c 0.5, CH2Cl2), HPLC: Chiralcel OD-H, n-
ꢄ
hexane/iPrOH (90:10), 1.0 mL/min, 44 bar, 254 nm (UVevis),
tR¼7.97 min (ent-8a), tR¼9.28 min (8a). 9a: ½a D20
þ40.0 (c 0.3,
ꢄ
4.2. 2-(2-Methoxyphenyl)-1-phenylethanol (rac-8a)28 and 2-
(2-methoxyphenyl)-2-phenylethanol (rac-9a)11 (Table 1, entry
7, general procedure)
CH2Cl2), HPLC: Chiralcel OD-H, n-hexane/iPrOH (90:10),1.0 mL/min,
44 bar, 254 nm (UVevis), tR¼8.86 min (ent-9a), tR¼10.09 min (9a).
4.4. 2-(3,5-Di-tert-butyl-2-methoxyphenyl)-1-phenylethanol
(rac-8b) and 2-(3,5-di-tert-butyl-2-methoxyphenyl)-2-
phenylethanol (rac-9b) (Table 2, entry 7)
An oven-dried 25 mL Schlenk tube that was capped with a glass
stopper and equipped with a magnetic stirring bar was evacuated
under heating with a blow-drier for 15 min. After the tube was
cooled down to room temperature, dry nitrogen was back-filled and
the glass stopper was replaced with a rubber septum under positive
An oven-dried 25 mL Schlenk tube that was capped with a glass
stopper and equipped with a magnetic stirring bar was evacuated
under heating with a blow-drier for 15 min. After the tube was
cooled down to room temperature, dry nitrogen was back-filled and
the glass stopper was replaced with a rubber septum under positive
pressure of nitrogen. 2,4-Di-tert-butylanisole (5b, 1.102 g, ca.
pressure of nitrogen. Anisole (5a, 324 mg, 325
mL, 3.0 mmol,
3.00 equiv) and TMEDA (70 mg, 90 L, 0.6 mmol, 0.60 equiv) were
m
added with a syringe in the tube succeeded by the addition of ab-
solute THF (8 mL) as the solvent. After the mixture was cooled in an
ice-bath, 1.875 mL of 1.6 M solution of nBuLi in hexanes (3.0 mmol,
3.00 equiv nBuLi) were dropwise added to the mixture. The mixture
was then stirred for 3 h while the temperature was allowed to rise
to room temperature. After the reaction tube was cooled down to
ꢁ78 ꢂC in a dry-ice/iso-propanol bath, styrene oxide (rac-7, 120 mg,
1.23 mL, 5.0 mmol, 5.00 equiv) and TMEDA (116 mg, 150 mL,
1.0 mmol, 1.00 equiv) were added with a syringe in the tube suc-
ceeded by the addition of absolute Et2O (15 mL) as the solvent. After
the mixture was cooled in an ice-bath, 3.125 mL of 1.6 M solution of
nBuLi in hexanes (5.0 mmol, 5.00 equiv nBuLi) were dropwise added
to the mixture. The mixture was then stirred overnight (ca. 16 h)
while the temperature was allowed to rise to room temperature.
After the reaction tube was cooled down to ꢁ78 ꢂC in a dry-ice/iso-
propanol bath, absolute THF (3 mL) was added. Styrene oxide (rac-
115 mL, 1.0 mmol, 1.00 equiv) and BF3$OEt2 (355 mg, 310 mL,
2.5 mmol, 2.50 equiv) were successively added to the reaction
mixture. After stirring the reaction mixture at ꢁ78 ꢂC for 1 h, re-
action was quenched by addition of saturated NaHCO3 solution
(8 mL). After THF was removed by rotary evaporation under re-
duced pressure, the aqueous residue was extracted with Et2O
(3ꢃ30 mL). Combined organic layers were dried over Na2SO4. After
all volatile components were removed by rotary evaporation in
vacuo, the residue was purified by silica gel column chromatogra-
phy eluting with hexanes/EtOAc (9:1). The o-2-hydroxyalkylanisole
rac-8a (180 mg, 0.79 mmol, 79%) was first isolated as a colorless
viscous oil, which gradually became a colorless solid by standing
whereas the o-2-hydroxyalkylanisole rac-9a (40 mg, 0.18 mmol,
18%) was obtained as a colorless oily product. rac-8a: mp:
72e74 ꢂC; Rf¼0.16 (silica gel; hexanes/EtOAc, 9:1); FT-IR (KBr): nmax
(cmꢁ1) 3354 (m), 3289 (m), 3064 (m), 2836 (m), 2057 (w), 1928 (w),
1798 (w), 1602 (m), 1587 (m), 1497 (s), 1466 (s), 1454 (s), 1245 (s),
1180 (m), 765 (m), 745 (s), 699 (s); 1H NMR (500 MHz, CDCl3):
7, 120 mg, 115
mL, 1.0 mmol, 1.00 equiv) and BF3$OEt2 (710 mg,
620 L, 5.0 mmol, 5.00 equiv) were successively added to the re-
m
action mixture. After stirring the reaction mixture at ꢁ78 ꢂC for 1 h,
reaction was quenched by addition of saturated NaHCO3 solution
(8 mL). After the ethereal solvents were removed by rotary evap-
oration under reduced pressure, the aqueous residue was extracted
with Et2O (3ꢃ30 mL). Combined organic layers were dried over
Na2SO4. After all volatile components were removed by rotary
evaporation in vacuo, the residue was purified by silica gel column
chromatography eluting with hexanes/EtOAc (9:1). Both the o-2-
hydroxyalkylanisoles rac-8b (221 mg, 0.65 mmol, 65%) and rac-9b
(41 mg, 0.12 mmol, 12%) were obtained as colorless solids. rac-8b:
mp: 63e65 ꢂC; Rf¼0.15 (silica gel; hexanes/EtOAc, 9:1); FT-IR (KBr):
nmax (cmꢁ1) 3307 (s), 2961 (s), 1601 (w), 1477 (s), 1454 (s), 1427 (m),
1389 (m), 1323 (w), 1271 (m), 1231 (s), 1203 (m), 1156 (w), 1116 (s),
1077 (w), 1034 (s), 1010 (s), 950 (m), 907 (w), 878 (m), 772 (w), 754
d
2.53 (d, J¼3.1 Hz, 1H, OH), 2.99 (dd, J¼13.7, 8.8 Hz, 1H), 3.12 (dd,
J¼13.7, 3.9 Hz, 1H), 3.86 (s, 3H), 4.97 (m, 1H), 6.90 (m, 2H), 7.08 (dd,
J¼7.8, 1.6 Hz, 1H), 7.22e7.28 (m, 2H), 7.33e7.36 (m, 2H),7.38e7.40
(m), 697 (s), 652 (w), 541 (w); 1H NMR (500 MHz, CDCl3):
d 1.23 (s,
9H), 1.41 (s, 9H), 2.97 (br d, J¼3.0 Hz, 1H), 3.09 (br d, J¼6.3 Hz, 2H),
3.83 (s, 3H), 4.98 (dt, J¼6.5, 2.9 Hz, 1H), 6.89 (br d, J¼2.5 Hz, 1H),
7.22e7.26 (m, 2H), 7.29e7.35 (m, 4H); 13C NMR (APT, 125 MHz,
(m, 2H); 13C NMR (APT, 125 MHz, CDCl3):
d
40.9 (CH2), 55.1 (CH3),
73.9 (CH), 110.2 (CH), 120.4 (CH), 125.6 (CH), 126.4 (C), 127.0 (CH),
127.7 (CH), 128.0 (CH), 131.3 (CH), 144.4 (C), 157.3 (C); GCeMS:
tR¼29.95 min (rac-8a), m/z (%)¼210 ([Mꢁ18]þ, 14), 194 ([Mꢁ34]þ,
1), 178 (2), 165 (8), 152 (4), 139 (1), 112 (100), 107 (32), 91 (29), 77
(21); HRMS (ESIþ): calcd for C15H16O2Na ([MþNa]þ) 251.1048,
CDCl3):
d 31.3 (CH3), 31.4 (CH3), 34.4 (C), 35.3 (C), 42.0 (CH2), 61.7
(CH3), 74.9 (CH), 123.1 (CH), 125.7 (CH), 126.8 (CH), 127.2 (CH), 128.2
(CH), 130.8 (C), 142.1 (C), 144.4 (C), 146.0 (C), 155.9 (C); GCeMS:

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E. Erturk et al. / Tetrahedron 68 (2012) 6463e6471
6469
tR¼33.41 min (rac-8b), m/z (%)¼322 ([Mꢁ18]þ, 14), 307 ([Mꢁ33]þ,
19), 234 (63), 219 (100), 203 (6), 177 (11), 163 (10), 105 (13); HRMS
(ESIþ): calcd for C23H32O2Na ([MþNa]þ) 363.2300, found 363.2277.
rac-9b: mp: 86e88 ꢂC; Rf¼0.09 (silica gel; hexanes/EtOAc, 9:1); FT-
IR (KBr): nmax (cmꢁ1) 3307 (s), 2961 (s), 1601 (w), 1477 (s), 1454 (s),
1427 (m), 1389 (m), 1323 (w), 1271 (m), 1231 (s), 1203 (m), 1156 (w),
1116 (s), 1077 (w), 1034 (s), 1010 (s), 950 (m), 907 (w), 878 (m), 772
(w), 754 (m), 697 (s), 652 (w), 541 (w); 1H NMR (500 MHz, CDCl3):
(ESIþ): calcd for C21H20O2Na ([MþNa]þ) 327.1361, found 327.1328.
rac-9c: Rf¼0.08 (silica gel; hexanes/EtOAc, 9:1); FT-IR (KBr): nmax
(cmꢁ1) 3434 (s), 3060 (s), 3028 (s), 2934 (s), 2835 (m), 2337 (w),
1950 (w),1883 (w), 1811 (w),1759 (w), 1672 (w),1602 (m), 1574 (w),
1547 (w), 1496 (s), 1442 (s), 1419 (s), 1329 (m), 1253 (s), 1219 (s),
1172 (s), 1093 (s), 1046 (s), 1007 (s), 914 (m), 844 (w), 794 (m), 759
(s), 700 (s), 629 (w), 598 (m); 1H NMR (500 MHz, CDCl3):
d 3.12 (s,
3H), 4.19 (m, 2H), 4.72 (t, J¼7.2 Hz, 1H), 7.17 (m, 1H), 7.21e7.25 (m,
d
1.30 (s, 9H), 1.40 (s, 9H), 3.66 (s, 3H), 4.03e4.08 (m, 1H), 4.10e4.15
(m,1H), 4.68 (t, J¼7.4 Hz,1H), 7.20e7.23 (m, 2H), 7.28e7.35 (m, 5H);
13C NMR (APT, 125 MHz, CDCl3):
31.3 (CH3), 31.5 (CH3), 34.6 (C),
2H), 7.30e7.34 (m, 5H), 7.38e7.41 (m, 3H), 7.56 (m, 2H); 13C NMR
(APT, 125 MHz, CDCl3):
d 46.8 (CH), 60.5 (CH3), 66.0 (CH2), 124.2
d
(CH), 126.6 (CH), 127.1 (CH), 127.5 (CH), 128.3 (CH), 128.4 (CH), 128.6
(CH), 128.9 (CH), 129.9 (CH), 135.0 (C), 135.1 (C), 138.7 (C), 141.7 (C),
156.0 (C); GCeMS: tR¼35.27 min (rac-9c), m/z (%)¼304 ([M]þ, 4),
286 ([Mꢁ18]þ, 4), 274 ([Mꢁ30]þ, 30), 257 (9), 239 (3), 227 (4), 207
(100), 191 (11), 177 (4), 165 (13), 133 (8), 115 (4), 103 (4), 91 (45), 73
(3); HRMS (ESIþ): calcd for C21H20O2Na ([MþNa]þ) 327.1361, found
327.1359.
35.4 (C), 46.4 (CH), 62.8 (CH3), 67.1 (CH2), 123.1 (CH), 123.7 (CH),
126.6 (CH), 128.3 (CH), 128.6 (CH), 133.2 (C), 141.6 (C), 142.3 (C),
145.7 (C), 156.4 (C); GCeMS: tR¼33.05 min (rac-9b), m/z (%)¼340
([M]þ, 37), 325 ([Mꢁ15]þ, 13), ([Mꢁ30]þ, 40), 295 (30), 281 (14),
253 (41), 207 (100), 191 (11), 178 (8), 165 (9), 147 (3), 133 (11), 119
(4), 105 (30); HRMS (ESIþ): calcd for C23H32O2Na ([MþNa]þ)
363.2300, found 363.2298.
4.6. trans-2-(2-Methoxyphenyl)-cyclohexanol (rac-11)10d
4.5. 2-(2-Methoxy-3-phenylphenyl)-1-phenylethanol (rac-8c)
and 2-(2-methoxy-3-phenylphenyl)-2-phenylethanol (rac-9c)
(Table 2, entry 9)
(Table 3, entry 1)
Cyclohexene oxide (10, 98 mg, ca. 101 mL, 1.0 mmol, 1.00 equiv)
was reacted with o-lithioanisole (6a, ca. 3.00 equiv) in the presence
of BF3$OEt2 according to the general procedure as described above.
The o-2-hydroxyalkylanisole rac-11 (204 mg, 0.99 mmol, 99%) was
first isolated by silica gel column chromatography eluting with
hexanes/EtOAc (9:1) as a colorless viscous oil, which gradually
became a colorless solid by standing. Mp: 52e54 ꢂC; Rf¼0.11 (silica
gel; hexanes/EtOAc, 9:1); FT-IR (KBr): nmax (cmꢁ1) 3372 (m), 3103
(w), 3073 (w), 3012 (w), 2919 (s), 2661 (w), 2008 (w),1911 (w),1876
(w),1756 (w) 1599 (s),1585 (s), 1492 (s), 1463 (s),1438 (s),1326 (m),
1290 (m), 1240 (s), 1191 (m), 1126 (m), 1090 (w), 1051 (s), 961 (m),
824 (w), 746 (s), 730 (s), 577 (w), 565 (w); 1H NMR (500 MHz,
An oven-dried 25 mL Schlenk tube that was capped with a glass
stopper and equipped with a magnetic stirring bar was evacuated
under heating with a blow-drier for 15 min. After the tube was
cooled down to room temperature, dry nitrogen was back-filled and
the glass stopper was replaced with a rubber septum under positive
pressure of nitrogen. 2-Phenylanisole (5b, 921 mg, ca. 985
mL,
5.0 mmol, 5.00 equiv) and TMEDA (116 mg, 150 L, 1.0 mmol,
m
1.00 equiv) were added with a syringe in the tube succeeded by the
addition of absolute Et2O (15 mL) as the solvent. After the mixture
was cooled in an ice-bath, 3.125 mL of 1.6 M solution of nBuLi in
hexanes (5.0 mmol, 5.00 equiv nBuLi) were dropwise added to the
mixture. The mixture was then stirred overnight (ca.16 h) while the
temperature was allowed to rise to room temperature. After the
reaction tube was cooled down to ꢁ78 ꢂC in a dry-ice/iso-propanol
bath, absolute THF (3 mL) was added. Styrene oxide (rac-7, 120 mg,
CDCl3):
d 1.33e1.54 (m, 4H), 1.73e1.86 (m, 4H), 2.12e2.16 (m, 1H),
2.98e3.04 (m, 1H), 3.71e3.77 (m, 1H), 3.83 (s, 3H), 6.89 (dd, J¼8.2,
1.0 Hz, 1H), 6.97 (dt, J¼7.5, 1.0 Hz,1H), 7.20 (m,1H), 7.23 (m, 1H); 13C
NMR (APT, 125 MHz, CDCl3):
d 25.1 (CH2), 26.1 (CH2), 32.3 (CH2),
35.1 (CH2), 45.0 (CH), 55.4 (CH3), 73.8 (CH), 110.7 (CH), 120.9 (CH),
127.2 (CH), 127.3 (CH), 131.5 (C), 157.6 (C); GCeMS: tR¼28.19 min
(rac-11), m/z (%)¼206 ([M]þ, 73), 188 ([Mꢁ18]þ, 7), 173 ([Mꢁ33]þ,
43), 147 (23), 134 (7), 121 (100), 107 (9), 91 (47), 77 (10); HRMS
(ESIþ): calcd for C13H18O2Na ([MþNa]þ) 229.1204, found 229.1196.
115 mL, 1.0 mmol, 1.00 equiv) and BF3$OEt2 (710 mg, 620 mL,
5.0 mmol, 5.00 equiv) were successively added to the reaction
mixture. After stirring the reaction mixture at ꢁ78 ꢂC for 1 h, re-
action was quenched by addition of saturated NaHCO3 solution
(8 mL). After the ethereal solvents were removed by rotary evap-
oration under reduced pressure, the aqueous residue was extracted
with Et2O (3ꢃ30 mL). Combined organic layers were dried over
Na2SO4. After all volatile components were removed by rotary
evaporation in vacuo, the residue was purified by silica gel column
chromatography eluting with hexanes/EtOAc (9:1). Both the o-2-
hydroxyalkylanisoles rac-8c (190 mg, 0.63 mmol, 63%) and rac-9c
(55 mg, 0.18 mmol, 18%) were isolated as colorless viscous oil by
silica gel column chromatography eluting with hexanes/EtOAc
(9:1). rac-8c: Rf¼0.15 (silica gel; hexanes/EtOAc, 9:1); FT-IR (KBr):
nmax (cmꢁ1) 3434 (s), 3060 (s), 3028 (s), 2934 (s), 2835 (m), 2337
(w), 1950 (w), 1883 (w), 1811 (w), 1759 (w), 1672 (w), 1602 (m), 1574
(w), 1547 (w), 1496 (s), 1442 (s), 1419 (s), 1329 (m), 1253 (s), 1219 (s),
1172 (s), 1093 (s), 1046 (s), 1007 (s), 914 (m), 844 (w), 794 (m), 759
4.7. trans-2-(2-Methoxyphenyl)-cyclopentanol (rac-13) (Table
3, entry 2)
Cyclopentene oxide (12, 84 mg, 87 mL, 1.0 mmol, 1.00 equiv) was
reacted with o-lithioanisole (6a, ca. 3.00 equiv) in the presence of
BF3$OEt2 according to the general procedure as described above.
The o-2-hydroxyalkylanisole rac-13 (190 mg, 0.99 mmol, 99%) was
obtained as a colorless viscous oil after silica gel column chroma-
tography eluting with hexanes/EtOAc (9:1). Rf¼0.09 (silica gel;
hexanes/EtOAc, 9:1); FT-IR (KBr): nmax (cmꢁ1) 3391 (s), 3064 (m),
3029 (m), 2955 (s), 2872 (s), 2835 (s), 2050 (w), 1893 (w), 1775 (w),
1599 (s), 1585 (s), 1492 (s), 1463 (s), 1438 (s), 1326 (m), 1290 (m),
1240 (s), 1175 (m), 1029 (s), 984 (m), 752 (s), 573 (w); 1H NMR
(s), 700 (s), 629 (w), 598 (m); 1H NMR (500 MHz, CDCl3):
d
3.0 (m,
(500 MHz, CDCl3): d 1.67e1.73 (m, 1H), 1.74e1.92 (m, 3H), 1.98e2.10
1H, OH), 3.03 (dd, J¼13.7, 8.7 Hz, 1H), 3.11 (dd, J¼13.7, 4.0 Hz, 1H),
3.33 (s, 3H), 4.99 (m, 1H), 7.06e7.11 (m, 2H), 7.18e7.26 (m, 2H), 7.33
(t, J¼7.4 Hz, 3H), 7.38e7.42 (m, 4H), 7.58 (d, J¼7.7 Hz, 2H); 13C NMR
(m, 2H), 2.44 (br s, 1H), 3.27 (dd, J¼15.5, 7.9 Hz, 1H), 3.83 (s, 3H),
4.17 (dd, J¼12.3, 6.8 Hz, 1H), 6.88 (dd, J¼8.4, 1.0 Hz, 1H), 6.93 (dt,
J¼7.5, 1.0 Hz, 1H), 7.17e7.21 (m, 2H); 13C NMR (APT, 125 MHz,
(APT, 125 MHz, CDCl3):
d
41.2 (CH2), 60.3 (CH3), 74.8 (CH), 124.2
CDCl3): d 22.8 (CH2), 30.3 (CH2), 34.3 (CH2), 48.6 (CH), 55.4 (CH3),
(CH), 125.7 (CH), 127.1 (CH), 127.3 (CH), 128.2 (CH), 128.3 (CH), 128.9
(CH), 130.0 (CH), 130.7 (CH), 131.7 (C), 134.8 (C), 138.6 (C), 144.4 (C),
155.9 (C); GCeMS: tR¼35.19 min (rac-8c), m/z (%)¼286 ([Mꢁ18]þ,
11), 270 ([Mꢁ34]þ, 1), 253 (3), 239 (3), 228 (2), 209 (40), 198 (100),
183 (20), 165 (17), 152 (16), 128 (3), 107 (21), 79 (17); HRMS
79.4 (CH), 110.4 (CH), 120.8 (CH), 126.9 (CH), 127.1 (CH), 131.5 (C),
157.5 (C); GCeMS: tR¼26.76 min (rac-13), m/z (%)¼192 ([M]þ, 68),
174 ([Mꢁ18]þ, 11), 159 ([Mꢁ33]þ, 9), 148 (14), 135 (11), 121 (100),
105 (10), 91 (50), 77 (14); HRMS (ESIþ): calcd for C12H16O2Na
([MþNa]þ) 215.1048, found 215.1042.

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6470
4.8. 1-(2-Methoxyphenyl)-2-octanol (rac-15) (Table 3, entry 3)
1,2-Epoxyoctane (rac-14, 128 mg, 153 L, 1.0 mmol, 1.00 equiv)
d 35.4 (CH2), 49.3 (CH2), 55.3 (CH3), 71.3 (CH),110.4 (CH),120.8 (CH),
125.4 (C), 128.2 (CH), 131.4 (CH), 157.4 (C); GCeMS: tR¼25.93 min
(rac-19), m/z (%)¼200 ([M]þ, 15), 202 ([Mꢁ18]þ, 1), 164 (20), 151 (9),
133 (4), 121 (100), 107 (9), 91 (95), 77 (15); HRMS (ESIþ): calcd for
C10H13ClO2Na ([MþNa]þ) 223.0502, found 223.0510.
m
was reacted with o-lithioanisole (6a, ca. 3.00 equiv) in the presence
of BF3$OEt2 according to the general procedure as described above.
Only the regioisomer rac-15 (182 mg, 0.77 mmol, 77%) was
obtained as a colorless viscous oil after silica gel column chroma-
tography eluting with hexanes/EtOAc (9:1). Rf¼0.23 (silica gel;
hexanes/EtOAc, 9:1); FT-IR (KBr): nmax (cmꢁ1) 3400 (s), 3065 (m),
3025 (m), 2999 (m), 2928 (s), 2856 (s), 2482 (w), 2057 (w), 1893
(w),1782 (w),1601 (s),1587 (s),1493 (s),1464 (s),1377 (s),1290 (m),
1240 (s), 1177 (s), 1122 (s), 1052 (s), 1031 (s), 968 (w), 944 (w), 860
(w), 800 (w), 752 (s), 727 (m), 612 (w), 571 (w); 1H NMR (500 MHz,
4.11. 1-(2-Methoxyphenyl)-2,2-diphenylethanol (rac-21)
(Table 3, entry 7)
After o-lithioanisole (6a) was generated by following the general
procedure, the reaction tube was cooled down to ꢁ78 ꢂC in a dry-
ice/iso-propanol bath. 2,2-Diphenyloxirane (20, 196 mg, 1.0 mmol,
1.00 equiv) and BF3$OEt2 (355 mg, 310 mL, 2.5 mmol, 2.50 equiv)
CDCl3):
d
0.88 (t, J¼6.8 Hz, 3H), 1.29 (m, 7H), 1.48 (m, 3H), 2.14 (br s,
were successively added to the reaction mixture. After the reaction
mixture was stirred at ꢁ78 ꢂC for 1 h, the reaction temperature was
allowed to rise slowly to 0 ꢂC. The reaction was quenched by ad-
dition of saturated NaHCO3 solution (8 mL) at this point. After the
usual working-up of the aqueous mixture according to the general
procedure as described above, the o-2-hydroxyalkylanisole rac-21
(138 mg, 0.45 mmol, 45%) was obtained as a colorless viscous oil via
column chromatographic purification. Rf¼0.16 (silica gel; hexanes/
EtOAc, 9:1); FT-IR (KBr): nmax (cmꢁ1) 3555 (m), 3445 (m), 3084 (m),
3060 (s), 3026 (s), 3002 (m), 2934 (s), 2836 (m), 2629 (w), 2343 (w),
2047 (w), 1946 (w), 1807 (w), 1661 (w), 1600 (s), 1587 (s), 1492 (s),
1451 (s), 1439 (s), 1389 (m), 1287 (s), 1239 (s), 1181 (m), 1114 (m),
1081 (s), 1030 (s), 936 (w), 878 (w), 846 (w), 825 (w), 780 (m), 753
1H), 2.67 (dd, J¼13.5, 8.2 Hz, 1H), 2.87 (dd, J¼13.5, 3.8 Hz, 1H), 3.80
(s, 3H), 3.82 (br s, 1H), 6.85 (d, J¼8.2 Hz, 1H), 6.90 (dt, J¼7.4, 0.8 Hz,
1H), 7.13 (dd, J¼7.3, 1.4 Hz, 1H), 7.20 (dt, J¼7.6, 0.8 Hz, 1H); 13C NMR
(APT, 125 MHz, CDCl3):
d 14.0 (CH3), 22.6 (CH2), 25.7 (CH2), 29.3
(CH2), 31.8 (CH2), 37.1 (CH2), 38.6 (CH2), 55.2 (CH3), 71.8 (CH), 110.3
(CH), 120.6 (CH), 127.2 (C), 127.6 (CH), 131.3 (CH), 157.5 (C); GCeMS:
tR¼29.14 min (rac-15), m/z (%)¼236 ([M]þ, 3), 218 ([Mꢁ18]þ, 2), 147
(4), 122 (100), 107 (12), 91 (18), 77 (5); HRMS (ESIþ): calcd for
C15H24O2Na ([MþNa]þ) 259.1674, found 259.1664.
4.9. 1-(o-Methoxybenzyl)-1-cyclohexanol (17) (Table 3, entry 4)
(s), 700 (s), 623 (m), 601 (m); 1H NMR (500 MHz, CDCl3):
d 2.66 (d,
Methylenecyclohexane oxide (16, 112 mg, ca. 115 mL, 1.0 mmol,
1.00 equiv) was reacted with o-lithioanisole (6a, ca. 3.00 equiv) in
the presence of BF3$OEt2 according to the general procedure as
described above. Only the regioisomer 17 (165 mg, 0.75 mmol, 75%)
was obtained as a colorless viscous oil after silica gel column
chromatography eluting with hexanes/EtOAc (9:1). Rf¼0.31 (silica
gel; hexanes/EtOAc, 9:1); FT-IR (KBr): nmax (cmꢁ1) 3543 (m), 3064
(w), 3025 (w), 2999 (w), 2931 (s), 2856 (s), 2661 (w), 1911 (w), 2481
(w), 2055 (w),1896 (w),1785 (w), 1600 (m), 1586 (m), 1493 (s), 1463
(s), 1439 (s), 1395 (m), 1321 (m), 1291 (m), 1242 (s), 1175 (m), 1148
(m), 1111 (s), 1051 (s), 1028 (s), 978 (s), 875 (w), 826 (w), 753 (s), 712
J¼6.6 Hz, 1H), 3.71 (s, 3H), 4.42 (d, J¼8.2 Hz, 1H), 5.66 (dd, J¼8.0,
6.8 Hz, 1H), 6.76e6.81 (m, 2H), 7.07 (m, 2H), 7.11e7.16 (m, 5H),
7.21e7.24 (m, 1H), 7.30 (t, J¼7.8 Hz, 2H), 7.35 (d, J¼7.3 Hz, 2H); 13C
NMR (APT,125 MHz, CDCl3): d 55.2 (CH3), 58.2 (CH), 72.8 (CH), 110.4
(CH), 120.5 (CH), 126.1 (CH), 126.5 (CH), 127.9 (CH), 128.1 (CH), 128.3
(CH), 128.5 (CH), 129.2 (CH), 130.4 (C), 141.4 (C), 142.3 (C), 156.5 (C);
GCeMS: tR¼35.30 min (rac-21), m/z (%)¼286 ([Mꢁ18]þ, 20), 271
([Mꢁ33]þ, 2), 253 (3), 239 (3), 225 (1), 191 (2), 167 (37), 152 (10),
137 (100), 121 (9), 107 (22), 91 (9), 77 (10); HRMS (ESIþ): calcd for
C21H20O2Na ([MþNa]þ) 327.1361, found 327.1349.
(w), 630 (w); 1H NMR (500 MHz, CDCl3):
d 1.24e1.30 (m, 1H),
1.38e1.44 (m, 2H), 1.46e1.55 (m, 5H), 1.57e1.64 (m, 2H), 2.66 (s,
1H), 2.83 (s, 2H), 3.82 (s, 3H), 6.88 (d, J¼8.2 Hz, 1H), 6.90 (dt, J¼7.4,
0.8 Hz, 1H), 7.12 (dd, J¼7.4, 1.6 Hz, 1H), 7.21 (dt, J¼8.2, 1.6 Hz, 1H);
Acknowledgements
This work was supported by the Scientific and Technological
Research Council of Turkey (TUBITAK).
13C NMR (APT, 125 MHz, CDCl3):
d 22.3 (CH2), 25.9 (CH2), 37.8 (CH2),
42.6 (CH2), 55.2 (CH3), 72.0 (C), 110.5 (CH), 120.6 (CH), 126.0 (C),
127.7 (CH), 132.5 (CH), 157.5 (C); GCeMS: tR¼28.41 min (17), m/z
(%)¼220 ([M]þ, 1), 202 ([Mꢁ18]þ, 23), 177 (2), 159 (4), 144 (3), 122
(100), 107 (10), 91 (36), 77 (8); HRMS (ESIþ): calcd for C14H20O2Na
([MþNa]þ) 243.1361, found 243.1365.
Supplementary data
The NMR spectra of all synthesized compounds, the HPLC
chromatograms of 8a and 9a as well as semiemprical PM3 geom-
etry optimized structures and Mulliken Population Analysis of the
aggregate II and IIIa. Supplementary data related to this article can
be found online at http://dx.doi.org/10.1016/j.tet.2012.05.116.
4.10. 1-Chloro-3-(2-methoxyphenyl)-1-propanol (rac-19)
(Table 3, entry 5)
Epichlorohydrin (rac-18, 93 mg, 78 mL, 1.0 mmol, 1.00 equiv) was
References and notes
reacted with o-lithioanisole (6a, ca. 3.00 equiv) in the presence of
BF3$OEt2 according to the general procedure as described above.
Only the regioisomer rac-19 (106 mg, 0.53 mmol, 53%) was
obtained as a colorless viscous oil after silica gel column chroma-
tography eluting with hexanes/EtOAc (9:1). Rf¼0.18 (silica gel;
hexanes/EtOAc, 9:1); FT-IR (KBr): nmax (cmꢁ1) 3434 (m), 3065 (w),
3003 (m), 2955 (m), 2837 (m), 2485 (s), 2053 (w), 1901 (w), 1786
(w), 1600 (s), 1587 (m), 1494 (s), 1464 (s), 1438 (s), 1314 (m), 1289
(m), 1244 (s), 1177 (m), 1161 (m), 1114 (s), 1079 (m), 1051 (s), 1029
(s), 934 (w), 886 (w), 846 (w), 754 (s), 735 (m) 697 (w), 569 (w); 1H
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