Application of phenolate ion mediated intramolecular epoxide ring opening in the enantioselective synthesis of functionalized 2,3-dihydrobenzofurans and 1-benzopyrans

Article abstract of DOI:10.1055/s-0028-1088077

The enantioselective synthesis of 2-isopropenyl-2,3-dihydrobenzofurans, 4-(2,3-dihydrobenzofuran-2-yl)-2-methylbut-3-en-2-ols, 2-hydroxymethyl chromans, and 4-chroman-2-yl-2-methylbut-3-en-2-ols has been achieved using Sharpless asymmetric epoxidation-der

Full text of DOI:10.1055/s-0028-1088077

1886
PAPER
Application of Phenolate Ion Mediated Intramolecular Epoxide Ring Opening
in the Enantioselective Synthesis of Functionalized 2,3-Dihydrobenzofurans
and 1-Benzopyrans1
P
henolate Ion
u
Mediate
d
Int
b
r
amolecular
a
E
poxide
R
l
O
pening
R
K
eactions umar Dinda, Sajal Kumar Das, Gautam Panda*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, UP, India
Fax +91(522)2223405; E-mail: gautam.panda@gmail.com
Received 21 January 2009; revised 9 February 2009
HO
O
O
O
Abstract: The enantioselective synthesis of 2-isopropenyl-2,3-di-
hydrobenzofurans, 4-(2,3-dihydrobenzofuran-2-yl)-2-methylbut-3-
en-2-ols, 2-hydroxymethyl chromans, and 4-chroman-2-yl-2-meth-
ylbut-3-en-2-ols has been achieved using Sharpless asymmetric ep-
oxidation-derived enantiomerically enriched epoxy alcohols as
chiral building blocks. A phenolate ion mediated intramolecular ep-
oxide ring-opening reaction was the key step for every cyclization
reaction.
O
OHC
O
1 (R)-(–)-tremetone
2 4-hydroxytremetone
3 fomannoxin
O
•
O
O
O
O
O
4 xyloallenoid B
Key words: 2-isopropenyl-2,3-dihydrobenzofuran,
2-hydroxy-
5 rotenone
methyl chromans, epoxidation, epoxides, polycycles, ring opening
OH
O
O
2,3-Dihydrobenzofuran and 1-benzopyran derivatives are
common in numerous natural products and unnatural mol-
ecules.2,3 The wide ranging biological properties of these
heterocycles have attracted the considerable attention of
organic and medicinal chemists.4,5 The 2-isopropenyl-2,3-
dihydrobenzofuran framework is an integral part of nu-
merous bioactive natural products6 such as tremetone (1),
4-hydroxytremetone (2), fomannoxin (3), and xyloalleno-
lide B (4) (Figure 1). In addition to these structurally sim-
ple molecules, more complex compounds such as
rotenone (5), 3¢,4¢-deoxypsorospermin (6), and xyloketal
J (7) also contain the same structural unit.
O
H
MeO
O
H
MeO
O
O
O
6 deoxypsorospermin
HO
H
R
O
OH
H
O
HO
O
7 xyloketal J
8a R = α-H, heliannuol G
8b R = β-H, heliannuol H
Figure 1 Representative examples of natural products containing
the 2-substituted 2,3-dihydrobenzofuran moiety
The history of the synthesis of this class of compounds
dates back to 1963 when the first asymmetric synthesis of
1 was achieved from the corresponding chiral 2,3-dihy-
drobenzofuran-2-carboxylic acid, both enantiomers of
which were obtained by a chiral resolution procedure.6a
Recently, Yamaguchi and co-workers achieved kinetic
resolution of the enantiomers of several racemic 2-isopro-
penyl-2,3-dihydrobenzofurans utilizing Sharpless asym-
metric dihydroxylation.7 However, the above two
methods of synthesizing chiral 2-isopropenyl-2,3-dihy-
drobenzofurans suffered from various drawbacks such as
very low yield of the resolution step and low enantiomeric
excess (ee) of the desired isomer. Very recently,
de Koning and co-workers achieved an efficient enantio-
selective synthesis of the 2-isopropenyl-2,3-dihydroben-
zofuran skeleton of tremetone and hydroxytremetone
from (E)-4-(2-hydroxyphenyl)-2-methylbut-2-enyl meth-
yl carbonate and (E)-4-(2,6-dihydroxyphenyl)-2-methyl-
but-2-enyl methyl carbonate, respectively.8 The key step
was a catalytic palladium-mediated reaction in the pres-
ence of the chiral Trost ligand.
Among various 2-substituted 1-benzopyran derivatives,
enantiomerically pure 2-hydroxymethyl chromans are im-
portant intermediates for the synthesis of numerous me-
dicinally important 2-substituted chroman derivatives
(Figure 2).9–14 It is worth mentioning that biological activ-
ities of 2-substituted chromans are dependent on the abso-
lute configuration of the stereogenic centre as illustrated
in the development of repinotan (11) and sarizotan (12) as
single enantiomers.
A literature survey shows that enantiomerically pure 2-
hydroxymethyl chromans can be synthesized from opti-
cally pure chroman-2-carboxylic acids,15 which, in turn
can be obtained via chemical16 as well as enzymatic17 res-
olution of the racemate for which facile syntheses18 have
been reported. However, we could find only two reported
enantioselective routes to 9. The first one involved the
synthesis of 2-hydroxymethyl chromans from enantio-
SYNTHESIS 2009, No. 11, pp 1886–1896
x
x.
x
x
.
2
0
0
9
Advanced online publication: 27.04.2009
DOI: 10.1055/s-0028-1088077; Art ID: Z01209SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Phenolate Ion Mediated Intramolecular Epoxide Ring Opening Reactions
1887
Our model synthesis to obtain enantiopure 2-isopropenyl-
2,3-dihydrobenzofurans commenced with the benzylation
of commercially available 2-hydroxy-3-methoxybenzal-
dehyde (18a) and 2-hydroxybenzaldehyde (18b) with
benzyl bromide in the presence of anhydrous potassium
carbonate in anhydrous acetone under reflux condition
furnishing 2-benzyloxybenzaldehydes 19a,b in good
yields (Scheme 2). Next, Wittig olefination of 19a,b with
methoxymethyltriphenylphosphonium chloride and
LHMDS in anhydrous tetrahydrofuran at 0 °C followed
by hydrolysis of the resulting olefins with aqueous 1.5 N
hydrochloric acid in tetrahydrofuran under reflux condi-
tion furnished corresponding one-carbon-homologated al-
dehydes 20a,b. Another Wittig olefination of aldehydes
20a,b with [(ethoxycarbonyl)methylene]triphenylphos-
phorane in anhydrous dichloromethane at room tempera-
ture furnished the corresponding trans-unsaturated esters
21a,b exclusively. Next, DIBAL-H reduction of 21a,b in
anhydrous toluene at 0 °C gave trans-allylic alcohols
22a,b, which were used for the subsequent Sharpless
asymmetric epoxidation reaction.22 Thus, 22a,b were
treated with titanium tetraisopropoxide and tert-butyl hy-
droperoxide (TBHP) in the presence of L-(+)-DIPT under
asymmetric epoxidation conditions to get chiral epoxides
23a,b in high yields (Scheme 2). The enantiomeric excess
values of 23a and 23b were determined to be 96% and
97%, respectively.23
2-aminomethyl chroman derivatives and
2-azaheterocyclylmethyl chroman derivatives
O
O
X
OH
2-alkyl chroman
derivatives
*
*
R
R
9
10
versatile intermediate
enantiomerically pure
X = leaving group
O
O
S
O
N
H
N
O
11 repinotan
F
O
N
H
N
12 sarizotan
Figure 2 Medicinally important 2-substituted chroman derivatives
merically enriched 2-vinylchroman (ee up to 53%), which
was synthesized by the palladium-catalyzed cyclization of
hydroxy allylic carbonate in the presence of various chiral
ligands.19 The second one described in an US patent in-
volved Sharpless asymmetric dihydroxylation reaction of
4-arylbut-1-ene derivatives furnishing 2-hydroxymethyl
chromans with very low ee.20
With compounds 23a,b in our hand, attention was then
turned to their elaboration into the corresponding 2-iso-
Taking into account all of these facts and our interest in
the asymmetric synthesis of heterocycles,21 we herein de-
scribe our results that illustrate efficient enantioselective
synthetic routes to 2-isopropenyl-2,3-dihydrobenzo-
furans, 4-(2,3-dihydrobenzofuran-2-yl)-2-methylbut-3-
en-2-ols, 2-hydroxymethyl chromans, and 4-chroman-2-
yl-2-methylbut-3-en-2-ols through phenolate ion mediat-
ed intramolecular ring-opening of Sharpless asymmetric
epoxidation-derived enantiomerically enriched epoxy al-
cohols.
R
R
R
OH
OBn
OBn
CHO
a
c
b
CHO
CHO
19a,b
20a,b
18a,b
SiH3
R
OBn
R
OBn
e
d
CO2Et
OH
Our envisioned retrosynthetic analysis for a general enan-
tioselective synthetic strategy to 2-isopropenyl-2,3-dihy-
drobenzofuran 13 is depicted in Scheme 1. The double
bond of the target molecule 13 was anticipated to be fash-
ioned by a Wittig reaction of 2-acetyl-2,3-dihydrobenzo-
furan obtained from the oxidation of alcohol 14.
Compound 14 was expected to be accessible from dihy-
droxy compound 15. Epoxide 16 was thought to be the
key intermediate to provide diol 15 via a phenolate ion
mediated intramolecular 5-exo-tet epoxide ring-opening
reaction.21c
21a,b
22a,b
OBn
a R = OMe
b R = H
O
OH
23a,b
Scheme 2 Reagents and conditions: (a) BnBr, anhyd K2CO3, anhyd
acetone, reflux, 4 h, 19a (85%), 19b (85%); (b) (i) MeOCH2Ph3P+Cl–,
LHMDS, anhyd THF, 0 °C–r.t., 3 h, (ii) 1.5 N HCl, THF, reflux, 3 h,
20a (70%), 20b (71%), based on two steps; (c) Ph3P=CHCO2Et, an-
hyd CH2Cl2, r.t., overnight, 21a (81%), 21b (75%); (d) DIBAL-H, an-
hyd toluene, 0 °C to r.t., 2 h, 22a (95%), 22b (94%); (e) L-(+)-DIPT,
Ti(Oi-Pr)4, TBHP, CH2Cl2, –25 °C, 18 h, 23a (85%), 23b (88%).
OH
OH
O
O
O
R
R
R
OH
15
14
13
OP
OP
R
O
R
CO2Et
OH
17
16
Scheme 1 Retrosynthetic analysis of 2-isopropenyl-2,3-dihydrobenzofurans
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

1888
S. K. Dinda et al.
PAPER
propenyl-2,3-dihydrobenzofuran derivatives. Thus de-
benzylation of 23a,b by means of 10% Pd/C-catalyzed
hydrogenolysis followed by treatment of the resulting
phenolic derivatives with 10% sodium hydroxide solution
saturated with sodium chloride furnished the correspond-
ing dihydroxy compound 24a,b via 5-exo-tet intramolec-
ular epoxide ring opening. Next, selective tosylation of
the primary hydroxy group of 24a,b gave monotosyloxy
products 25a,b.24 Lithium aluminum hydride mediated re-
ductive removal of the tosyloxy functionality of 25a,b fol-
R
R
OH
CO2Et
O
O
a
b
24a,b
28a,b
29a,b
Scheme 4 Reagents and conditions: (a) (i) NaIO4, MeOH–H2O,
0 °C, 2 h, (ii) Ph3P=CHCO2Et, anhyd CH2Cl2, r.t., overnight, 28a
(85%), 28b (87%), based on two steps; (b) MeMgI, anhyd Et2O, 0 °C,
reflux, 4 h, 29a (94%), 29b (93%).
lowed by PDC oxidation of the resulting alcohols yielded products 31a,b in excellent yields (Scheme 5). Next, hy-
2-acetyl-2,3-dihydrobenzofuran derivatives 26a,b. Final- droboration of 31a,b with 9-BBN followed by oxidation
ly, Wittig olefination of 26a,b with methyltriphenylphos- with sodium hydroxide and hydrogen peroxide furnished
phonium iodide and potassium tert-butoxide in anhydrous the primary alcohols 32a,b in high yields. PCC oxidation
tetrahydrofuran gave 2-isopropenyl-2,3-dihydrobenzofu- of 32a,b followed by Wittig olefination of the resulting al-
ran derivatives 27a,b (Scheme 3). The enantiomeric ex- dehydes 33a,b gave the corresponding trans-unsaturated
cess values of 27a and 27b were determined to be 94% esters 34a,b. Diisobutylaluminum hydride reduction of
and 96%, respectively.25
34a,b gave trans-allyl alcohols 35a,b. Next, 35a,b were
treated with titanium tetraisopropoxide and tert-butyl hy-
droperoxide in the presence of D-(–)-DIPT under asym-
R
R
metric epoxidation conditions to obtain chiral epoxides
36a,b in good yields. The enantiomeric excess values of
36a,b were determined to be 98% and 97%, respective-
ly.23 Epoxides 36a,b were then converted into diols 37a,b
as solid crystalline compounds by essentially following
the same route as that described for the synthesis of 24a,b
from 23a,b.28 Sodium periodate mediated cleavage reac-
tion of 37a,b furnished the corresponding 2-formylben-
zopyrans, which were then reduced by sodium
borohydride in methanol to their respective 2-hydroxy-
methyl chromans 38a,b. The enantiomeric excess values
of 38a,b were determined to be >99%.29
OH
O
OH
O
a
c
b
23a,b
OTs
OH
24a,b
25a,b
R
R
O
O
O
d
26a,b
27a,b
Scheme 3 Reagents and conditions: (a) (i) 10% Pd/C, EtOAc, H2, 2
h, (ii) aq 10% NaOH solution saturated with NaCl, 0 °C, 3 h, 24a
(80%), 24b (78%), based on two steps; (b) TsCl, anhyd Et3N, anhyd
CH2Cl2, 0 °C, overnight, 25a (75%), 25b (77%); (c) (i) LiAlH4, anhyd
THF, 0 °C to r.t., 3 h, (ii) PDC, anhyd CH2Cl2, 0 °C to r.t., 24 h, 26a
(68%), 26b (66%), based on the last two steps; (d) MePh3P+I–,
t-BuOK, anhyd THF, 0 °C to r.t., 12 h, 27a (78%), 27b (75%).
OH
OBn
OBn
a
b
OH
R
R
R
32a,b
31a,b
30a,b
After the enantioselective synthesis of 2-isopropenyl-2,3-
dihydrobenzofurans, our next attention was to synthesize
4-(2,3-dihydrobenzofuran-2-yl)-2-methylbut-3-en-2-ols.
This type of structural motif is the core structure of the re-
vised structure of heliannuol G (8a) and heliannuol H (8b)
(Figure 1).26 Towards that objective, diols 24a,b were
cleaved with sodium periodate in aqueous methanol fur-
nishing the corresponding 2-formyl 2,3-dihydrobenzo-
furans, which on treatment with [(ethoxycarbonyl)meth-
ylene]triphenylphosphorane in anhydrous dichloro-
methane at room temperature furnished the corresponding
trans-unsaturated esters 28a,b (Scheme 4). Next, treat-
ment of the esters 28a,b with an excess of methylmagne-
sium iodide furnished the tertiary alcohols 29a,b in very
high yields.
OBn
OBn
e
c
d
R
CO2Et
R
CHO
34a,b
33a,b
OBn
OBn
g
f
OH
OH
R
R
R
O
36a,b
35a,b
OH
O
O
OH
OH
h
a R = OMe
b R = H
R
38a,b
37a,b
Scheme 5 Reagents and conditions: (a) BnBr, anhyd K2CO3, anhyd
acetone, reflux, 4 h, 31a (95%), 31b (96%); (b) (i) 9-BBN, anhyd
THF, r.t., 4 h. (ii) 30% H2O2, NaOH, reflux, 2 h, 32a (94%), 32b
(96%); (c) PCC, anhyd CH2Cl2, 0 °C to r.t., 5 h, 33a (76%), 33b
(72%); (d) Ph3P=CHCO2Et, anhyd CH2Cl2, r.t., overnight, 34a (80%),
34b (77%); (e) DIBAL-H, anhyd toluene, 0 °C to r.t., 4 h, 35a (96%),
35b (95%); (f) D-(–)-DIPT, Ti(Oi-Pr)4, TBHP, CH2Cl2, –25 °C, 18 h,
36a (88%), 36b (90%); (g) (i) 10% Pd/C, EtOAc, H2, 2 h, (ii) aq 10%
NaOH solution saturated with NaCl, 0 °C, 3 h, 37a (83%), 37b (84%),
based on two steps; (h) (i) NaIO4, MeOH–H2O, 0 °C, 2 h, (ii) NaBH4,
Our next aim was to synthesize enantiomerically pure 2-
hydroxymethyl chromans applying a similar strategy. To-
wards that objective, known 5-methoxy-2-allylphenol
(30a)27 and commercially available 2-allylphenol (30b)
were treated with benzyl bromide in the presence of anhy-
drous potassium carbonate in anhydrous acetone under re-
flux condition to get the corresponding benzylated MeOH, 0 °C to r.t., 0.5 h, 38a (87%), 38b (89%), based on two steps.
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

PAPER
Phenolate Ion Mediated Intramolecular Epoxide Ring Opening Reactions
1889
OH
O
CO2Et
O
a
b
37a,b
R
R
39a,b
40a,b
Scheme 6 Reagents and conditions: (a) (i) NaIO4, MeOH–H2O, 0 °C, 2 h, (ii) Ph3P=CHCO2Et, anhyd CH2Cl2, r.t., overnight, 39a (88%), 39b
(90%), based on two steps; (b) MeMgI, anhyd Et2O, 0 °C to reflux, 4 h, 40a (93%), 40b (95%).
(Na2SO4), and concentrated under reduced pressure. Purification of
the crude product by silica gel column chromatography (6% EtOAc
in n-hexane) afforded 19a (8.12 g, 85%) as a colorless solid; mp 59–
60 °C.
Next, we were interested to utilize diols 37a,b for the syn-
thesis of 1-benzopyran analogues of 2-(2,3-dihydroben-
zofuran-2-yl)-2-methylbut-3-en-2-ols. Toward that end,
37a,b were converted into 40a,b using the same reaction
sequence as that described for the synthesis of 29a,b from
24a,b (Scheme 6).
IR (KBr): 2929, 2363, 1687, 1586, 1479, 1371, 1257, 1070, 755
cm–1.
1H NMR (200 MHz, CDCl3): d = 10.22 (s, 1 H), 7.40–7.32 (m, 6 H),
7.16–7.12 (m, 2 H), 5.17 (s, 2 H), 3.93 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 190.5, 153.3, 151.3, 136.6, 130.6,
In conclusion, an efficient asymmetric synthesis of 2-iso-
propenyl-2,3-dihydrobenzofurans, 4-(2,3-dihydrobenzo-
furan-2-yl)-2-methylbut-3-en-2-ols,
2-hydroxymethyl
129.0, 128.9, 128.8, 124.5, 119.3, 118.3, 76.6, 56.3.
chromans, and 4-chroman-2-yl-2-methylbut-3-en-2-ols
has been developed. Key steps include Sharpless asym-
metric epoxidation on suitable allyl alcohols and con-
struction of the 2,3-dihydrobenzofuran and 1-benzopyran
nuclei by phenolate ion mediated intramolecular epoxide
ring-opening reactions. Further applications of these and
related intermediates for the construction of biologically
important molecules will be disclosed in due course.
MS (ESI): m/z = 242 [M]+, 91 [C6H5CH2]+.
Anal. Calcd for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.43; H,
5.95.
The above physical and spectroscopic data were consistent with the
literature data.30
2-Benzyloxybenzaldehyde (19b)
Using the above procedure compound 19b was prepared from 18b
in 85% yield and its physical and spectroscopic data were in full
agreement with our previously reported data of the same com-
pound.21c
All dry reactions were carried out under N2 in oven-dried glassware
using standard gas-tight syringes, cannulas, and septa. All reagents
and solvents were dried prior to use according to the standard meth-
ods. Commercial reagents were used without further purification
unless otherwise stated. Reactions were monitored on silica gel
TLC plates (coated with TLC grade silica gel, obtained from
Merck). Detecting agents used (for TLC) were I2 vapors and/or spray-
ing with an aq solution of vanillin in 10% H2SO4 followed by heating
at 150 °C. Column chromatography was performed over silica gel
(100–200 mesh) procured from Qualigens (India) using freshly dis-
tilled solvents. Mass spectra were recorded using electron spray
ionization (ESI-MS) or fast atom bombardment spectra (FAB-MS)
on a Jeol SX 102 spectrometer using argon/xenon as the FAB gas.
Elemental analyses were done on Varian EL-III C H N analyzer.
Melting points were determined on COMPLAB melting point
apparatus and are uncorrected. IR spectra were recorded on a
2-(2-Benzyloxy-3-methoxyphenyl)acetaldehyde (20a)
To a stirred suspension of methoxymethyltriphenylphosphonium
chloride (16.97 g, 49.52 mmol) in anhyd THF (60 mL) was added a
solution of LHMDS (1 M in THF, 50 mL, 50 mmol) dropwise un-
der N2 at 0 °C. The resulting red solution was stirred at this temper-
ature for 45 min, and then compound 19a (6.00 g, 24.76 mmol) in
THF (30 mL) was added dropwise over 15 min. The reaction mix-
ture was allowed to stir at r.t. for 2 h followed by the addition of sat.
aq NH4Cl (50 mL). The resulting mixture was extracted with Et2O
(3 × 50 mL) and the combined organic extracts were dried
(MgSO4), and evaporated to give a yellow oil. The resulting oil was
loaded on a small pad of silica gel and eluted with Et2O to remove
the baseline impurities. The crude product thus obtained was used
in the next step without further purification. A solution of the above
crude product in THF (60 mL) and aq 1.5 N HCl (25 mL) was re-
fluxed for 3 h. The mixture was then diluted with H2O (50 mL) and
extracted with Et2O (2 × 100 mL). The combined organic layers
were washed with aq NaHCO3 (20 mL) and brine (30 mL), and
dried (MgSO4). Evaporation of the solvent and purification of the
residue over a silica gel column using 6% EtOAc in n-hexane as elu-
ent furnished aldehyde 20a as a colorless oil (4.76 g, 70%).
1
Perkin-Elmer FT-IR RXI spectrometer. H NMR and 13C NMR
spectra were recorded on Bruker DPX-200 (operating at 200 MHz
for 1H and 50 MHz for 13C) or DPX-300 (operating at 300 MHz for
1H and 75 MHz for 13C) spectrometer using CDCl3 or CDCl3 plus
CCl4 as solvent. Tetramethylsilane (0.00 ppm) served as an internal
standard in 1H NMR and CDCl3 (77.0 ppm) in 13C NMR spectral de-
terminations. All spectra were recorded at 25 °C. Coupling con-
stants (J values) are given in hertz (Hz). Chemical shifts were
expressed in parts per million. Optical rotations were measured at
the sodium D-line at r.t. with a Perkin-Elmer 141 polarimeter.
IR (neat): 3019, 2360, 1722, 1588, 1476, 1270, 1215, 1082, 759
cm–1.
1H NMR (200 MHz, CDCl3): d = 9.51 (t, J = 2.0 Hz, 1 H), 7.40–7.27
(m, 5 H), 7.06–6.98 (m, 1 H), 6.87 (dd, J = 1.6, 8.2 Hz, 1 H), 6.69
(dd, J = 1.4, 8.2 Hz, 1 H), 5.00 (s, 2 H), 3.85 (s, 3 H), 3.52 (d, J = 2.0
Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 199.4, 152.7, 145.9, 137.2, 128.2,
128.1, 127.8, 126.6, 124.1, 122.6, 111.8, 74.3, 55.5, 45.0.
2-Benzyloxy-3-methoxybenzaldehyde (19a)
To a solution of commercially available 2-hydroxy-3-methoxyben-
zaldehyde (18a; 6.00 g, 39.43 mmol) in anhyd acetone (100 mL)
was added anhyd K2CO3 (8.17 g, 59.14 mmol) and benzyl bromide
(5.63 mL, 47.31 mmol) and the resulting mixture was refluxed for
4 h. The mixture was filtered through Celite and the filter cake was
washed with acetone (100 mL). The filtrate was concentrated and
the resulting residue was dissolved in EtOAc (100 mL). The EtOAc
layer was washed with H2O (2 × 100 mL) and brine (100 mL), dried
MS (ESI): m/z = 256 [M]+.
Anal. Calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 74.85; H,
6.42.
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

1890
S. K. Dinda et al.
PAPER
2-(2-Benzyloxyphenyl)acetaldehyde (20b)
IR (neat): 3385, 3032, 2921, 2863, 1597, 1493, 1452, 1240, 1010,
974, 750, 697 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.44–7.33 (m, 5 H), 7.17–7.13 (m,
2 H), 6.94–6.87 (m, 2 H), 5.84–5.80 (m, 1 H), 5.72–5.67 (m, 1 H),
5.07 (s, 2 H), 4.07 (d, J = 5.6 Hz, 2 H), 3.43 (d, J = 6.6 Hz, 2 H).
Using the above procedure compound 20b was also prepared from
compound 19b in 71% yield and its physical and spectroscopic data
were in full agreement with our previously reported data of the same
compound.21c
13C NMR (75 MHz, CDCl3): d = 156.3, 137.2, 131.1, 129.94,
129.91, 128.8, 128.4, 127.7, 127.4, 127.1, 120.8, 111.7, 69.8, 63.6,
33.0.
(E)-Ethyl 4-(2-Benzyloxy-3-methoxyphenyl)but-2-enoate (21a)
To a solution of 20a (4.00 g, 15.6 mmol) in anhyd CH2Cl2 (40 mL)
was added [(ethoxycarbonyl)methylene]triphenylphosphorane
(7.06 g, 20.28 mmol) at r.t. The reaction mixture was stirred over-
night at r.t. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography (4%
EtOAc in n-hexane) to afford 21a (4.10 g, 81%) as a colorless oil.
MS (ESI): m/z = 237 [M – OH]+, 272 [M + NH4]+.
Anal. Calcd for C17H18O2: C, 80.28; H, 7.13. Found: C, 80.21; H,
7.26.
IR (KBr): 3019, 2361, 1709, 1475, 1271, 1216, 1082, 756, 669
cm–1.
[(2S,3S)-3-(2-Benzyloxy-3-methoxybenzyl)oxiran-2-yl]meth-
anol (23a)
1H NMR (300 MHz, CDCl3): d = 7.43–7.27 (m, 5 H), 7.04–6.95 (m,
2 H), 6.83 (dd, J = 1.2, 8.1 Hz, 1 H), 6.71 (dd, J = 1.2, 7.6 Hz, 1 H),
5.70 (td, J = 1.5, 15.6 Hz, 1 H), 4.99 (s, 2 H), 4.13 (q, J = 7.1 Hz, 2
H), 3.91 (s, 3 H), 3.43 (dd, J = 1.4, 6.6 Hz, 2 H), 1.23 (t, J = 7.1 Hz,
2 H).
13C NMR (75 MHz, CDCl3): d = 166.4, 152.8, 147.2, 145.7, 137.6,
131.8, 128.3, 128.0, 127.8, 124.0, 122.0, 111.0, 74.6, 60.0, 55.6,
32.5, 14.1.
To a cooled (–25 °C) suspension of activated and powdered 4 Å MS
(2.00 g) in anhyd CH2Cl2 (30 mL) were added L-(+)-DIPT
(1.80 mL, 10.55 mmol) and Ti(Oi-Pr)4 (2.87 mL, 9.67 mmol). The
resulting mixture was then stirred for 20 min at the same tempera-
ture and then TBHP (5.6 M in n-decane, 4.7 mL, 26.37 mmol) was
added dropwise. After 20 min, a solution of 22a (2.50 g, 8.79 mmol)
in anhyd CH2Cl2 (20 mL) was added dropwise over 15 min. The re-
sulting mixture was kept at –25 °C for 18 h. The mixture was al-
lowed to warm to 0 °C and poured into a freshly prepared and
cooled (0 °C) solution of FeSO4 and tartaric acid (2.50 g and 1.00 g,
respectively) in deionized H2O (20 mL). The two-phase mixture
was stirred for 30 min, the aqueous phase separated and extracted
with CH2Cl2 (3 × 30 mL). The combined organic phases were treat-
ed with a precooled (0 °C) solution of aq 30% NaOH (20 mL) in
brine. The two-phase mixture was then stirred for 1 h at r.t., the
aqueous layer separated, and extracted with CH2Cl2 (2 × 30 mL).
The combined organic extracts were washed with brine (30 mL),
dried (Na2SO4), and concentrated under reduced pressure. Purifica-
tion of the crude product by silica gel column chromatography
(30% EtOAc in n-hexane) afforded 23a (2.24 g, 85%) as a colorless
oil; [a]D25 –12.37 (c 2.6, CHCl3).
MS (FAB): m/z = 327 [M + 1]+, 281 [M – OEt]+.
Anal. Calcd for C20H22O4: C, 73.60; H, 6.79. Found: C, 73.67; H,
6.92.
(E)-Ethyl 4-(2-Benzyloxyphenyl)but-2-enoate (21b)
Using the above procedure compound 21b was also prepared from
20b in 75% yield and its physical and spectroscopic data were in full
agreement with our previously reported data of the same com-
pound.21c
(E)-4-(2-Benzyloxy-3-methoxyphenyl)but-2-en-1-ol (22a)
To an ice-cooled stirred solution of 21a (3.50 g, 10.72 mmol) in an-
hyd toluene (30 mL) was added DIBAL-H (1 M in toluene, 27 mL,
27 mmol) dropwise under N2. The reaction mixture was stirred at
r.t. for 2 h, cooled to 0 °C, carefully quenched with MeOH (5 mL)
and sat. aq potassium sodium tartrate (25 mL). The resulting mix-
ture was vigorously stirred for 45 min at r.t. and then extracted with
EtOAc (2 × 50 mL). The combined organic extracts were washed
with H2O (50 mL) and brine (100 mL), dried (Na2SO4), and concen-
trated under reduced pressure. Purification of the crude product by
silica gel column chromatography (20% EtOAc in n-hexane) af-
forded 22a (2.90 g, 95%) as a colorless gum.
IR (neat): 3020, 2360, 1730, 1474, 1216, 760, 670 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46–7.32 (m, 5 H), 7.04–6.99 (m,
1 H), 6.87–6.82 (m, 2 H), 5.10–4.9 (m, 2 H), 3.90 (s, 3 H), 3.77 (d,
J = 12.5 Hz, 1 H), 3.50 (d, J = 11.4 Hz, 1 H), 3.07–3.03 (m, 1 H),
2.92–2.76 (m, 3 H), 2.17 (s, 1 H).
13C NMR (75 MHz, CDCl3 + CCl4): d = 152.7, 146.0, 137.8, 131.2,
128.3, 127.9, 124.0, 122.4, 111.2, 74.6, 61.6, 58.5, 55.7, 55.5, 32.2.
MS (ESI): m/z = 301 [M + 1]+, 318 [M + NH4]+.
Anal. Calcd for C18H20O4: C, 71.98; H, 6.71. Found: C, 72.17; H,
6.68.
IR (KBr): 3421, 3017, 2361, 1638, 1474, 1272, 1216, 1081, 759
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42–7.28 (m, 5 H), 7.01–6.93 (m,
1 H), 6.81–6.68 (m, 2 H), 5.74–5.65 (m, 1 H), 5.59–5.50 (m, 1 H),
4.97 (s, 2 H), 3.99 (d, J = 5.6 Hz, 2 H), 3.86 (s, 3 H), 3.29 (d, J = 6.3
Hz, 2 H).
13C NMR (75 MHz, CDCl3 + CCl4): d = 152.9, 145.9, 138.1, 134.2,
131.2, 130.2, 128.5, 128.3, 128.0, 127.8, 123.9, 121.2, 110.8, 74.6,
63.5, 55.8, 32.8.
[(2S,3S)-3-(2-Benzyloxybenzyl)oxiran-2-yl]methanol (23b)
From 22b (2.50 g, 9.83 mmol), the title compound was prepared in
the same manner as that described for 23a. Purification of the crude
product by silica gel column chromatography (30% EtOAc in
n-hexane) afforded 23b (2.34 g, 88%) as a colorless oil; [a]D25 –1.7
(c 2.2, CHCl3).
IR (neat): 3434, 3019, 2926, 1495, 1216, 1020, 760, 669 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.43–7.30 (m, 5 H), 7.24–7.17 (m,
2 H), 6.94–6.87 (m, 2 H), 5.05 (s, 2 H), 3.85–3.74 (m, 1 H), 3.59–
3.48 (m, 1 H), 3.22–3.17 (m, 1 H), 2.99–2.89 (m, 3 H), 2.15 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 156.7, 137.1, 130.7, 128.67,
128.62, 128.1, 128.0, 127.4, 127.3, 125.7, 120.9, 111.7, 70.0, 61.6,
58.7, 55.2, 32.6.
MS (ESI): m/z = 302 [M + NH4]+, 267 [M – OH]+.
Anal. Calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 76.15; H,
7.21.
(E)-4-(2-Benzyloxyphenyl)but-2-en-1-ol (22b)
From 21b (3.50 g, 11.8 mmol), the title compound was prepared in
the same manner as that described for 22a. Purification of the crude
product by silica gel column chromatography (18% EtOAc in n-
hexane) afforded 22b (2.82 g, 94%) as a colorless gum.
MS (ESI): m/z = 271 [M + 1]+, 288 [M + NH4]+.
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.47; H,
6.88.
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

PAPER
Phenolate Ion Mediated Intramolecular Epoxide Ring Opening Reactions
1891
(R)-1-[(S)-7-Methoxy-2,3-dihydrobenzofuran-2-yl]ethane-1,2-
diol (24a)
MS (ESI): m/z = 382 [M + NH4]+, 387 [M + Na]+.
Anal. Calcd for C18H20O6S: C, 59.33; H, 5.53. Found: C, 59.42; H,
5.71.
To a stirred solution of 23a (2.00 g, 6.65 mmol) in EtOAc (30 mL)
was added 10% Pd/C (250 mg). After stirring for 2 h at r.t. under an
H2-filled balloon, the reaction mixture was filtered through a pad of
Celite and the filtrate was concentrated under reduced pressure to
get the corresponding debenzylated product as a colorless solid,
which was used for the next step without further purification. To an
ice-cooled stirred solution of the above debenzylated product in
CH2Cl2 (20 mL) was added a precooled (0 °C) solution of aq 30%
NaOH (20 mL) in brine. The two-phase mixture was then stirred for
3 h at r.t., the aqueous layer separated, and extracted with CH2Cl2
(2 × 30 mL). The combined organic extracts were washed with
brine (30 mL), dried (Na2SO4), and concentrated under reduced
pressure. Purification of the crude product by silica gel column
chromatography (35% EtOAc in n-hexane) afforded 24a (1.12 g,
80%) as a colorless crystalline solid; mp 102–103 °C; [a]D25 –7.4
(c 1.07, MeOH).
(R)-2-[(S)-2,3-Dihydrobenzofuran-2-yl]-2-hydroxyethyl
4-Methylbenzenesulfonate (25b)
From 24b (1.00 g, 5.55 mmol), the title compound was prepared in
the same manner as that described for 25a. Purification of the crude
product by silica gel column chromatography (20% EtOAc in n-
hexane) afforded 25b (1.43 g, 77%) as a colorless semi-solid; [a]D
–7.66 (c 0.95, EtOH).
IR (KBr): 3429, 2921, 1635, 1474, 1357, 1175, 757 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.81 (d, J = 8.3 Hz, 2 H), 7.35 (d,
J = 8.1 Hz, 2 H), 7.17–7.05 (m, 2 H), 6.88–6.80 (m, 1 H), 6.70 (d,
J = 7.9 Hz, 2 H), 4.70–4.62 (m, 1 H), 4.33–4.26 (m, 1 H), 4.19–4.11
(m, 1 H), 3.97–3.95 (m, 1 H), 3.22 (d, J = 8.2 Hz, 2 H), 2.45 (s, 3 H).
25
MS (ESI): m/z = 352 [M + NH4]+, 357 [M + Na]+.
IR (KBr): 3408, 3020, 2360, 1710, 1215, 761, 670 cm–1.
Anal. Calcd for C17H18O5S: C, 61.06; H, 5.43. Found: C, 61.23; H,
5.28.
1H NMR (300 MHz, CDCl3): d = 6.84–6.80 (m, 2 H), 6.75–6.70 (m,
1 H), 4.84–4.76 (m, 1 H), 4.04–3.99 (m, 1 H), 3.84 (s, 3 H), 3.79–
3.68 (m, 2 H), 3.33–3.12 (m, 2 H), 3.00 (s, 1 H), 2.63 (s, 1 H).
(R)-1-(7-Methoxy-2,3-dihydrobenzofuran-2-yl)ethanone (26a)
To an ice-cooled suspension of LiAlH4 (0.26 g, 6.85 mmol) in an-
hyd THF (10 mL) was added a solution of 25a (1.00 g, 2.74 mmol)
in anhyd THF (15 mL) dropwise and the resulting mixture was
stirred for 3 h at r.t. It was quenched by dropwise addition of EtOAc
(5 mL) and H2O (20 mL) at 0 °C. The mixture was extracted with
EtOAc (2 × 30 mL). The combined extracts were washed with brine
(25 mL), dried (Na2SO4), and concentrated under reduced pressure.
The crude product obtained as a colorless gum was used in the next
step without further purification. To an ice-cooled stirring solution
of the above crude product in anhyd CH2Cl2 (30 mL) was added
PDC (2.78 g, 7.38 mmol). The mixture was then stirred for 24 h at
r.t. After evaporating the CH2Cl2, the mixture was diluted with Et2O
(50 mL) and filtered through a small pad of silica gel. Concentration
of the filtrate and purification of the residue by silica gel column
chromatography (10% EtOAc in n-hexane) afforded 26a (0.37 g,
68%) as a colorless semi-solid; [a]D25 +4.7 (c 1.0, CHCl3).
13C NMR (75 MHz, CDCl3): d = 147.2, 144.2, 127.8, 121.3, 117.2,
110.8, 83.6, 72.7, 63.1, 55.8, 31.2.
MS (ESI): m/z = 211 [M + 1]+, 228 [M + NH4]+.
Anal. Calcd for C11H14O4: C, 62.85; H, 6.71. Found: C, 62.95; H,
6.55.
(R)-1-[(S)-2,3-Dihydrobenzofuran-2-yl]ethane-1,2-diol (24b)
From 23b (2.00 g, 7.39 mmol), the title compound was prepared in
the same manner as that described for 24a. Purification of the crude
product by silica gel column chromatography (35% EtOAc in n-
hexane) afforded 24b (1.04 g, 78%) as a colorless crystalline solid;
mp 55–56 °C; [a]D25 –6.68 (c 0.49, MeOH).
IR (KBr): 3430, 3021, 2924, 1216, 1020, 760, 669 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.26–7.07 (m, 2 H), 6.89–6.75 (m,
2 H), 4.83–4.72 (m, 1 H), 3.99–3.92 (m, 1 H), 3.88–3.79 (m, 2 H),
3.25 (d, J = 8.6 Hz, 2 H), 2.38 (br s, 1 H), 2.04 (br s, 1 H).
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.1, 128.0, 126.4, 125.1,
120.8, 109.3, 82.7, 73.0, 63.3, 31.3.
IR (KBr): 3021, 2360, 1719, 1493, 1289, 1215, 1086, 760, 670
cm–1.
1H NMR (200 MHz, CDCl3): d = 6.91–6.75 (m, 3 H), 5.13–5.04 (m,
1 H), 3.90 (s, 3 H), 3.57–3.26 (m, 2 H), 2.33 (s, 3 H).
13C NMR (75 MHz, CDCl3 + CCl4): d = 208.5, 147.1, 144.5, 126.3,
121.9, 116.9, 111.5, 86.1, 56.0, 33.1, 26.0.
MS (ESI): m/z = 210 [M + NH4]+.
MS (ESI): m/z = 181 [M + 1]+, 198 [M + NH4]+.
Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found: C, 66.79; H,
6.51.
(R)-2-Hydroxy-2-[(S)-7-methoxy-2,3-dihydrobenzofuran-2-
yl]ethyl 4-Methylbenzenesulfonate (25a)
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.85; H,
6.37.
To a solution of diol 24a (1.00 g, 4.75 mmol) in anhyd CH2Cl2
(15 mL) at 0 °C was added anhyd Et3N (1.16 mL, 8.31 mmol) fol-
lowed by TsCl (0.91 g, 4.75 mmol) and the mixture was kept over-
night in the refrigerator. The mixture was diluted with H2O (15 mL)
and extracted with CH2Cl2 (2 × 30 mL). The combined organic lay-
ers were washed with H2O (25 mL), brine (25 mL), and dried
(Na2SO4). The solvent was removed under reduced pressure and pu-
rification of the crude product by silica gel column chromatography
(20% EtOAc in n-hexane) afforded 25a (1.30 g, 75%) as a colorless
solid; mp 108–110 °C; [a]D25 –1.9 (c 2.58, MeOH).
(S)-1-(2,3-Dihydrobenzofuran-2-yl)ethanone (26b)
From 25b (1.00 g, 2.99 mmol), the title compound was prepared in
the same manner as that described for 26a. Purification of the crude
product by silica gel column chromatography (10% EtOAc in n-
hexane) afforded 26b (0.35 g, 66%) as a light yellow gum; [a]D
+3.7 (c 3.2, CHCl3).
IR (KBr): 3021, 2927, 2361, 1729, 1217, 1045, 761, 670 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.20–7.12 (m, 2 H), 6.93–6.86 (m,
2 H), 5.08–4.99 (m, 1 H), 3.48–3.31 (m, 2 H), 2.29 (s, 3 H).
MS (ESI): m/z = 180 [M + NH4]+.
25
IR (KBr): 3493, 2363, 1593, 1490, 1192, 1088, 809 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.79 (d, J = 8.4 Hz, 2 H), 7.34 (d,
J = 8.1 Hz, 2 H), 6.84–6.70 (m, 3 H), 4.86–4.69 (m, 1 H), 4.30–3.95
(m, 3 H), 3.81 (s, 3 H), 3.30–3.14 (m, 2 H), 2.71–2.65 (m, 1 H), 2.44
(s, 3 H).
Anal. Calcd for C10H10O2: C, 74.06; H, 6.21. Found: C, 74.22; H,
6.31.
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

1892
S. K. Dinda et al.
PAPER
(R)-7-Methoxy-2-(prop-1-en-2-yl)-2,3-dihydrobenzofuran
(27a)
1H NMR (300 MHz, CDCl3): d = 6.94 (dd, J = 5.2, 15.6 Hz, 1 H),
6.75–6.66 (m, 3 H), 6.06 (dd, J = 1.4, 15.6 Hz, 1 H), 5.36–5.28 (m,
1 H), 4.12 (q, J = 7.1 Hz, 2 H), 3.81 (s, 3 H), 3.44–3.36 (m, 1 H),
3.03–2.95 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.7, 147.3, 145.3, 144.5, 126.5,
121.5, 121.4, 117.0, 111.7, 81.0, 60.3, 55.8, 35.9, 14.1.
To a suspension of methyltriphenylphosphonium iodide (1.88 g,
4.65 mmol) in anhyd THF (15 mL) under N2 at 0 °C was added t-
BuOK (0.52 g, 4.65 mmol). The reaction mixture was stirred for
15 min at 0 °C and was then warmed to r.t. while stirring was con-
tinued for 45 min. The solution was then recooled to 0 °C, and a so-
lution of ketone 22a (0.30 g, 1.55 mmol) in anhyd THF (10 mL)
was added dropwise. The mixture was then warmed to r.t. and
stirred for an additional 12 h. The reaction was quenched with sat.
aq NH4Cl (10 mL) and extracted with Et2O (3 × 10 mL). The com-
bined organic extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (4% EtOAc in n-
MS (ESI): m/z = 266 [M + NH4]+.
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.85; H,
6.63.
(R,E)-Ethyl 3-(2,3-Dihydrobenzofuran-2-yl)acrylate (28b)
From 24b (100 mg, 0.55 mmol), the title compound was prepared
in the same manner as that described for 28a. Purification of the
crude product by silica gel column chromatography (4% EtOAc in
25
hexane) to give alkene 27a (0.23 g, 78%) as a colorless oil; [a]D
+12.9 (c 0.79, EtOH).
25
n-hexane) afforded 28b (104 mg, 87%) as a colorless gum; [a]D
IR (neat): 3020, 2928, 2361, 1490, 1287, 1216, 1087, 761, 669 cm–1.
+18.08 (c 1.46, MeOH).
IR (neat): 3021, 2929, 2361, 1726, 1475, 1216, 1087, 761 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.83–6.72 (m, 3 H), 5.29–5.19 (m,
1 H), 5.10 (s, 1 H), 4.91 (s, 1 H), 3.87 (s, 3 H), 3.37–3.29 (m, 1 H),
3.12–3.03 (m, 1 H), 1.78 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 148.1, 144.3, 143.6, 127.8, 120.8,
117.0, 112.4, 111.3, 86.5, 56.0, 35.1, 17.1.
1H NMR (300 MHz, CDCl3): d = 7.15–7.10 (m, 2 H), 7.01 (dd,
J = 5.0, 15.6 Hz, 1 H), 6.88–6.80 (m, 2 H), 6.12 (dd, J = 0.8, 15.6
Hz, 1 H), 5.38–5.31 (m, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 3.51–3.43
(m, 1 H), 3.08–3.00 (m, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.7, 159.1, 145.7, 128.3, 125.2,
124.8, 121.4, 120.8, 109.6, 80.4, 60.4, 35.6, 14.2.
MS (ESI): m/z = 190 [M]+, 208 [M + NH4]+.
Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.83; H,
7.31.
MS (ESI): m/z = 236 [M + NH4]+.
Anal. Calcd for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.68; H,
6.37.
(R)-2-(Prop-1-en-2-yl)-2,3-dihydrobenzofuran (27b)
From 26b (0.30 g, 1.85 mmol), the title compound was prepared in
the same manner as that described for 27a. Purification of the crude
product by silica gel column chromatography (4% EtOAc in n-hex-
ane) afforded 27b (0.22 g, 75%) as a colorless oil;27 [a]D25 +10.6 (c
1.0, EtOH) {Lit.31 [a]D25 +10.9 (EtOH)}.
(R,E)-4-(7-Methoxy-2,3-dihydrobenzofuran-2-yl)-2-methylbut-
3-en-2-ol (29a)
To a freshly prepared, magnetically stirred, ice-cold suspension of
MeMgI [prepared from MeI (0.28 mL, 3.5 mmol) and Mg turnings
(0.085 g, 3.5 mmol) in anhyd Et2O (10 mL)] was added a solution
of ester 28a (75 mg, 0.30 mmol) in anhyd THF (5 mL). The reaction
mixture was refluxed for 4 h, cooled, and quenched with aq NH4Cl
(10 mL). The mixture was extracted with EtOAc (2 × 25 mL). The
combined organic extracts were washed with H2O (25 mL) and
brine (25 mL), dried (Na2SO4), and concentrated under reduced
pressure. Purification of the crude product by silica gel column
chromatography (12% EtOAc in n-hexane) afforded 29a (0.07 mg,
94%) as a colorless gum; [a]D25 –2.08 (c 0.75, MeOH).
IR (KBr): 3020, 2927, 2360, 1216, 1045, 761, 670 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.16–7.08 (m, 2 H), 6.85–6.78 (m,
2 H), 5.16 (t, J = 8.9 Hz, 1 H), 5.09 (s, 1 H), 4.91 (s, 1 H), 3.37–3.29
(m, 2 H), 3.08–3.00 (m, 2 H), 1.77 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.7, 144.0, 128.0, 126.5, 124.7,
120.3, 111.9, 109.2, 85.6, 34.7, 17.2.
MS (ESI): m/z = 160 [M]+, 178 [M + NH4]+.
Anal. Calcd for C10H10O2: C, 74.06; H, 6.21. Found: C, 74.22; H,
6.31.
IR (neat): 3021, 2361, 1593, 1216, 763 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.77–6.66 (m, 3 H), 5.93–5.75 (m,
2 H), 5.21–5.13 (m, 1 H), 3.79 (s, 3 H), 3.33–3.25 (m, 1 H), 2.99–
2.9 (m, 1 H), 1.26 (s, 6 H).
The above physical and spectroscopic data were consistent with the
literature data.8
(R,E)-Ethyl3-(7-Methoxy-2,3-dihydrobenzofuran-2-yl)acrylate
(28a)
13C NMR (75 MHz, CDCl3): d = 147.6, 144.4, 141.2, 127.8, 125.8,
121.0, 117.0, 111.0, 83.9, 70.5, 55.8, 36.6, 29.6.
To a stirred solution of diol 24a (100 mg, 0.47 mmol) in MeOH (5
mL) at 0 °C was added a solution of NaIO4 (152 mg, 0.71 mmol) in
H2O (2 mL). After stirring the reaction mixture at 0 °C for 2 h,
MeOH was evaporated in vacuo at low temperature. The aqueous
solution was extracted with CH2Cl2 (2 × 10 mL). The combined or-
ganic layers were washed with H2O (10 mL), brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure to yield the
crude aldehyde as a colorless gum, which was used for the next step
without further purification. To a solution of the above crude alde-
hyde in anhyd CH2Cl2 (5 mL) was added [(ethoxycarbonyl)methyl-
ene]triphenylphosphorane (235 mg, 0.67 mmol) at r.t. The mixture
was stirred overnight at r.t. The solvent was removed under reduced
pressure and the residue was purified by silica gel column chroma-
tography (4% EtOAc in n-hexane) to afford 28a (99 mg, 85%) as a
colorless gum; [a]D25 +18.08 (c 0.62, MeOH).
MS (ESI): m/z = 217 [M – OH]+, 233 [M – 1]+.
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found C, 71.90; H,
7.67.
(R,E)-4-(2,3-Dihydrobenzofuran-2-yl)-2-methylbut-3-en-2-ol
(29b)
From 28b (75 mg, 0.34 mmol), the title compound was prepared in
the same manner as that described for 29a. Purification of the crude
product by silica gel column chromatography (12% EtOAc in n-
hexane) afforded 29b (65 mg, 93%) as a light yellow gum; [a]D
–7.72 (c 0.6, MeOH).
IR (neat): 3430, 3019, 2361, 1729, 1478, 1219, 761 cm–1.
25
1H NMR (200 MHz, CDCl3): d = 7.15–7.08 (m, 2 H), 6.86–6.76 (m,
2 H), 6.01–5.83 (m, 2 H), 5.23–5.15 (m, 1 H), 3.41–3.33 (m, 1 H),
3.04–2.96 (m, 1 H).
IR (neat): 3020, 2935, 2361, 1715, 1492, 1273, 1216, 1087, 759
cm–1.
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

PAPER
Phenolate Ion Mediated Intramolecular Epoxide Ring Opening Reactions
1893
13C NMR (75 MHz, CDCl3 + CCl4): d = 159.3, 140.9, 128.1, 126.4,
3-[2-(Benzyloxy)-5-methoxyphenyl]propanal (33a)
126.2, 124.8, 120.5, 109.4, 82.9, 70.5, 36.3, 29.8.
MS (ESI): m/z = 287 [M – OH]+, 203 [M – 1]+.
To a stirred solution of 32a (3.00 g, 11.01 mmol) in anhyd CH2Cl2
(50 mL) was added 4 Å molecular sieves (3.85 g) and PCC (3.20 g,
14.84 mmol) at 0 °C and the mixture was stirred at r.t. for 5 h. After
evaporating CH2Cl2, the mixture was diluted with Et2O (50 mL) and
filtered through a small pad of silica gel. Concentration of the fil-
trate and purification of the residue by silica gel column chromatog-
raphy (4% EtOAc in n-hexane) afforded 33a (2.26 g, 76%) as a
colorless gum.
1H NMR (200 MHz, CDCl3): d = 9.69 (t, J = 1.5 Hz, 1 H), 7.36–7.29
(m, 5 H), 6.81–6.64 (m, 3 H), 4.96 (s, 2 H), 3.68 (s, 3 H), 2.93 (t,
J = 7.3 Hz, 2 H), 2.70–2.63 (m, 2 H).
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.63; H,
7.99.
3-Allyl-4-benzyloxyanisole (31a)
To a solution of 30a (4.00 g, 24.36 mmol) in anhyd acetone (50 mL)
was added anhyd K2CO3 (5.0 g, 36.17 mmol) and benzyl bromide
(2.9 mL, 24.36 mmol) and the mixture was refluxed for 4 h. The
mixture was then filtered through Celite and the filter cake was
washed well with acetone (100 mL). The filtrate was concentrated
and the resulting residue was dissolved in EtOAc (100 mL). The
EtOAc layer was washed with H2O (2 × 50 mL) and brine (50 mL).
The organic layer was dried (Na2SO4), filtered, and then concentrat-
ed under vacuo. Purification of the crude product by silica gel col-
umn chromatography (2% EtOAc in n-hexane) afforded 31a (5.88
g, 95%) as a colorless oil.
13C NMR (50 MHz, CDCl3): d = 202.5, 154.2, 151.1, 137.8, 130.8,
129.0, 128.3, 127.6, 117.4, 113.3, 112.3, 71.0, 56.0, 44.3, 24.0.
MS (FAB): m/z = 270 [M]+–.
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.63; H,
6.88.
IR (neat): 2924, 2362, 1639, 1495, 1558, 1216, 1043, 731, 693 cm–1.
3-(2-Benzyloxyphenyl)propanal (33b)
1H NMR (200 MHz, CDCl3): d = 7.40–7.29 (m, 5 H), 6.84–6.66 (m,
3 H), 6.01–5.92 (m, 1 H), 5.09 (m, 2 H), 5.00 (s, 2 H), 3.73 (s, 3 H),
3.42 (d, J = 6.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 154.2, 151.0, 138.0, 137.2, 130.8,
128.9, 128.1, 127.6, 116.5, 116.2, 113.5, 111.7, 78.1, 71.2, 56.0,
35.0.
Using the above procedure compound 33b was prepared from 32b
in 72% yield and its physical and spectroscopic data were in full
agreement with our previously reported data of the same com-
pound.21c
(E)-Ethyl 5-[2-(Benzyloxy)-5-methoxyphenyl]pent-2-enoate
(34a)
MS (ESI): m/z = 254 [M]+, 91 [C6H5CH2]+.
To a solution of 33a (2.00 g, 7.39 mmol) in anhyd CH2Cl2 (30 mL)
was added [(ethoxycarbonyl)methylene]triphenylphosphorane
(3.21 g, 9.21 mmol) at r.t. The reaction mixture was stirred over-
night at r.t. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography (4%
EtOAc in n-hexane) to afford 34a (2.01 g, 80%) as a colorless gum.
Anal. Calcd for C17H18O2: C, 80.28; H, 7.13. Found: C, 80.35; H,
7.32.
1-Allyl-2-benzyloxybenzene (31b)
Using the above procedure compound 31b was prepared from 30b
in 96% yield and its physical and spectroscopic data were in full
agreement with our previously reported data of the same com-
pound.21c
IR (KBr): 2926, 2359, 1708, 1649, 1496, 1211, 1035, 736 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.37–7.22 (m, 5 H), 7.04–6.94 (m,
1 H), 6.77–6.60 (m, 3 H), 5.79 (d, J = 15.6 Hz, 1 H), 4.93 (s, 2 H),
4.14–4.07 (m, 2 H), 3.65 (s, 3 H), 2.77–2.72 (m, 2 H), 2.48–2.41 (m,
2 H), 1.20 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.1, 153.4, 150.3, 148.1, 137.2,
130.5, 128.1, 127.3, 126.7, 121.2, 115.9, 112.4, 110.9, 70.1, 59.6,
55.0, 32.1, 28.8, 13.9.
3-(2-Benzyloxy-5-methoxyphenyl)propan-1-ol (32a)
To a stirred solution of 31a (4.00 g, 15.72 mmol) in anhyd THF
(30 mL) was added a 0.5 M THF solution of 9-BBN (47 mL) drop-
wise under N2 at 0 °C and the mixture was stirred at r.t. for 4 h. H2O
(5 mL) was added followed by aq 3 N NaOH (40 mL) and aq 30%
H2O2 (30 mL). The reaction mixture was stirred for 2 h at 60 °C and
then extracted with EtOAc (2 × 50 mL). The combined EtOAc ex-
tracts were washed with H2O (150 mL) and brine (150 mL), dried
(Na2SO4), and concentrated under reduced pressure. Purification of
the crude product by silica gel column chromatography (8% EtOAc
in n-hexane) afforded alcohol 32a (4.02 g, 94%) as a colorless gum;
Rf = 0.32 (20% EtOAc in n-hexane).
MS (FAB): m/z = 340 [M]+.
Anal. Calcd for C21H24O4: C, 74.09; H, 7.11. Found: C, 74.21; H,
7.03.
(E)-Ethyl 5-(2-Benzyloxyphenyl)pent-2-enoate (34b)
Using the above procedure compound 34b was prepared from 33b
in 77% yield and its physical and spectroscopic data were in full
agreement with our previously reported data of the same com-
pound.21c
IR (neat): 3431, 2929, 2361, 1497, 1214, 1042, 756, 698 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.44–7.34 (m, 5 H), 7.85 (d,
J = 8.7 Hz, 1 H), 6.76–6.66 (m, 2 H), 5.02 (s, 2 H), 3.75 (s, 3 H),
3.57 (t, J = 6.3 Hz, 2 H), 2.74 (t, J = 7.2 Hz, 2 H), 1.88–1.70 (m, 2
H), 1.77 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 154.3, 151.3, 137.7, 132.3, 129.0,
128.3, 127.7, 116.8, 113.5, 111.6, 71.5, 62.1, 56.0, 33.4, 26.7.
(E)-5[2-(Benzyloxy)-5-methoxyphenyl]pent-2-en-1-ol (35a)
Starting from 34a (2.00 g, 5.87 mmol), the title compound was pre-
pared in the same manner as that described for 22a. Purification of
the crude product by silica gel column chromatography (20%
EtOAc in n-hexane) afforded 35a (1.68 g, 96%) as a colorless semi-
solid.
MS (ESI): m/z = 272 [M]+, 255 [M – OH]+, 91 [C6H5CH2]+.
IR (neat): 3417, 2930, 2361, 1499, 1217, 1043, 754 cm–1.
Anal. Calcd for C17H20O3: C, 74.97; H, 7.40. Found: C, 74.88; H,
7.58.
1H NMR (300 MHz, CDCl3): d = 7.42–7.27 (m, 5 H), 6.81 (d,
J = 8.8 Hz, 1 H), 6.73 (d, J = 3.0 Hz, 1 H), 6.66 (dd, J = 3.1, 8.7 Hz,
1 H), 5.78–5.55 (m, 2 H), 5.01 (s, 2 H), 4.04 (d, J = 5.5 Hz, 2 H),
3.74 (s, 3 H), 2.75–2.70 (m, 2 H), 2.35 (m, 2 H).
3-(2-Benzyloxyphenyl)propan-1-ol (32b)
Using the above procedure compound 32b was prepared from 31b
in 96% yield and its physical and spectroscopic data were in full
agreement with our previously reported data of the same com-
pound.21c
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

1894
S. K. Dinda et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 153.6, 150.8, 137.6, 132.6, 131.8,
129.3, 128.4, 127.6, 127.0, 116.3, 112.8, 110.9, 70.6, 63.6, 55.5,
32.4, 30.2.
EtOAc in n-hexane) afforded 37a (0.74 g, 83%) as a colorless solid;
mp 87–88 °C; [a]D25 +16.56 (c 0.56, MeOH).
IR (KBr): 3397, 2924, 2360, 1496, 1219, 1041, 761 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.72 (d, J = 8.8 Hz, 1 H), 6.65 (dd,
J = 2.7, 8.8 Hz, 1 H), 6.59 (d, J = 2.5 Hz, 1 H), 4.01–3.96 (m, 1 H),
3.88–3.84 (m, 3 H), 3.74 (s, 3 H), 2.90–2.71 (m, 3 H), 2.34–2.29 (m,
1 H), 2.14–2.07 (m, 1 H), 1.91–1.77 (m, 2 H).
MS (ESI): m/z = 316.1 [M + NH4]+.
Anal. Calcd for C19H22O3: C, 76.48; H, 7.43. Found: C, 76.35; H,
7.68.
(E)-5-(2-Benzyloxyphenyl)pent-2-en-1-ol (35b)
MS (ESI): m/z = 285 [M + 1]+, 302 [M + NH4]+.
Starting from 34b (2.00 g, 6.44 mmol), the title compound was pre-
pared in the same manner as that described for 22a. Purification of
the crude product by silica gel column chromatography (20%
EtOAc in n-hexane) afforded 35b (1.64 g, 95%) as a colorless gum.
Anal. Calcd for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.19; H,
7.32.
(R)-1-[(S)-Chroman-2-yl]ethane-1,2-diol (37b)
IR (neat): 3417, 2930, 2361, 1499, 1217, 1043, 754, 697 cm–1.
Starting from 36b (1.25 g, 4.39 mmol), the title compound was pre-
pared in the same manner as that described for 24a. Purification of
the crude product by silica gel column chromatography (40%
EtOAc in n-hexane) afforded 37b (0.71 g, 84%) as a colorless solid;
mp 63–64 °C; [a]D25 +26.28 (c 0.76, MeOH).
1H NMR (200 MHz, CDCl3): d = 7.42–7.35 (m, 5 H), 7.29–7.13 (m,
2 H), 6.91(d, J = 6.0, 2 H), 5.75–5.58 (m, 2 H), 5.08 (s, 2 H), 4.05
(d, J = 5.0 Hz, 2 H), 2.77 (t, J = 7.2 Hz, 2 H), 2.43–2.42 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 157.0, 137.9, 133.3, 130.9, 129.7,
128.9, 128.2, 127.5, 127.4, 121.1, 112.0, 70.2, 64.1, 32.8, 30.6.
IR (KBr): 3385, 3020, 2361, 1586, 1216, 761 cm–1.
MS (ESI): m/z = 268 [M]+.
1H NMR (300 MHz, CDCl3): d = 7.12–7.05 (m, 2 H), 6.89–6.79 (m,
2 H), 4.08–4.03 (m, 1 H), 3.92–3.84 (m, 3 H), 2.88–2.81 (m, 3 H),
2.55 (br s, 2 H), 2.18–2.12 (m, 1 H), 1.92–1.85 (m, 1 H).
Anal. Calcd for C18H20O2: C, 80.56; H, 7.51. Found: C, 80.59; H,
7.45.
13C NMR (75 MHz, CDCl3): d = 152.9, 128.3, 126.0, 120.8, 119.2,
[(2R,3R)-3-(2-Benzyloxy-5-methoxyphenethyl)oxiran-2-
yl]methanol (36a)
115.3, 75.1, 72.0, 62.1, 23.0, 22.0.
MS (ESI): m/z = 285 [M + 1]+, 302 [M + NH4]+.
Starting from 35a (1.50 g, 5.02 mmol), the title compound was pre-
pared in the same manner as that described for 23a. Purification of
the crude product by silica gel column chromatography (30%
EtOAc in n-hexane) afforded 36a (1.39 g, 88%) as a colorless gum;
[a]D25 +15.2 (c 1.9, CHCl3).
Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 68.16; H,
7.29.
(S)-(6-Methoxychroman-2-yl)methanol (38a)
To a stirred solution of diol 37a (250 mg, 1.11 mmol) in MeOH (8
mL) at 0 °C was added a solution of NaIO4 (380 mg, 1.77 mmol) in
H2O (4 mL). After stirring the reaction mixture at 0 °C for 2 h,
MeOH was evaporated in vacuo at low temperature. The aqueous
solution was extracted with CH2Cl2 (2 × 10 mL). The combined or-
ganic layers were washed with H2O (10 mL), brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure to yield the
crude aldehyde as a colorless gum, which was used in the next step
without further purification. To an ice-cooled solution of the above
crude aldehyde in MeOH (6 mL) was added NaBH4 (50 mg, 1.31
mmol) and the mixture was stirred for 30 min at r.t. MeOH was re-
moved under reduced pressure and the residue was dissolved in
EtOAc (15 mL) and H2O (15 mL). The organic layer was separated
and washed with brine (10 mL), dried (Na2SO4), and concentrated
under reduced pressure. Purification of the crude product by silica
gel column chromatography (20% EtOAc in n-hexane) afforded
38a (18 mg, 87%) as a colorless gum; [a]D20 +104.8 (c 1.5, CHCl3).
IR (neat): 3425, 2926, 1621, 1500, 1219, 1042, 745, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.28 (m, 5 H), 6.83 (d,
J = 8.8 Hz, 1 H), 6.75 (d, J = 3.0 Hz, 1 H), 6.68 (dd, J = 3.1, 8.8 Hz,
1 H), 5.01 (s, 2 H), 3.79–3.78 (m, 1 H), 3.75 (s, 3 H), 3.55–3.48 (m,
1 H), 2.98–2.94 (m, 1 H), 2.87–2.70 (m, 3 H), 1.99–1.72 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 153.0, 148.4, 139.7, 126.2, 121.9,
117.2, 113.8, 113.2, 75.3, 70.3, 55.3, 29.6, 29.5, 27.8, 24.5.
MS (ESI): m/z = 315 [M + 1]+, 332 [M + NH4]+.
Anal. Calcd for C19H22O4: C, 72.59; H, 7.05. Found: C, 72.71; H,
7.11.
[(2R,3R)-3-(2-Benzyloxyphenethyl)oxiran-2-yl]methanol (36b)
Starting from 35b (1.50 g, 5.59 mmol), the title compound was pre-
pared in the same manner as that described for 23a. Purification of
the crude product by silica gel column chromatography (30%
EtOAc in n-hexane) afforded 36b (1.43 g, 90%) as a colorless gum;
[a]D25 +24.7 (c 1.54, CHCl3).
IR (neat): 3397, 2924, 2360, 1496, 1219, 1041, 761 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.76 (d, J = 8.8 Hz, 1 H), 6.65 (dd,
J = 2.9, 8.8 Hz, 1 H), 6.60 (d, J = 2.8 Hz, 1 H), 4.10–4.02 (m, 1 H),
3.87–3.66 (m, 5 H), 2.94–2.70 (m, 2 H), 2.10 (br, s, 1 H), 1.97–1.76
(m, 2 H).
13C NMR (75 MHz, CDCl3): d = 153.4, 148.4, 122.4, 117.2, 114.0,
113.3, 76.2, 65.6, 55.7, 24.7, 23.7.
IR (neat): 3434, 2927, 1598, 1495, 1240, 1023, 752 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.29 (m, 5 H), 7.20–7.15 (m,
2 H), 6.92–6.87 (m, 2 H), 5.07 (s, 2 H), 3.79–3.75 (m, 1 H), 3.55–
3.47 (m, 1 H), 2.98–2.74 (m, 4 H), 2.00–1.78 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 156.5, 137.2, 130.0, 129.8, 128.5,
127.8, 127.4, 127.1, 120.8, 111.7, 69.9, 61.7, 58.6, 55.7, 31.7, 26.9.
MS (ESI): m/z = 194 [M]+.
MS (ESI): m/z = 285 [M + 1]+, 302 [M + NH4]+.
Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 68.11; H,
7.35.
Anal. Calcd for C18H20O3: C, 76.03; H, 7.09. Found: C, 76.19; H,
7.16.
(S)-Chroman-2-ylmethanol (38b)
Starting from 37b (250 mg, 1.28 mmol), the title compound was
prepared in the same manner as that described for 38a. Purification
of the crude product by silica gel column chromatography (20%
EtOAc in n-hexane) afforded 38b (188 mg, 89%) as a colorless
(R)-1-[(S)-6-Methoxychroman-2-yl]ethane-1,2-diol (37a)
Starting from 36a (1.25 g, 3.97 mmol), the title compound was pre-
pared in the same manner as that described for 24a. Purification of
the crude product by silica gel column chromatography (40%
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

PAPER
Phenolate Ion Mediated Intramolecular Epoxide Ring Opening Reactions
1895
gum; [a]D +110.6 (c 1.55, MeOH) {Lit.32 [a]D +113.4 (c 1.1,
13C NMR (75 MHz, CDCl3 + CCl4): d = 153.0, 148.4, 139.7, 126.2,
20
25
MeOH)}.
121.9, 117.2, 113.8, 113.2, 75.3, 70.3, 55.3, 29.6, 29.5, 27.8, 24.5.
IR (neat): 3422, 2933, 1651, 1430, 1054, 706 cm–1.
MS (ESI): m/z = 231 [M – OH]+, 247 [M – 1]+.
1H NMR (300 MHz, CDCl3): d = 7.14–7.07 (m, 2 H), 6.90–6.84 (m,
2 H), 4.18–4.11 (m, 1 H), 3.89–3.76 (m, 2 H), 2.92–2.81 (m, 2 H),
2.02 (br s, 1 H), 1.98–1.86 (m, 2 H).
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.43; H,
8.18.
(S,E)-4-(Chroman-2-yl)-2-methylbut-3-en-2-ol (40b)
Starting from 39b (75 mg, 0.32 mmol), the title compound was pre-
pared in the same manner as that described for 29a. Purification of
the crude product by silica gel column chromatography (18%
EtOAc in n-hexane) afforded 40b (67 mg, 95%) as a colorless gum;
[a]D25 +7.5 (c 0.4, CHCl3).
13C NMR (75 MHz, CDCl3): d = 153.2, 128.3, 126.0, 120.6, 119.2,
115.4, 75.1, 64.3, 23.2, 22.4.
MS (ESI): m/z = 164 [M]+.
Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 73.27; H,
7.48.
IR (neat): 3410, 3019, 2361, 1713, 1586, 1216, 760 cm–1.
The above spectral data agreed with the literature data.32
1H NMR (300 MHz, CDCl3): d = 7.10–7.01 (m, 2 H), 6.84–6.82 (m,
2 H), 5.97 (d, J = 15.8 Hz, 1 H), 5.81 (dd, J = 5.8, 15.7 Hz, 1 H),
4.55–4.49 (m, 1 H), 2.91–2.70 (m, 2 H), 2.08–1.99 (m, 1 H), 1.89–
1.76 (m, 1 H), 1.67 (br s, 1 H), 1.34 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.4, 139.9, 129.4, 127.2, 126.2,
121.7, 120.1, 116.7, 75.6, 70.55, 29.3, 29.6, 27.9, 24.3.
(S,E)-Ethyl 3-(6-Methoxychroman-2-yl)acrylate (39a)
Starting from 37a (0.10 g, 0.44 mmol), the title compound was pre-
pared in the same manner as that described for 28a. Purification of
the crude product by silica gel column chromatography (4% EtOAc
in n-hexane) afforded 39a (0.10 g, 88%) as a colorless gum; [a]D
+5.4 (c 1.21, MeOH).
25
MS (ESI): m/z = 201 [M – OH]+, 217 [M – 1]+.
IR (neat): 3020, 2400, 1708, 1496, 1426, 1216, 761, 699 cm–1.
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 77.19; H,
8.47.
1H NMR (300 MHz, CDCl3): d = 6.98 (dd, J = 4.1, 15.7 Hz, 1 H),
6.78 (d, J = 8.9 Hz, 1 H), 6.67 (dd, J = 2.8, 8.9, 1 H), 6.56 (d, J = 2.7
Hz, 1 H), 6.14 (dd, J = 1.7, 15.7 Hz, 1 H), 4.69–4.64 (m, 1 H), 4.21
(q, J = 7.1, 2 H), 3.74 (s, 3 H), 2.91–2.69 (m, 2 H), 2.16–2.07 (m, 1
H), 1.91–1.78 (m, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).
Acknowledgment
This research project was supported by Department of Science and
Technology (SR/S1/OC-23/2005) and Indian Council of Medical
Research (ICMR) New Delhi, India. S. K. Dinda and S. K. Das
thank the CSIR, New Delhi for providing fellowships.
13C NMR (75 MHz, CDCl3 + CCl4): d = 166.0, 153.5, 147.9, 146.1,
121.7, 121.4, 117.3, 113.8, 113.5, 73.7, 60.3, 55.4, 27.0, 24.3, 14.2.
MS (ESI): m/z = 280 [M + NH4]+.
Anal. Calcd for C15H18O4: C, 68.68; H, 6.92. Found: C, 68.83; H,
6.88.
References
(S,E)-Ethyl 3-(Chroman-2-yl)acrylate (39b)
(1) CDRI communication number 7184.
Starting from 37b (0.10 g, 0.51 mmol), the title compound was pre-
pared in the same manner as that described for 28a. Purification of
the crude product by silica gel column chromatography (4% EtOAc
in n-hexane) afforded 39b (0.11 g, 90%) as a colorless gum; [a]D
–17.8 (c 1.46, MeOH).
(2) For selected recent examples of 2,3-dihydrobenzofuran
containing natural and unnatural molecules, see: (a) Chu,
G.-H.; Gu, M. H.; Cassel, J. A.; Belanger, S.; Graczyk, T.
M.; DeHaven, R. N.; Conway-James, N.; Koblish, M.;
Little, P. J.; DeHaven-Hudkins, D. L.; Dolle, R. E. Bioorg.
Med. Chem. Lett. 2005, 15, 5114. (b) Shi, G. Q.; Dropinski,
J. F.; Zhang, Y.; Santini, C.; Sahoo, S. P.; Berger, J. P.;
MacNaul, K. L.; Zhou, G.; Agrawal, A.; Alvaro, R.; Cai,
T.-q.; Hernandez, M.; Wright, S. D.; Moller, D. E.; Heck,
J. V.; Meinke, P. T. J. Med. Chem. 2005, 48, 5589.
(c) Yang, X.-W.; Zhao, P.-J.; Ma, Y.-L.; Xiao, H.-T.; Zuo,
Y.-Q.; He, H.-P.; Li, L.; Hao, X.-J. J. Nat. Prod. 2007, 70,
521. (d) Xu, F.; Zhang, Y.; Wang, J.; Pang, J.; Huang, C.;
Wu, X.; She, Z.; Vrijmoed, L. L. P.; Jones, E. B. G.; Lin, Y.
J. Nat. Prod. 2008, 71, 1251.
(3) For selected recent examples of 1-benzopyran-containing
natural and unnatural molecules, see: (a) Wang, Y.; Mo,
S.-Y.; Wang, S.-J.; Li, S.; Yang, Y.-C.; Shi, J.-G. Org. Lett.
2005, 7, 1675. (b) Rukachaisirikul, V.; Tadpetch, K.;
Watthanaphanit, A.; Saengsanae, N.; Phongpaichit, S.
J. Nat. Prod. 2005, 68, 1218. (c) Breschi, M. C.; Calderone,
V.; Martelli, A.; Minutolo, F.; Rapposelli, S.; Testai, L.;
Tonelli, F.; Balsamo, A. J. Med. Chem. 2006, 49, 7600.
(d) Frederick, R.; Robert, S.; Charlier, C.; Wouters, J.;
Masereel, B.; Pochet, L. J. Med. Chem. 2007, 50, 3645.
(e) Richardson, T. I.; Norman, B. H.; Lugar, C. W.; Jones, S.
A.; Wang, Y.; Durbin, J. D.; Krishnan, V.; Dodge, J. A.
Bioorg. Med. Chem. Lett. 2007, 17, 3570.
25
IR (neat): 3020, 2361, 1713, 1480, 1217, 763, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.12–6.96 (m, 3 H), 6.86–6.82 (m,
2 H), 6.15 (dd, J = 1.8, 15.7 Hz, 1 H), 4.75–4.69 (m, 1 H), 4.20 (q,
J = 7.2 Hz, 2 H), 2.90–2.70 (m, 2 H), 2.17–2.08 (m, 1 H), 1.90–1.78
(m, 1 H), 1.29 (t, J = 7.1, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.2, 153.8, 146.0, 129.4, 127.4,
121.4, 120.5, 116.7, 73.8, 60.4, 26.9, 23.9, 14.1.
MS (ESI): m/z = 250 [M + NH4]+.
Anal. Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.53; H,
6.85.
(S,E)-4-(6-Methoxychroman-2-yl)-2-methylbut-3-en-2-ol (40a)
Starting from 39a (75 mg, 0.28 mmol), the title compound was pre-
pared in the same manner as that described for 29a. Purification of
the crude product by silica gel column chromatography (18%
EtOAc in n-hexane) afforded 40a (66 mg, 93%) as a colorless gum;
[a]D25 +13.91 (c 1.75, MeOH).
IR (neat): 3413, 3019, 2361, 1713, 1496, 1216, 758, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.75 (d, J = 8.9 Hz, 1 H), 6.64 (dd,
J = 2.8, 8.9 Hz, 1 H), 6.55 (d, J = 2.8 Hz, 1 H), 5.94 (dd, J = 0.9,
15.7, 1 H), 5.77 (dd, J = 5.8, 15.7 Hz, 1 H), 4.46–4.41 (m, 1 H), 3.72
(s, 3 H), 2.88–2.64 (m, 2 H), 2.29 (br s, 1 H), 2.04–1.95 (m, 1 H),
1.85–1.72 (m, 1 H), 1.34 (s, 6 H).
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York

1896
S. K. Dinda et al.
PAPER
(4) For the enantioselective synthesis of 2,3-dihydrobenzo-
furans, see: (a) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura,
S.; Anada, M.; Hashimoto, S. Org. Lett. 2002, 4, 3887.
(b) Li, X.; Branum, S.; Russell, R. K.; Jiang, W.; Sui, Z. Org.
Process Res. Dev. 2005, 9, 640. (c) Sun, L.-Q.; Chen, J.;
Takaki, K.; Johnson, G.; Iben, L.; Mahle, C. D.; Ryan, E.;
Xu, C. Bioorg. Med. Chem. Lett. 2004, 14, 1197.
(12) De Vry, J.; Schohe-Loop, R.; Heine, H.-G.; Greuel, J. M.;
Mauler, F.; Schmidt, B.; Sommermeyer, H.; Glaser, T.
J. Pharmacol. Exp. Ther. 1998, 284, 1082.
(13) Lutsep, H. L. Curr. Opin. Invest. Drugs 2002, 3, 924.
(14) McIntyre, J. A.; Castaner, J.; Bayes, M. Drugs Fut. 2006, 31,
314.
(15) Palucki, M.; Yasuda, N. Tetrahedron Lett. 2005, 46, 987.
(16) Schaaf, T. K.; Johnson, M. R.; Constantine, J. W.; Bindra, J.
S.; Hess, H.-J.; Elger, W. J. Med. Chem. 1983, 26, 328.
(17) Urban, F. J.; Moore, B. S. J. Heterocycl. Chem. 1992, 29,
431.
(18) (a) Augstein, J.; Monro, A. M.; Potter, G. W. H.; Scholfield,
P. J. Med. Chem. 1968, 11, 844. (b) Witiak, D. T.; Stratford,
E. S.; Nazareth, R.; Wagner, G.; Feller, D. R. J. Med. Chem.
1971, 14, 758.
(d) Kurosawa, W.; Kobayashi, H.; Kan, T.; Fukuyama, T.
Tetrahedron 2004, 60, 9615. (e) Silveira, G. P. C.; Coelho,
F. Tetrahedron Lett. 2005, 46, 6477.
(5) For recent examples of enantioselective synthesis of 1-
benzopyrans, see: (a) Trost, B. M.; Shen, H. C.; Dong, L.;
Surivet, J.-P. J. Am. Chem. Soc. 2003, 125, 9276.
(b) Pitsinos, E. N.; Cruz, A. Org. Lett. 2005, 7, 2245.
(c) Tian, X.; Rychnovsky, S. D. Org. Lett. 2007, 9, 4955.
(d) Pitsinos, E. N.; Moutsos, V. I.; Vageli, O. Tetrahedron
Lett. 2007, 48, 1523. (e) Fukamizu, K.; Miyake, Y.;
Nishibayashi, Y. J. Am. Chem. Soc. 2008, 130, 10498.
(6) (a) Bowen, D. M.; DeGraw, J. I. Jr.; Shah, V. R.; Bonner, W.
A. J. Med. Chem. 1963, 6, 315. (b) Banskota, A. H.;
Tezuka, Y.; Prasain, J. K.; Matsushige, K.; Saiki, I.; Kadota,
S. J. Nat. Prod. 1998, 61, 896. (c) Bittner, M.; Jakupovic,
J.; Bohlmann, F.; Silva, M. Phytochemistry 1989, 28, 2867.
(d) Bohlmann, F.; Jakupovic, J.; Schuster, A.; King, R.;
Robinson, H. Phytochemistry 1982, 21, 161. (e) Cespedes,
C. L.; Uchoa, A.; Salazar, J. R.; Perich, F.; Pardo, F. J. Agric.
Food Chem. 2002, 50, 2283. (f) Singer, T. P.; Ramsay, R. R.
Biochim. Biophys. Acta: Bioenergetics 1994, 1187, 198.
(g) Haley, T. J. J. Environ. Pathol. Toxicol. 1978, 1, 315.
(h) Cockerill, G. S.; Levett, P. C.; Whiting, D. A. J. Chem.
Soc., Perkin Trans. 1 1995, 1103. (i) Habib, A. M.; Ho, D.
K.; Masuda, S.; McCloud, T.; Reddy, K. S.; Aboushoer, M.;
McKenzie, A.; Byrn, S. R.; Chang, C.-J.; Cassady, J. M.
J. Org. Chem. 1987, 52, 412.
(19) Labrosse, J.-R.; Poncet, C.; Lhoste, P.; Sinou, D.
Tetrahedron: Asymmetry 1999, 10, 1069.
(20) Stack, G. P.; Gross, J. L. US Patent 264947, 2004; Chem.
Abstr. 2003, 138, 321133.
(21) (a) Das, S. K.; Dinda, S. K.; Panda, G. Eur. J. Org. Chem.
2009, 204. (b) Srivastava, A. K.; Panda, G. Chem. Eur. J.
2008, 14, 4675. (c) Das, S. K.; Panda, G. Tetrahedron 2008,
64, 4162. (d) Mishra, J. K.; Panda, G. J. Comb. Chem. 2007,
9, 321. (e) Mishra, J. K.; Garg, P.; Dohare, P.; Kumar, A.;
Siddiqi, M. I.; Ray, M.; Panda, G. Bioorg. Med. Chem. Lett.
2007, 17, 1326. (f) Mishra, J. K.; Panda, G. Synthesis 2005,
1881.
(22) (a) Katsuki, T.; Sharplesss, K. B. J. Am. Chem. Soc. 1980,
102, 5974. (b) Pfenninger, A. Synthesis 1986, 89. (c)Baker,
S. R.; Boot, J. R.; Morgan, S. E.; Osborne, D. T.; Ross, W.
J.; Shrubsall, P. R. Tetrahedron Lett. 1983, 24, 4469.
(23) The enantiomeric excess values were determined by
converting the epoxy alcohols into their Mosher ester
derivatives and analyzing the 1H NMR spectra of the
corresponding Mosher esters.
(7) Yamaguchi, S.; Muro, S.; Kobayashi, M.; Miyazawa, M.;
Hirai, Y. J. Org. Chem. 2003, 68, 6274.
(24) In the tosylation reaction of 24a,b, formation of minor
amount of the corresponding ditosylated products was also
observed and these undesired products were eliminated by
column chromatography.
(25) The enantiomeric excess values of 27a,b were determined
by chiral HPLC analysis.
(8) Pelly, S. C.; Govender, S.; Fernandes, M. A.; Schmalz, H.-
G.; de Koning, C. B. J. Org. Chem. 2007, 72, 2857.
(9) Heine, H.-G.; Schohe-Loop, R.; Glaser, T.; De Vry, J. M. V.;
Dompert, W.; Sommermeyer, H. US Patent 5371094, 1994;
Chem. Abstr. 1993, 119, 203413.
(10) Jacobsen, E. J.; van Doornik, F. J.; Ayer, D. E.; Belonga, K.
L.; Braughler, J. M.; Hall, E. D.; Houser, D. J. J. Med. Chem.
1992, 35, 4464.
(11) (a) Mewshaw, R. E.; Kavanagh, J.; Stack, G.; Marquis, K.
L.; Shi, X.; Kagan, M. Z.; Webb, M. B.; Katz, A. H.; Park,
A.; Kang, Y. H.; Abou-Gharbia, M.; Scerni, R.; Wasik, T.;
Cortes-Burgos, L.; Spangler, T.; Brennan, J. A.; Piesla, M.;
Mazandarani, H.; Cockett, M. I.; Ochalski, R.; Coupet, J.;
Andree, T. H. J. Med. Chem. 1997, 40, 4235.
(26) Morimoto, S.; Shindo, M.; Yoshida, M.; Shishido, K.
Tetrahedron Lett. 2006, 47, 7353.
(27) Darling, S. D.; Wills, K. D. J. Org. Chem. 1967, 32, 2794.
(28) Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56,
6339.
(29) The enantiomeric excess values of 38a,b were determined
by chiral HPLC analysis (Chiral Cel OD, petroleum ether
(bp 30–60 °C)–i-PrOH (98:2) 1 mL/min, 254 mm.
(30) Lin, C.-F.; Yang, J.-S.; Chang, C.-Y.; Kuo, S.-C.; Lee, M.-
R.; Huang, L.-J. Bioorg. Med. Chem. 2005, 13, 1537.
(31) Kawase, Y.; Yamaguchi, S.; Inoue, O.; Sannomiya, M.;
Kawabe, K. Chem. Lett. 1980, 1981.
(b) Mewshaw, R. E.; Zhao, R.; Shi, X.; Marquis, K.;
Brennan, J. A.; Mazandarani, H.; Coupet, J.; Andree, T. H.
Bioorg. Med. Chem. Lett. 2002, 12, 271.
(32) Urban, F. I.; Moore, B. S. J. Heterocycl. Chem. 1992, 29,
431.
Synthesis 2009, No. 11, 1886–1896 © Thieme Stuttgart · New York