A new synthetic approach to enantiomerically enriched dihydrobenzofurans: Use of a hydrolytic kinetic resolution and an intramolecular epoxide ring opening protocol using 1-benzyloxy-2-oxiranylmethylbenzenes

Article abstract of DOI:10.1016/j.tetlet.2005.04.120

A novel approach towards the preparation of racemic 1-benzyloxy-2- oxiranylmethylbenzenes using dimethyldioxirane and their hydrolytic kinetic resolution using (R,R)(Salen)Co(III)(OAc) (Jacobsen's catalyst) to afford the (R)-epoxides and (S)-1,2-diols, en

Full text of DOI:10.1016/j.tetlet.2005.04.120

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5239–5242
A new synthetic approach to enantiomerically
enriched dihydrobenzofurans: use of a hydrolytic kinetic
resolution and an intramolecular epoxide ring opening
protocol using 1-benzyloxy-2-oxiranylmethylbenzenes
Umadevi Bhoga*
Organic Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 7 January 2005; revised 29 March 2005; accepted 15 April 2005
Abstract—A novel approach towards the preparation of racemic 1-benzyloxy-2-oxiranylmethylbenzenes using dimethyldioxirane
and their hydrolytic kinetic resolution using (R,R)(Salen)Co(III)(OAc) (JacobsenÕs catalyst) to afford the (R)-epoxides and (S)-
1,2-diols, enantioselectively, is described. The (R)-1-benzyloxy-2-oxiranylmethylbenzenes were then cyclized via an intramolecular
epoxide opening reaction to give (S)-2-hydroxymethyl-2,3-dihydrobenzofurans.
ꢀ 2005 Published by Elsevier Ltd.
Naturally occurring 2-substituted-2,3-dihydrobenzo-
furans are an important class of biologically active
oxygen-containing heterocycles.1–6 Natural products
possessing the dihydrobenzofuran nucleus, exhibit a
wide range of biological activities. For example,
arthrographol is an anti-fungal,7 megapodiol is an anti-
leukaemic,8 2-(3,4-dimethoxyphenyl)-3-hydroxymethyl-
5-(3-hydroxypropyl)-2,3-dihydrobenzofuran-7-ol9 and
conocarpan are anti-cancer agents,10 tremetone causes
milk sickness in cattle11 and furaquinocines are antibio-
tics.12 There are only a few methods, to the best of our
knowledge, established for the synthesis of enantiomeri-
cally enriched dihydrobenzofurans.7–12
using the chiral salen cobalt complex, (R,R)(Salen)-
Co(III)(OAc),22,23 gave the optically pure (R)-epoxides
5a–c and (S)-1,2-diols 6a–c in 80–90% eeÕs and 78–85%
eeÕs, respectively (Scheme 1).24
Similarly, o-allylnaphthol 8 was converted to benzyl
ether 9 on reaction with benzyl bromide and anhydrous
potassium carbonate in acetone. Benzyl ether 9 was sub-
sequently treated with dimethyldioxirane to afford race-
mic epoxide 10, which underwent solvent-free HKR
using JacobsenÕs catalyst to give (R)-epoxide 11 and
(S)-1,2-diol 12 in 80% ee and 78% ee, respectively
(Scheme 1).
Herein, we report a new synthesis of enantiomerically
enriched dihydrobenzofuran derivatives and naph-
tho[1,2-b]furans. o-Allylphenols 2a–c13–15 were con-
verted to the corresponding benzylethers 3a–c,16 in
order to be able to isolate the epoxy derivatives in the
subsequent step. The resulting o-allylbenzylethers 3a–c
were reacted with dimethyldioxirane17–20 generated in
situ from Oxone and acetone to furnish racemic 1-benz-
yloxy-2-oxiranylmethylbenzenes 4a–c.21 Next, the sol-
vent-free hydrolytic kinetic resolution (HKR) of the
racemic 1-benzyloxy-2-oxiranylmethylbenzenes 4a–c,
The racemic epoxides 4a–c and 10 and (R)-epoxides 5a–c
and 11 were debenzylated and cyclized in situ via an
intramolecular epoxide opening reaction. This was
accomplished using 10% Pd–C in methanol under a H2
atmosphere and adding a catalytic amount of triethyl-
amine and anhydrous potassium carbonate at room tem-
perature25 to furnish the desired products, racemates
7a–c and 13 and enantiomerically enriched 1a–c and
13a in 85–92% eeÕs and 75% ee, respectively,26 via a
25
D
SN2 mechanism (Schemes 2 and 3). The ½aꢀ of 1b was
+20.0 (c 1.5, CHCl3), which compared favourably with
that published, (lit. +21.0, c 1.0, CHCl3).27 The forma-
tion of (S)-5-methyl-2-hydroxymethyl-2,3-dihydro-
benzofuran 1b from (R)-epoxide 5b was confirmed by
*E-mail: ubhoga@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.04.120

5240
U. Bhoga / Tetrahedron Letters 46 (2005) 5239–5242
R1
R1
R1
R2
R3
R2
R2
Oxone/acetone/CH3CN
OH
BnBr/K2CO3
OBn
OBn
O
acetone reflux
12 h/85-95%
NaHCO3/Na2. EDTA
0 0C-1 0C / 1.3 h
50-60%
R3
R3
R4
R4
R4
3a-c
4a-c
2a-c
a : R1 = R2 = R4 = H; R3 = NO2
b : R1 = R2 = R4 = H; R3 = CH3
c : R1 = CH3; R3 = Cl; R2 = R4 = H
R1
R1
(R,R)(Salen)Co(III)(OAc)
0.55 eq H2O
R2
R3
R2
+
OBn
OH
OBn
O
OH
0 oC-rt / 12 h
43-45%
R3
R4
R4
5a-c
6a-c
5a : 85% ee
5b : 90% ee
5c : 80% ee
6a : 80% ee
6b : 85% ee
6c : 78% ee
O
OBn
OBn
OH
Oxone/acetone/CH3CN
NaHCO3/Na2.EDTA
BnBr/K2CO3
acetone reflux
0 0C-1 0C/1.3 h
60%
12 h/90%
9
8
10
OH
HO
OBn
O
OBn
(R,R)(Salen)Co(III)(OAc)
0.55 eq H2O
+
0 oC-rt/12 h
45%
(R)-11
(80% ee)
(S)-12
(78% ee)
Scheme 1.
R1
H
HD
HC
R1
HD
HE
R2
R3
OH
HB
HA
HC
OBn
R2
R3
10%Pd-C/MeOH
O
O
OH
O
K2CO3/Et3N
H2 /12 h/rt / 45-50%
O
HB
OBn
10% Pd-C/MeOH
HA
R4
R4
K2CO3/Et3N
H2/12 h/rt /68%
4a-c
7a-c
R1
10
13
R1
R2
R3
R2
10%Pd-C/MeOH
OBn
O
OH
OH
O
K2CO3/Et3N
H2/12 h/rt / 45-50%
O
OBn
R3
O
R4
R4
(S)-1a-c
10% Pd-C/MeOH
(R)-5a-c
K2CO3/Et3N
H2 /12 h/rt /70%
1a : R1=R2=R4=H; R3=NO2 (92% ee)
1b : R1=R2=R4=H; R3=CH3 (89% ee)
1c : R1=CH3; R2=R4=H; R3=Cl (85% ee)
(S)-13a
(75% ee)
(R)-11
Scheme 3.
Scheme 2.
comparison with a sample prepared from enzymatic
kineticresolutionbyastandardprocedure27 usingalipase.
tho[1,2-b]furan in 85–92% eeÕs and 75% ee, respectively,
was accomplished by debenzylation and in situ cycliza-
tion via an intramolecular epoxide ring opening reaction
of 5a–c and 11, which in turn were prepared from HKR
in 80–90% eeÕs and 78% ee, respectively.
In summary, a new synthesis of optically pure 2-
hydroxymethyl-2,3-dihydrobenzofurans and a naph-

U. Bhoga / Tetrahedron Letters 46 (2005) 5239–5242
5241
18. Curci, R. In Advances in Oxygenated Processes; Baum-
stark, A., Ed.; JAI: Greenwich, CT, 1990; Vol. 2, Chapter
1, p 1.
Acknowledgements
The author thanks Dr. J. S. Yadav, Director, IICT,
Hyderabad, Dr. B. V. Rao and the late Dr. A. K. Singh
for their constant encouragement and fruitful discus-
sions during this work. U.B. also thanks CSIR, New
Delhi for financial support and for a Senior Research
Fellowship.
19. (a) Murray, R. W. Chem. Rev. 1989, 89, 1187; (b)
Dimethyldioxirane is a selective, reactive oxidizing agent,
capable of epoxidation of alkenes, arenes, imines and
sulfides. It can be prepared by portionwise addition of
solid Oxone (potassium monoperoxysulfate) to a vigor-
ously stirred solution of NaHCO3 in a mixture of reagent
grade acetone and distilled water at 0 ꢁC. Here, Oxone
serves as a stoichiometric oxidizing agent under a variety
of conditions. Therefore, an aqueous solution of Oxone
can be used to perform oxidations in homogeneous
solution and in biphasic systems using an immiscible co-
solvent and a phase transfer catalyst at pH 7 to prevent
hydrolysis of the epoxide.
References and notes
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21. Typical procedure for the synthesis of ( )-1-benzyloxy-2-
oxiranylmethyl-4-nitrobenzene 4a. To an acetonitrile solu-
tion (54 mL) of olefin 3a (1.74 g, 7.3 mmol) was added Na2.
EDTA solution (36.3 mL, 4 · 10ꢁ4 M) and the resulting
homogeneous solution was cooled to 0 ꢁC. To this was
added precooled acetone (7.3 mL) using a precooled
syringe. After 10 min, a mixture of NaHCO3 (4.75 g,
56 mmol) and Oxone (22.5 g, 36 mmol) was added in
portions over a period of 1 h while maintaining a pH of 7.
The reaction was complete in 1.3 h by TLC. The reaction
mixture was poured into water (100 mL) and extracted with
CH2Cl2 (250 mL). The combined extracts were washed with
brine and then dried over anhydrous Na2SO4. Evaporation
of the solvent gave a residue, which was purified by column
chromatography using pet. ether to afford 4a as an oil
(50%). Similarly, 4b,c and 10 were prepared in 50–60%
yields, respectively. 1H NMR (200 MHz, CDCl3): d 2.50 (m,
1H), 2.69 (m, 1H), 2.99 (m, 2H), 3.20 (m, 1H), 5.20 (s, 2H),
6.99 (d, J = 10.0 Hz, 1H), 7.40 (m, 5H), 8.20 (m, 2H); MS
(EI): m/z (M+, 285, 100%).
22. Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J.
F.; Tokunaga, M. Tetrahedron Lett. 1997, 38, 773.
23. Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem.
Soc. 1996, 118, 7420.
24. General procedure for the hydrolytic kinetic resolution of
( )-1-benzyloxy-2-oxiranylmethyl benzenes. To the neat
epoxide 4a (270 mg, 0.95 mmol) was added 0.2 mol % of
(R,R)(Salen)Co(III)(OAc) catalyst (50 mg), portionwise,
over a period of 15 min. To the reaction mixture was
added 9.30 lL of water (0.55 equiv), dropwise, using a
Hamilton syringe over a period of 10 min at 0 ꢁC. The
resulting slurry was allowed to stir for 12 h at room
temperature, then the reaction mixture was filtered and the
residue washed with chloroform (5 mL). The filtrate was
evaporated to afford a residue, which was chromato-
graphed over neutral alumina using 1:19 ethyl acetate–pet.
ether to furnish (R)-epoxide 5a and (S)-1,2-diol 6a in 85%
ee and 80% ee, respectively.
14. Svanholm, U.; Parker, V. D. J. Chem. Soc., Perkin Trans.
2 1974, 169.
15. Lasek, W.; Makosza, M. Synthesis 1993, 8, 780.
16. General procedure for the synthesis of 1-benzyloxy-2-allyl-
4-nitrobenzene 3a. A mixture of 2-allyl-4-nitrophenol
(350 mg, 1.95 mmol) and anhydrous K2CO3 (540 mg,
4 mmol) in dry acetone (10 mL) was allowed to stir for
30 min at room temperature. To this was added benzyl
bromide (334 mg, 1.95 mmol) dropwise and the resulting
mixture refluxed for 12 h at 60 ꢁC. After completion of the
reaction (TLC), the solvent was evaporated under reduced
pressure to afford a residue, which was extracted with
dichloromethane (5 · 10 mL). The combined organic layer
was washed with water and dried over anhydrous Na2SO4.
Evaporation of the solvent gave a residue, which was
purified by column chromatography over silica gel using
pet. ether as eluent to furnish 3a as a semi-solid (490 mg,
94%), (3b,c and 9 were prepared similarly). 1H NMR
(200 MHz, CDCl3): d 3.41 (m, 2H) 5.20 (m, 4H), 5.99 (m,
1H), 6.89 (m, 1H), 7.40 (m, 5H), 8.00 (m, 2H); MS (EI):
m/z 269 (M+, 100%).
(a) (R)-1-Benzyloxy-2-oxiranylmethyl-4-nitrobenzene 5a.
25
Yield: 45%, ½aꢀD +12.2 (c 1.0, CHCl3), HPLC {column
chiracel OD, 0.5:9.5 iPrOH/n-hexane, flow rate: 1 mL/min,
ee: 85%}.
(b) (S)-1-Benzyloxy-2-(20,30-dihydroxy)propanyl-4-nitro-
1
benzene 6a. Yield: 43%, H NMR (200 MHz, CDCl3): d
2.40 (br s, 1H), 2.82 (m, 2H), 3.30 (m, 3H), 4.10 (m, 1H),
5.20 (s, 2H), 6.90 (d, J = 10.0 Hz, 1H), 7.40 (m, 5H), 8.10
25
(m, 2H); ½aꢀD +10.1 (c 1.0, CHCl3), HPLC {column
chiracel OD, 0.5:9.5 iPrOH/n-hexane, flow rate: 1 mL/min,
ee: 80%}.
17. Adam, W.; Hadjiarapoglou, L. P.; Curci, R.; Mello, R.. In
Organic Peroxides; Ando, W., Ed.; Wiley: New York,
1992; Chapter 4, p 195.
25. Rao, B. V.; Sitharamaiah, D. Unpublished results, Indian
Institute of Chemical Technology, Hyderabad, India, 1998.

5242
U. Bhoga / Tetrahedron Letters 46 (2005) 5239–5242
26. Typical procedure for the preparation of ( )-and (S)-2-
hydroxymethyl-2,3-dihydrobenzofurans and naphtho-
1H, OH), 3.20 (m, 1H, HA), 3.40 (m, 1H, HB), 3.80 (m,
1H, HD), 3.95 (m, 1H, HE), 5.10 (m, 1H, HC), 6.80 (d, J =
10.0 Hz, 1H), 8.10 (m, 2H); MS (EI): m/z 195 (M+, 100%),
149 (M+ꢁNO2, 80%), 164 (55), 141 (34), 118 (25), 89 (10);
furans:
A mixture of racemic epoxide 4a (280 mg,
1.10 mmol), 10% Pd–C (20 mg), a catalytic amount of
triethylamine and anhydrous potassium carbonate (5 mg)
in methanol (10 mL) was stirred under H2 balloon
pressure for 12 h at room temperature. After the reaction
was complete (TLC), the catalyst and the solid impurities
were removed by filtration and washed with methanol
(15 mL). The combined filtrate was evaporated under
reduced pressure to furnish a residue, which was purified
by column chromatography using 1:19 ethyl acetate–pet.
ether as eluent to afford 7a. Compounds 1a–c, 7b,c, 13 and
13a were prepared similarly.
25
½aꢀD +14.00 (c 1.5, CHCl3); HPLC {column chiracel OD,
i
0.5:9.5 PrOH/n-hexane, flow rate: 1 mL/min, ee: 92%}.
(b) (S)-2-Hydroxymethyl-2,3-dihydronaphtho[1,2-b]furan
1
13a. Yield: 70%; H NMR (200 MHz, CDCl3): d 2.00 (br
s, 1H, OH), 3.25 (m, 1H, HA), 3.50 (m, 1H, HB), 3.80 (m,
1H, HD), 3.90 (m, 1H, HE), 5.10 (m, 1H, HC), 7.00 (m,
1H), 7.30 (m, 1H), 7.45 (m, 1H), 7.52 (m, 1H), 7.65
25
(m, 1H), 7.80 (m, 1H); MS (EI): m/z 200 (M+, 100%); ½aꢀD
+38.0 (c 1.0, CHCl3); HPLC {column chiracel OD, 0.5:9.5
iPrOH/n-hexane, flow rate: 1 mL/min, ee: 75%}.
27. Ramdas, S.; Krupadanam, D. G. L. Tetrahedron: Asym-
metry 2000, 11, 3375.
(a) (S)-5-Nitro-2-hydroxymethyl-2,3-dihydrobenzofuran
1a. Yield: 50%; 1H NMR (200 MHz, CDCl3): d 1.80 (s,