Efficient synthesis of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol

Article abstract of DOI:10.1080/00397911003797841

The article reports a practical, simple, and inexpensive procedure for the synthesis of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol (1). 2-Methoxy phenol on treatment offers the oxirane compound, which undergoes ring cleavage under acidic conditions to give a chlorohydrin, which on acylation and cyclization in the presence of stannic chloride followed by hydrolysis of the acetyl group, yields the desired compound (1).

Full text of DOI:10.1080/00397911003797841

1
Synthetic Communications , 41: 1141–1145, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003797841
EFFICIENT SYNTHESIS OF 8-METHOXY-
,4-DIHYDRO-2H-1-BENZOPYRAN-3-OL
3
A. V. Shindikar and C. L. Viswanathan
Bombay College of Pharmacy, Mumbai, India
GRAPHICAL ABSTRACT
Abstract The article reports a practical, simple, and inexpensive procedure for the synthesis
of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol (1). 2-Methoxy phenol on treatment
offers the oxirane compound, which undergoes ring cleavage under acidic conditions to give
a chlorohydrin, which on acylation and cyclization in the presence of stannic chloride
followed by hydrolysis of the acetyl group, yields the desired compound (1).
Keywords Benzopyranol; 3-chromanol; nipradilol; vasodilator
INTRODUCTION
Benzopyranols have emerged as an important class of heterocycles and have
attracted significant synthetic interest because of their pharmacological and thera-
[
1–3]
peutic properties.
moieties exibit antibacterial, antioxidant, and photoprotective action.
Several bioactive natural products containing benzopyranol
4,5]
[
Addition-
ally, 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol (1) is a key intermediate in the
synthesis of Nipradilol (A), a b-adrenoreceptor blocking agent with vasodilator
action.
[
6,7]
Methods for the synthesis of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol are
reported in the literature. These include, for example, sodium borohydride reduction
[8]
of 3-chromanone, epoxidation of methoxy-2-allyl phenyl acetates followed by
breaking of the epoxide ring, cyclization of chlorohydrin in the presence of a base
[7,9]
to get benzopyranol,
and oxidative cyclization of p-substituted allylphenyl ether
Received December 27, 2009.
Address correspondence to A. V. Shindikar, Bombay College of Pharmacy, Kalina, Santacruz (E),
Mumbai 400 098, India. E-mail: anandshindikar@gmail.com
1
141

1
142
A. V. SHINDIKAR AND C. L. VISWANATHAN
10]
[
derivatives using Ti (SO ) -H SO . These methods have disadvantages such as a
2
4 3
2
4
large number of steps, harsh reaction conditions, or tedious procedures. We there-
fore aimed at overcoming the disadvantages of the reported methods and provide
a simple and efficient synthetic protocol for 1.
RESULTS AND DISCUSSION
Synthesis of 1 was carried out as shown in Scheme 1. 2-Methoxyphenol (2) on
treatment with epichlorhydrin in alkaline conditions afforded (3), which led to
chlorohydrin (4) with the opening of the epoxide ring by treatment with HCl. Then
4
was acetylated using acetic anhydride to get 5. Ring closure of 5 with stannic chlor-
ide gave 6, which on hydrolysis of the 3-acetyl group gave the desired
-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol (1). The advantages offered by this
8
method are (i) easily available starting material, (ii) simple operation (e.g., no
high-temperature reactions are involved), and insensitivity to air, (iii) cost-
effectiveness (e.g., avoids use of costly reagents such as m-chloroperbenzoic acid,
used in other methods), and (iv) good product yields.
Friedel–Craft’s alkyation using stannic chloride as the catalyst, which offers
good yields, is reported in the literature.
[11,12]
Thus, in the present method, the ability
of stannic chloride to effect alkylation=ring closure with less possibility of generation
of undesired material resulted in good yields. These advantages make the present
method useful for large-scale operations.
Scheme 1. Synthesis of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-ol.

8
-METHOXY-3,4-DIHYDRO-2H-1-BENZOPYRAN-3-OL
1143
EXPERIMENTAL
Reactions were monitored by thin-layer chromatography (TLC) using silica-gel
GF-254 precoated plates from Merck. Infrared (IR) spectra were recorded on a
1
Shimadzu IR spectrometer. H NMR spectra were recorded using tetramethylsilane
(TMS) as an internal standard on a Varian 300-MHz instrument.
Procedure for Compound 3
Epichlorhydrin (83.25 g, 0.9 M) was added to a solution of guaiacol (2) (37.2 g,
.3 M) in 2 N aqueous sodium hydroxide (150 ml), and the mixture was stirred at
0
room temperature for 6 h. The reaction mixture was poured into water (150 ml)
and extracted with chloroform (3 Â 150 ml). The chloroform layer was washed with
aqueous sodium hydroxide solution (2 Â 100 ml), dried over MgSO , and evaporated
4
in vacuo to afford compound 3.
Procedure for Compound 4
A solution of 3 (34 g, 0.19 M) in tetrahydrofuran (THF; 210 ml) was cooled to
C in an ice bath. To it was added 210 ml of HCl in dioxane (dry dioxane contain-
ꢀ
5
ꢀ
ing 18.5% w=w of hydrogen chloride), and the mixture was stirred at 5–10 C for 2 h.
The reaction mixture was poured into cold water (450 ml) and extracted with ethyl
acetate (3 Â 200 ml). The ethyl acetate layer was washed with water (2 Â 100 ml),
dried over MgSO , and evaporated in vacuo to give the compound 4.
4
Procedure for Compound 5
Triethylamine (0.9 g, 0.009 M) and acetic anhydride (9.18 g, 0.09 M) were suc-
cessively added to a solution of 4 (20 g, 0.09 M) in 200 ml of chloroform, and the mix-
ture was stirred at room temperature for 12 h. Then 100 ml of 10% aqueous K CO3
2
was added to the reaction mixture, and the layers were separated. The chloroform
layer was washed with water (2 Â 100 ml), dried over MgSO , and evaporated in
4
vacuo to give compound 5.
Procedure for Compound 6
Stannic chloride (26.20 g, 0.1 M) was added to a solution of 5 (20 g, 0.07 M) in
00 ml benzene, and the mixture was stirred at room temperature for 4 h under a
1
nitrogen stream. The reaction mixture was then poured over ice-cold water
(
200 ml) and extracted with chloroform (3 Â 100 ml). The organic layer was washed
with diluted HCl (100 ml), saturated NaHCO (100 ml), and water (2 Â 100 ml); dried
3
over MgSO ; and evaporated in vacuo to give compound 6.
4
Procedure for Compound 1
To a solution of 6 (6.6 g, 0.03 M) in methanol (65 ml) was added 2 N aqueous
sodium hydroxide (20 ml). The mixture was stirred at room temperature for 1.5 h and

1144
A. V. SHINDIKAR AND C. L. VISWANATHAN
then neutralized with 1 N hydrochloric acid. The neutralized mixture was extracted
with chloroform (3 Â 100 ml). The chloroform layer was dried over MgSO and eva-
4
porated in vacuo to give a viscous residue, which on stirring with benzene–hexane
mixture gave a crystalline product (1).
SPECTRAL DATA
2-(2-Methoxyphenoxymethyl)oxirane (3)
À1
1
Yield 70%; colorless liquid; IR (KBr) n: 1255 (C-O), 1224 (C-O-C) cm ; H
NMR (300 MHz, CDCl ) (d ppm): 6.98–6.92 (2H, m, ArH), 6.80–6.76 (2H, m,
3
ArH), 4.24 (2H, d, -CH -), 3.85 (3H, m, O-CH ), 3.34–3.32 (1H, m, C-H),
.85–2.72 (2H, m, -CH -). Anal. calcd. for C H O : C, 66.67; H, 6.67; O, 26.66.
2 10 12 3
2
3
2
Found: C, 66.60; H, 6.70; O, 26.59.
1-Chloro-3-(2-methoxyphenoxy)propan-2-ol (4)
À1
1
Yield 51%; colorless liquid; IR (KBr) n: 3427 (O-H), 1255 (C-O) cm ; H
NMR (300 MHz, CDCl ) (d ppm): 6.98–6.94 (2H, m, ArH), 6.82–6.74 (2H, m,
3
ArH), 4.24 (2H, d, -CH -), 4.10 (1H, m, C-H), 3.85 (3H, s, O-CH ), 3.81–3.79
(2H, d, -CH -), 3.02 (1H, s, O-H). Anal. calcd. for C H ClO : C, 55.55; H, 6.02;
Cl, 16.43; O, 22.22. Found: C, 55.60; H, 5.97; Cl, 16.50; O, 22.31.
2
3
2 10 13 3
1
-Chloro-3-(2-methoxyphenoxy)propan-2-yl Acetate (5)
Yield 85%; colorless liquid; IR (KBr) n: 1745 (C=O) cm
300 MHz, CDCl ) (d ppm): 6.98–6.89 (2H, m, ArH), 6.82–6.75 (2H, m, ArH),
À1
1
;
H NMR
(
3
4
O-H). Anal. calcd. for C H ClO : C, 55.70; H, 5.81; Cl, 13.76; O, 24.81. Found:
.34 (2H, d, -CH -), 3.85 (3H, s, O-CH ), 3.74–3.69 (2H, d, -CH -), 2.03 (1H, s,
2 3 2
1
2
15
4
C, 55.81; H, 5.89; Cl, 13.68; O, 24.71.
8-Methoxy-3,4-dihydro-2H-1-benzopyran-3-yl Acetate (6)
À1
1
Yield 72%; pale yellow liquid; IR (KBr) n: 1745 (C=O) cm ; H NMR
(
300 MHz, CDCl ) (d ppm): 6.98–6.89 (2H, m, ArH), 6.82–6.75 (2H, m, ArH),
3
4
O-H). Anal. calcd. for C H O : C, 64.86; H, 6.30; O, 28.83. Found: C, 64.98; H,
.34 (2H, d, -CH -), 3.85 (3H, s, O-CH ), 3.74–3.69 (2H, d, -CH -), 2.03 (1H, s,
2 3 2
1
2
14
4
6
.41; O, 28.70.
8-Methoxy-3,4-dihydro-2H-1-benzopyran-3-ol (1)
ꢀ
À1
1
Yield 73%; mp 77–79 C; IR (KBr) n: 3427 (O-H), 1269 (C-O) cm ; H NMR
(
300 MHz, CDCl ) (d ppm): 7.00–6.86 (2H, m, ArH), 6.77–6.73 (1H, m, ArH),
3
4
.30–4.25 (1H, m, C-H), 3.88 (3H, s, O-CH ), 2.96–2.92 (2H, m, -CH -), 2.91–2.86
3 2
(2H, m, -CH -), 2.10 (1H, m, O-H). Anal. calcd. for C H O : C, 66.67; H, 6.67;
O, 26.66. Found: C, 66.59; H, 6.58; O, 26.60.
2 10 12 3

8
-METHOXY-3,4-DIHYDRO-2H-1-BENZOPYRAN-3-OL
1145
ACKNOWLEDGMENT
The authors are thankful to the All-India Council for Technical Education,
Government of India, for funding the project.
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