Synthesis of functionalized benzopyrans via intramolecular 1,3-dipolar cycloaddition of nitrile oxides

Article abstract of DOI:10.1080/00397910802138744

Various functionalized benzopyran derivatives have been synthesized in good yields by a sequence of reactions viz. intramolecular cyclization of nitrile oxides, reductive cleavage, and acetylation. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802138744

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Synthesis of Functionalized
Benzopyrans via Intramolecular
1,3-Dipolar Cycloaddition of
Nitrile Oxides
Vipraja V. Vaidya a , Karuna S. Wankhede a
,
Manikrao M. Salunkhe a & Girish K. Trivedi a
a Department of Chemistry , Institute of Science ,
Mumbai, India
Published online: 11 Jul 2008.
To cite this article: Vipraja V. Vaidya , Karuna S. Wankhede , Manikrao M. Salunkhe
& Girish K. Trivedi (2008) Synthesis of Functionalized Benzopyrans via Intramolecular
1,3-Dipolar Cycloaddition of Nitrile Oxides, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:14,
2392-2403, DOI: 10.1080/00397910802138744
To link to this article: http://dx.doi.org/10.1080/00397910802138744
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Synthetic Communications1, 38: 2392–2403, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802138744
Synthesis of Functionalized Benzopyrans via
Intramolecular 1,3-Dipolar Cycloaddition
of Nitrile Oxides
Vipraja V. Vaidya, Karuna S. Wankhede, Manikrao M. Salunkhe,
and Girish K. Trivedi
Department of Chemistry, Institute of Science, Mumbai, India
Abstract: Various functionalized benzopyran derivatives have been synthesized
in good yields by a sequence of reactions viz. intramolecular cyclization of nitrile
oxides, reductive cleavage, and acetylation.
Keywords: Benzopyrans; INOC; isoxazolines
INTRODUCTION
The 1,3-dipolar cycloaddition reaction using nitrile oxides is one of the
versatile methods for the preparation of synthetically useful intermediates—
isoxazolines and isoxazoles. Further synthetic manipulation of these
products provides easy access to a,b-unsaturated carbonyls, b-hydroxy
carbonyls, b-hydroxy nitriles, b-hydroxy acids, esters, c-amino alcohols,
and so on[1a] Thus, isoxazolines and isoxazoles are potential precursors
for the synthesis of a variety of heterocycles and molecules of both syn-
thetic and natural origin. Many compounds of biological interest have
been synthesized via the intramolecular nitrile oxide cycloaddition
(INOC) pathway. These compounds include sarkomycin,[1b] prosta-
glandins,[1c] (þ)-paliclavine,[1d] and (ꢀ)-vermiculine.[1e] The benzopyra-
noisoxazolidines and corresponding isoxazoles are of considerable
interest because of their industrial and biological importance. 7,8-
Dihydroxy-4-(2-imidazolinyl)chroman is reported to be an a2-adrenergic
Received March 14, 2007
Address correspondence to Manikrao M. Salunkhe, Department of Chemistry,
15, Madam Cama Road, Mumbai, 400 032. E-mail: mmsalunkhe@hotmail.com
2392

Synthesis of Functionalized Benzopyrans
2393
Figure 1. Isoxazolines, 1–5, and isoxazole 6.
agonist.[2] 3-Hydroxymethyl chromans find application as intermediates
in the synthesis of a2-adrenergic blocking agents and inotropic drugs.[3]
b-Hydroxybenzopyranone 16 has been reported as an intermediate in
the synthesis of nonsteroidal anti-inflammatory agents.[4]
Keeping in view the versatility of these intermediates, we report the
synthesis of some simple isoxazolines (Fig. 1) and some chemical
transformations of the isoxazoline 1 to different benzopyran derivatives
7 to 14. This article also deals with the preparation of 2,3-dihydro-3-
hydroxymethyl-4H-benzopyran-4-ones, 15 and 16.
RESULTS AND DISCUSSION
2-Allyloxybenzaldoxime, a precursor of isoxazoline 1, could easily be
prepared from 2-hydroxybenzaldehyde as illustrated in Scheme 1. 2-
Allyloxybenzaldehyde was obtained from 2-hydroxybenzaldehyde upon
treatment with 3-bromo-1-propene and potassium carbonate, which on
further treatment with hydroxylamine hydrochloride and a base afforded
Scheme 1. Reagents and conditions: (i) K2CO3, CH3COCH3, allyl bromide, D;
(ii) NH2OHꢁHCl, NaOH, EtOH, 0 ꢂC; (iii) 4% NaOCl, CH2Cl2, Et3N, 0 ꢂC;
(iv) Raney-Ni, H2, boric acid, MeOH:H2O (5:1); (v) NaBH4, MeOH, 0 ꢂC;
(vi) Ac2O, I2, rt.

2394
V. V. Vaidya et al.
Scheme 2. Reagents and conditions: (i) mesyl chloride, CH2Cl2, Et3N, 0ꢂC.
desired oxime. An intramolecular cyclization of the oxime afforded the
well-known isoxazoline 1 in 83% yields.[5] Further synthetic manipula-
tions on isoxazoline 1 were conceptualized with an objective to devise a
route for diverse synthetically useful compounds that commonly serve
as potential precursors to several natural and synthetic products. Various
chemical transformations such as reductive cleavage followed by acety-
lation or dehydration were attempted. It is interesting to note that the
preparation of isoxazoline 1 via INOC has been reported by several
workers; however, to the best of our knowledge there are no reports in
literature concerning reductive studies on this simple molecule.
This prompted us to undertake the present work. Being a
heterocyclic aldol equivalent, isoxazoline 1 on reductive cleavage with
Raney-Ni[6] gave
a b-hydroxycarbonyl compound, 2,3-dihydro-3-
hydroxymethyl-4H-benzopyran-4-one 7.[7] Further, sodium borohydride
reduction of 7 in methanolic media gave a dihydroxy derivative 8, which
on subsequent acetylation with acetic anhydride furnished a diastereo-
meric mixture of the diacetate 9 in quantitative yields (Scheme 1).[8]
b-Hydroxyketone 7, on treatment with methanesulfonylchloride and
triethylamine, underwent facile dehydration to afford enone 10
(Scheme 2). Such types of enones, Michael acceptors, are reported to
have antimicrobial activity. Incidentally, this enone has been synthesized
earlier by a radical addition process.[9] To prepare amino alcohol 11 and
its corresponding diacetate 12, the isoxazoline 1 was subjected to
reductive cleavage employing LiAlH4 in diethyl ether, and the resultant
amino alcohol 11 was subsequently acetylated to the respective diacetate
12 using acetic anhydride (Scheme 3).
When sodium cyanoborohydride was used as a reducing agent, isoxa-
zoline 1 was reduced to isoxazolidine derivative 13, which on treatment
Scheme 3. Reagents and conditions: (i) LAH, Et2O, D; (ii) Ac2O, I2, rt.

Synthesis of Functionalized Benzopyrans
2395
Scheme 4. Reagents and conditions: (i) NaBH3CN, AcOH (gl); (ii) NaH, THF,
BnBr, 0ꢂC, rt.
with NaH in tetrahydrofuran (THF) followed by addition of benzyl
bromide at 0 ꢂC gave the N-benzylated derivative 14 (Scheme 4).
Once this isoxazoline synthetic sequence was optimized, we went on
to explore the synthesis of different substituted and hitherto unreported
benzopyrano analogs via INOC reaction. Following the sequence
depicted in Scheme 1, allyl ether of 2-hydroxy-3-methoxybenzaldehyde,
2-methylpropenyl ether of 2-hydroxybenzaldehyde, 2-cinnamyloxyben-
zaldehyde, and allyl ether of 2-hydroxynaphthaldehyde were transformed
to their respective aldoximes. These aldoximes, upon subjection to the
INOC reaction following Lee’s protocol, afforded the isoxazolines 2, 3,
4, and 5 respectively. The reaction sequence proved to be quite versatile
and gave comparable yields of isoxazolines 2–5. For example, the INOC
reaction of 2-allyloxy-3-methoxybenzaldoxime under identical conditions
yielded corresponding isoxazoline 2 in 73% yields. Similarly, 2-(2-methy-
lallyloxy)benzaldoxime and 2-cinnamyloxybenzaldoxime under similar
conditions yielded isoxazolines 3 (78%) and 4 (82%) respectively.
Recently the synthesis of isoxazoline 4 was reported via 1,3-dipolar
cycloaddition in water.[10] 2-Allyloxynapthaldoxime underwent intramol-
ecular nitrile oxide cycloaddition to give isoxazoline 5 in 80% yield.
Alternatively, isoxazole 6 was obtained in 81% yield when 2-propargy-
loxybenzaldoxime was subjected to the same reaction conditions.
Like isoxazoline 1, compounds 2 and 3, on hydrogenolysis in
the presence of Raney Ni=boric acid, afforded the 2,3-dihydro-3-
hydroxymethyl-4H-benzopyran-4-ones 15 and 16 respectively (Fig. 2).
Figure 2. 2,3-Dihydro-3-hydroxymethyl-4H-benzopyran-4-ones 15 and 16.

2396
V. V. Vaidya et al.
CONCLUSION
Following the convenient and inexpensive INOC reactions, we have
synthesized several simple isoxazolines, which could be transformed into
a variety of benzopyran derivatives of biological importance. We are
extending this methodology to synthesize cyclic homologs of benzopyran,
namely benzoxepanes.
EXPERIMENTAL
General Procedure for the Preparation of 2-Allyloxyaldehydes
To the solution of aldehyde (10 mmol) in dry acetone (10 mL), K2CO3
(1.4 g, 10 mmol) and allyl bromide (1 mL, 10 mmol) were added. The
reaction mixture was heated under reflux for 8–10 h with stirring. The
resulting mixture was cooled and poured into 10 mL of H2O. The product
was extracted with three 10-mL portions of ether. The organic extracts
were washed with 2 M NaOH and brine, dried over anhydrous sodium
sulphate, and evaporated under reduced pressure to give corresponding
2-allyloxyaldehyde (yield 85%).
General Procedure for the Preparation of 2-Allyloxyaldoximes
Ethanol (2.5 mL), ice-cold water (5 mL), and 50% NaOH (25 mmol) were
added to a stirred solution of 2-allyloxyaldehyde (10 mmol) and hydroxy-
lamine hydrochloride (11 mmol) in water (2.5 mL). The temperature was
maintained between 25 and 30 ꢂC during the addition of alkali. The reac-
tion mixture was stirred for 1 h, extracted with 10 mL of ether to remove
neutral impurities, acidified with conc. HCl to pH 6 (maintaining tem-
perature between 20 and 30 ꢂC), and extracted with two 20-mL portions
of ether (or dichloromethane). These latter two extracts were combined,
washed with brine, dried, and concentrated under vacuum to afford
oxime (yield 70%).
4H-[1]Benzopyrano[4,3-c]-2-isoxazoline, 1
To a solution of 2-allyoxybenzaldoxime (1.77 g, 10 mmol) and triethylamine
(0.01 mmol) in dichloromethane (100 mL), sodium hypochlorite (4%,
100 mL, 10 mL per 1 mmol) was added dropwise with stirring at 0 ꢂC. On
disappearance of the starting material (TLC), the reaction phases were
separated and the aqueous phase was extracted with dichloromethane.

Synthesis of Functionalized Benzopyrans
2397
The combined layers were washed with brine and dried with sodium
sulphate, and the solvent was evaporated under reduced pressure to yield
crude cycloadduct. The crude product was recrystallized from hexane
(1.45 g, 83%), mp 62 ꢂC [mp 62–63 ꢂC]; IR (CCl4): nmax 2976, 1606, 1480,
1215, 1048cmꢀ1; 1H NMR (400MHz, CDCl3): d 7.80–7.78 (dd, J ¼ 1.6 Hz,
Hz, 8 Hz, 1H), 7.36–7.30 (m, 1H), 7.00–6.90 (m, 2H), 4.70–4.60 (m, 2H),
4.20–4.10 (m, 1H), 4.00–3.90 (m, 2H) ppm; 13C NMR (75MHz, CDCl3):
d 155.58, 152.77, 132.48, 125.69, 121.86, 117.40, 113.03, 70.59, 69.25,
45.88 ppm; MS: (Mþ þ 1) 176.
Isoxazoline 2
2-Allyloxy-3-methoxybenzaldoxime (1.00 g, 5 mmol) was transformed to
isoxazoline 2 similarly as isoxazoline 1. The crude product upon purifi-
cation using silica-gel column chromatography afforded solid (0.72 g,
73%), mp 95–96 ꢂC; IR (CHCl3): nmax 2930, 2869, 1576, 1491, 1266,
1
1058 cmꢀ1; H NMR (300 MHz, CDCl3): d 7.42–7.39 (dd, J ¼ 2.1 Hz,
6.9 Hz, 1H), 6.99–6.91 (m, 2H), 4.85–4.80 (dd, J ¼ 4.5 Hz, 10.5 Hz,
1H), 4.73–4.69 (t, J ¼ 6 Hz, 1H), 4.16–4.09 (m, 1H), 3.99–3.90 (m,
overlapping peaks, 5H) ppm; 13C NMR (75 MHz, CDCl3): d 152.63,
148.69, 121.63, 117.28, 113.74, 113.65, 70.71, 69.77, 56.07, 45.79 ppm;
MS: Mþ 205.
Isoxazoline 3
The conversion of 2-(2-methylallyloxy)benzaldoxime (1.91 g, 10 mmol) in
a similar manner, as in the preparation of isoxazoline 1, gave
isoxazoline 3. The crude product upon purification using silica-gel
column chromatography gave a solid (1.48 g, 78%), mp 86–87 ꢂC; IR
1
(CHCl3): nmax 2926, 1601, 1456, 1253, 1218 cmꢀ1; H NMR (300 MHz,
CDCl3): d 7.80–7.78 (dd, J ¼ 1.5 Hz, 7.5 Hz, 1H), 7.37–7.32 (m, 1H),
7.03–6.95 (m, 2H), 4.40–4.32 (dd, J ¼ 8.1 Hz, 10.5 Hz, 2H), 4.20–4.16
(d, J ¼ 10.5 Hz, 1H), 4.02–3.99 (d, J ¼ 8.1 Hz, 1H), 1.42 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3): d 156.67, 154.78, 132.42, 126.10, 121.90,
117.40, 112.20, 77.66, 74.13, 49.56, 19.24 ppm; MS: (Mþ þ 1) 190.
Isoxazoline 4
The conversion of 2-cinnamyloxybenzaldoxime (1.26 g, 5 mmol) in a similar
manner, as in the preparation of isoxazoline 1, gave isoxazoline 4. The crude
product was recrystallized from hexane (1.02 g, 82%), mp 162–163ꢂC; IR

2398
V. V. Vaidya et al.
1
(CHCl3): nmax 3020, 1609, 1520, 1422, 1216, 771, 669 cmꢀ1; H NMR
(300MHz, CDCl3): d 7.78–7.76 (d, J ¼ 8 Hz, 1H), 7.37–7.24 (m, 6H),
6.97–6.86 (m, 2H), 5.19–5.15 (d, J ¼ 12 Hz, 1H), 4.59–4.54 (dd, J ¼ 6 Hz,
10.5Hz, 1H), 4.20–4.12 (dd, J ¼ 10.5 Hz, 12 Hz, 1H), 3.87–3.77 (ddd,
J ¼ 6 Hz, 12 Hz, 12 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): d 156.39,
154.17, 138.03, 133.37, 129.74, 127.45, 126.37, 122.74, 118.25, 113.96,
86.55, 69.83, 53.71 ppm; MS: Mþ 251.
Isoxazoline 5
The conversion of 2-allyloxynapthaldoxime (1.13 g, 5 mmol), in a manner
similar to the preparation of isoxazoline 1, gave isoxazoline 5. The crude
product was recrystallized from hexane (0.89 g, 80%), mp 72–73 ꢂC; IR
(CHCl3): nmax 3059, 2930, 2873, 1622, 1595, 1514, 1443, 1346, 1222,
1023 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d 9.02–8.99 (d, J ¼ 8.7 Hz,
1H), 7.75–7.71 (m, 2H), 7.59–7.54 (m, 1H), 7.40–7.37 (m, 1H), 7.05–7.02
(d, J ¼ 8.7 Hz, 1H), 4.73–4.62 (m, 2H), 4.2–4.16 (m, 1H), 4.13–3.96
(m, 1H), 3.9–3.84 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3): d 155.39,
152.94, 133.11, 130.21, 128.97, 128.20, 128.15, 126.26, 124.44, 117.98,
105.79, 69.23, 68.91, 46.58 ppm; MS: Mþ 225.
Isoxazole 6
The conversion of 2-propargyloxybenzaldoxime (1.75 g, 10 mmol), in a
manner similar to the preparation of isoxazoline 1, gave isoxazole 6.
The crude product was purified by silica-gel column chromatography
to afford a liquid (1.4 g, 81%); IR (CHCl3): nmax 3026, 2926, 1601,
1
1456, 1253, 1218 cmꢀ1; H NMR (300 MHz, CDCl3): d 8.21 (s, 1H),
7.89–7.86 (dd, J ¼ 1.6 Hz, 8 Hz, 1H), 7.38–7.33 (m, 1H), 7.10–7.01 (m,
2H), 5.24–5.23 (d, J ¼ 3 Hz, 2H); 13C NMR (75 MHz, CDCl3): d
154.82, 153.67, 150.61, 132.10, 124.56, 122.37, 117.82, 113.92, 111.17,
61.25 ppm; MS: Mþ 173.
2,3-Dihydro-3-hydroxymethyl-4H-benzopyran-4-one 7
Boric acid (0.227 g, 3.7 mmol) and a spatula tip (estimated 10–20 mg) of
W2 Raney Ni were added to a solution of isoxazoline 1 (0.31 g, 1.8 mmol)
in methanol–H2O (5:1, 10 mL). The reaction was placed under hydrogen
by repeated (ꢃ5 times) evacuation and flushing with H2 gas by means of
a balloon attached to a three-way stopcock. The mixture was stirred for
4 h and then filtered through Celite1 into a separating funnel containing

Synthesis of Functionalized Benzopyrans
2399
water and dichloromethane. After separation, the aqueous layer was
extracted with dichloromethane two more times, and the combined
organic layers were washed with brine, dried over Na2SO4, and concen-
trated under vacuum to yield crude b-hydroxyketone. The crude product
was purified by column chromatography on silica gel to afford a liquid
(0.24 g, 77%); IR (CHCl3): nmax 3687, 1680, 1216 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 7.89–7.87 (dd, J ¼ 1.6 Hz, 8 Hz, 1H), 7.50–7.48
(m, 1H), 7.04–6.98 (m, 2H), 4.61–4.57 (dd, J ¼ 5.4 Hz, 11.2 Hz, 1H),
4.45–4.39 (t, J ¼ 11.2 Hz, 1H), 4.05–4.00 (dd, J ¼ 5.4 Hz, 11.2 Hz, 1H),
3.93–3.88 (dd, J ¼ 5.4 Hz, 11.4 Hz, 1H), 3.03–2.99 (m, 1H), 2.6 (bs, 1H)
ppm; 13C NMR (75 MHz, CDCl3): d 194.12, 161.82, 136.21, 127.06,
121.39, 120.74, 117.86, 68.56, 59.11, 47.74 ppm; MS: Mþ 178.
2,3-Dihydro-3-hydroxymethyl-8-methoxy-4H-benzopyran-4-ones 15
The conversion of isoxazoline 2 (0.37 g, 1.8 mmol), in a manner similar to the
preparation of b-hydroxyketone 7, gave b-hydroxyketone 15. The crude pro-
duct was purified by column chromatography on silica gel to afford a liquid.
(0.27 g, 72%); IR (CHCl3) nmax 3687, 1680, 1386, 1218, 1053 cmꢀ1; 1H NMR
(300 MHz, CDCl3): d 7.50–7.48 (d, J ¼ 6.9Hz, 1H), 7.08–7.06 (d,
J ¼ 7.2Hz, 1H), 7.00–6.94 (t, J ¼ 7.8 Hz, 1H), 4.73–4.68 (dd, J ¼ 5.4 Hz,
7.5 Hz, 1H), 4.52–4.44 (t, J ¼ 11.4Hz, 1H), 4.05–4.00 (dd, J ¼ 5.4 Hz,
11.4 Hz, 1H), 3.94–3.88 (m, overlapping peaks, 4H), 3.08–2.94 (m, 1H),
2.45 (bs, 1H) ppm; 13C NMR (75 MHz, CDCl3): d 194.15, 151.78, 148.77,
121.37, 120.96, 118.19, 116.83, 69.15, 59.23, 56.20, 47.55 ppm; MS: Mþ 208.
2,3-Dihydro-3-hydroxymethyl-3-methyl-4H-benzopyran-4-ones 16
The conversion of isoxazoline 3 (0.34 g, 1.8 mmol), in a manner similar to
the preparation of b-hydroxyketone 7, gave b-hydroxyketone 16. The
crude product purified by column chromatography on silica gel afforded
a liquid (0.26 g, 75%); IR (CHCl3): nmax 3687, 3021, 1680, 1607, 1474,
1
1320, 1216, 1039 cmꢀ1; H NMR (300 MHz, CDCl3): d 7.90–7.87 (dd,
J ¼ 1.6 Hz, 7.8 Hz 1H), 7.52–7.49 (m, 1H), 7.05–6.99 (m, 2H), 4.54–4.50
(d, J ¼ 11.4 Hz, 1H), 4.20–4.16 (d, J ¼ 11.4 Hz, 1H), 3.95–3.91 (d, J ¼
11.4 Hz, 1H), 3.60–3.56 (d, J ¼ 11.4 Hz, 1H), 2.44 (bs, 1H), 1.23 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3): d 197.16, 161.27, 136.09, 127.48,
121.50, 119.82, 117.77, 73.29, 64.63, 46.99, 16.37 ppm; MS: Mþ 192.
2,3-Dihydro-3-hydroxymethyl-4H-benzopyran-4-ol 8
b-Hydroxyketone 7 (0.18 g, 1 mmol) was dissolved in 2 mL of MeOH.
The solution was cooled at ꢀ10 ꢂC, and NaBH4 (0.064 g, 1.69 mmol)

2400
V. V. Vaidya et al.
was added in portions. The mixture was stirred for 2 h before quenching
by the addition of water and dichloromethane. The organic layers were
washed with brine, dried over sodium sulphate, and concentrated under
reduced pressure to give the product. The crude product was purified by
column chromatography on silica gel to afford a white solid (0.16 g,
89%); mp 86–88 ꢂC. IR (CHCl3): nmax 3687, 3246, 2995, 2939, 1452,
1375, 1230, 1039 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.38–7.36
.
(d, J ¼ 7.5 Hz, 1H), 7.29–7.17 (m, 1H), 6.97–6.80 (m, 2H), 4.70–4.68
(d, J ¼ 6 Hz, 1H), 4.28–4.21 (m, 1H), 4.10–4.04 (m, 1H), 3.71–3.67
(m, 2H), 2.30–2.15 (bs merged with multiplet, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d 154.00, 129.50, 129.02, 123.87, 121.02, 116.74,
66.42, 64.29, 61.74, 61.71, 42.38 ppm; MS: Mþ 180.
Diacetate of 2,3-Dihydro-3-hydroxymethyl-4H-benzopyran-4-ol 9
I2 (0.1 mmol) was added to a solution of diol 8 (0.18 g, 1 mmol) in Ac2O
(2.1 mmol) and stirred at room temperature for 10 min. The reaction was
quenched by the addition of aq. sodium thiosulphate and extracted with
dichloromethane. The organic extracts were washed with sodium bicar-
bonate and water and dried over sodium sulphate. Evaporation of vola-
tiles under reduced pressure gave the product diacetate 9 in a
diastereomeric mixture. The crude product was purified by column chro-
matography on silica gel to afford a liquid (0.23 g, 89%). IR (CHCl3):
1
nmax 3020, 1738, 1218, 1045, 1020, 771, 669 cmꢀ1; H NMR (300 MHz,
CDCl3): d 7.37–7.21 (m, 2H), 6.94–6.84 (m, 2H), [6.10–6.09 (d), 5.88–
5.87 (d), J ¼ 3 Hz, 1H)], 4.32–3.97 (m, 4H) [2.63–2.58 (m), 2.43–2.38
(m), 1H], 2.09 (s, 3H), 2.08 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d 170.37, 170.25, 154.52, 154.45, 131.07, 130.82, 130.38, 130.32, 121.06,
120.71, 119.97, 118.62, 116.94, 116.79, 65.87, 65.08, 63.32, 63.16, 61.64,
60.82, 37.16, 36.29, 21.21, 20.69 ppm; MS: Mþ 264.
2,3-Dihydro-3-methylene-4H-benzopyran-4-one 10
Mesyl chloride (0.11 mL, 1.5 mmol) and triethylamine (0.2 mL, 1.5 mmol)
were added to a solution of b-hydroxyketone 7 (0.18 g, 1 mmol) in
dichloromethane at 0 ꢂC. The reaction mixture was stirred. On disappear-
ance of the starting material (TLC), the mixture was washed with water,
dried over sodium sulphate, and evaporated to yield the enone. The crude
enone was purified by column chromatography to afford a syrupy liquid
(0.13 g, 81%); IR (CHCl3): nmax 3037, 2946, 1692, 1610, 1476, 1226, 1029,
759 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 8.00–7.98 (d, J ¼ 6 Hz, 1H);
7.48–7.46 (m, 1H); 7.08–6.96 (m, 2H); 6.31 (s, 1H); 5.58 (s, 1H); 5.00

Synthesis of Functionalized Benzopyrans
2401
(s, 2H) ppm; 13C NMR (75 MHz, CDCl3): d 182.00, 161.88, 138.83,
135.98, 127.93, 122.41, 121.89, 118.05, 71.15 ppm; MS: Mþ 160.
(4-Amino-2,3-dihydro-4H-benzopyran-3-yl)methanol 11
A solution of isoxazoline, 1 (0.17 g, 1 mmol), in anhydrous diethyl ether
(7.5 mL) was added drop wise at rt under N2 to lithium aluminium
hydride (LAH) (0.08 g, 2.2 mmol) suspended in 2.5 mL of anhydrous
ether. The mixture was refluxed for 8 h, cooled, and quenched with conc.
sodium sulphate (dropwise). The reaction mixture was extracted with
ether (four times). The organic extracts were combined, dried over
sodium sulphate, and evaporated to yield crude amino alcohol. The pro-
duct was purified by column chromatography on silica gel to afford a
liquid (0.15 g, 84%); IR (CHCl3): nmax 3685, 3345, 3200, 2400, 1216,
771 cmꢀ1; 1H NMR (300 MHz, CDCl3): d 7.20–7.14 (t, J ¼ 8.1 Hz,
2H), 6.93–6.88 (t, J ¼ 7 Hz, 1H), 6.85–6.82 (d, J ¼ 8.1 Hz, 1H) [4.25–
4.22 (m), 4.13–4.12 (d, J ¼ 4.2 Hz), 4.07–4.02 (dd, J ¼ 3.6 Hz, 11 Hz),
4H] 3.88–3.83 (dd, J ¼ 5.1 Hz, 11 Hz, 1H), 2.77 (s, 3H), 2.18–2.12 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3): d 153.87, 129.51, 128.65,
126.25, 120.51, 116.75, 63.55, 60.95, 47.28, 39.20 ppm; MS: Mþ 179.
Diacetate of (4-Amino-2,3-dihydro-4H-benzopyran-3-yl)methanol 12
The conversion of amino alcohol 11 (0.18 g, 1 mmol) in a manner similar
to the one followed for the preparation of diacetate of diol 9 gave diace-
tate of amino alcohol 12 as a liquid (0.22 g, 85%); IR (CHCl3): nmax 3288,
2921, 1741, 1649, 1488, 1370, 1045; 1H NMR (300 MHz, CDCl3): d 7.26–
7.19 (m, 2H), 6.95–6.82 (m, 2H), 5.75–5.72 (d, J ¼ 8.4 Hz, 1H), 5.45–5.40
(dd J ¼ 7.8 Hz, 9 Hz, 1H), 4.31–4.24 (m, 2H), 4.14–4.01 (m, 2H), 2.60–
2.55 (m, 1H), 2.06 (s, 3H), 2.02 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d 171.81, 171.55, 154.40, 129.46, 129.11, 121.26, 121.08, 116.96, 64.47,
61.85, 45.05, 36.05, 22.98, 19.47 ppm; MS: Mþ 263.
Isoxazolidine 13
To a cold solution of isoxazoline, 1 (0.18 g, 1 mmol) in glacial AcOH
(2.5 mL) and NaBH3CN (0.31 g, 5 mmol) were added, and the mixture
was stirred at room temperature. Then, dichloromethane (100 mL) and
saturated aqueous NaHCO3 (20 mL) were added. When the evolution
of gas ceased, the organic layer was separated, washed with brine
(40 mL), and dried over sodium sulphate. The solvent was evaporated

2402
V. V. Vaidya et al.
to give isoxazolidine 13. The product was purified by column chromato-
graphy on silica gel to afford a white solid (0.10 g, 56%); mp 178–180 ꢂC,
;
IR (KBr) nmax 3371, 3019, 1645, 1457, 1225, 1024 cmꢀ1 1H NMR
(300 MHz, DMSO-d6): d 10.48–10.46 (d, J ¼ 7.8 Hz, 1H), 7.42–7.40 (d,
J ¼ 7.8 Hz, 1H), 7.35–7.31 (t, J ¼ 7 Hz, 1H), 7.04–6.99 (t, J ¼ 7.5 Hz,
1H), 6.95–6.92 (d, J ¼ 8.1 Hz, 1H), [4.44–4.33 (m), 4.29–4.24 (dd,
J ¼ 5.1 Hz, 11 Hz), 3H], 4.01–3.89 (m, 2H), 3.31–3.18 (m, 1H) ppm;
13C NMR (75 MHz, CDCl3): d 155.21, 132.16, 130.91, 121.08, 117.23,
114.40, 70.61, 63.32, 60.77, 38.86 ppm; MS: Mþ 177.
N-Benzylisoxazolidine 14
Sodium hydride (60% suspension in mineral oil, washed with hexane,
1.2 mmol, 0.028 g) was suspended in dry THF under N2 at 0ꢂC. A sol-
ution of isoxazolidine (0.18 g, 1 mmol) in dry THF (20 mL) was added
dropwise using a dropping funnel, and the mixture was stirred for 0.5 h
at 0 ꢂC. Then, benzylbromide (0.11 mL, 1 mmol) was added slowly at
0 ꢂC. The mixture was stirred for 5 h at room temperature. After quench-
ing the reaction mixture with water, the solvent was evaporated. Then it
was extracted with dichloromethane and dried over sodium sulphate. The
extracts were combined and concentrated under reduced pressure to give
N-benzylisoxazolidine. The product was purified by column chromato-
graphy on silica gel to afford a liquid (0.21 g, 78%); IR (CHCl3): nmax
3020, 2930, 2869, 1576, 1232 cmꢀ1 1H NMR (300 MHz, CDCl3): d
;
7.43–7.25 (m, 5H), 7.19–7.16 (d, J ¼ 7.5 Hz, 2H), 6.94–6.87 (m, 2H),
4.34–4.22 (m, 2H), 4.18–4.16 (d, J ¼ 6 Hz, 2H), 4.05–4.01 (d, J ¼ 12 Hz,
Hz, 1H), 3.93 (d, J ¼ 8 Hz, 1H), 3.84–3.80 (dd, J ¼ 4.8 Hz, 8.1 Hz, 1H),
3.14–3.04 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3): d 137.42, 130.87,
129.08, 128.99, 128.43, 127.45, 121.26, 117.04, 67.60, 65.72, 61.71,
39.86 ppm; MS: Mþ 267.
ACKNOWLEDGMENTS
We thank University Grants Commission (UGC), New Delhi, for the
award of a fellowship and financial support [F-12–25= (2003)] and the
director, Institute of Science, Mumbai.
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