Intramolecular 1,3-dipolar nitrile oxide cycloaddition using Baylis-Hillman derivatives: Stereoselective synthesis of tricyclic chromenoisoxazolines

Article abstract of DOI:10.1055/s-0031-1289707

A novel protocol for the construction of tricyclic chromenoisoxazoline frameworks via an intramolecular 1,3-dipolar nitrile oxide cycloaddition (INOC) reaction using Baylis-Hillman derivatives is described for the first time. The INOC reaction leads to a

Full text of DOI:10.1055/s-0031-1289707

PAPER
755
Intramolecular 1,3-Dipolar Nitrile Oxide Cycloaddition Using Baylis–Hillman
Derivatives: Stereoselective Synthesis of Tricyclic Chromenoisoxazolines
Stereoselective
Synthe
a
sis of Tricy
n
clic
C
hrome
i
noisoxa
c
zolines kam Bakthadoss,* Jayakumar Srinivasan, Raman Selvakumar
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
Fax +91(44)22352494; E-mail: bhakthadoss@yahoo.com
Received 20 October 2011; revised 15 December 2011
b-hydroxy ketones and g-amino alcohols.5 There are nu-
Abstract: A novel protocol for the construction of tricyclic
chromenoisoxazoline frameworks via an intramolecular 1,3-dipolar
nitrile oxide cycloaddition (INOC) reaction using Baylis–Hillman
derivatives is described for the first time. The INOC reaction leads
merous examples of these N,O-heterocycles being used as
a key building block in the total synthesis of natural and
unnatural compounds such as biotin,6a sarkomycin,6b spe-
to
a
novel class of angularly substituted fused tricyclic cionin,6c phyllanthocin,6d testosterone,6e epothilones,6f
macrospelides,6g L-carbafuranomycin6h and gabosine.6i
chromenoisoxazolines, with the creation of two rings and two adja-
cent stereocenters, one of them being an all-carbon quaternary cen-
ter, in a unique fashion. The tricyclic chromenoisoxazolines are
obtained in a highly stereoselective fashion with good yields.
There has been a flurry of activity in the synthesis of ben-
zopyran derivatives due to their proven biological activity
and medicinal utility. For example, benzopyran deriva-
tives posses antiplatelet,7a antipsychotic and antidepres-
sant activities.7b Some benzopyran derivatives also have
anti-HIV activity.7c–f
Key words: 1,3-dipolar nitrile oxide cycloaddition, chromenoisox-
azolines, stereoselective synthesis, tricyclic framework
The Baylis–Hillman (BH) reaction is one of the important
carbon–carbon bond-forming reactions and has seen enor-
mous growth in the recent past. The utility of the Baylis–
Hillman adducts can be found in the synthesis of a variety
of natural products and medicinally relevant com-
pounds.8,9
1,3-Dipolar cycloaddition reactions afford complex het-
erocycles with multiple stereocenters, which are useful in
the construction of many natural products and pharmaceu-
ticals.1 The synthesis of complex heterocyclic compounds
is a very challenging and attractive area in the field of or-
ganic chemistry.2 The 1,3-dipolar cycloaddition of nitrile
oxides to alkenes and alkynes affords isoxazolines and
isoxazoles.3 It is pertinent to note that isoxazolines exhibit
important biological activities, such as antibacterial,4a
antiplatelet,4b antiviral,4c anticonvulsant,4d immuno-
stimulatory4e and antihypertensive,4f besides being valu-
able synthons in the synthesis of a,b-unsaturated ketones,
The isoxazoline and benzopyran moieties are interesting
targets (Figure 1) in the development of new drug leads in
medicinal chemistry and in the synthesis of a wide variety
of natural products, which attracted us to develop a new
protocol for the synthesis of substituted tricyclic
H2N
O
S
O
O
NH
N
O
O
N
N
N
N
CF3
R
O
O
O
(anti-inflammatory)
(antagonists of cloned human 5-HT2B)
N-phenyl-3,3a,4,9b-tetrahydro-1H-
(antifertility)
2H-acetyl-3-aryl-3,3a-dihydropyrazolo-
[4,3-c][2H]chromenes
4-(3-(trifluoromethyl)chromeno[4,3-c]-
pyrazol-1(4H)-yl)benzenesulfonamide chromeno[4,3-c]isoxazole-1-carboxamide
O
N
N
O
N
O
O
R1
R2
N
COOH
O
Ar
(antidepressant)
3-piperazinylmethyl-3a,4-dihydro-3H-[1]-
benzopyrano[4,3-c]isoxazoles
(immunosuppressive)
5-aryl-3,3a,4,5-tetrahydronapthol-
[1,2-c]isoxazole-4-carboxylic acids
Figure 1 Some benzopyran- and isoxazole-containing bioactive compounds
SYNTHESIS 2012, 44, 755–766
x
x
.x
x
.2
0
1
2
Advanced online publication: 13.02.2012
DOI: 10.1055/s-0031-1289707; Art ID: Z98911SS
© Georg Thieme Verlag Stuttgart · New York

756
M. Bakthadoss et al.
PAPER
chromenoisoxazoline derivatives using Baylis–Hillman
chemistry. It is well documented that tricyclic compounds
containing isoxazole and benzopyran units are known for
their various bioactive properties such as antidepressant,10
immunosuppressive,11 antifertility12 and anti-inflammato-
ry activities.13 They also act as selective antagonists of
14
cloned human 5-HT2B (Figure 1). Thus, we speculated
that newly synthesized libraries of tricyclic
chromenoisoxazolines may also have similar activity.
In continuation of our interest in Baylis–Hillman chemis-
try,15 herein we report the first synthesis of angularly sub-
stituted fused tricyclic chromenoisoxazoline frameworks
through in situ formation of nitrile oxide followed by an
intramolecular 1,3-dipolar nitrile oxide cycloaddition
(INOC) reaction sequence. The retrosynthetic approach to
the fused tricyclic chromenoisoxazoline derivative 5 in-
volves a nitrile oxide precursor B as the key intermediate,
which would be derived from aldoxime derivative 4 via
benzohydroximinoyl chloride intermediate A. The ald-
oxime derivative 4 can be synthesized from the O-cin-
namyl salicylaldehyde derivative 3 and hydroxylamine
hydrochloride (NH2OH·HCl). Finally, the O-cinnamyl
salicylaldehyde derivative 3 can be generated from the
bromo derivative 2 of the Baylis–Hillman adduct accord-
ing to the retrosynthetic strategy shown in Scheme 1.
Figure 2 X-ray crystal structure of 5a
derivatives 4b–m and treated them with N-chlorosuccin-
imide in the presence of triethylamine at 0–10 °C for five
hours, which successfully led to the desired fused tricyclic
chromenoisoxazolines 5b–m in 72–82% yield (Table 1,
entries 2–13). It is worth mentioning that this is the first
report for the formation of a fused tricyclic skeleton with
an electron-withdrawing functional group at the angular
position via an INOC reaction as a key step. Interestingly,
the Baylis–Hillman derivatives were utilized as a sub-
strate for the INOC reaction for the first time.
To synthesize the fused tricyclic chromenoisoxazoline
compound 5a, we first prepared O-cinnamyl salicylalde-
hyde derivative 3a and treated it with hydroxylamine hy-
drochloride in the presence of 50% aqueous sodium
hydroxide, which furnished the necessary aldoxime deriv-
ative 4a in excellent yield (96%). Aldoxime derivative 4a
was treated with N-chlorosuccinimide in the presence of
triethylamine at 0–10 °C for five hours, which successful-
ly afforded the desired compound 5a in 70% yield. En-
couraged by this result, we prepared a variety of aldoxime
To check the generality of the reaction and its applicabil-
ity to the Baylis–Hillman derivatives 6a–g synthesized
from acrylonitrile, we prepared a variety of aldoxime de-
rivatives 8a–l from 7a–l in very good yields. Treatment of
the aldoxime derivatives 8a–l with N-chlorosuccinimide
OH
N
O–
+
N
N
O
O
nitrile oxide
formation
Cl
O
INOC
O
OMe
O
OMe
O
O
OMe
5a
OH
B
A
CO2Me
chlorination
BH adduct
O
OH
H
N
O
CHO
O
O
O
oxime
formation
OMe
O-alkylation
OMe
OMe
Br
2a
3a
4a
Scheme 1 Retrosynthetic approach to the tricyclic chromenoisoxazolines
Synthesis 2012, 44, 755–766
© Thieme Stuttgart · New York

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Stereoselective Synthesis of Tricyclic Chromenoisoxazolines
757
in the presence of triethylamine at 0–10 °C for five hours compound 3a. We have also confirmed the relative stereo-
smoothly led to the desired tricyclic chromenoisoxazo- chemistry of compound 9d by X-ray crystallographic
lines 9a–l with the nitrile functionality at the angular po- analysis16 (Figure 3). The crystal structure of compound
sition in 62–70% yield (Table 2, entries 1–12).
9d shows that the nitrile moiety and the aryl group are in
the syn orientation, which is presumably due to the initial
cis geometry of the aryl and nitrile groups in the double
bond of compound 7d.
The stereochemistry of compound 5a was confirmed by
1H NMR data and X-ray crystal analysis16 (Figure 2). The
crystal structure of compound 5a shows that the relative
stereochemistry of the aryl group and the adjacent ester In conclusion, we have developed an efficient and general
moiety is in the anti orientation, which is presumably due route for the synthesis of fused tricyclic chromenoisox-
to the initial E geometry of the double bond present in azoline frameworks via an intramolecular 1,3-dipolar ni-
Table 1 Synthesis of Tricyclic Chromenoisoxazolines Using Baylis–Hillman Derivatives 2a–g
O
O
CHO
O
O
K2CO3
R1
H
OMe
R1
R2
+
OMe
MeCN
r.t., 3 h
OH
Br
1a–c
2a–g
R2
3a–m
NH2OH•HCl
NaOH
EtOH–H2O
r.t., 1.5 h
OH
N
O
N
O
H
O
NCS, Et3N
R1
R1
R2
O
OMe
CCl4, 0–10 °C
5 h
O
OMe
5a–m
R2
4a–m
Entry
1
R1
R2
Aldoximea,b
Yieldc (%)
Isoxazolineb,d
Yielde (%)
H
H
4a
4b
4c
4d
4e
4f
96
97
95
91
89
96
94
87
88
85
93
94
92
5af
5b
5c
5d
5e
5f
70
72
73
74
82
80
81
79
75
76
79
78
74
2
H
2-Me
4-Me
4-Et
4-i-Pr
2-OMe
4-Cl
H
3
H
4
H
5
H
6
H
7
H
4g
4h
4i
5g
5h
5i
8
5-Br
5-Br
5-Br
3-OEt
3-OEt
3-OEt
9
4-Me
4-Et
H
10
11
12
13
4j
5j
4k
4l
5k
5l
4-Me
4-Et
4m
5m
a All reactions were carried out using the O-cinnamyl derivative 3a–m (4 mmol) and NH2OH·HCl (6 mmol).
b All products gave satisfactory IR, 1H NMR, 13C NMR and mass spectra.
c Pure products 4a–m were obtained by recrystallization (EtOAc).
d All reactions were carried out using aldoxime 4a–m (2 mmol) with NCS (4 mmol) in the presence of Et3N (4 mmol).
e Yield of the pure product 5a–m obtained after column chromatography (silica gel 60–120 mesh; EtOAc–hexanes, 5:95).
f Structure was further confirmed by single-crystal X-ray analysis.16
© Thieme Stuttgart · New York
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M. Bakthadoss et al.
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Table 2 Synthesis of Tricyclic Chromenoisoxazolines Using Baylis–Hillman Derivatives 6a–g
O
CHO
R1
K2CO3
H
Br
CN
R1
R2
+
O
CN
MeCN, r.t., 3 h
OH
R2
6a–g
1a–c
7a–l
NH2OH•HCl
NaOH
EtOH–H2O
r.t., 1.5 h
OH
H
N
O
N
O
NCS, Et3N
R1
CN
R2
R1
CN
CCl4, 0–10 °C
5 h
O
9a–l
R2
8a–l
Entry
1
R1
R2
H
Aldoximea,b
Yieldc (%)
Isoxazolineb,d
Yielde (%)
H
8a
8b
8c
8d
8e
8f
87
97
96
95
93
96
98
86
94
88
88
92
9a
9b
9c
9df
9e
9f
62
67
65
66
63
68
62
63
67
68
70
69
2
H
2-Me
4-Me
4-Et
4-i-Pr
2-OMe
4-Cl
H
3
H
4
H
5
H
6
H
7
H
8g
8h
8i
9g
9h
9i
8
5-Br
5-Br
5-Br
3-OEt
3-OEt
9
4-Me
4-Et
H
10
11
12
8j
9j
8k
8l
9k
9l
4-i-Pr
a All reactions were carried out using the O-cinnamyl derivative 7a–l (4 mmol) and NH2OH·HCl (6 mmol).
b All products gave satisfactory IR, 1H NMR, 13C NMR and mass spectra.
c Pure products 8a–l were obtained by recrystallization (EtOAc).
d All reactions were carried out using aldoxime 8a–l (2 mmol) with NCS (4 mmol) in the presence of Et3N (4 mmol).
e Yield of the pure product 9a–l obtained after column chromatography (silica gel 60–120 mesh; EtOAc–hexanes, 7:93).
f Structure was further confirmed by single-crystal X-ray analysis.16
Figure 3 X-ray crystal structure of 9d
Synthesis 2012, 44, 755–766
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Stereoselective Synthesis of Tricyclic Chromenoisoxazolines
759
13C NMR (75 MHz, CDCl3): d = 21.40, 52.33, 63.65, 112.95,
121.30, 121.35, 125.93, 126.35, 129.54, 129.74, 131.24, 131.53,
140.16, 146.08, 146.54, 156.65, 167.68.
trile oxide cycloaddition strategy using Baylis–Hillman
derivatives for the first time. The new [3+2]-cycloaddi-
tion reaction leads to a novel class of angularly substituted
fused tricyclic chromenoisoxazolines, with the creation of
two rings and two contiguous stereocenters, one of them
being an all-carbon quaternary center, in a unique fashion.
The fused tricyclic chromenoisoxazolines were obtained
in a highly stereoselective fashion with good yields.
Methyl (E)-3-(4-Ethylphenyl)-2-({2-[(E)-(hydroxyimino)meth-
yl]phenoxy}methyl)acrylate (4d)
Yield: 1.23 g (91%); mp 122–124 °C.
IR (neat): 3264, 1716, 1629, 1579, 1240 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.5 Hz, 3 H), 1.84 (br
s, 1 H), 2.65 (q, J = 7.5 Hz, 2 H), 3.86 (s, 3 H), 4.89 (s, 2 H), 6.99
(t, J = 8.7 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.33–7.40 (m, 3 H),
7.78 (d, J = 7.8 Hz, 1 H), 8.06 (s, 1 H), 8.52 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 15.25, 28.74, 52.36, 63.69, 113.00,
121.34, 121.38, 125.93, 126.45, 128.36, 129.87, 131.25, 131.77,
146.15, 146.36, 146.42, 156.69, 167.76.
Commercial reagents were used as received without further purifi-
cation. Solvents were distilled prior to use. Column chromatogra-
phy was performed on silica gel. Melting points were measured on
a Superfit (India) capillary apparatus and are uncorrected. IR spec-
1
tra were run neat on a Bruker Tensor 27 spectrophotometer. H
NMR (300 MHz) and 13C NMR (75 MHz or 100 MHz) spectra were
recorded in CDCl3 as solvent and TMS as internal standard on a
Bruker instrument. Mass spectra were recorded on a Thermo Finnigan
spectrometer. All products were isolated as colorless solids
Methyl (E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}meth-
yl)-3-(4-isopropylphenyl)acrylate (4e)
Yield: 1.26 g (89%); mp 123 °C.
IR (neat): 3190, 1709, 1630, 1586, 1237 cm–1.
Methyl (E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}meth-
yl)-3-phenylacrylate (4a); Typical Procedure
1H NMR (300 MHz, CDCl3): d = 1.23 (d, J = 6.9 Hz, 6 H), 2.90
(septet, J = 6.9 Hz, 1 H), 3.85 (s, 3 H), 4.89 (s, 2 H), 6.99 (t, J = 7.8
Hz, 2 H), 7.24 (d, J = 8.1 Hz, 2 H), 7.38 (t, J = 8.1 Hz, 3 H), 7.78 (d,
J = 7.8 Hz, 1 H), 8.06 (s, 1 H), 8.30 (br s, 1 H), 8.52 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.76, 34.04, 52.38, 63.67, 112.97,
121.38, 125.89, 126.47, 126.97, 129.94, 131.25, 131.89, 146.16,
146.28, 151.02, 156.69, 167.80.
To a stirred soln of O-allylic salicylaldehyde derivative 3a (1.20 g,
4 mmol) in EtOH–H2O (1:1, 10 mL) was added NH2OH·HCl (0.42
g, 6 mmol) in the presence of 50% aq NaOH (0.48 mL) at r.t. Then,
the reaction mixture was stirred at r.t. for 1.5 h. After completion of
the reaction as evidenced by TLC, the reaction mixture was concen-
trated under reduced pressure. The resulting crude mass was diluted
with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The com-
bined organic layer was washed with brine (2 × 10 mL) and dried
(Na2SO4). The solvent was evaporated under reduced pressure and
the crude product was purified by recrystallization (EtOAc) to ob-
tain pure aldoxime 4a as a colorless solid; yield: 1.19 g (96%); mp
122–124 °C.
Methyl (E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}meth-
yl)-3-(2-methoxyphenyl)acrylate (4f)
Yield: 1.31 g (96%); mp 120–121 °C.
IR (neat): 3254, 1697, 1627, 1592, 1232 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.77 (br s, 1 H), 3.86 (s, 3 H), 3.87
(s, 3 H), 4.84 (s, 2 H), 6.88–7.00 (m, 4 H), 7.29–7.41 (m, 3 H), 7.76
(d, J = 7.5 Hz, 1 H), 8.24 (s, 1 H), 8.51 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 52.30, 55.53, 64.17, 110.55,
113.03, 120.70, 121.29, 123.52, 126.34, 126.71, 130.22, 131.21,
131.31, 141.85, 146.43, 156.76, 157.84, 167.55.
IR (neat): 3251, 1718, 1634, 1592, 1239 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.75 (br s, 1 H), 3.87 (s, 3 H), 4.88
(s, 2 H), 6.95–7.46 (m, 8 H), 7.78 (d, J = 7.5 Hz, 1 H), 8.08 (s, 1 H),
8.52 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 52.45, 63.64, 113.04, 121.35,
121.47, 126.52, 126.92, 128.81, 129.62, 129.72, 131.28, 134.36,
146.01, 146.31, 156.65, 167.61.
Methyl (E)-3-(4-Chlorophenyl)-2-({2-[(E)-(hydroxy-
imino)methyl]phenoxy}methyl)acrylate (4g)
Yield: 1.30 g (94%); mp 142 °C.
IR (neat): 3284, 1717, 1635, 1592, 1237 cm–1.
Methyl (E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}meth-
yl)-3-o-tolylacrylate (4b)
Yield: 1.26 g (97%); mp 78–79 °C.
1H NMR (300 MHz, CDCl3): d = 1.69 (br s, 1 H), 3.86 (s, 3 H), 4.84
(s, 2 H), 6.95–7.04 (m, 2 H), 7.33–7.41 (m, 5 H), 7.77 (dd, J1 = 1.7
Hz, J2 = 7.7 Hz, 1 H), 8.01 (s, 1 H), 8.48 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 52.53, 63.42, 112.95, 121.29,
121.61, 126.59, 127.37, 129.09, 130.90, 131.32, 132.74, 135.91,
144.64, 146.23, 156.44, 167.33.
IR (neat): 3241, 1720, 1634, 1594, 1238 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.79 (br s, 1 H), 2.32 (s, 3 H), 3.88
(s, 3 H), 4.79 (s, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.97 (t, J = 7.5 Hz,
1 H), 7.14–7.33 (m, 5 H), 7.75 (d, J = 7.2 Hz, 1 H), 8.13 (s, 1 H),
8.49 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.98, 52.42, 63.93, 113.22,
121.41, 126.10, 126.45, 127.77, 128.92, 129.50, 130.24, 131.18,
133.68, 137.19, 144.84, 146.32, 156.68, 167.44.
Methyl (E)-2-({4-Bromo-2-[(E)-(hydroxyimino)methyl]phen-
oxy}methyl)-3-phenylacrylate (4h)
Yield: 1.36 g (87%); mp 148 °C.
IR (neat): 3381, 1700, 1621, 1589, 1234 cm–1.
Methyl (E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}meth-
yl)-3-p-tolylacrylate (4c)
1H NMR (300 MHz, CDCl3): d = 1.94 (br s, 1 H), 3.86 (s, 3 H), 4.85
(s, 2 H), 6.83 (d, J = 9.0 Hz, 1 H), 7.37–7.43 (m, 6 H), 7.89 (d,
J = 2.4 Hz, 1 H), 8.08 (s, 1 H), 8.41 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 52.49, 63.95, 114.00, 114.78,
123.30, 126.54, 128.84, 129.05, 129.53, 129.82, 133.66, 134.22,
145.18, 146.22, 155.56, 167.46.
Yield: 1.24 g (95%); mp 140 °C.
IR (neat): 3262, 1717, 1629, 1587, 1242 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.73 (br s, 1 H), 2.36 (s, 3 H), 3.86
(s, 3 H), 4.88 (s, 2 H), 6.96–7.03 (m, 2 H), 7.19 (d, J = 7.8 Hz, 2 H),
7.36 (d, J = 7.5 Hz, 3 H), 7.88 (d, J = 7.8 Hz, 1 H), 8.05 (s, 1 H),
8.51 (s, 1 H).
© Thieme Stuttgart · New York
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M. Bakthadoss et al.
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Methyl (E)-2-({4-Bromo-2-[(E)-(hydroxyimino)methyl]phe-
noxy}methyl)-3-p-tolylacrylate (4i)
Yield: 1.42 g (88%); mp 163–165 °C.
IR (neat): 3436, 1706, 1632, 1594, 1236 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 3 H), 3.86 (s, 3 H), 4.86
(s, 2 H), 6.85 (d, J = 8.7 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 2 H), 7.32 (d,
J = 8.1 Hz, 2 H), 7.42 (dd, J1 = 2.4 Hz, J2 = 8.7 Hz, 1 H), 7.70 (br s,
1 H), 7.90 (d, J = 2.4 Hz, 1 H), 8.05 (s, 1 H), 8.40 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.40, 52.40, 64.03, 113.95,
114.77, 123.33, 125.58, 129.03, 129.58, 129.67, 131.41, 133.63,
140.31, 145.19, 146.35, 155.60, 167.62.
Methyl 3-Phenyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbox-
ylate (5a); Typical Procedure
To a soln of aldoxime 4a (0.63 g, 2 mmol) in CCl4 (10 mL) at 0–
10 °C was added NCS (0.54 g, 4 mmol) over 3 h. After this period,
Et3N (0.57 mL, 4 mmol) was added and the reaction mixture was
stirred well at r.t. for 2 h. After completion of the reaction, the reac-
tion mixture was concentrated under reduced pressure, and the re-
sulting crude mass was diluted with H2O (15 mL) and extracted
with EtOAc (3 × 15 mL). The combined organic layer was washed
with brine (2 × 10 mL) and dried (Na2SO4). The organic layer was
concentrated and the residue was purified by column chromatogra-
phy (silica gel 60–120 mesh; EtOAc–hexanes, 5:95) to provide the
desired pure product 5a as a colorless solid; yield: 0.43 g (70%); mp
130–132 °C.
Methyl (E)-2-({4-Bromo-2-[(E)-(hydroxyimino)methyl]phe-
noxy}methyl)-3-(4-ethylphenyl)acrylate (4j)
Yield: 1.45 g (85%); mp 164–165 °C.
IR (neat): 3434, 1716, 1600, 1590, 1242 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.5 Hz, 3 H), 2.66 (q,
J = 7.5 Hz, 2 H), 3.86 (s, 3 H), 4.87 (s, 2 H), 6.85 (d, J = 8.7 Hz, 1
H), 7.22 (d, J = 8.1 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 3 H), 7.43 (dd,
J1 = 2.4 Hz, J2 = 9.0 Hz, 1 H), 7.92 (d, J = 2.4 Hz, 1 H), 8.05 (s, 1
H), 8.40 (s, 1 H).
IR (neat): 1737, 1608, 1570, 1256 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.23 (d, J = 11.1 Hz, 1 H), 3.79 (s,
3 H), 4.51 (d, J = 10.8 Hz, 1 H), 5.91 (s, 1 H), 6.88 (d, J = 8.4 Hz, 1
H), 7.05 (t, J = 7.5 Hz, 1 H), 7.26–7.37 (m, 6 H), 7.95 (d, J = 7.5 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 53.60, 62.46, 69.78, 87.30,
113.63, 117.42, 122.17, 125.13, 125.91, 128.92, 129.01, 132.39,
132.24, 149.24, 154.57, 170.94.
13C NMR (75 MHz, CDCl3): d = 15.25, 28.74, 52.40, 63.99, 113.92,
114.73, 123.26, 125.53, 128.40, 129.00, 129.79, 131.62, 133.65,
145.24, 146.37, 146.57, 155.60, 167.61.
MS: m/z = 310 [M+ + 1].
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C,
69.82; H, 4.84; N, 4.62.
Methyl (E)-2-({2-Ethoxy-6-[(E)-(hydroxyimino)methyl]phe-
noxy}methyl)-3-phenylacrylate (4k)
Yield: 1.32 g (93%); mp 102–104 °C.
IR (neat): 3426, 1722, 1627, 1560, 1234 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (t, J = 6.9 Hz, 3 H), 3.85 (s,
3 H), 4.02 (q, J = 6.9 Hz, 2 H), 4.99 (s, 2 H), 6.89 (d, J = 7.5 Hz, 1
H), 7.02 (t, J = 7.8 Hz, 1 H), 7.33–7.63 (m, 6 H), 8.02 (s, 1 H), 8.15
(br s, 1 H), 8.57 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.81, 52.30, 64.11, 67.40, 114.27,
117.58, 124.26, 126.43, 127.87, 128.56, 129.40, 129.99, 134.48,
145.55, 147.11, 152.21, 167.98.
Methyl 3-o-Tolyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbox-
ylate (5b)
Yield: 0.46 g (72%); mp 152–153 °C.
IR (neat): 1736, 1608, 1572, 1286 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H), 3.31 (d, J = 10.8 Hz,
1 H), 3.80 (s, 3 H), 4.51 (d, J = 10.8 Hz, 1 H), 6.12 (s, 1 H), 6.88 (d,
J = 8.4 Hz, 1 H), 7.05 (t, J = 7.2 Hz, 1 H), 7.15–7.35 (m, 5 H), 7.96
(dd, J1 = 1.5 Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 19.04, 53.58, 62.62, 69.31, 85.17,
113.66, 117.41, 122.13, 125.91, 125.96, 126.75, 128.72, 130.86,
132.32, 133.39, 133.61, 149.01, 154.62, 170.94.
Methyl (E)-2-({2-Ethoxy-6-[(E)-(hydroxyimino)methyl]phe-
noxy}methyl)-3-p-tolylacrylate (4l)
Yield: 1.39 g (94%); mp 124 °C.
IR (neat): 3244, 1711, 1630, 1511, 1234 cm–1.
MS: m/z = 324 [M+ + 1].
Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33. Found: C,
70.51; H, 5.22; N, 4.40.
Methyl 3-p-Tolyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbox-
ylate (5c)
Yield: 0.47 g (73%); mp 98–100 °C.
IR (neat): 1742, 1610, 1571, 1259 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H), 3.25 (d, J = 10.8 Hz,
1 H), 3.79 (s, 3 H), 4.49 (d, J = 11.1 Hz, 1 H), 5.88 (s, 1 H), 6.88 (d,
J = 8.4 Hz, 1 H), 7.05 (t, J = 6.9 Hz, 1 H), 7.12–7.34 (m, 5 H), 7.95
(dd, J1 = 1.5 Hz, J2 = 7.8 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.35 (t, J = 6.9 Hz, 3 H), 2.38 (s,
3 H), 3.83 (s, 3 H), 4.04 (q, J = 6.9 Hz, 2 H), 5.01 (s, 2 H), 6.89 (d,
J = 8.1 Hz, 1 H), 7.02 (t, J = 8.1 Hz, 1 H), 7.22 (d, J = 7.8 Hz, 2 H),
7.34 (d, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 2 H), 7.99 (s, 1 H),
8.58 (s, 1 H), 8.80 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.83, 21.47, 52.28, 64.15, 67.60,
114.31, 117.59, 124.27, 126.45, 126.87, 129.35, 130.20, 131.65,
139.82, 145.75, 146.99, 147.17, 152.24, 168.19.
13C NMR (100 MHz, CDCl3): d = 21.14, 53.55, 62.38, 69.78, 87.37,
113.70, 117.40, 122.12, 125.08, 125.89, 129.64, 132.26, 132.32,
138.79, 149.20, 154.58, 171.00.
Methyl (E)-2-({2-Ethoxy-6-[(E)-(hydroxyimino)methyl]phe-
noxy}methyl)-3-(4-ethylphenyl)acrylate (4m)
Yield: 1.41 g (92%); mp 112–114 °C.
IR (neat): 3289, 1710, 1631, 1506, 1266 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 1.35 (t,
J = 6.9 Hz, 3 H), 2.68 (q, J = 7.5 Hz, 2 H), 3.83 (s, 3 H), 4.04 (q,
J = 6.9 Hz, 2 H), 5.01 (s, 2 H), 6.89 (d, J = 7.5 Hz, 1 H), 7.02 (t,
J = 8.1 Hz, 1 H), 7.25 (d, J = 7.8 Hz, 2 H), 7.35 (d, J = 7.8 Hz, 1 H),
7.56 (d, J = 8.1 Hz, 2 H), 7.99 (s, 1 H), 8.38 (br s, 1 H), 8.57 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.83, 15.41, 28.80, 52.23, 64.12,
67.54, 114.26, 117.59, 124.24, 126.47, 126.94, 128.14, 130.25,
131.91, 145.74, 146.06, 147.11, 152.24, 168.17.
MS: m/z = 324 [M+ + 1].
Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33. Found: C,
70.63; H, 5.21; N, 4.42.
Methyl 3-(4-Ethylphenyl)-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5d)
Yield: 0.50 g (74%); mp 128–130 °C.
IR (neat): 1740, 1611, 1573, 1250 cm–1.
Synthesis 2012, 44, 755–766
© Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Tricyclic Chromenoisoxazolines
IR (neat): 1701, 1609, 1530, 1264 cm–1.
761
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.5 Hz, 3 H), 2.63 (q,
J = 7.5 Hz, 2 H), 3.25 (d, J = 11.1 Hz, 1 H), 3.79 (s, 3 H), 4.50 (d,
J = 11.1 Hz, 1 H), 5.88 (s, 1 H), 6.88 (d, J = 8.4 Hz, 1 H), 7.05 (t,
J = 7.5 Hz, 1 H), 7.15–7.34 (m, 5 H), 7.95 (dd, J1 = 1.4 Hz, J2 = 8.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.43, 28.52, 53.56, 62.41, 69.79,
87.39, 113.71, 117.40, 122.12, 125.15, 125.89, 128.46, 132.32,
132.48, 145.13, 149.20, 154.58, 171.02.
1H NMR (300 MHz, CDCl3): d = 3.19 (d, J = 11.1 Hz, 1 H), 3.81 (s,
3 H), 4.50 (d, J = 11.1 Hz, 1 H), 5.93 (s, 1 H), 6.78 (d, J = 9.0 Hz, 1
H), 7.23–7.42 (m, 6 H), 8.08 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 53.71, 61.97, 69.90, 87.57,
114.55, 115.42, 119.27, 125.04, 128.26, 129.05, 129.08, 134.92,
135.09, 148.27, 153.47, 170.64.
MS: m/z = 390 [M+ + 2].
MS: m/z = 338 [M+ + 1].
Anal. Calcd for C18H14BrNO4: C, 55.69; H, 3.63; N, 3.61. Found: C,
55.74; H, 3.51; N, 3.72.
Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C,
71.14; H, 5.77; N, 4.23.
Methyl 8-Bromo-3-p-tolyl-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5i)
Yield: 0.60 g (75%); mp 136–138 °C.
IR (neat): 1711, 1606, 1512, 1260 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H), 3.21 (d, J = 11.1 Hz,
1 H), 3.80 (s, 3 H), 4.48 (d, J = 11.1 Hz, 1 H), 5.90 (s, 1 H), 6.77 (d,
J = 8.7 Hz, 1 H), 7.14 (q, J = 8.1 Hz, 4 H), 7.39 (dd, J1 = 2.4 Hz,
J2 = 9.0 Hz, 1 H), 8.07 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.15, 53.66, 61.90, 69.91, 87.67,
114.52, 115.51, 119.25, 125.00, 128.25, 129.73, 131.95, 135.03,
138.97, 148.24, 153.49, 170.72.
Methyl 3-(4-Isopropylphenyl)-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5e)
Yield: 0.58 g (82%); mp 132–133 °C.
IR (neat): 1735, 1610, 1571, 1255 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.22 (d, J = 6.9 Hz, 6 H), 2.88
(septet, J = 6.9 Hz, 1 H), 3.25 (d, J = 11.1 Hz, 1 H), 3.79 (s, 3 H),
4.51 (d, J = 11.1 Hz, 1 H), 5.88 (s, 1 H), 6.88 (d, J = 8.4 Hz, 1 H),
7.05 (t, J = 7.5 Hz, 1 H), 7.16–7.35 (m, 5 H), 7.95 (dd, J1 = 1.5 Hz,
J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.83, 23.91, 33.83, 53.56, 62.42,
69.81, 87.39, 113.72, 117.40, 122.12, 125.14, 125.90, 127.03,
132.31, 132.59, 149.19, 149.76, 154.58, 171.03.
MS: m/z = 404 [M+ + 2].
MS: m/z = 352 [M+ + 1].
Anal. Calcd for C19H16BrNO4: C, 56.73; H, 4.01; N, 3.48. Found: C,
56.83; H, 4.10; N, 3.54.
Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99. Found: C,
71.83; H, 6.09; N, 4.09.
Methyl 8-Bromo-3-(4-ethylphenyl)-3H-chromeno[4,3-c]isox-
azole-3a(4H)-carboxylate (5j)
Yield: 0.63 g (76%); mp 141 °C.
IR (neat): 1720, 1605, 1462, 1247 cm–1.
Methyl 3-(2-Methoxyphenyl)-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5f)
Yield: 0.54 g (80%); mp 114–115 °C.
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.5 Hz, 3 H), 2.63 (q,
J = 7.5 Hz, 2 H), 3.21 (d, J = 11.1 Hz, 1 H), 3.80 (s, 3 H), 4.49 (d,
J = 11.1 Hz, 1 H), 5.90 (s, 1 H), 6.77 (d, J = 8.7 Hz, 1 H), 7.17 (q,
J = 8.4 Hz, 4 H), 7.39 (dd, J1 = 2.6 Hz, J2 = 8.9 Hz, 1 H), 8.07 (d,
J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 15.41, 28.52, 53.66, 61.91, 69.91,
87.67, 114.51, 115.50, 119.25, 125.06, 128.24, 128.53, 132.15,
135.02, 145.30, 148.23, 153.47, 170.72.
IR (neat): 1737, 1610, 1490, 1249 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.37 (d, J = 11.1 Hz, 1 H), 3.80 (s,
3 H), 3.89 (s, 3 H), 4.76 (d, J = 11.1 Hz, 1 H), 6.21 (s, 1 H), 6.86–
7.33 (m, 7 H), 7.92 (dd, J1 = 1.5 Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 53.39, 55.38, 62.10, 68.93, 83.73,
110.13, 113.37, 117.42, 121.10, 121.90, 123.53, 125.85, 126.90,
129.82, 132.29, 149.51, 154.89, 155.45, 170.25.
MS: m/z = 340 [M+ + 1].
MS: m/z = 418 [M+ + 2].
Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C,
67.23; H, 4.96; N, 4.22.
Anal. Calcd for C20H18BrNO4: C, 57.71; H, 4.36; N, 3.36. Found: C,
57.78; H, 4.29; N, 3.47.
Methyl 3-(4-Chlorophenyl)-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5g)
Yield: 0.56 g (81%); mp 140–142 °C.
IR (neat): 1737, 1610, 1572, 1298 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.23 (d, J = 11.1 Hz, 1 H), 3.79 (s,
3 H), 4.50 (d, J = 11.1 Hz, 1 H), 5.88 (s, 1 H), 6.89 (d, J = 8.1 Hz, 1
H), 7.06 (t, J = 7.2 Hz, 1 H), 7.20–7.37 (m, 5 H), 7.94 (dd, J1 = 1.7
Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 53.70, 62.48, 69.70, 86.56,
113.44, 117.46, 122.29, 125.91, 126.62, 129.27, 132.57, 133.77,
134.86, 149.35, 154.54, 170.73.
Methyl 6-Ethoxy-3-phenyl-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5k)
Yield: 0.56 g (79%); mp 155–157 °C.
IR (neat): 1768, 1603, 1484, 1254 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40 (t, J = 6.9 Hz, 3 H), 3.23 (d,
J = 11.1 Hz, 1 H), 3.79 (s, 3 H), 4.03 (q, J = 6.9 Hz, 2 H), 4.62 (d,
J = 11.1 Hz, 1 H), 5.94 (s, 1 H), 6.90 (d, J = 8.1 Hz, 1 H), 6.98 (t,
J = 7.8 Hz, 1 H), 7.25–7.38 (m, 5 H), 7.56 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.66, 53.60, 62.40, 64.50, 70.26,
87.45, 114.53, 115.03, 117.24, 121.97, 125.05, 128.89, 128.98,
135.22, 144.59, 147.99, 149.32, 170.73.
MS: m/z = 345 [M+ + 1].
MS: m/z = 354 [M+ + 1].
Anal. Calcd for C18H14ClNO4: C, 62.89; H, 4.10; N, 4.07. Found: C,
62.78; H, 3.98; N, 4.17.
Anal. Calcd for C20H19NO5: C, 67.98; H, 5.42; N, 3.96. Found: C,
67.91; H, 5.36; N, 4.06.
Methyl 8-Bromo-3-phenyl-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5h)
Yield: 0.61 g (79%); mp 156–158 °C.
Methyl 6-Ethoxy-3-p-tolyl-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carboxylate (5l)
Yield: 0.57 g (78%); mp 160–161 °C.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 755–766

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M. Bakthadoss et al.
PAPER
(E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}methyl)-
IR (neat): 1764, 1602, 1489, 1256 cm–1.
3-p-tolylacrylonitrile (8c)
Yield: 1.12 g (96%); mp 134 °C.
IR (neat): 3228, 2210, 1600, 1581, 1239 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.76 (br s, 1 H), 2.39 (s, 3 H), 4.79
(s, 2 H), 6.93 (d, J = 8.1 Hz, 1 H), 7.03 (t, J = 7.8 Hz, 1 H), 7.24 (d,
J = 8.1 Hz, 2 H), 7.36 (t, J = 8.1 Hz, 1 H), 7.73 (q, J = 7.8 Hz, 3 H),
8.39 (s, 1 H), 8.57 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.57, 69.90, 104.95, 112.96,
117.53, 121.53, 122.15, 127.19, 129.27, 129.70, 129.98, 131.28,
141.74, 146.13, 146.18, 155.75.
1H NMR (300 MHz, CDCl3): d = 1.40 (t, J = 6.9 Hz, 3 H), 2.32 (s,
3 H), 3.25 (d, J = 11.1 Hz, 1 H), 3.78 (s, 3 H), 4.03 (q, J = 6.9 Hz, 2
H), 4.61 (d, J = 11.1 Hz, 1 H), 5.90 (s, 1 H), 6.89 (dd, J1 = 1.2 Hz,
J2 = 8.1 Hz, 1 H), 6.97 (t, J = 7.8 Hz, 1 H), 7.14 (s, 4 H), 7.55 (dd,
J1 = 1.5 Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.64, 21.38, 53.49, 62.31, 64.46,
70.18, 87.44, 114.56, 115.03, 117.16, 121.93, 125.26, 129.59,
132.27, 138.69, 144.61, 148.00, 149.27, 170.80.
MS: m/z = 368 [M+ + 1].
Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76; N, 3.81. Found: C,
68.72; H, 5.68; N, 3.90.
(E)-3-(4-Ethylphenyl)-2-({2-[(E)-(hydroxyimino)methyl]phen-
oxy}methyl)acrylonitrile (8d)
Yield: 1.16 g (95%); mp 104–106 °C.
IR (neat): 3282, 2215, 1601, 1585, 1243 cm–1.
Methyl 6-Ethoxy-3-(4-ethylphenyl)-3H-chromeno[4,3-c]isox-
azole-3a(4H)-carboxylate (5m)
Yield: 0.56 g (74%); mp 154–156 °C.
IR (neat): 1768, 1606, 1486, 1258 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.5 Hz, 3 H), 2.69 (q,
J = 7.5 Hz, 2 H), 4.79 (s, 2 H), 6.94 (d, J = 8.4 Hz, 1 H), 7.03 (t,
J = 7.5 Hz, 1 H), 7.26 (t, J = 6.9 Hz, 3 H), 7.36 (t, J = 7.5 Hz, 1 H),
7.75 (t, J = 6.9 Hz, 3 H), 8.36 (br s, 1 H), 8.58 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 15.22, 28.87, 69.92, 105.02,
112.95, 117.51, 121.58, 122.15, 127.10, 128.52, 129.37, 129.61,
130.19, 131.24, 146.15, 147.98, 155.74.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, J = 7.5 Hz, 3 H), 1.40 (t,
J = 6.9 Hz, 3 H), 2.61 (q, J = 7.5 Hz, 2 H), 3.25 (d, J = 11.1 Hz, 1
H), 3.78 (s, 3 H), 4.03 (q, J = 6.9 Hz, 2 H), 4.61 (d, J = 11.1 Hz, 1
H), 5.91 (s, 1 H), 6.89 (d, J = 7.5 Hz, 1 H), 6.98 (t, J = 8.1 Hz, 1 H),
7.14–7.19 (m, 4 H), 7.55 (dd, J1 = 1.2 Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.63, 15.46, 28.47, 53.48, 62.33,
64.43, 70.19, 87.44, 114.55, 114.98, 117.13, 121.94, 125.25,
128.16, 132.51, 144.58, 145.03, 148.00, 149.24, 170.73.
(E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}methyl)-3-(4-
isopropylphenyl)acrylonitrile (8e)
Yield: 1.19 g (93%); mp 139 °C.
MS: m/z = 382 [M+ + 1].
IR (neat): 3256, 2220, 1626, 1591, 1241 cm–1.
Anal. Calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67. Found: C,
69.26; H, 5.99; N, 3.76.
1H NMR (300 MHz, CDCl3): d = 1.24 (d, J = 6.9 Hz, 6 H), 2.92
(septet, J = 6.9 Hz, 1 H), 4.78 (s, 2 H), 6.92 (d, J = 8.4 Hz, 1 H), 7.01
(t, J = 7.5 Hz, 1 H), 7.23–7.37 (m, 4 H), 7.74 (d, J = 7.8 Hz, 3 H),
8.57 (s, 1 H), 9.11 (br s, 1 H).
(E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}methyl)-3-phe-
nylacrylonitrile (8a); Typical Procedure
To a stirred soln of O-allylic salicylaldehyde derivative 7a (1.06 g,
4 mmol) in EtOH–H2O (1:1, 10 mL) was added NH2OH·HCl (0.42
g, 6 mmol) in the presence of 50% aq NaOH (0.48 mL) at r.t. Then,
the reaction mixture was stirred at r.t. for 1.5 h. After completion of
the reaction as evidenced by TLC, the reaction mixture was concen-
trated under reduced pressure. The resulting crude mass was diluted
with H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The com-
bined organic layer was washed with brine (2 × 10 mL) and dried
(Na2SO4). The solvent was evaporated under reduced pressure and
the crude product was purified by recrystallization (EtOAc) to ob-
tain pure aldoxime 8a as a colorless solid; yield: 0.97 g (87%); mp
136–138 °C.
13C NMR (75 MHz, CDCl3): d = 23.72, 34.17, 69.86, 104.98,
112.96, 117.59, 121.49, 122.15, 127.12, 127.23, 129.44, 130.33,
131.31, 146.13, 146.22, 152.55, 155.73.
(E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}methyl)-3-(2-
methoxyphenyl)acrylonitrile (8f)
Yield: 1.18 g (96%); mp 148–149 °C.
IR (neat): 3214, 2273, 1629, 1594, 1231 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.87 (s, 3 H), 4.18 (s, 2 H), 6.91–
7.79 (m, 9 H), 8.09 (d, J = 7.5 Hz, 1 H), 8.60 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.62, 69.89, 106.08, 110.85,
112.87, 117.50, 120.85, 121.57, 121.87, 122.02, 126.92, 128.48,
131.20, 132.46, 141.36, 146.22, 155.81, 157.70.
IR (neat): 3415, 2217, 1625, 1589, 1237 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.82 (br s, 1 H), 4.82 (s, 2 H), 6.94
(d, J = 8.4 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 H), 7.26–7.81 (m, 8 H),
8.58 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 69.71, 106.32, 112.88, 117.25,
121.50, 122.21, 127.23, 129.00, 129.22, 131.08, 131.30, 132.65,
146.06, 146.12, 155.66.
(E)-3-(4-Chlorophenyl)-2-({2-[(E)-(hydroxyimino)meth-
yl]phenoxy}methyl)acrylonitrile (8g)
Yield: 1.23 g (98%); mp 146–147 °C.
IR (neat): 3327, 2215, 1627, 1598, 1234 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.81 (s, 2 H), 6.93 (d, J = 8.4 Hz,
1 H), 7.05 (t, J = 7.5 Hz, 1 H), 7.25 (d, J = 7.5 Hz, 1 H), 7.35–7.44
(m, 3 H), 7.76 (t, J = 8.4 Hz, 4 H), 8.57 (s, 1 H).
(E)-2-({2-[(E)-(Hydroxyimino)methyl]phenoxy}methyl)-3-o-
tolylacrylonitrile (8b)
Yield: 1.13 g (97%); mp 135–136 °C.
13C NMR (75 MHz, CDCl3): d = 69.56, 107.05, 112.87, 116.91,
121.58, 122.31, 127.20, 129.30, 130.41, 131.08, 131.27, 137.08,
144.36, 146.10, 155.57.
IR (neat): 3248, 2210, 1590, 1490, 1246 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.30 (s, 3 H), 4.85 (s, 2 H), 6.96
(d, J = 8.1 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 7.21–7.41 (m, 4 H),
7.53 (s, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 6.9 Hz, 1 H),
8.03 (br s, 1 H), 8.58 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.71, 69.24, 108.32, 112.32,
116.98, 121.54, 122.25, 126.46, 127.40, 127.91, 130.56, 130.61,
131.27, 132.00, 137.33, 144.82, 146.08, 155.55.
(E)-2-({4-Bromo-2-[(E)-(hydroxyimino)methyl]phenoxy}meth-
yl)-3-phenylacrylonitrile (8h)
Yield: 1.23 g (86%); mp 166–167 °C.
IR (neat): 3360, 2231, 1620, 1592, 1242 cm–1.
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Stereoselective Synthesis of Tricyclic Chromenoisoxazolines
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1H NMR (300 MHz, CDCl3): d = 1.65 (br s, 1 H), 4.79 (s, 2 H), 6.82
(d, J = 8.7 Hz, 1 H), 7.44–7.47 (m, 4 H), 7.79 (d, J = 3.3 Hz, 3 H),
7.92 (d, J = 2.4 Hz, 1 H), 8.49 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 70.12, 105.92, 114.57, 114.82,
117.12, 123.56, 129.05, 129.24, 129.60, 131.26, 132.46, 133.67,
144.85, 146.40, 154.61.
Et3N (0.57 mL, 4 mmol) was added and the reaction mixture was
stirred well at r.t. for 2 h. After completion of the reaction, the reac-
tion mixture was concentrated under reduced pressure, and the re-
sulting crude mass was diluted with H2O (15 mL) and extracted
with EtOAc (3 × 15 mL). The combined organic layer was washed
with brine (2 × 10 mL) and dried (Na2SO4). The organic layer was
concentrated and the residue was purified by column chromatogra-
phy (silica gel 60–120 mesh; EtOAc–hexanes, 7:93) to provide the
desired pure product 9a as a colorless solid; yield: 0.34 g (62%); mp
136–138 °C.
(E)-2-({4-Bromo-2-[(E)-(hydroxyimino)methyl]phenoxy}meth-
yl)-3-p-tolylacrylonitrile (8i)
Yield: 1.39 g (94%); mp 156–157 °C.
IR (neat): 3380, 2229, 1617, 1592, 1242 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H), 4.77 (s, 2 H), 6.82
(d, J = 9.0 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 4 H), 7.44 (dd, J1 = 2.3 Hz,
J2 = 8.9 Hz, 1 H), 7.71 (d, J = 8.1 Hz, 2 H), 7.90 (d, J = 2.1 Hz, 1
H), 8.49 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.60, 70.29, 94.36, 104.48,
114.60, 114.74, 123.53, 129.30, 129.44, 129.56, 129.76, 133.66,
142.00, 144.90, 146.56, 154.67.
IR (neat): 2232, 1614, 1490, 1250 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.41 (d, J = 10.8 Hz, 1 H), 4.82 (d,
J = 10.5 Hz, 1 H), 5.46 (s, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 7.12 (t,
J = 7.5 Hz, 1 H), 7.42–7.52 (m, 6 H), 7.88 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 54.16, 70.61, 87.75, 111.15,
114.01, 117.99, 123.12, 126.07, 126.72, 129.11, 130.11, 131.88,
133.89, 150.13, 154.72.
MS: m/z = 277 [M+ + 1].
Anal. Calcd for C17H12N2O2: C, 73.90; H, 4.38; N, 10.14. Found: C,
73.81; H, 4.31; N, 10.18.
(E)-2-({4-Bromo-2-[(E)-(hydroxyimino)methyl]phenoxy}meth-
yl)-3-(4-ethylphenyl)acrylonitrile (8j)
Yield: 1.35 g (88%); mp 132 °C.
IR (neat): 3345, 2211, 1623, 1591, 1244 cm–1.
3-o-Tolyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbonitrile
(9b)
Yield: 0.39 g (67%); mp 144–146 °C.
IR (neat): 2234, 1613, 1513, 1290 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.5 Hz, 3 H), 2.68 (q,
J = 7.5 Hz, 2 H), 4.76 (s, 2 H), 6.80 (d, J = 8.7 Hz, 1 H), 7.25 (t,
J = 7.8 Hz, 3 H), 7.43 (dd, J1 = 2.3 Hz, J2 = 8.9 Hz, 1 H), 7.73 (d,
J = 8.1 Hz, 2 H), 7.87 (d, J = 2.4 Hz, 1 H), 8.48 (br s, 1 H), 8.52 (s,
1 H).
13C NMR (75 MHz, CDCl3): d = 15.23, 28.89, 70.25, 104.47,
114.65, 114.72, 117.46, 123.48, 128.57, 129.43, 129.65, 130.00,
133.69, 144.91, 146.65, 148.21, 154.68.
1H NMR (300 MHz, CDCl3): d = 2.30 (s, 3 H), 4.44 (d, J = 10.8 Hz,
1 H), 4.87 (d, J = 10.5 Hz, 1 H), 5.77 (s, 1 H), 7.05 (d, J = 8.4 Hz, 1
H), 7.12 (t, J = 7.8 Hz, 1 H), 7.23–7.82 (m, 5 H), 7.88 (dd, J1 = 1.4
Hz, J2 = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 19.42, 54.33, 70.78, 85.06,
111.22, 114.11, 117.89, 123.10, 126.04, 126.78, 127.46, 129.82,
129.96, 130.82, 133.76, 135.11, 149.65, 154.52.
(E)-2-({2-Ethoxy-6-[(E)-(hydroxyimino)methyl]phenoxy}meth-
yl)-3-phenylacrylonitrile (8k)
MS: m/z = 291 [M+ + 1].
Yield: 1.13 g (88%); mp 142–144 °C.
IR (neat): 3246, 2043, 1631, 1579, 1265 cm–1.
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C,
74.56; H, 4.79; N, 9.70.
1H NMR (300 MHz, CDCl3): d = 1.47 (t, J = 6.9 Hz, 3 H), 4.09 (q,
J = 6.9 Hz, 2 H), 4.78 (s, 2 H), 6.94 (d, J = 8.1 Hz, 1 H), 7.06 (t,
J = 8.1 Hz, 1 H), 7.25 (s, 1 H), 7.33 (d, J = 7.2 Hz, 1 H), 7.42 (t,
J = 3.6 Hz, 3 H), 7.78 (dd, J1 = 2.6 Hz, J2 = 6.7 Hz, 2 H), 8.57 (s, 1
H), 8.77 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.93, 64.51, 74.13, 107.27,
114.78, 117.78, 118.19, 124.99, 126.31, 128.93, 129.18, 130.86,
132.92, 145.56, 146.19, 146.49, 151.88.
3-p-Tolyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbonitrile
(9c)
Yield: 0.38 g (65%); mp 155–157 °C.
IR (neat): 2243, 1609, 1511, 1290 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H), 4.39 (d, J = 10.8 Hz,
1 H), 4.80 (d, J = 10.8 Hz, 1 H), 5.43 (s, 1 H), 7.06 (d, J = 8.4 Hz, 1
H), 7.12 (td, J1 = 1.1 Hz, J2 = 7.6 Hz, 1 H), 7.28–7.47 (m, 5 H), 7.88
(dd, J1 = 1.5 Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 21.34, 54.06, 70.67, 87.89,
111.23, 114.06, 117.96, 123.08, 126.07, 126.68, 128.69, 129.77,
133.80, 140.18, 150.11, 154.69.
(E)-2-({2-Ethoxy-6-[(E)-(hydroxyimino)methyl]phenoxy}meth-
yl)-3-(4-isopropylphenyl)acrylonitrile (8l)
Yield: 1.33 g (92%); mp 159 °C.
IR (neat): 3387, 2216, 1578, 1464, 1268 cm–1.
MS: m/z = 291 [M+ + 1].
1H NMR (300 MHz, CDCl3): d = 1.25 (d, J = 6.9 Hz, 6 H), 1.48 (t,
J = 6.9 Hz, 3 H), 2.93 (septet, J = 6.9 Hz, 1 H), 4.09 (q, J = 6.9 Hz,
2 H), 4.78 (s, 2 H), 6.93 (d, J = 8.1 Hz, 1 H), 7.05 (t, J = 7.8 Hz, 1
H), 7.29–7.34 (m, 4 H), 7.73 (d, J = 8.1 Hz, 2 H), 8.57 (s, 1 H), 8.78
(br s, 1 H).
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C,
74.52; H, 4.78; N, 9.72.
3-(4-Ethylphenyl)-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbo-
nitrile (9d)
13C NMR (75 MHz, CDCl3): d = 14.93, 23.70, 34.14, 64.52, 74.31,
105.96, 114.79, 118.07, 118.18, 124.91, 126.36, 127.04, 129.37,
130.56, 145.60, 146.22, 146.68, 151.90, 152.26.
Yield: 0.40 g (66%); mp 148 °C.
IR (neat): 2251, 1620, 1578, 1237 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.5 Hz, 3 H), 2.70 (q,
J = 7.5 Hz, 2 H), 4.39 (d, J = 10.8 Hz, 1 H), 4.80 (d, J = 10.8 Hz, 1
H), 5.43 (s, 1 H), 7.05 (d, J = 8.4 Hz, 1 H), 7.12 (t, J = 7.5 Hz, 1 H),
7.32 (d, J = 8.1 Hz, 2 H), 7.42 (d, J = 8.1 Hz, 2 H), 7.47 (d, J = 1.2
Hz, 1 H), 7.87 (dd, J1 = 1.2 Hz, J2 = 7.8 Hz, 1 H).
3-Phenyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbonitrile
(9a); Typical Procedure
To a soln of aldoxime 8a (0.56 g, 2 mmol) in CCl4 (10 mL) at 0–
10 °C was added NCS (0.54 g, 4 mmol) over 3 h. After this period,
© Thieme Stuttgart · New York
Synthesis 2012, 44, 755–766

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M. Bakthadoss et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 15.30, 28.68, 54.02, 70.64, 87.90,
111.23, 114.11, 117.97, 123.08, 126.05, 126.82, 128.57, 128.87,
133.81, 146.41, 150.14, 154.71.
13C NMR (75 MHz, CDCl3): d = 54.17, 70.54, 87.09, 110.98,
113.77, 118.01, 123.22, 126.14, 128.14, 129.44, 130.34, 134.02,
136.21, 150.13, 154.68.
MS: m/z = 305 [M+ + 1].
MS: m/z = 357 [M+ + 2].
Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N, 9.20. Found: C,
75.02; H, 5.21; N, 9.21.
Anal. Calcd for C17H11BrN2O2: C, 57.49; H, 3.12; N, 7.89. Found:
C, 57.56; H, 3.19; N, 7.93.
3-(4-Isopropylphenyl)-3H-chromeno[4,3-c]isoxazole-3a(4H)-
carbonitrile (9e)
Yield: 0.40 g (63%); mp 152–154 °C.
8-Bromo-3-p-tolyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-carbo-
nitrile (9i)
Yield: 0.49 g (67%); mp 170–172 °C.
IR (neat): 2247, 1604, 1568, 1254 cm–1.
IR (neat): 2235, 1605, 1462, 1253 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.28 (d, J = 6.9 Hz, 6 H), 2.96
(septet, J = 6.9 Hz, 1 H), 4.40 (d, J = 10.8 Hz, 1 H), 4.81 (d, J = 10.8
Hz, 1 H), 5.43 (s, 1 H), 7.06 (dd, J1 = 0.6 Hz, J2 = 8.4 Hz, 1 H), 7.12
(td, J1 = 0.9 Hz, J2 = 7.7 Hz, 1 H), 7.33–7.47 (m, 5 H), 7.88 (dd,
J1 = 1.5 Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 23.80, 23.88, 34.00, 53.97, 70.66,
87.97, 111.26, 114.08, 117.99, 123.10, 126.08, 126.91, 127.18,
128.89, 133.81, 150.17, 151.05, 154.72.
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H), 4.36 (d, J = 10.8 Hz,
1 H), 4.80 (d, J = 10.8 Hz, 1 H), 5.44 (s, 1 H), 6.95 (d, J = 9.0 Hz, 1
H), 7.29 (d, J = 7.8 Hz, 2 H), 7.38 (d, J = 8.1 Hz, 2 H), 7.52 (dd,
J1 = 2.7 Hz, J2 = 8.7 Hz, 1 H), 7.99 (d, J = 2.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.37, 53.63, 70.75, 88.20, 112.91,
113.70, 115.53, 119.83, 126.67, 128.36, 129.35, 129.83, 136.57,
140.36, 149.08, 153.59.
MS: m/z = 371 [M+ + 2].
MS: m/z = 319 [M+ + 1].
Anal. Calcd for C18H13BrN2O2: C, 58.56; H, 3.55; N, 7.59. Found:
C, 58.62; H, 3.48; N, 7.62.
Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C,
75.56; H, 5.78; N, 8.89.
8-Bromo-3-(4-ethylphenyl)-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carbonitrile (9j)
Yield: 0.52 g (68%); mp 163 °C.
3-(2-Methoxyphenyl)-3H-chromeno[4,3-c]isoxazole-3a(4H)-
carbonitrile (9f)
Yield: 0.42 g (68%); mp 163–165 °C.
IR (neat): 2236, 1608, 1573, 1259 cm–1.
IR (neat): 2241, 1598, 1467, 1282 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.5 Hz, 3 H), 2.70 (q,
J = 7.5 Hz, 2 H), 4.37 (d, J = 11.1 Hz, 1 H), 4.80 (d, J = 10.8 Hz, 1
H), 5.44 (s, 1 H), 6.96 (d, J = 9.0 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 2 H),
7.41 (d, J = 8.1 Hz, 2 H), 7.52 (dd, J1 = 2.4 Hz, J2 = 9.0 Hz, 1 H),
7.99 (d, J = 2.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 15.29, 28.69, 53.59, 70.74, 88.26,
112.92, 113.69, 115.54, 119.83, 126.81, 128.37, 128.52, 128.64,
136.56, 146.61, 149.10, 153.59.
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H), 4.43 (d, J = 11.1 Hz,
1 H), 5.01 (d, J = 11.1 Hz, 1 H), 5.77 (s, 1 H), 6.95–7.46 (m, 6 H),
7.77 (d, J = 7.2 Hz, 1 H), 7.86 (dd, J1 = 1.5 Hz, J2 = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 53.64, 55.40, 71.64, 83.55,
110.18, 111.31, 114.26, 117.84, 121.13, 121.39, 122.84, 126.01,
127.04, 130.55, 133.61, 150.07, 154.85, 156.03.
MS: m/z = 307 [M+ + 1].
MS: m/z = 385 [M+ + 2].
Anal. Calcd for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found: C,
70.64; H, 4.52; N, 9.22.
Anal. Calcd for C19H15BrN2O2: C, 59.55; H, 3.95; N, 7.31. Found:
C, 59.62; H, 3.89; N, 7.40.
3-(4-Chlorophenyl)-3H-chromeno[4,3-c]isoxazole-3a(4H)-car-
bonitrile (9g)
Yield: 0.39 g (62%); mp 160–162 °C.
6-Ethoxy-3-phenyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-car-
bonitrile (9k)
Yield: 0.45 g (70%); mp 168–170 °C.
IR (neat): 2248, 1607, 1468, 1268 cm–1.
IR (neat): 2241, 1602, 1497, 1252 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.39 (d, J = 11.1 Hz, 1 H), 4.83 (d,
J = 10.8 Hz, 1 H), 5.48 (s, 1 H), 6.97 (d, J = 9.0 Hz, 1 H), 7.49–7.55
(m, 6 H), 8.01 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 53.71, 70.68, 88.06, 112.81,
113.60, 115.53, 119.85, 126.69, 128.34, 129.27, 130.24, 131.53,
136.62, 149.08, 153.60.
1H NMR (300 MHz, CDCl3): d = 1.48 (t, J = 6.9 Hz, 3 H), 4.13 (q,
J = 6.9 Hz, 2 H), 4.42 (d, J = 10.8 Hz, 1 H), 4.93 (d, J = 10.5 Hz, 1
H), 5.48 (s, 1 H), 6.99–7.50 (m, 8 H).
13C NMR (100 MHz, CDCl3): d = 14.68, 53.98, 64.82, 70.92, 87.92,
111.86, 113.83, 116.39, 117.26, 122.88, 126.73, 129.10, 130.11,
131.84, 144.82, 148.24, 150.21.
MS: m/z = 312 [M+ + 1].
MS: m/z = 321 [M+ + 1].
Anal. Calcd for C17H11ClN2O2: C, 65.71; H, 3.57; N, 9.02. Found:
C, 65.62; H, 3.47; N, 9.09.
Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C,
71.32; H, 4.94; N, 8.85.
8-Bromo-3-phenyl-3H-chromeno[4,3-c]isoxazole-3a(4H)-car-
bonitrile (9h)
Yield: 0.45 g (63%); mp 165–167 °C.
6-Ethoxy-3-(4-isopropylphenyl)-3H-chromeno[4,3-c]isoxazole-
3a(4H)-carbonitrile (9l)
Yield: 0.49 g (69%); mp 165–166 °C.
IR (neat): 2248, 1609, 1464, 1266 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.28 (d, J = 6.9 Hz, 6 H), 1.48 (t,
J = 6.9 Hz, 3 H), 2.96 (septet, J = 6.9 Hz, 1 H), 4.12 (q, J = 6.9 Hz,
2 H), 4.40 (d, J = 10.8 Hz, 1 H), 4.91 (d, J = 10.8 Hz, 1 H), 5.44 (s,
1 H), 6.99–7.47 (m, 7 H).
IR (neat): 2244, 1605, 1456, 1254 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.40 (d, J = 10.8 Hz, 1 H), 4.81 (d,
J = 10.8 Hz, 1 H), 5.44 (s, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 7.13 (t,
J = 7.5 Hz, 1 H), 7.44–7.50 (m, 5 H), 7.87 (dd, J1 = 1.4 Hz, J2 = 8.0
Hz, 1 H).
Synthesis 2012, 44, 755–766
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Stereoselective Synthesis of Tricyclic Chromenoisoxazolines
765
13C NMR (100 MHz, CDCl3): d = 14.68, 23.79, 23.85, 33.98, 53.75,
64.81, 70.94, 88.07, 111.95, 113.98, 116.34, 117.24, 122.84,
126.93, 127.17, 128.88, 144.82, 148.22, 150.24, 151.00.
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Uskovic, M. R. J. Am. Chem. Soc. 1980, 102, 1954.
(b) Kozikowski, A. P.; Stein, P. D. J. Am. Chem. Soc. 1982,
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Kim, B. H. J. Am. Chem. Soc. 1987, 109, 5280. (d) Martin,
S. F.; Dappen, M. S.; Dupre, B.; Murphy, C. J.; Colapret, J.
A. J. Org. Chem. 1989, 54, 2209. (e) Ihara, M.; Tokunaga,
Y.; Fukumoto, K. J. Org. Chem. 1990, 55, 4497. (f) Bode,
J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611.
(g) Paek, S.-M.; Seo, S.-Y.; Kim, S.-H.; Jung, J.-W.; Lee,
Y.-S.; Jung, J.-K.; Suh, Y.-G. Org. Lett. 2005, 7, 3159.
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2317. (i) Shing, T. K. M.; So, K. M.; Kwok, W. S. Org. Lett.
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MS: m/z = 363 [M+ + 1].
Anal. Calcd for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C,
72.80; H, 6.02; N, 7.84.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
We thank CSIR, UGC and DST-PURSE (New Delhi) for financial
support. We also thank DST-FIST for the NMR facility. J.S. thanks
UGC for his fellowship, and R.S. thanks CSIR for his JRF.
(7) (a) Lin, G. N.; Lu, C. M.; Lin, H. C.; Fang, S. C.; Shieh, B.
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Prod. 1996, 59, 834. (b) Winn, M.; Arendsen, D.; Dodge,
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© Thieme Stuttgart · New York
Synthesis 2012, 44, 755–766

766
M. Bakthadoss et al.
PAPER
with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 791956 (5a) and
791957 (9d). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk] or via www.ccdc.cam.ac.uk/
data_request/cif.
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Lett. 2008, 49, 820. (g) Bakthadoss, M.; Sivakumar, N.;
Devaraj, A.; Sharada, D. S. Synthesis 2011, 2136.
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(16) The structures of compounds 5a and 9d were confirmed by
single-crystal X-ray data. These data have been deposited
Synthesis 2012, 44, 755–766
© Thieme Stuttgart · New York