Baylis-Hillman reaction assisted synthesis of substituted 5,8-dihydroisoxazolo[4,5-c]azepin-4-ones: A novel isoxazole-annulated heterocycle

Article abstract of DOI:10.1055/s-2004-831179

The novel synthesis of a new isoxazole-annulated heterocycle namely, 5,8-dihydroisoxazolo[4,5-c]azepin-4-one, described herein is based on the reaction of benzylamine with acetates of Baylis-Hillman adducts generated from 3-aryl-5-formyl-isoxazole-4-carboxylate.

Full text of DOI:10.1055/s-2004-831179

2550
PAPER
Baylis–Hillman Reaction Assisted Synthesis of Substituted 5,8-Dihydroisoxa-
zolo[4,5-c]azepin-4-ones: A Novel Isoxazole-Annulated Heterocycle1
Synthesis of
S
a
ubstitute
d
5
n
,8-Dihydroi
j
soxazol
a
o[4,5-
c
]aze
y
pin-4-ones Batra,* Amrendra K. Roy
Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow-226001, India
Fax +91(522)2223405, +91(522)2223938; E-mail: batra_san@yahoo.co.uk
Received 21 May 2004
polar impurities as major product. After a series of optimi-
Abstract: The novel synthesis of a new isoxazole-annulated het-
erocycle namely, 5,8-dihydroisoxazolo[4,5-c]azepin-4-one, de-
scribed herein is based on the reaction of benzylamine with acetates
of Baylis–Hillman adducts generated from 3-aryl-5-formyl-isox-
azole-4-carboxylate.
zation studies for ascertaining the optimum reaction con-
dition to achieve best yields of products, the anhydrous
conditions using dry THF was found to be the most suit-
able. Though this reaction condition furnished the Baylis–
Hillman adduct in excellent yields with methyl, ethyl and
butyl acrylates, only moderate yield could be achieved
with tert-butyl acrylate (Scheme 1). It will be appropriate
to mention here that the presence of moisture during the
Baylis–-Hillman reaction of these substrates significantly
reduced the yield of the products. It was envisaged that the
reaction of primary amine with the acetate of the Baylis–
Hillman adducts followed by subsequent intramolecular
cyclization involving ester on the isoxazole nucleus and
the NH groups could furnish the desired isoxazole-annu-
lated ring system. However, this optimistic presumption
was based on considerations that Z stereochemistry across
the double bond in the generated allylic amine alone could
help intramolecular ring closure reaction. Acetylation of
the Baylis–Hillman adducts 2a–c, 4a–c, 5a,c and 6a with
acetyl chloride and pyridine furnished the corresponding
acetates 7a–c, 8a–c, 9a,c and 10a in good yields. The re-
action of acetate 6a–c with benzylamine in methanol led
to completion of reaction within short periods. The TLC
profile of the reaction mixture indicated the formation of
two products. On the basis of spectral analysis of these
products, the minor products were assigned the structure
11a–c, while the major products were found to be 12a–c.
The stereochemistry of the product 12 was assigned as E
by comparison with the reported data.12,22 This result was
in accordance with the literature precedence that the nu-
cleophilic addition of amines on the acetates of Baylis–
Hillman adducts derived from acrylic esters leads to prod-
ucts with E-stereochemistry. Contrary to this observation,
reactions of compounds 7a–c with benzylamine yielded
the cyclized derivatives 13a–c and uncyclized derivative
14a–c in almost equal quantity, while compounds 8a,c
yielded 15a,c as the major products as compared to allylic
amines 16a,c. In the light of this observation it could be
argued that n-butyl or tert-butyl ester group present in
compounds 7,8 possibly facilitated the formation of Z-iso-
mers of allylic amine intermediates in higher yields,
which after ring closure furnished better yields of cyclized
derivatives 13 and 15. In view of these results it was con-
sidered appropriate to evaluate the formation of isoxazo-
lo[4,5-c]azepin-4-one system in the Baylis–Hillman
products derived from acrylonitrile since it is documented
that the nucleophilic substitution in these compounds
Key words: Baylis–Hillman reaction, acetates, 3-aryl-5-formyl-
isoxazole-4-carboxylates, 5,8-dihydroisoxazole[4,5-c]azepine-4-
ones
The Baylis–Hillman reaction is extremely useful in fur-
nishing products of high functional density and it has been
extensively applied to achieve the synthesis of heterocy-
cles and benzannulated compounds.2,3 These compounds
have been obtained either directly as products of Baylis–
Hillman reaction or by appropriate modification of deriv-
atives of the Baylis–Hillman adducts.2–11
Our research efforts are concerned with the exploration of
the Baylis–Hillman reaction of substituted isoxazolecar-
baldehydes and the synthetic utility of the resulting prod-
ucts.12–14 In this context we have recently reported the
synthesis of 5-aryl-3-formylisoxazole-4-carboxylate.15 It
occurred to us that in these compounds the presence of an
electron-withdrawing group at 4-position of the isoxazole
ring would not only provide a fast reacting substrate for
Baylis–Hillman reaction but also would lead to a scaffold
to construct 5,8-dihydro-isoxazole[4,5-c]azepine-4-one, a
novel isoxazole-annulated ring system. The scanning of
literature does not reveal the synthesis of this heterocyclic
system though various other ring systems including ben-
zoxepino,16 pyridazine,17 pyrazine,18 pyrrole,19 pyrimi-
dine,20 triazole21 annulated to isoxazole have been
reported. As was expected, the Baylis–Hillman reaction
of 3-aryl-5-formylisoxazole-4-carboxylate was found to
be unusually fast and the resulting product did provide the
scaffold for the synthesis of 5,8-dihydroisoxazolo[4,5-
c]azepin-4-one, a new isoxazole annulated heterocyclic
system. The details of our preliminary investigations are
presented here.
The Baylis–Hillman reaction of 3-aryl-5-formyl-4-isox-
azolecarboxylate 1a–c with activated alkenes without any
solvent was significantly fast to afford the corresponding
Baylis–Hillman adducts 2–6 along with the unidentified
SYNTHESIS 2004, No. 15, pp 2550–2554
x
x.
x
x
.
2
0
0
4
Advanced online publication: 19.08.2004
DOI: 10.1055/s-2004-831179; Art ID: P05104SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Substituted 5,8-Dihydroisoxazolo[4,5-c]azepin-4-ones
2551
Ar
Ar
Ar
Ar
O
N
N
O
a
N
O
N
O
c
b
CO2Me
CO2Me
OH
CO2Me
OAc
O
NBn
CHO
1a-c
EWG
11a-c
13a-c
15a,c
17a
EWG
2a-c
3a
4a-c
5a,c
6a-b
EWG
7a-c
8a-c
9a,c
10a
Compd. no Ar
a
b
c
Ph
4-Cl-Ph
2,4-(Cl)2-Ph
c
+
Ar
Ar
Compd.
no.
2, 7, 11, 12
3
EWG
N
CO2Me
N
O
CO2Me
OH
CO2Me
CO2Et
CO2Bu-n
O
BnHN
BnHN
4, 8, 13, 14
EWG
12a-c
14a-c
16a-c
18a
5, 9, 15, 16, 19 CO2Bu-t
6, 10, 17, 18 CN
EWG
19a Ar= Ph
Scheme 1 Reagents and Conditions: a. CH2=CHEWG, DABCO, anhyd THF, r.t., 5 min; b. AcCl, pyridine, anhyd CH2Cl2, 0–5 °C, 5 min;
c. PhCH2NH2, MeOH, r.t., 2–5 h.
leads to products with Z stereochemistry. However in a In conclusion, we have described yet another isoxazole-
model reaction, the compound 10a upon reaction with based fast-reacting substrate for Baylis–Hillman reaction
benzylamine afforded the cyclized derivative 17a in mi- and have accomplished the synthesis of a new isoxazole-
nor yields only, though the stereochemistry of the allylic annulated heterocycle through the Baylis–Hillman ad-
amine 18a obtained as the major product was found to be ducts derived from it. We are further exploring the details
Z. Thus it can be presumed that presence of a bulky group and scope of this reaction and its application towards sol-
such as n-butyl or tert-butyl in the side chain facilitates the id-phase combinatorial synthesis.
cyclization. Interestingly, the Baylis–Hillman adducts 5a
on reaction with benzylamine yielded only the diastereo-
isomeric mixture of amine 15.
Table 1 Compounds 3–19 Prepared
Producta Yieldb Physical
Appearance
Mp
(°C)
Mass (FAB+ or ES+) IR (cm–1)
m/z
(%)
95
84
82
79
87
83
88
57
62
79
77
88
81
82
2a
2b
2c
3a
4a
4b
4c
5a
5c
6a
6b
7a
7b
7c
yellow oil
–
318 (M+ + 1)
1727 (2 ester C=O, CO2Me), 3462 (OH)
yellow oil
–
374.60 (M+ + Na)
386.27 (M+ + 1)
354.60 (M+ + Na)
360 (M+ + 1)
1730 (2 ester C=O, CO2Me), 3429 (OH)
yellow oil
–
1713 (ester C=O, CO2Me), 1734 (ester C=O, CO2Me), 3370 (OH)
1726 (br, ester C=O, CO2Et and CO2Me), 3446 (OH)
1739 (ester C=O, CO2Bu and CO2Me), 3465 (OH)
1721 (ester C=O, CO2Bu and CO2Me), 3448 (OH)
1732 (ester C=O, CO2Bu and CO2Me), 3422 (OH)
1721 (ester C=O, CO2t-Bu and CO2Me), 3445 (OH)
1722 (ester C=O, CO2t-Bu and CO2Me), 3356 (OH)
1735 (ester C=O, CO2Me), 2231 (C≡N), 3429 (OH)
1733 (ester C=O, CO2Me), 2232 (C≡N), 3423 (OH)
1733 (br, 2 ester C=O, CO2Me and COCH3)
yellow oil
–
yellow oil
–
yellow oil
–
394 (M+ + 1)
yellow oil
–
450.43 (M+ + Na)
381.93 (M+ + Na)
450.27 (M+ + Na)
285 (M+ + 1)
pale yellow oil
pale yellow solid
yellow oil
–
131–133
–
–
–
–
–
yellow oil
319 (M+ + 1)
pale yellow oil
pale yellow oil
pale yellow oil
360 (M+ + 1)
416.20 (M+ + Na)
450.20 (M+ + Na)
1733 (br, 2 ester C=O, CO2Me and COCH3)
1731 (br, 2 ester C=O, CO2Me and COCH3)
Synthesis 2004, No. 15, 2550–2554 © Thieme Stuttgart · New York

2552
S. Batra, A. K. Roy
PAPER
Table 1 Compounds 3–19 Prepared (continued)
Producta Yieldb Physical
Mp
Mass (FAB+ or ES+) IR (cm–1)
(%)
77
77
80
92
90
87
9
Appearance
(°C)
m/z
8a
8b
pale yellow oil
pale yellow oil
pale yellow oil
white solid
–
402 (M+ + 1)
458.47 (M+ + Na)
470 (M+ + 1)
420 (M+ + 1)
471 (M+ + 1)
1731 (ester C=O, CO2Bu and CO2Me), 1745 (COCH3)
–
1732 (ester C=O, CO2Bu and CO2Me), 1745 (COCH3)
1732 (ester C=O, CO2Me and CO2Bu), 1742 (COCH3)
1730 (br, ester C=O, CO2t-Bu, CO2Me and COCH3)
8c
–
9a
99–101
9c
colorless oil
–
1731 (br, ester C=O, CO2t-Bu and CO2Me), 1745 (COCH3)
1731 (ester C=O, CO2Me), 1745 (COCH3), 2217 (C≡N)
1649 (CONH), 1725 (ester C=O, CO2Me)
1644 (amide C=O, CONH), 1721 (CO2Me)
1650 (amide C=O, CONH), 1725 (ester C=O, CO2Me)
1725 (2 ester C=O, CO2Me), 3427 (NH)
1724 (2 ester C=O, CO2Me), 3410 (NH)
1726 (2 ester C=O, CO2Me), 3427 (NH)
1647 (C=O), 1722 (CO2Me)
10a
11a
11b
11c
12a
12b
12c
13a
13b
colorless oil
–
white solid
112–113
349.80 (M+ + Na)
410.33 (M+ + 1)
443.20 (M+ + 1)
406 (M+ + 1)
10
7
white solid
154–156
colorless oil
–
63
48
51
49
41
pale yellow solid
pale yellow oil
pale yellow oil
light brown oil
light brown oil
129–131
–
–
–
–
441.33 (M+ + 1)
497.27 (M+ + Na)
439.53 (M+ + Na)
449.40 (M+ + 1),
471.53 (M+ + Na)
1724 (ester C=O, CO2Me), 3362 (NH)
13c
14a
14b
14c
15a
15c
16a
16c
17a
18a
19a
43
30
29
27
57
41
10
14
20
43
67
light brown oil
light brown oil
light brown oil
light brown oil
pale yellow solid
white solid
–
517.00 (M+ + Na)
471.53 (M+ + Na)
483.40 (M+ + 1)
539.23 (M+ + 1)
417 (M+ + 1)
1647 (C=O), 1722 (ester C=O, CO2Me)
–
1724 (ester C=O, CO2Me and CO2Bu), 3362 (NH)
1726 (ester C=O, CO2Me and CO2Bu), 3394 (NH)
1722 (ester C=O, CO2Me and CO2Bu), 3450 (NH)
1647 (amide C=O, CONH), 1710 (ester C=O, CO2Bu-t)
1710 (ester C=O, CO2t-Bu), 1654 (amide C=O, CONH)
1720 (ester C=O, CO2Me and CO2Bu-t)
–
–
123–125
138–140
485 (M+ + 1)
yellow oil
–
449 (M+ + 1)
yellow oil
–
517 (M+ + 1)
1723 (ester C=O, CO2Me and CO2Bu-t), 3350 (NH)
1641 (C=O), 2222 (C≡N)
white solid
157–159
342 (M+ + 1)
light brown oil
light brown oil
–
–
374.53 (M+ + 1)
467.23 (M+ + 1)
1726 (ester C=O, CO2Me), 2193 (C≡N)
1726 (ester C=O, CO2Me), 2193 (C≡N)
a All compounds gave satisfactory microanalyses: C 0.4; H 0.4; N 0.3.
b Yields described are the one obtained after column chromatography over silica gel.
Melting points are uncorrected and were determined in capillary
tubes on a hot stage apparatus containing silicon oil. IR spectra were
recorded using Perkin-Elmer Spectrum RX I FTIR spectrophotom-
eter as KBr disc or neat. 1H NMR spectra were recorded either on a
Bruker DPX-200 FT or Bruker Avance DRX-300 spectrometers,
using TMS as an internal standard (chemical shifts in d values, J in
Hz). The ESMS were recorded through direct flow injections in
Merck M-8000 LCMS system and FABMS spectra were recorded
on JEOL/SX-102 spectrometer. Elemental analyses were per-
formed on Elementar’s Vario EL III microanalyzer.
hyd THF. After 5 min, 10% aq HCl was added to the reaction
mixture and it was extracted with EtOAc. Usual workup of the or-
ganic layer furnished an oily residue that was passed through a
small band of silica gel using a mixture of hexane–EtOAc (85:15)
to yield the pure product.
Methyl 5-(1-Hydroxy-2-methoxycarbonylallyl)-3-phenylisox-
azole-4-carboxylate (2a)
1H NMR (CDCl3, 200 MHz): d = 3.77 (s, 3 H, CO2CH3), 3.79 (s, 3
H, CO2CH3), 4.72, 4.75 (d, 1 H, J = 7.2 Hz, OH), 6.07 (d, 1 H,
J = 7.2 Hz, CH), 6.21 (s, 1 H, =CHH), 6.56 (s, 1 H, =CHH), 7.44–
7.49 (m, 3 H, ArH), 7.55–7.60 (m, 2 H, ArH).
Baylis–Hillman Reaction of 1a–c; General Procedure
To a stirred mixture of DABCO (60 mg, 1.8 mmol) and alkyl acry-
late (4.3 mmol) was added a solution of aldehyde (4.3 mmol) in an-
13C NMR (CDCl3, 50.32 MHz): d = 52.62 (CH3), 53.26 (CH3),
65.97 (CH), 127.47 (CH2), 128.52 (CH), 129.69 (CH), 130.38 (CH),
Synthesis 2004, No. 15, 2550–2554 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted 5,8-Dihydroisoxazolo[4,5-c]azepin-4-ones
2553
137.25 (C), 162.62 (C), 163.52 (C), 166.00 (C), 171.65 (C), 177.67
(C), 178.67 (C).
Methyl 5-(1-Acetoxy-2-tert-butoxycarbonylallyl)-3-phenylisox-
azole-4-carboxylate (9a)
1H NMR (CDCl3, 200 MHz): d = 1.45 [s, 9 H, C(CH3)3], 2.18 (s, 3
H, COCH3), 3.79 (s, 3 H, CO2CH3), 5.88 (d, 1 H, J = 1.2 Hz, CH),
6.51 (s, 1 H, =CHH), 7.21 (s, 1 H, =CHH), 7.44–7.48 (m, 3 H,
ArH), 7.63–7.67 (m, 2 H, ArH).
Methyl 5-(2-Ethoxycarbonyl-1-hydroxyallyl)-3-phenylisox-
azole-4-carboxylate (3a)
1H NMR (CDCl3, 200 MHz): d = 1.29 (t, 3 H, J = 7.0 Hz, CH3),
3.74 (s, 3 H, CO2CH3), 3.90 (s, 3 H, CO2CH3), 4.62 (br s, 1 H, OH),
6.07 (s, 1 H, CH), 6.19 (s, 1 H, =CHH), 6.56 (s, 1 H, =CHH), 7.44–
7.69 (m, 5 H, ArH).
Methyl 5-(1-Acetoxy-2-cyanoallyl)-3-phenylisoxazole-4-car-
boxylate (10a)
1H NMR (CDCl3, 200 MHz): d = 2.23 (s, 3 H, COCH3), 3.81 (s, 3
H, CO2CH3), 6.26 (s, 1 H, =CHH), 6.28 (s, 1 H, =CHH), 7.03 (s, 1
H, CH), 7.45–52 (m, 3 H, ArH), 7.56–7.65 (s, 2 H, ArH).
Methyl 5-(2-Butoxycarbonyl-1-hydroxyallyl)-3-phenylisox-
azole-4-carboxylate (4a)
1H NMR (CDCl3, 200 MHz): d = 0.92 (t, 3 H, J = 7.2 Hz, CH3),
1.31–1.42 (m, 2 H, CH2), 1.60–1.67 (m, 2 H, CH2), 3.77 (s, 3 H,
CO2CH3), 4.18 (t, 2 H, J = 6.4 Hz, CO2CH2), 4.65 (br, 1 H, OH),
6.07 (s, 1 H, CH), 6.19 (s, 1 H, =CHH), 6.56 (s, 1 H, =CHH), 7.43–
7.48 (m, 3 H, ArH), 7.55–7.60 (m, 2 H, ArH)
Reaction of 7–10 with Benzylamine; General Procedure
To the appropriate solution of acetate (1.2 mmol) in MeOH was
added benzylamine (0.27 mL, 2.5 mmol) under stirring at r.t. The
reaction was allowed to proceed for 2–5 h. The excess solvent was
evaporated and the residue was subjected to column chromatogra-
phy over silica gel using hexane–EtOAc (75:25) mixture to yield
the products as solid or oil.
Methyl 5-(2-tert-Butoxycarbonyl-1-hydroxyallyl)-3-phenylisox-
azole-4-carboxylate (5a)
1H NMR (CDCl3, 200 MHz): d = 1.46 [s, 9 H, C(CH3)3], 3.76 (s, 3
H, CO2CH3), 4.6 (br, 1 H, OH), 6.02 (s, 1 H, CH), 6.10 (d, 1 H,
J = 0.8 Hz, =CHH), 6.47 (d, 1 H, J = 0.8 Hz, =CHH), 7.44–7.47 (m,
3 H, ArH), 7.55–7.57 (m, 2 H, ArH)
Methyl 5-Benzyl-4-oxo-3-phenyl-5,6-dihydro-4H-isoxazolo[4,5-
c]azepine-7-carboxylate (11a)
1H NMR (CDCl3, 200 MHz): d = 3.76 (s, 3 H, CO2CH3), 4.20 (s, 2
H, CH2), 4.72 (s, 2 H, CH2), 7.46–7.53 (m, 5 H, ArH), 7.61–7.65 (m,
2 H, ArH), 7.69 (s, 1 H, =CH), 7.84–7.89 (m, 2 H, ArH).
Methyl 5-(2-Cyano-1-hydroxyallyl)-3-phenylisoxazole-4-car-
boxylate (6a)
1H NMR (CDCl3, 200 MHz): d = 3.78 (s, 3 H, CO2CH3), 4.97 (br s,
1 H, OH), 5.80 (d, 1 H, J = 1.4 Hz, CH), 6.24 (s, 1 H, J = 1.4
Hz, =CHH), 6.31 (d, 1 H, J = 1.4 Hz, =CHH), 7.45–7.59 (m, 5 H,
ArH).
Methyl 5-(3-Benzylamino-2-methoxycarbonylpropenyl)-3-phe-
nylisoxazole-4-carboxylate (12a)
1H NMR (CDCl3, 200 MHz): d = 3.74 (s, 2 H, CH2), 3.76 (s, 3 H,
CO2CH3), 3.78 (s, 3 H, CO2CH3), 3.95 (s, 2 H, CH2), 7.21–7.26 (m,
5 H, ArH), 7.44–7.49 (m, 3 H, ArH), 7.58–7.61 (m, 2 H, ArH), 7.85
(s, 1 H, =CH).
Methyl 3-(4-Chlorophenyl)-5-(2-cyano-1-hydroxyallyl)isox-
azole-4-carboxylate (6b)
1H NMR (CDCl3, 200 MHz): d = 3.80 (s, 3 H, CO2CH3), 4.97 (br s,
1 H, OH), 5.79 (s, 1 H, CH), 6.24 (d, 1 H, J = 1.2 Hz, =CHH), 6.32
(s, 1 H, J = 1.2 Hz, =CHH), 7.37–7.62 (m, 4 H, ArH).
Butyl 5-Benzyl-4-oxo-3-phenyl-5,6-dihydro-4H-isoxazolo[4,5-
c]azepine-7-carboxylate (13a)
1H NMR (CDCl3, 200 MHz): d = 0.93 (t, 3 H, J = 7.2 Hz, CH3),
1.25–1.42 (m, 2 H, CH2), 1.58–1.71 (m, 2 H, CH2), 3.98 (s, 2 H,
CH2), 4.20 (t, 2 H, J = 6.4 Hz, CO2CH2), 4.72 (s, 2 H, CH2), 7.23 (s,
1 H, =CH), 7.29–7.30 (m, 3 H, ArH), 7.44 (s, 2 H, ArH).
Acetylation of 2–6; General Procedure
To a stirred solution of appropriate compound from 2–6 (3.25
mmol) in anhyd CH2Cl2 (5 mL) was added pyridine (0.39 mL, 4.9
mmol) followed by a dropwise addition of solution of acetyl chlo-
ride (0.46 mL, 6.5 mmol) in anhyd CH2Cl2 (3 mL) at 0 °C. After the
addition was complete, the reaction was continued at 0 °C for 5 min.
The reaction mixture was extracted with CH2Cl2 (2 × 15 mL) and
H2O (30 mL). The organic layers were combined, washed with
brine, dried (Na2SO4) and evaporated to obtain an oily residue. The
residue was purified on a small band of silica gel using hexane–
EtOAc (85:15) as eluent to obtain pure acetates.
Methyl 5-(3-Benzylamino-2-butoxycarbonylpropenyl)-3-phenyl-
isoxazole-4-carboxylate (14a)
1H NMR (CDCl3, 200 MHz): d = 0.90 (t, 3 H, J = 7.2 Hz, CH3),
1.25–1.39 (m, 2 H, CH2), 1.40–1.60 (m, 2 H, CH2), 3.70 (s, 2 H,
CH2), 3.77 (s, 3 H, CO2CH3), 3.87 (s, 2 H, CH2), 4.27 (t, 2 H, J = 6.4
Hz, CO2CH2), 7.19–7.69 (m, 11 H, ArH and =CH)
tert-Butyl 5-Benzyl-4-oxo-3-phenyl-5,6-dihydro-4H-isoxazo-
lo[4,5-c]azepine-7-carboxylate (15a)
1H NMR (CDCl3, 200 MHz): d = 1.50 [s, 9 H, C(CH3)3], 4.21 (s, 2
H, CH2), 4.74 (s, 2 H, CH2), 7.28–7.35 (m, 5 H, ArH), 7.45–7.52 (m,
3 H, ArH), 7.63 (s, 1 H, =CH), 7.85–7.89 (m, 2 H, ArH)
Methyl 5-(1-Acetoxy-2-methoxycarbonylallyl)-3-phenylisox-
azole-4-carboxylate (7a)
1H NMR (CDCl3, 300 MHz): d = 2.21 (s, 3 H, COCH3), 3.82 (s, 3
H, CO2CH3), 3.83 (s, 3 H, CO2CH3), 6.05 (s, 1 H, =CHH), 6.62 (s,
1 H, =CHH), 7.32 (s, 1 H, CH), 7.47–7.51 (m, 3 H, ArH), 7.66–7.69
(m, 2 H, ArH).
13C NMR (CDCl3, 50.32 MHz): d = 27.92 [C(CH3)3], 44.47 (CH2),
51.12 (CH2), 82.87 (CH), 125.05 (CH), 127.75 (CH), 128.29 (CH),
128.42 (CH), 128.69 (CH), 129.11 (CH), 130.30 (CH), 137.30 (C),
138.66 (C), 162.66 (C), 163.52 (C), 166.00 (C), 171.65 (C).
Methyl 5-(1-Acetoxy-2-butoxycarbonylallyl)-3-phenylisox-
azole-4-carboxylate (8a)
Methyl 5-(3-Benzylamino-2-tert-butoxycarbonylpropenyl)-3-
phenylisoxazole-4-carboxylate (16a)
1H NMR (CDCl3, 200 MHz): d = 0.85 (t, 3 H, J = 7.2 Hz, CH3),
1.18–1.35 (m, 2 H, CH2), 1.48–1.60 (m, 2 H, CH2), 2.12 (s, 3 H,
COCH3), 3.67 (s, 3 H, CO2CH3), 4.11 (t, 2 H, J = 6.4 Hz, CO2CH2),
5.91 (s, 1 H, =CHH), 6.53 (s, 1 H, =CHH), 7.23 (s, 1 H, CH), 7.29–
7.30 (m, 3 H, ArH), 7.44 (s, 2 H, ArH).
1H NMR (CDCl3, 200 MHz): d = 1.54 [s, 9 H, C(CH3)3], 3.73 (s, 2
H, CH2), 3.74 (s, 3 H, CO2CH3), 4.02 (s, 2 H, CH2), 7.15–7.19 (m,
5 H, ArH), 7.40–7.50 (m, 3 H, ArH), 7.57–7.62 (m, 2 H, ArH), 7.76
(s, 1 H, =CH).
Synthesis 2004, No. 15, 2550–2554 © Thieme Stuttgart · New York

2554
S. Batra, A. K. Roy
PAPER
5-Benzyl-4-oxo-3-phenyl-5,6-dihydro-4H-isoxazolo[4,5-c]aze-
pine-7-carbonitrile (17a)
(4) Kaye, P. T.; Musa, M. A.; Nocanda, X. W. Synthesis 2003,
531.
(5) Lee, K. Y.; Kim, J. M.; Kim, J. N. Synlett 2003, 357.
(6) Song, Y. S.; Lee, C. H.; Lee, K.-J. J. Heterocycl. Chem.
2003, 40, 939.
1H NMR (CDCl3, 300 MHz): d = 4.09 (s, 2 H, CH2), 4.76 (s, 2 H,
CH2), 7.27–7.50 (s, 9 H, ArH and =CH), 7.50–7.53 (m, 2 H, ArH).
Methyl 5-(3-Benzylamino-2-cyanopropenyl)-3-phenylisox-
azole-4-carboxylate (18a)
(7) Basavaiah, D.; Rao, J. S. Tetrahedron Lett. 2004, 45, 1621.
(8) Basavaiah, D.; Satyanarayana, T. Chem. Commun. 2004, 32.
(9) Basavaiah, D.; Sharda, D. S.; Veerandhar, A. Tetrahedron
Lett. 2004, 45, 3081.
1H NMR (CDCl3, 300 MHz): d = 3.63 (s, 2 H, CH2), 3.76 (s, 3 H,
CO2CH3), 3.86 (s, 2 H, CH2), 7.20–7.63 (s, 11 H, ArH and =CH).
(10) Lee, K. Y.; Lee, C. G.; Kim, T. H.; Kim, J. N. Bull. Korean
Chem. Soc. 2004, 25, 33.
(11) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2004, 45, 3089.
(12) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
Bhaduri, A. P. Synthesis 2001, 276.
(13) Roy, A. K.; Batra, S. Synthesis 2003, 1347.
(14) Roy, A. K.; Batra, S. Synthesis 2003, 2325.
(15) Roy, A. K.; Rajaraman, B.; Batra, S. Tetrahedron 2004, 60,
2301.
Methyl 5-(3-Benzylamino-2-tert-butoxycarbonyl-1-hydroxy-
propyl)-3-phenylisoxazole-4-carboxylate (19a) (Diastereomeric
Mixture)
1H NMR (CDCl3, 200 MHz): d = 1.46, 1.48 [2 s, 18 H, 2 C(CH3)3],
3.03–3.06 (m, 1 H, CH), 3.33–3.37 (m, 1 H, CH), 3.76, 3.81 (2 s, 4
H, CH2), 3.86 (s, 6 H, 2 CO2CH3), 3.92, 3.96 (2 s, 4 H, CH2), 5.73,
5.74 (d, 1 H, 2.6 Hz, CH), 5.93, 5.94 (d, 1 H, 2.6 Hz, CH), 7.28–7.37
(m, 10 H, ArH), 7.46–7.49 (m, 6 H, ArH), 7.65–7.67 (m, 6 H, ArH).
(16) Deshayes, G.; Chabnet, M.; Najib, B.; Gelin, S.
Heterocycles 1985, 23, 1651.
(17) Erichomovitch, L.; Chubb, F. L. Can. J. Chem. 1966, 44,
2095.
(18) Desimoni, G.; Minoli, G. Tetrahedron 1968, 24, 4907.
(19) Jones, R. C. F.; Bhalay, G.; Carter, P. A.; Duller, K. A. M.;
Dunn, S. H. J. Chem. Soc., Perkins Trans. 1 1994, 2513.
(20) Desimoni, G.; Grunanger, P.; Finzi, V. P. Tetrahedron 1967,
23, 687.
(21) Desimoni, G.; Minoli, G. Tetrahedron 1970, 26, 1393.
(22) Lee, J. L.; Chung, Y. M.; Lee, K. Y.; Kim, J. N. Bull. Korean
Chem. Soc. 2000, 21, 843; Chem. Abstr. 2001, 134, 41755.
Acknowledgment
AKR acknowledges the financial support from CSIR in the form of
a Senior Research Fellowship. This work was supported through fi-
nancial grant under DST Project no. SR/SI/OC-04/2003.
References
(1) CDRI Communication No 6510.
(2) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811.
(3) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627.
Synthesis 2004, No. 15, 2550–2554 © Thieme Stuttgart · New York