Insights into the bromination of 3-aryl-5-methyl-isoxazole-4-carboxylate: Synthesis of 3-aryl-5-bromomethyl-isoxazole-4-carboxylate as precursor to 3-aryl-5-formyl-isoxazole-4-carboxylate

Article abstract of DOI:10.1016/j.tet.2004.01.009

Results of the detailed investigations on the bromination of the methyl group of 3-aryl-5-methyl-isoxazole-4-carboxylate, a precursor to obtain 3-aryl-5-formyl-isoxazole-4-carboxylate, are described. The products generated during the study have been utilized as substrates for the synthesis of isoxazole-fused heterocycles.

Full text of DOI:10.1016/j.tet.2004.01.009

Tetrahedron 60 (2004) 2301–2310
Insights into the bromination of
3-aryl-5-methyl-isoxazole-4-carboxylate:
synthesis of 3-aryl-5-bromomethyl-isoxazole-4-carboxylate
as precursor to 3-aryl-5-formyl-isoxazole-4-carboxylateq
†
*
Amrendra K. Roy, Rajaraman B. and Sanjay Batra
Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
Received 11 November 2003; revised 4 December 2003; accepted 8 January 2004
Abstract—Results of the detailed investigations on the bromination of the methyl group of 3-aryl-5-methyl-isoxazole-4-carboxylate, a
precursor to obtain 3-aryl-5-formyl-isoxazole-4-carboxylate, are described. The products generated during the study have been utilized as
substrates for the synthesis of isoxazole-fused heterocycles.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
subsequent hydrolysis followed by oxidation could yield
the desired aldehyde. Oxidation of the 3-aryl-5-methyl-
isoxazole-4-carboxylate (1) by SeO2, KMnO4 or CAN6–8
failed in our hands to deliver the desired aldehyde. Search
for literature precedence revealed that the bromination of
the methyl group at 5-position of isoxazole ring was widely
reported.9–18 It is not only a key step in synthesis of a
variety of AMPA agonists9–14 but has also been utilized for
the generation of intermediates towards the synthesis of
isoxazole-fused derivatives which are precursor to cyclic
trione system present in natural products.15–17
This study owes its origin to our continued interest in the
Baylis–Hillman reaction of isoxazolecarbaldehydes. We
have reported earlier1–3 that compared to substituted-4-
isoxazolecarbaldehyde, 3- and 5-isoxazolecarbaldehydes
undergo significantly faster Baylis–Hillman reaction and
the reason ascribed to this was the proximity of the
heteroatom to the formyl group for the higher reactivity of
aldehydes. This perception prompted us to conceive that the
presence of an electron-withdrawing group, such as the
carboxylate at 4-position in the 3-substituted-5-isoxazole-
carbaldehyde would provide a more fast reacting substrate
than the one reported by us earlier. Such an isoxazole-
carbaldehyde had previously been synthesized through the
cycloaddition of nitrile oxides to methyl 4,4-di-methoxybut-
2-ynoate and (E)-4,4-dimethoxy-3-(pyrrolidin-l-yl)but-2-
enoate or p-toluene-sulfinyl derivatives in respectable
yields.4,5 In view of the fact that we had 3-aryl-5-methyl-
isoxazole-4-carboxylate, we directed our efforts to obtain
the desired aldehyde from this compound. In principle this
aldehyde can be obtained through direct oxidation of the
methyl group of 3-aryl-5-methyl-isoxazole-4-carboxylate or
by generating the bromo-methyl derivative, which on
Initial efforts to brominate the methyl group of the 3-aryl-5-
methyl-isoxazole-4-carboxylate did not yield the desired
results. It was observed that bromination was extremely
sensitive to the reaction conditions, which led us to carry out
detailed investigations on the bromination of the methyl
group in 3-aryl-5-methyl-isoxazole-4-carboxylates (1a–d).
This study furnished a number of novel observations and
helped us to develop an optimized procedure for obtaining
3-aryl-5-bromomethyl- and 5-dibromomethyl isoxazole-4-
carboxylate, which then easily furnished the desired
aldehyde (2). The intermediates generated facilitate access
to isoxazole-annulated ring systems. The details of our
study are presented here.
q CDRI Communication no. 6489.
Keywords: Isoxazole; Bromination; NBS; 3-Aryl-5-bromomethyl-
isoxazole-4-carboxylate; 3-Aryl-5-formyl-isoxazole-4-carboxylate.
2. Results and discussion
*
Corresponding author. Tel.: þ91-522-2212411-18x4368; fax: þ91-522-
The oxidation of the 3-aryl-5-methyl-4-isoxazole-carb-
oxylate (1) failed to deliver the desired aldehyde (2)
(Scheme 1). In a different strategy, compound 1 was
2223405/2223938; e-mail address: batra_san@yahoo.co.uk
Graduate Trainee for 6 months (July 2003 to December 2003) from Birla
Institute of Technology, Pilani Rajasthan.
†
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.009

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A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
Scheme 1. Reagents and conditions: (a) SeO2, KMnO4 or CAN, heat, 48 h; (b) CrO2(OAc)2, AcOH, heat; (c) HCl; (d) NBS, UV light, CCl4, 40–45 8C, 24 h;
(e) DMSO, H2O, 4 h, heat; (f) PCC, CH2Cl2, 10 h.
subjected to chromium diacetate-promoted oxidation to
furnish the diacetate 3, which hydrolyzed in the presence of
acid to furnish aldehyde 2.19 However, this reaction led to a
complex mixture and the purification of the desired product
was difficult. We, therefore, opted to brominate the methyl
group, which on the basis of literature precedence appeared
to be easy and straightforward. However, our observations
were contrary to these reports.9–18 Our findings are reported
below.
1.5 equiv. of NBS and a radical initiator) of the methyl
group instead of mono-bromo derivatives (4a–d)
(CAUTION—see Section 3), furnished the gem-dibromo-
derivatives (6a–d) (CAUTION—see Section 3) in excellent
yields (Scheme 2). These results were contrary to previous
reports, except by Dannhardt et al.11 and Lecrec et al.18
where the formation of a gem-dibromo derivative was
initially reported in 22 and 8% yields, respectively, from a
NBS-promoted bromination reaction. In the light of our
objective to obtain the 5-formyl derivatives (2a–d), the
formation of gem-dibromo-derivatives initially was not
considered to be disadvantageous, since the hydrolysis of
gem-dibromo compounds to the corresponding aldehyde is a
well-documented procedure.20–27 It was disappointing to
note that our attempts to generate the formyl derivatives
(2a–d) directly from the gem-dibromo derivative (6a–d) in
the presence of strong acid or alkali were unsuccessful. We,
therefore, decided to modulate the bromination reaction to
furnish the mono-bromo product 4 exclusively. This led to
evaluation of various conditions in which the radical
2.1. Studies on the bromination of 3-aryl-5-methyl-4-
isoxazolecarboxylate
Bromination of the 5-methyl group in isoxazole is
reported9–19 to be accomplished with either bromine or
NBS in CCl4 in the presence of a radical initiator that could
be UV light, AIBN or benzoyl peroxide (BP) or bromine in
dark (Fig. 1). Based on these reports, the brominations of
3-aryl-5-methyl-4-isoxazolecarboxylates (1a–d) were
carried out. The NBS-mediated bromination (using 2.0 or
Figure 1. Few examples showing the variation in nature of products and yields of brominated derivative in reported procedures.

A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
2303
Scheme 2. Reagents and conditions: (a) NBS (2.0 equiv.), UV light, CCl4, reflux, 12 h for compound 6 as major product or NBS (0.8 equiv.), UV light, CCl4,
40–45 8C, 24 h for compound 4 as major product; (b) Conc. H2SO4, heat, 48 h or CaCO3, heat, 48 h; (c) NH2OH·HCl, NaOAc, MeOH, reflux, 6–7 h; (d) aq.
HCHO (30%), conc. HCl, rt, 1 h or PDC, CH2Cl2, 14 h; (e) NaOMe, MeOH, rt, 30 min; (f) HCl, rt, 30 min; (g) (i) DMSO, H2O, 4 h, heat; (ii) PCC, CH2Cl2,
10 h.
initiator, amount of NBS, temperature and solvent dilution
were varied to determine the optimum reaction conditions to
obtain the mono-brominated derivative (4) in good yields.
The bromination of compound 1a in CCl4 as the solvent was
chosen for the model study and the details of various
conditions evaluated during this study are presented in
Table 1. It would be appropriate here to mention that since
the components for the starting substrate (1a), mono-bromo
(4a) and gem-dibromo (6a) compounds do not resolve well
on TLC, the progress of the reaction was monitored using
HPLC. A gradient of 10–98% methanol/water containing
0.1% TFA in 45 min at a flow rate of 2 mL/min. on a RP-18
column (4.6£250 mm) resolved the three components of the
reaction mixture (Rt; 1a¼16.6 min; 4a¼17.5 min;
6a¼20.3 min). As is evident in the table, the reaction
under reflux invariably led to the formation of compound 6a
as the major product. However, when the reaction was
carried out with 0.8 equiv. NBS with respect to compound
1a at a temperature between 40 and 45 8C the mono-bromo
derivative 4a was obtained in high yields. Thus reaction
conditions to obtain exclusively either mono-bromo or gem-
dibromo derivative could be developed. Contrary to the
NBS-promoted bromination, all attempts to brominate
compound 1a with neat bromine in dark led to a complex
mixture. In order to confirm that the gem-dibromo
derivative was formed through the corresponding mono-
bromo derivative, compound 4a was subjected to further
bromination with NBS under UV light to afford the
product 6a almost instantaneously. This observation
suggested that the mono-bromo compound was extremely
susceptible to bromination and could explain the sensitivity
of the reaction conditions for the bromination of the
5-methyl group in 3-aryl-5-methyl-isoxazole-4-carboxyl-
ates (1a–d).
Table 1. Results of bromination of 3-phenyl-5-methyl-isoxazole-4-carboxylate 1a with NBS under various conditions
Entry
Reaction variables
NBS (equiv.)a
Radical initiator Temperature Time (h) Ratio of the product as % area observed in HPLC
Monobromo 4a Dibromo 6a Unreacted 1a
Solvent CCl4 (g/mL)
1
2
3
4
2.0
2.0
1.5
1.5
1:50
1:50
1:50
1:50
BP or AIBN
UV
BP
Reflux
Reflux
Reflux
Reflux
12
12
12
12
24
12
24
12
24
12
24
12
12
24
12
24
12
24
12
24
24
144
0
0
9
11
0
13
0
28
14
14
3
2
24
9
12
55
19
20
15
81 (76)b,d
100 (80)b
0
0
100 (84)b
37
49
87
56
83
0
43
58
81
68
2
76
0
31
0
75
0
3
54
40
13
31
17
72
43
28
16
30
74
15
84
14
81
5
AIBN
5
1.5
1:50
UV
Reflux
40–45 8C
Reflux
6
1.5 (3£0.5 1.5 h interval) 1:50
UV
7
8
1.5
1.0
1:200
1:50
UV
UV
Reflux
Reflux
40–45 8C
Reflux
9c
0.8
1:50
UV
40–45 8C
85
16
71
10
11
0.5
Neat Br2
1:50
—
UV
Dark
40–45 8C
rt
27
Mixture of products
2
a
3.0 equiv. of NBS leads to compound 6a within 4 h of reaction time.
Figure in parentheses are yields.
This condition holds true for 50 g batch size too.
b
c
d
The yield of compound 4a is based on the amount of the alcohol 5a obtained after hydrolysis.

2304
A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
2.2. Studies on the hydrolysis of mono- and gem-dibromo
derivatives
reaction times and in excellent yields. As reported earlier16
no cyclization was observed at this stage. Thereafter, the
ester was saponified in the presence of methanolic KOH to
afford the corresponding acids 12a–c. These acids were
then subjected to EDCI mediated coupling to furnish the
bicyclic lactams (13a–c).
Since compounds 1, 4 and 6 present in the residue obtained
after work up could not be separated efficiently by column
chromatography, the residue was directly used for studying
the fate of hydrolysis. The hydrolysis of the mono-bromo
compounds 4a–d was accomplished in the presence of
DMSO–water. The resulting mixture of hydroxy-derivative
(5), gem-dibromo derivative (6) and the starting substrate
(1) was separated through column chromatography. Sub-
sequent oxidation of alcohols (5a–d), in the presence of
PCC, furnished the corresponding aldehydes (2a–d) in
good yields.
The synthesis of another isoxazole-fused ring system 3-(2-
chlorophenyl)-6H-furo[3,4-d]isoxazol-4-one (15d) was
carried out from the acid (14d). The latter was obtained
after the saponification of the alcohol 5d. A DIC-promoted
cyclization of this hydroxy acid 14d furnished 15d. The
formation of 3-phenyl-5H-isoxazolo [4,5-d]pyridazin-4-one
(16a) is reported as a one pot two step procedure, where the
formyl derivative (2a) generated in situ is reacted with
hydrazine hydrate in water/acetic acid (v/v) mixture.5 In
contrast to this report, when the reactions of pure formyl
derivatives (2a–c) were carried out with hydrazine hydrate
we isolated the 3-substituted phenyl-5H-isoxazolo [4,5-
d]pyridazin-4-ones (16a–c) in excellent yields at room
temperature, without any additive.
The dibromo derivative (6c), on reaction with freshly
prepared NaOMe, furnished the dimethoxy acetal (7c) that
upon acid hydrolysis furnished the formyl derivative 2c in
modest yield.28 In another strategy the reaction of gem-
dibromo derivatives (6a–d) with hydroxylamine hydro-
chloride, under prolonged heating yielded the correspond-
ing oximes (8a–d),29,30 from which the corresponding
formyl derivatives (2a–d) could again be generated by acid
hydrolysis in presence of formaldehyde in high yields.31 The
PDC method32 of hydrolysis of oximes was also evaluated
to give the aldehydes in moderate yields (Scheme 3).
In conclusion, we have established an optimized procedure
for the bromination of 3-aryl-5-methyl-isoxazole-4-carb-
oxylates (1a–d) to obtain, exclusively, either the mono-
bromo or gem-dibromo methyl derivative in excellent
yields. The mono-bromo methyl derivatives (4a–d) have
been shown to be an excellent substrate for obtaining the
3-aryl-5-formyl-isoxazole-4-carboxylate. The substrates
generated during the study are exemplified for facile synthesis
of isoxazole-annulated ring systems. Evaluation of Baylis–
Hillman reaction of this highly substituted-5-isoxazolecarbal-
dehyde will form part of our future communications.
2.3. Access to isoxazole-annulated heterocycles
In our efforts to exemplify the usefulness of the compounds
generated during this study, the syntheses of 5,6-dihydro-
4H-pyrrolo[3,4-d]isoxazol-4-ones (13a–c), isoxazolo[4,5-
d]furanone (15d) and isoxazole [4, 5-d] pyridazin-4-ones
(16a–c) were carried out. Synthesis of 5,6-dihydro-4H-
pyrrolo[3,4-d]isoxazol-4-ones (11a–c) were analogous to
the example reported by Jones et al.16 The required bromo-
derivatives (4a–d) were obtained from alcohols (5a–d) via
PBr3-mediated bromination in quantitative yields; com-
pounds 4a–c on nucleophilic substitution with various
amines furnished the secondary amines (9–11a–c) in short
3. Experimental
3.1. General
Melting points are uncorrected and were determined in
Scheme 3. Reagents and conditions: (a) PBr3, CH2Cl2, 0 8C, 30 min; (b) PCC, CH2Cl2, 10 h; (c) R’NH2, Et3N, anhyd. Benzene, reflux, 30 min; (d) KOH in
MeOH/H2O, rt, 1 h; (e) EDCI, DIEA, DMAP, CH2Cl2, rt, 45 min; (f) DIC, DMAP, rt, 24 h; (g) NH2NH2·H2O, MeOH, rt, 15 min.

A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
2305
capillary tubes on a hot stage apparatus containing silicon
oil. IR spectra were recorded using Perkin–Elmer’s
Spectrum RX I FTIR spectrophotometer. 1H NMR and
13C NMR spectra were recorded on Bruker DPX-200 FT
spectrometer, using TMS as an internal standard (chemical
shifts in d values, J in Hz). The FABMS were recorded on
JEOL/SX-102 spectrometer and ESMS were recorded
through direct flow injections in Merck M-8000 LCMS
system. Elemental analyses were performed on a Carlo Erba
1108 microanalyzer or Elementar’s Vario EL III micro-
analyzer. CAUTION: the gem-dibromo (6a–d) and mono-
bromo (4a–d) derivatives cause severe irritation on
exposure leading to small blisters occasionally. The stated
yields of the alcohols (5a–d) are the ones obtained by
hydrolysis of pure mono-bromo-derivatives (4a–d). Simi-
larly, the yields of the mono-bromo derivatives (4a–d) are
those observed during the PBr3-promoted bromination of
alcohols (5a–d). The yields of dibromo-derivatives (6a–d)
are those obtained from the bromination reaction carried out
with 2 mol of NBS under UV light.
pound obtained as pale yellow solid, mp 87–88 8C; [found
C, 35.57; H, 2.06; N, 3.69. C12H8Br2ClNO3 requires C,
35.20; H, 1.97; N, 3.42]; nmax (KBr) 1707 (CO2Me) cm21
;
1H NMR (CDCl3, 200 MHz) d¼3.85 (s, 3H, CO2CH3), 7.29
(s, 1H, CHBr2), 7.43, 7.47 (d, 2H, J¼8.4 Hz, ArH), 7.56, 7.60
(d, 2H, J¼8.4 Hz, ArH); mass (FABþ) m/z % 410 (Mþþ1).
3.2.3. 5-Dibromomethyl-3-(2,4-dichloro-phenyl)-isoxa-
zole-4-carboxylic acid methyl ester (6c). Yield 76%;
compound obtained as white solid, mp 128–130 8C; [found
C, 32.56; H, 1.73; N, 3.25. C12H7Br2Cl2NO3 requires C,
32.47; H, 1.59; N, 3.16]; nmax (KBr) 1704 (CO2Me) cm21
;
1H NMR (CDCl3, 200 MHz) d¼3.76 (s, 3H, CO2CH3), 7.28
(s, 1H, CHBr2), 7.39 (s, 2H, ArH), 7.52 (s, 1H, ArH); mass
(FABþ) m/z % 444 (Mþþ1).
3.2.4. 3-(2-Chloro-phenyl)-5-dibromomethyl-isoxazole-
4-carboxylic acid methyl ester (6d). Yield 82%; com-
pound obtained as white solid, mp 74–75 8C; [found C,
35.41; H, 1.87; N, 3.23. C12H8Br2ClNO3 requires C, 35.20;
1
H, 1.97; N, 3.42]; nmax (KBr) 1728 (CO2Me) cm21; H
3.2. Bromination and hydrolysis—general procedure
NMR (CDCl3, 200 MHz) d¼3.74 (s, 3H, CO2CH3), 7.29 (s,
1H, CHBr2), 7.33–7.49 (m, 4H, ArH); mass (FABþ) m/z %
410 (Mþþ1).
To the appropriate solution of compounds 1a–d
(46.0 mmol) in CCl4 (250 mL), was added NBS in the
required quantity (from Table 1) and the reaction was
allowed to stir either under refluxing conditions or at
40–45 8C (maintained by placing the reaction in a water
bath and changing the water after every 2–3 h). The
optimum reaction time for phenyl and 4-chlorophenyl
substitutions was 24 h while that for 2-chloro-phenyl and
2, 4-dichlorophenyl was observed to be 40 h. On com-
pletion, the reaction was cooled to 10 8C, and the
precipitated succinimide was filtered. The filtrate was
evaporated under vacuum to furnish a reddish brown oil.
This residue consists of an inseparable mixture of gem-
dibromo derivative, starting material and mono-bromo
derivative. This residue was taken up in DMSO/water
(100 mL, 90:10, v/v) and stirred at 80 8C for 4 h. The
reaction mixture was quenched with excess of cold water
(250 mL) and extracted with diethyl ether (2£150 mL). The
combined and dried (Na2SO4), the organic phase was
evaporated under reduced pressure and the residue sub-
jected to column chromatography over silica gel (60–120
mesh) using hexane/ethyl acetate mixture as eluent.
(9.5:0.5, v/v) to give the gem-dibromo derivative. Further
elution with 8.5:1.5 (v/v) hexane/ethyl acetate yielded the
unreacted starting material while a mixture of hexane/ethyl
acetate (1:1, v/v) furnished the alcohol.
3.2.5. 5-Hydroxymethyl-3-phenyl-isoxazole-4-carboxylic
acid methyl ester (5a). Yield 93%; compound obtained as
pale yellow solid; mp 62–64 8C; [found: C, 61.81; H, 4.76;
N, 6.06. C12H11NO4 requires C, 61.80; H, 4.75; N, 6.01].
nmax (KBr) 1735 (CO2Me), 3498 (OH) cm21 1H NMR
;
(CDCl3, 200 MHz) d¼3.78 (s, 3H, CO2CH3), 4.97 (s, 2H,
CH2), 7.44–7.49 (m, 3H, ArH), 7.57–7.62 (m, 2H, ArH);
13C NMR (CDCl3, 50.32 MHz) d¼52.61, 57.17, 109.35,
128.27, 128.54, 129.75, 130.42, 162.77, 163.35, 178.01;
mass (FABþ) m/z % 234 (Mþþ1).
3.2.6. 3-(4-Chloro-phenyl)-5-hydroxymethyl-isoxazole-
4-carboxylic acid methyl ester (5b). Yield 87%; com-
pound obtained as light brown solid; mp 95–96 8C; [found
C, 53.69; H, 3.69; N, 5.39. C12H10ClNO4 requires C, 53.85;
H, 3.77; N, 5.23]; nmax (KBr) 1728 (CO2Me), 3427
1
(OH) cm21; H NMR (CDCl3, 200 MHz) d¼3.79 (s, 3H,
CO2CH3), 4.97 (s, 2H, CH2), 7.41, 7.45 (d, 2H, J¼8.4 Hz,
ArH), 7.53, 7.57 (d, 2H, J¼8.4 Hz, ArH); mass (FABþ) m/z
% 268 (Mþþ1).
3.2.7. 3-(2,4-Dichloro-phenyl)-5-hydroxymethyl-isoxa-
zole-4-carboxylic acid methyl ester (5c). Yield 79%;
compound obtained as pale yellow oil; [found C, 47.77; H,
3.30; N, 4.49. C12H9Cl2NO4 requires C, 47.71; H, 3.00; N,
1
3.2.1. 5-Dibromomethyl-3-phenyl-isoxazole-4-carboxylic
acid methyl ester (6a). Yield 84%; compound obtained as
white solid; mp 69–71 8C; [found C, 38.78; H, 2.51; N,
4.00. C12H9Br2NO3 requires C, 38.43; H, 2.42; N, 3.74];
4.64]; nmax (Neat) 1725 (CO2Me), 3405 (OH) cm21; H
NMR (CDCl3, 200 MHz) d¼3.75 (s, 3H, CO2CH3), 4.99 (s,
2H, CH2), 7.359, 7.364 (d, 2H, J¼1.1 Hz, ArH), 7.52 (s, 1H,
ArH); mass (FABþ) m/z % 302 (Mþþ1).
nmax (KBr) 1706 (CO2Me) cm21
;
1H NMR (CDCl3,
200 MHz) d¼3.82 (s, 3H, CO2CH3), 7.30 (s, 1H, CHBr2),
7.46–7.52 (m, 3H, ArH), 7.59–7.64 (m, 2H, ArH); 13C
NMR (CDCl3, 50.32 MHz) d¼23.03, 52.91, 105.98, 127.71,
128.67, 129.84, 130.76, 161.26, 162.86, 171.88; mass
(FABþ) m/z % 376 (Mþþ1).
3.2.8. 3-(2-Chloro-phenyl)-5-hydroxymethyl-isoxazole-
4-carboxylic acid methyl ester (5d). Yield 76%; com-
pound obtained as white solid; mp 94–96 8C; [found: C,
53.55; H, 4.14; N, 5.24. C12H10ClNO4 requires C, 53.85; H,
3.77; N, 5.23]; nmax (KBr) 1735 (CO2Me), 3427
1
(OH) cm21; H NMR (CDCl3, 200 MHz) d¼3.69 (s, 3H,
3.2.2. 3-(4-Chloro-phenyl)-5-dibromomethyl-isoxazole-
4-carboxylic acid methyl ester (6b). Yield 77%; com-
CO2CH3), 4.99 (s, 2H, CH2), 7.35–7.47 (m, 4H, ArH); mass
(FABþ) m/z % 268 (Mþþ1);

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A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
3.3. Oxidation of alcohol with PCC—general procedure
3.4.1. 5-Bromomethyl-3-phenyl-isoxazole-4-carboxylic
acid methyl ester (4a). Yield 99%; compound obtained
as yellow oil; [found C, 48.92; H, 3.70; N, 4.58.
C12H10BrNO3 requires C, 48.67; H, 3.40; N, 4.73]; nmax
To a solution of the appropriate alcohol from 5a–d
(46 mmol) in dry CH2Cl2 was added PCC (11.0 g,
51 mmol) and the resulting mixture was stirred at rt for
10–12 h. Thereafter, the reaction mixture was passed
through a column of silica gel (60–120 mesh) using ethyl
acetate/hexane (1:1, v/v) to afford the aldehydes.
1
(Neat) 1727 (CO2Me) cm21; H NMR (CDCl3, 200 MHz)
d¼3.82 (s, 3H, CO2CH3), 4.81 (s, 2H, CH2Br), 7.43–7.48
(m, 3H, ArH), 7.59–7.66 (m, 2H, ArH); mass (FABþ) m/z
% 296 (Mþþ1).
3.3.1. 5-Formyl-3-phenyl-isoxazole-4-carboxylic acid
methyl ester (2a). Yield 82%; compound obtained as off
white solid; mp 65–67 8C; [found 62.49; H, 4.18; N, 5.91.
C12H9NO4 requires C, 62.34; H, 3.92; N, 6.06]; nmax
(KBr)1730 (CO2Me), 1701 (CHO) cm21; 1H NMR (CDCl3,
200 MHz) d¼3.91 (s, 3H, CO2CH3), 7.44–7.52 (m, 3H,
ArH), 7.65–7.70 (m, 2H, ArH), 10.34 (s, 1H, CHO); mass
(FABþ) m/z % 232 (Mþþ1).
3.4.2. 5-Bromomethyl-3-(4-chloro-phenyl)-isoxazole-4-
carboxylic acid methyl ester (4b). Yield 92%; compound
obtained as dark yellow oil; [found C, 43.40; H, 2.87; N,
4.11. C12H9BrClNO3 requires C, 43.60; H, 2.74; N, 4.24];
nmax (Neat) 1729 (CO2Me) cm21
;
1H NMR (CDCl3,
200 MHz) d¼3.85 (s, 3H, CO2CH3), 4.80 (s, 2H, CH2Br),
7.42, 7.46 (d, 2H, J¼8.2 Hz, ArH), 7.58, 7.62 (d, 2H,
J¼8.2 Hz, ArH); mass (FABþ) m/z % 332 (Mþþ1).
3.3.2. 3-(4-Chloro-phenyl)-5-formyl-isoxazole-4-car-
boxylic acid methyl ester (2b). Yield 64%; compound
obtained as off white solid; mp 88–90 8C; [found: C, 54.46;
H, 3.40; N, 4.98. C12H8ClNO4 requires C, 54.26; H, 3.04; N,
3.4.3. 5-Bromomethyl-3-(2,4-dichloro-phenyl)-isoxazole-
4-carboxylic acid methyl ester (4c). Yield 86%; compound
obtained as light brown oil; [found C, 39.11; H, 2.23; N,
4.01. C12H8BrCl2NO3 requires C, 39.49; H, 2.21; N, 3.84];
1
5.27]; nmax (KBr) 1728 (CO2Me), 1700 (CHO) cm21; H
nmax (Neat) 1730 (CO2Me) cm21 1H NMR (CDCl3,
;
NMR (CDCl3, 200 MHz) d¼3.93 (s, 3H, CO2CH3), 7.45,
7.49 (d, 2H, J¼8.4 Hz, ArH), 7.62, 7.66 (d, 2H, J¼8.4 Hz,
ArH), 10.34 (s, 1H, CHO); mass (FABþ) m/z % 266
(Mþþ1).
200 MHz) d¼3.82 (s, 3H, CO2CH3), 4.80 (s, 2H, CH2Br),
7.42–7.50 (m, 1H, ArH), 7.60–7.66 (m, 2H, ArH); mass
(FABþ) m/z % 365 (Mþþ1).
3.4.4. 5-Bromomethyl-3-(2-chloro-phenyl)-isoxazole-4-
carboxylic acid methyl ester (4d). Yield 69%; compound
obtained as yellow oil; [found C, 43.87; H, 2.79; N, 4.00.
Anal. C12H9BrClNO3 requires C, 43.60; H, 2.74; N, 4.24];
3.3.3. 3-(2,4-Dichloro-phenyl)-5-formyl-isoxazole-4-car-
boxylic acid methyl ester (2c). Yield 67%; compound
obtained as white solid; mp 58–59 8C; [found 48.03; H,
2.35; N, 4.67. C12H7Cl2NO4 requires C, 47.88; H, 1.99; N,
nmax (Neat) 1730 (CO2Me) cm21
;
1H NMR (CDCl3,
1
4.66]; nmax (KBr) 1724 (CO2Me), 1697 (CHO) cm21; H
200 MHz) d¼3.74 (s, 3H, CO2CH3), 4.83 (s, 2H, CH2Br),
7.35–7.47 (m, 4H, ArH); mass (FABþ) m/z % 332
(Mþþ1).
NMR (CDCl3, 200 MHz) d¼3.79 (s, 3H, CO2CH3), 7.359,
7.364 (d, 2H, J¼1.1 Hz, ArH), 7.52 (s, 1H, ArH), 10.37 (s,
1H, CHO); mass (FABþ) m/z % 300 (Mþþ1).
3.5. Oximation of gem-dibromo derivatives—general
procedure
3.3.4. 3-(2-Chloro-phenyl)-5-formyl-isoxazole-4-car-
boxylic acid methyl ester (2d). Yield 60%; compound
obtained as brown oil; [found C, 54.55; H, 2.81; N, 5.29.
C12H8ClNO4 requires C, 54.26; H, 3.04; N, 5.27]; nmax
A mixture of the appropriate gem-dibromo derivative from
6a–d (11.3 mmol), NaOAc (2.78 g, 33.9 mmol) and NH2-
OH·HCl (2.37 g, 33.9 mmol) in methanol (75 mL) mixture
was refluxed for 6–7 h. The excess solvent was removed
and the reaction mixture quenched with water to furnish the
oximes as white solids. Analytical samples of the products
were obtained by column chromatography over silica gel
using hexane/ethyl acetate (3:2, v/v) mixture as eluent.
(Neat) 1730 (CO2Me), 1700 (CHO) cm21
;
1H NMR
(CDCl3, 200 MHz) d¼3.82 (s, 3H, CO2CH3), 7.39–7.51
(m, 4H, ArH), 10.37 (s, 1H, CHO); mass (FABþ) m/z % 266
(Mþþ1).
3.4. Bromination of alcohol—general procedure
To a stirred solution of the appropriate alcohol from 5a–d
(5.0 mmol) in anhyd. CH2Cl2 (5 mL) was added a solution
of PBr3 (0.475 mL, 5.0 mmol) in anhyd. CH2Cl2 (10 mL) at
0 8C dropwise. The reaction was continued at the same
temperature for 30 min. Thereafter, the solvent was
evaporated to obtain a residue which was partitioned
between ethyl acetate (30 mL) and water (25 mL)
(extraction with CH2Cl2 led to a micelle that was difficult
to separate). The organic layer was separated, dried
(Na2SO4) and evaporated under reduced pressure to
obtain an oily residue that was used as such for further
reaction. However, the analytical samples were obtained
through column chromatography over silica gel (100–200
mesh) using hexane/ethyl acetate (9.5:0.5, v/v) mixture as
eluent.
3.5.1. 5-(Hydroxyimino-methyl)-3-phenyl-isoxazole-4-
carboxylic acid methyl ester (8a). Yield 85%; compound
obtained as white solid; mp 164–165 8C; [found: C, 58.26;
H, 3.77; N, 11.15. C12H10N2O4 requires C, 58.54; H, 4.09;
N, 11.38]; nmax (KBr) 1732 (CO2Me), 3260 (OH) cm21; 1H
NMR (CDCl3þDMSOd6, 200 MHz) d¼3.83 (CO2CH3),
7.46–7.51 (m, 3H, Ar-H), 7.63–7.67 (m, 2H, Ar-H), 8.67
(s, 1H, vCH), 8.98 (s, 1H, NOH); 13C NMR (CDCl3,
50.32 MHz) d¼52.06, 127.76, 128.63, 129.77, 130.62,
139.09, 161.69, 163.12, 166.28; mass (FABþ) m/z % 247
(Mþþ7).
3.5.2. 3-(4-Chloro-phenyl)-5-(hydroxyimino-methyl)-isox-
azole-4-carboxylic acid methyl ester (8b). Yield 80%;
compound obtained as white solid; mp 130–132 8C; [found

A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
2307
C, 51.69; H, 3.61; N, 9.60. C12H9ClN2O4 requires C, 51.35;
H, 3.23; N, 9.98]; nmax (KBr) 1732 (CO2Me), 3260
3.7.2. PDC method. To a stirred solution of oxime
(5 mmol) in 50 mL of anhyd. CH2Cl2 was added PDC
(3.76 g, 10 mmol) at rt. The reaction was continued for 14 h.
Thereafter the reaction mass was filtered through silica gel
column (60–120 mesh) using a mixture of hexane/ethyl
acetate (7:3, v/v) to obtain the pure aldehydes in 45–50%
yields.
(OH) cm21
;
1H NMR (CDCl3þDMSOd6, 200 MHz)
d¼3.83 (CO2CH3), 7.46–7.51 (m, 3H, Ar-H), 7.63–7.67
(m, 2H, Ar-H), 8.67 (s, 1H, vCH), 8.98 (s, 1H, NOH); mass
(FABþ) m/z % 247 (Mþ).
3.5.3. 3-(2,4-Dichloro-phenyl)-5-(hydroxyimino-methyl)-
isoxazole-4-carboxylic acid methyl ester (8c). Yield 78%;
compound obtained as white solid; mp 184–186 8C; [found
C, 45.68; H, 2.93; N, 9.01. C12H8Cl2N2O4 requires C, 45.74;
H, 2.56; N, 8.89] IR (KBr); 1715 (CO2Me), 3402
3.8. Reaction with amines—general procedure
A mixture of the bromide (4a–c) (5.0 mmol), Et3N (0.9 mL,
6.5 mmol) and the appropriate amine (5.5 mmol) in anhyd.
benzene (5 mL) was refluxed under stirring at 80 8C. After
1 h the reaction was cooled to rt and extracted with water
(30 mL) and ethyl acetate (2£35 mL). The organic layers
were combined, dried (Na2SO4) and evaporated under
reduced pressure to obtain an oily residue. The products
from benzyl amine and cyclopropyl amine were purified
through column chromatography over silica gel (100–200
mesh) while that obtained from amino diethyl ethyl amine
were purified on basic alumina. A mixture of hexane and
ethyl acetate (3:2, v/v) was used as eluent on either
stationary phase.
(OH) cm21
;
1H NMR (CDCl3þDMSOd6, 200 MHz)
d¼3.77 (CO2CH3), 7.39 (s, 2H, Ar-H), 7.53 (m, 1H, Ar-
H), 8.65 (s, 1H, vCH), 9.15 (s, 1H, NOH); mass (FABþ)
m/z % 314 (Mþ).
3.5.4. 3-(2-Chloro-phenyl)-5-(hydroxyimino-methyl)-isox-
azole-4-carboxylic acid methyl ester (8d). Yield 75%;
compound obtained as white solid; mp 164–165 8C; [found:
C, 51.18; H, 3.61; N, 10.02. C12H9ClN2O4 requires C,
51.35; H, 3.23; N, 9.98]; nmax (KBr) 1730 (CO2Me), 3280
(OH) cm21
;
1H NMR (CDCl3þDMSOd6, 200 MHz)
d¼3.75 (CO2CH3), 7.35–7.51 (m, 4H, Ar-H), 8.67 (s, 1H,
vCH), 9.18 (brs, 1H, NOH); mass (FABþ) m/z % 281
(Mþ).
3.8.1. 5-(Benzylamino-methyl)-3-phenyl-isoxazole-4-carb-
oxylic acid methyl ester (9a). Yield 74%; compound was
obtained as yellow oil; oxalate salt as white solid; mp 199–
200 8C; [found: C, 65.73; H, 5.76; N, 7.59. C19H18N2O3·
CO2H)2 requires C, 65.96; H, 5.80; N, 7.33]; nmax (Neat)
3.6. Formation of dimethoxy acetal—typical procedure
To a stirred solution of sodium methoxide (10.0 mmol) in
methanol (30 mL) was added compound 6c (5.0 mmol) at
0 8C and the reaction was allowed to proceed for 30 min at
the same temperature. The excess methanol was evaporated
and the reaction mixture was extracted with water (40 mL)
and ethyl acetate (2£50 mL). The organic layers were
combined, dried (Na2SO4) and reduced under vacuum to
give a residue which was purified by column chromato-
graphy with silica gel (230–400 mesh) using a mixture of
hexane/ethyl acetate (4:1, v/v) furnished the acetal.
1728 (CO2Me), 3341 (NH) cm21 1H NMR (CDCl3,
;
200 MHz) d¼3.66 (s, 3H, CO2CH3), 3.85 (s, 2H,
NH–CH2), 4.22 (s, 2H, NH–CH2), 7.27–7.59 (m, 10H,
ArH); mass (ESþ) m/z % 323.87 (Mþþ1).
3.8.2. 5-(Benzylamino-methyl)-3-(4-chloro-phenyl)-isox-
azole-4-carboxylic acid methyl ester (9b). Yield 69%;
compound obtained as yellow oil; oxalate salt as white
solid; mp 191–193 8C; [found C, 56.83; H, 4.18; N, 6.00.
C19H17ClN2O3·(CO2H)2 requires C, 56.45; H, 4.29; N,
6.27]; nmax (Neat) 1726 (CO2Me), 3429 (NH) cm21; H
1
3.6.1. 3-(2,4-Dichloro-phenyl)-5-dimethoxymethyl-isoxa-
zole-4-carboxylic acid methyl ester (7c). Yield 28%;
compound was obtained as white solid; mp 175–78 8C;
[found: C, 48.74; H, 3.71; N, 4.32. C14H13Cl2NO5 requires
C, 48.58; H, 3.79; N, 4.05;]; nmax (KBr) 1719 (CO2-
NMR (CDCl3, 200 MHz) d¼3.74 (s, 3H, CO2CH3), 3.85 (s,
2H, NH–CH2), 4.23 (s, 2H, NH–CH2), 7.27–7.35 (m, 5H,
ArH), 7.41, 7.44 (d, 2H, J¼8.2 Hz, Ar-H), 7.54, 7.58 (d, 2H,
J¼8.2 Hz, Ar-H); mass (ESþ) m/z % 357.53 (Mþþ1).
1
Me) cm21; H NMR (CDCl3, 200 MHz) d¼3.53 (s, 6H,
3.8.3. 5-(Benzylamino-methyl)-3-(2,4-dichloro-phenyl)-
isoxazole-4-carboxylic acid methyl ester (9c). Yield
67%; compound obtained as yellow oil; [found C 58.47;
H, 4.51; N, 7.35. C19H16Cl2N2O3 requires C, 58.33; H, 4.12;
N, 7.16]; nmax (Neat) 1726 (CO2Me), 3427 (NH) cm21; 1H
NMR (CDCl3, 200 MHz) d¼3.68 (s, 3H, CO2CH3), 3.86 (s,
2H, NH–CH2), 4.26 (s, 2H, NH–CH2), 7.28–7.42 (m, 7H,
ArH), 7.50 (s, 1H, Ar-H); mass (FABþ) m/z % 391
(Mþþ1).
2£OCH3), 3.73 (s, 3H, CO2CH3), 6.08 (s, 1H, CH), 7.36 (s,
2H, ArH), 7.51 (s, 1H, ArH); mass (FABþ) m/z % 346
(Mþþ1).
3.7. Hydrolysis of oxime—general procedure
3.7.1. HCHO/HCl method. To a stirred solution of
formaldehyde (33% aq.): conc. HCl (16 mL, 50:50, v/v)
was added appropriate oxime from 8a–d (3.5 mmol) and
the reaction was continued at rt for 1 h. The reaction mixture
was quenched with water (50 mL) and extracted with ethyl
acetate (2£50 mL). The organic layers were pooled, dried
(Na2SO4) and concentrated under reduced pressure to give a
residue. This residue was purified by column chromato-
graphy over silica gel using a mixture of hexane/ethyl
acetate (7:3, v/v) as eluent yielded the pure aldehyde in
85–91% yields.
3.8.4. 5-(2-Diethylamino-ethylamino)-3-phenyl-isoxa-
zole-4-carboxylic acid methyl ester (10a). Yield 71%;
compound obtained as yellow oil; oxalate salt as white
solid; mp 181–183 8C; [found C, 50.47; H, 6.14; N, 7.98.
C17H23N3O3·2(CO2H)2·1/2H2O requires C, 50.79; H, 5.81;
N, 8.07]; nmax (Neat) 1728 (CO2Me) cm21 1H NMR
;
(CDCl3, 200 MHz) d¼1.00 (t, 6H, J¼7.0 Hz, 2£CH3),
2.42–2.75 (m, 8H, N–CH2), 3.78 (s, 3H, CO2CH3), 4.25 (s,

2308
A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
2H, N–CH2), 7.44–7.49 (m, 3H, ArH), 7.56–7.64 (m, 2H,
ArH); mass (ESþ) m/z % 332.87 (Mþþ1).
white solid separates out from the reaction mixture that was
filtered and washed thoroughly with water to furnish the
pure acid derivatives.
3.8.5. 3-(4-Chloro-phenyl)-5-[(2-diethylamino-ethyl-
amino)-methyl]-isoxazole-4-carboxylic acid methyl
ester (10b). Yield 66%; compound obtained as dark yellow
oil; oxalate salt as white solid; mp 183–185 8C; [found C,
48.02; H, 5.16; N, 7.55. C18H24ClN3O3. 2(CO2H)2 requires
C, 48.40; H, 5.17; N, 7.70]; nmax (Neat) 1727 (CO2Me),
3.9.1. 5-(Benzylamino-methyl)-3-phenyl-isoxazole-4-carb-
oxylic acid (12a). Yield 99%; compound obtained as white
solid; mp 202–205 8C; [found C, 68.04; H, 5.49; N, 8.55.
C18H16N2O3·1/2 H2O requires C, 68.12; H, 5.39; N, 8.80];
n
max (KBr) 1619 (CO2H), 3001 (NH), 3461 (OH) cm21; 1H
1
3331 (NH) cm21; H NMR (CDCl3, 200 MHz) d¼1.00 (t,
NMR (DMSOd6, 200 MHz) d¼4.01 (s, 2H, NH–CH2), 4.34
(s, 2H, NH–CH2), 7.35–7.46 (m, 8H, ArH), 7.62–7.66 (m,
2H, ArH); mass (FABþ) m/z % 309 (Mþþ1).
6H, J¼7.0 Hz, 2£CH3), 2.46–2.75 (m, 8H, N–CH2), 3.79
(s, 3H, CO2CH3), 4.25 (s, 2H, NH–CH2), 7.41, 7.45 (d, 2H,
J¼8.4 Hz, ArH), 7.56, 7.60 (d, 2H, J¼8.4 Hz, ArH); mass
(ESþ) m/z % 366.80 (Mþþ1).
3.9.2. 5-(Benzylamino-methyl)-3(4-chloro-phenyl)-isoxa-
zole-4-carboxylic acid (12b). Yield 96%; compound
obtained as white solid; mp 213–215 8C; [found C, 59.61;
H, 4.42; N, 7.88. C18H15ClN2O3·H2O requires C, 59.92; H,
4.75; N, 7.76]; nmax (KBr) 1616 (CO2H), 3002 (NH), 3448
(OH) cm21; 1H NMR (DMSOd6, 200 MHz) d¼4.05 (s, 2H,
NH–CH2), 4.38 (s, 2H, NH–CH2), 7.30–7.42 (m, 5H,
ArH), 7.51, 7.55 (d, 2H, J¼8.4 Hz, ArH), 7.71, 7.75 (d, 2H,
J¼8.4 Hz, ArH); mass (ESþ) m/z % 343.53 (Mþþ1).
3.8.6. 3-(2,4-Dichloro-phenyl)-5-[(2-diethylamino-ethyl-
amino)-methyl]-isoxazole-4-carboxylic acid methyl ester
(10c). Yield 67%; compound obtained as dark yellow oil;
[found: C, 54.16; H, 6.14; N, 10.18. C18H23Cl2N3O2
requires C, 54.01; H, 5.79; N, 10.50]; nmax (Neat) 1728
1
(CO2Me) cm21; H NMR (CDCl3, 200 MHz) d¼1.01 (t,
6H, J¼7.0 Hz, 2£CH3), 2.44–2.74 (m, 8H, N–CH2), 3.71
(s, 3H, CO2CH3), 4.27 (s, 2H, NH–CH2), 7.348, 7.353 (d,
2H, J¼1.0 Hz, ArH), 7.50 (s, 1H, ArH); mass (FABþ) m/z
% 400 (Mþþ1).
3.9.3. 5-(Benzylamino-methyl)-3-(2,4-dichloro-phenyl)-
isoxazole-4-carboxylic acid (12c). Yield 98%; compound
obtained as white solid; mp 145–146 8C; [found C, 54.38;
H, 4.20; N, 6.89. C18H14Cl2N2O3·H2O requires C, 54.70; H,
4.08; N, 7.09]; nmax (KBr) 1623 (CvO), 2999 (NH), 3443
3.8.7. 5-Cyclopropylaminomethyl-3-phenyl-isoxazole-4-
carboxylic acid methyl ester (11a). Yield 73%; compound
obtained as yellow oil; [found C, 64.42; H, 5.89; N, 9.64.
C15H16N2O3·1/2H2O requires C, 64.09; H, 6.09; N, 9.96];
(OH) cm21
;
1H NMR (CDCl3þDMSOd6, 200 MHz)
d¼3.98 (s, 2H, NH–CH2), 4.29 (s, 2H, NH–CH2), 7.28–
1
nmax (Neat) 1726 (CO2Me), 3317 (NH) cm21; H NMR
7.47 (m, 8H, ArH); mass (ESþ) m/z % 377.53 (Mþþ1).
(CDCl3, 200 MHz) d¼0.46–0.51 (m, 4H, CH2), 2.16–2.22
(m, 1H, CH), 3.78 (s, 3H, CO2CH3), 4.27 (s, 2H, NH–CH2),
7.44–7.48 (m, 3H, ArH), 7.60–7.65 (m, 2H, ArH); mass
(ESþ) m/z % 273.80 (Mþþ1).
3.9.4. 3-(2-Chloro-phenyl)-5-hydroxymethyl-isoxazole-
4-carboxylic acid (14d). Yield 92%; compound obtained
as off white solid; mp 174–176 8C; [found C, 51.83; H,
3.40; N, 5.44. C11H8ClNO4 requires C, 52.09; H, 3.18; N,
1
3.8.8. 3-(4-Chloro-phenyl)-5-cyclopropylaminomethyl-
isoxazole-4-carboxylic acid methyl ester (11b). Yield
68%; compound obtained as brown oil; oxalate salt as white
solid; mp 156–158 8C; [found C, 51.71; H, 4.22; N, 6.90.
C15H15ClN2O3. (CO2H)2 requires C, 51.46; H, 4.32; N,
5.52]; nmax (KBr) 1693 (CO2H) cm21; H NMR (CDCl3þ
DMSOd6, 200 MHz) d¼5.01 (s, 2H, CH2OH), 7.66 (s, 2H,
ArH), 7.36–7.45 (m, 2H, ArH); mass (FABþ) m/z % 254
(Mþþ1).
1
7.06]; nmax (Neat) 1725 (CO2Me), 3309 (NH) cm21; H
3.10. EDCI-promoted cyclization—general procedure
NMR (CDCl3, 200 MHz) d¼0.43–0.54 (m, 4H, CH2),
2.14–2.20 (m, 1H, CH), 3.80 (s, 3H, CO2CH3), 4.26 (s, 2H,
NH–CH2), 7.42, 7.46 (d, 2H, J¼8.4 Hz, ArH), 7.56–7.60 (m,
2H, J¼8.4 Hz, ArH); mass (ESþ) m/z % 307.67 (Mþþ1).
To a stirred solution of 11a–c (2.5 mmol) in anhyd. CH2Cl2
were added DIEA (0.87 mL, 5.0 mmol), EDCI·HCl
(0.720 g, 3.75 mmol) and a catalytic amount of DMAP at
ambient temp. The reaction was allowed to proceed for 1 h.
The change of color of the reaction to red was indicative of
complete reaction. After confirming the completion of
reaction through TLC, the reaction was quenched with
water (40 mL) and extracted with CH2Cl2 (2£50 mL). The
organic layers were pooled, dried (Na2SO4) and evaporated
to yield a brown residue that on column chromatography
over silica gel (100–200 mesh) using hexane/ethyl acetate
mixture (4:1, v/v) furnished the pure bi-lactams as solids.
3.8.9. 5-Cyclopropylaminomethyl-3-(2,4-dichloro-
phenyl)-isoxazole-4-carboxylic acid methyl ester (11c).
Yield 59%; compound obtained as brown oil; [found: C,
52.71; H, 4.22; N, 8.11. C15H14Cl2N2O3 requires C, 52.80;
H, 4.14; N, 8.21]; nmax (Neat) 1725 (CO2Me), 3424
(NH) cm21
;
1H NMR (CDCl3, 200 MHz) d¼0.44–0.53
(m, 4H, CH2), 2.11–2.19 (m, 1H, CH), 3.72 (s, 3H,
CO2CH3), 4.24 (s, 2H, NH–CH2), 7.36 (s, 2H, ArH), 7.52
(m, 1H, ArH); mass (ESþ) m/z % 307.67 (Mþþ1).
3.10.1. 5-Benzyl-3-phenyl-5,6-dihydro-pyrrolo[3,4-d]isox-
azol-4-one (13a). Yield 75%; compound obtained as pale
yellow solid; mp 110–115 8C; [found C, 70.41; H, 5.51; N;
9.18. C18H14N2O2 H2O requires C, 70.12; H, 5.23; N, 9.09];
3.9. Saponification of the ester—general procedure
The appropriate ester (9a–c or 5d) (5.0 mmol) was stirred in
15% solution of aq. methanol for 2 h at ambient temp. On
completion of the reaction, 5% aq. HCl solution was added
dropwise with constant monitoring of pH. At around pH 6.5
nmax (KBr) 1697 (CvO) cm21
;
1H NMR (CDCl3,
200 MHz) d¼4.30 (s, 2H, N–CH2), 4.74 (s, 2H, N–CH2),
7.29–7.38 (m, 5H, ArH), 7.49–7.51 (m, 3H, ArH),

A. K. Roy et al. / Tetrahedron 60 (2004) 2301–2310
2309
8.30–8.33 (m, 2H, ArH); 13C NMR (CDCl3, 50.32 MHz)
d¼45.55, 47.33, 117.73, 127.34, 128.47, 128.94, 131.53,
136.98, 158.16, 162.19, 183.64; mass (ESþ) m/z % 313.73
(MþþNa).
(m, 3H, ArH and HCvN), 13.20 (brs, 1H, NH); mass
(FABþ) m/z % 214 (Mþþ1).
3.12.2. 3-(4-Chloro-phenyl)-5H-isoxazolo[4,5-d] pyrida-
zin-4-one (16b). Yield 93%; compound obtained as white
solid; mp 180–181 8C; [found C, 52.98; H, 2.48; N, 16.63.
C11H6ClN3O2 requires C, 53.35; H, 2.44; N, 16.97]; nmax
(KBr) 1671 (CvONH) cm21; 1H NMR (CDCl3þDMSOd6
(a drop), 200 MHz) d¼7.47, 7.51 (d, 2H, J¼8.4 Hz, ArH),
8.39 (s merged with d of Ar-H, 1H, CHvN), 8.40, 8.44 (d,
2H, J¼8.4 Hz, ArH), 13.00 (brs, 1H, NH); mass (FABþ)
m/z % 248 (Mþþ1).
3.10.2. 5-Benzyl-3-(4-chloro-phenyl)-5,6-dihydro-
pyrrolo[3,4-d]isoxazol-4-one (13b). Yield 69%; compound
obtained as white solid; mp 161–164 8C; [found C, 61.53;,
H, 4.78; N; 8.10. C18H13ClN2O2. 1.5 H2O requires C, 61.46;
H, 4.58; N, 7.96]; nmax (KBr) 1681 (CvO) cm21; Anal. 1H
NMR (CDCl3, 200 MHz) d¼4.32 (s, 2H, N–CH2), 4.75 (s,
2H, N–CH2), 7.30–7.37 (m, 5H, ArH), 7.46, 7.49 (d, 2H,
J¼8.4 Hz, ArH), 8.26, 8.29 (d, 2H, J¼8.4 Hz, ArH); mass
(FABþ) m/z % 325 (Mþþ1).
3.12.3. 3-(2,4-Dichloro-phenyl)-5H-isoxazolo[4,5-d] pyri-
dazin-4-one (16c). Yield 90%; compound obtained as white
solid; mp 193–194 8C; [found C, 46.45; H, 2.07; N, 14.61.
C11H5Cl2N3O2 requires C, 46.84; H, 1.79; N, 14.90]; nmax
(KBr) 1691 (CvONH) cm21; 1H NMR (CDCl3þDMSOd6,
200 MHz) d¼7.40 (s, 2H, ArH), 7.59 (s, 1H, ArH), 8.45 (s,
1H, CHvN), 12.71 (brs, 1H, NH); mass (FABþ) m/z % 282
(Mþþ1).
3.10.3. 5-Benzyl-3-(2,4-dichloro-phenyl)-5,6-dihydro-
pyrolo[3,4-d]isoxazole-4-one (13c). Yield 70%; compound
obtained as white solid; mp 105–106 8C; [found C,
59.05; H, 357; N, 7.97. C18H12Cl2N2O2·1/2H2O
requires C, 58.90; H, 3.57; N, 7.63]; nmax (KBr) 1688
(CvO) cm21; 1H NMR (CDCl3, 200 MHz) d¼4.32 (s, 2H,
N–CH2), 4.73 (s, 2H, N–CH2), 7.27–7.58 (m, 6H, ArH),
8.03, 8.07 (d, 2H, J¼8.4 Hz, ArH); mass (ESþ) m/z %
359.67 (Mþþ1).
Acknowledgements
3.11. DIC-promoted cyclization—typical procedure
A. K. R. acknowledges the financial support from ICMR in
the form of fellowship. This work was supported by
financial grant under DST Project no. SR/SI/OC-04/2003.
To a stirred solution of 14d (2.5 mmol) in anhyd. CH2Cl2
were added DIC (0.720 g, 3.75 mmol) and a catalytic
amount of DMAP at ambient temperature and the reaction
was continued for 24 h. The reaction mixture was quenched
with water and extracted with CH2Cl2 (2£25 mL). The
organic layers were pooled, dried (Na2SO4) and evaporated
in vacuo yield a brown oily residue. This residue was
purified by column chromatography over silica gel (100–
200 mesh) using hexane/ethyl acetate mixture (4:1, v/v)
furnished the pure product.
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