One-pot synthesis of pyrrolo-[3,4-d]isoxazoline-4,6-diones via nitrile oxides

Article abstract of DOI:10.1007/s10593-009-0265-z

1,3-Dipolar cycloaddition of nitrile oxides generated in situ in the presence of variously substituted N-arylmaleimides and N-benzylmaleimide provides new pyrrolo[3,4-d]izoxazoline-4,6-diones in good yields. The whole procedure could be performed in a pra

Full text of DOI:10.1007/s10593-009-0265-z

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
one-pot SYNTHESIS OF PYRROLO-
[3,4-d]ISOXAZOLINE-4,6-DIONES via
NITRILE OXIDES
J. Rajput1*, B. Singh2, K. K. Singal2
1,3-Dipolar cycloaddition of nitrile oxides generated in situ in the presence of variously substituted
N-arylmaleimides and N-benzylmaleimide provides new pyrrolo[3,4-d]izoxazoline-4,6-diones in good
yields. The whole procedure could be performed in a practical and efficient one-pot operation. All the
cycloadducts were isolated in excellent yields and identified by spectral studies.
Keywords: maleimides, nitrile oxides, regiospecific 1,3-dipolar cycloaddition.
The 1,3-dipolar cycloaddition is an important and versatile method for the construction of five-membered
heterocycles [1–3]. Nitrile oxides are an important class of 1,3-dipolar species of propargyl-allenyl type [4−6]. Since
1973 we have reported many syntheses of various heterocycles using 1,3-dipolar cycloaddition (see, for example,
our last publications [7, 8], the former containing a rather complete bibliography). As an extention of our studies on
1,3-dipolar cycloaddition, in this communication we describe the one-pot synthesis of new pyrrolo-
[3,4-d]isoxazoline-4,6-diones from the reaction of nitrile oxides and variously substituted N-arylmaleimides
and N-benzylmaleimide. A series of seven maleimides has been prepared. These maleimides are evaluated as
potential dipolarophiles for 1,3-dipolar cycloadditions, as having electron-releasing and electron-withdrawing
substituents as well as one-atom spacer between nitrogen and the aryl ring.
Variously substituted N-arylmaleimides 3a–f [9] and N-benzylmaleimide 3g [10] have been prepared by
an identical procedure as reported in the literature. The 1,3-dipolar cycloadditions of these maleimides with
nitrile oxides prepared in situ by dehydrohalogenation of the corresponding aldoximes 1 and 2 [11−13] in the
presence of chloramine T [14], were carried out in refluxing ethanol and led directly to the corresponding
pyrrolo-[3,4-d]isoxazoline-4,6-diones 4a–g and 5a–g on workup (Table 1). On the basis of IR spectrum,
1H NMR and mass-spectral studies, all the new products were identified as 5-aryl- or 5-benzyl-substituted
3-(3',4'-methylenedioxyphenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-diones and 3-(3'-nitro-
phenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-diones.
_______
* To whom correspondence should be addressed, e-mail: drjaspreet@hotmail.com.
1Department of Chemistry, Dr. B. R. Ambedkar National Institute of Technology, Jalandhar 144011, Punjab,
India.
2Department of Chemistry, Punjabi University, Patiala 147 002, Punjab, India.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 444-448, March, 2009. Original
article received June 19, 2007.
0009-3122/09/4503-0361©2009 Springer Science+Business Media, Inc.
361

The cycloadditions of nitrile oxides proved to be highly regio- and stereospecific, leading to a single cis
isomer. The IR spectra of the cycloadducts showed a strong absorption band around 1765−1795 cm-1 and a weak
absorption band around 1717−1732 cm-1 corresponding to carbonyl functions of an imide moiety. The 1H NMR
spectra showed two doublets at δ 4.81–5.20 and 5.58−5.72 assigned to H-3a and H-6a, respectively. The
coupling constant of the coupled protons is around 9−10 Hz showing the cis addition.
O
N
O
O
H
Ethanol
O
(CH2)n
N
CH=NOH
(CH2)n
N
O
+
Chloramine T
Y
X
Y
H
3a–g
1, 2
X
4a–g, 5a–g
To conclude, the products were obtained in good yields with no side reaction, as no other product has
been isolated. The substituents at the N-aryl part of the N-arylmaleimides have very little influence on the
reaction rate, but one atom spacer between the nitrogen and the aryl part of N-benzylmaleimide increases it
considerably (Table 1).
EXPERIMENTAL
Melting points were determined on a Gallenkamp equipment and are uncorrected. IR spectra were recorded
in nujol on a Perkin-Elmer Spectrum RX-I series FT IR spectrophotometer at the Department of Chemistry, Punjabi
University, Patiala. 1H NMR spectra were recorded on a Bruker AC-300F (300 MHz) spectrometer in CDCl3 using
TMS as internal standard. Mass spectra were obtained on a VG-70-S mass spectrometer (70 eV) by SAIF, Punjab
University, Chandigarh.
TABLE 1. Preparation of isoxazoline-4,6-diones 4 and 5
Products
X
Y
n
Refluxing time, min Yield, %*
3,4-OCH2O
3,4-OCH2O
3,4-OCH2O
3,4-OCH2O
3,4-OCH2O
3,4-OCH2O
3,4-OCH2O
3-NO2
H
0
0
0
0
0
0
1
0
0
0
0
0
0
1
120
100
90
73
72
78
72
80
65
71
72
75
79
78
71
69
72
4a
4b
4c
4d
4e
4f
4-Me
4-OMe
4-OEt
4-Cl
90
90
4-NO2
H
110
20*2
150
130
130
120
140
160
30*2
4g
5a
5b
5c
5d
5e
5f
H
3-NO2
4-Me
4-OMe
4-OEt
4-Cl
3-NO2
3-NO2
3-NO2
3-NO2
4-NO2
H
3-NO2
5g
_______
* Isolated yield.
*2 Refluxing time for the reactions involving N-benzylmaleimide as a
dipolarophile.
362

Preparation of 4a–g, 5a–g. (General Method). In a 250 ml round bottom flask fitted with reflux
condensor, a mixture of aldoxime (0.01 mol), maleimide (0.01 mol), and chloramine T (0.01 mol) in ethanol (100
ml) was refluxed with stirring for the appropriate time (Table 1). Sodium chloride formed in the reaction was filtered
off and washed with ethanol. The filtrate and washings were concentrated under reduced pressure, and the residue
was extracted with CH2Cl2. The extract was first washed with distilled water and then with 1N aqueous NaOH and
dried over anhydrous Na2SO4. The solvent was evaporated under vaccum, and the viscous residue was crystallized.
3-(3,4-Methylenedioxyphenyl)-5-phenyl-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-dione
(4a). Mp 188–190°C. IR spectrum, ν, cm−1: 1786, 1719 (>C=O), 930 (C−O). 1H NMR spectrum, δ, ppm (J, Hz): 4.87
(1H, d, J = 9.7, H-3a); 5.61 (1H, d, J = 9.7, H-6a); 6.02 (2H, s, OCH2O); 6.85–7.54 (8H, m, H arom.). Mass spectrum,
m/z: 336 [M]+. Found, %: C 64.51; H 3.43; N 8.39. C18H12N2O5. Calculated, %: C 64.28; H 3.57; N 8.33.
3-(3,4-Methylenedioxyphenyl)-5-(4-tolyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo-[3,4-d]isoxazoline-
1
4,6-dione (4b). Mp 193–195°C. IR spectrum, ν, cm−1: 1784, 1718 (>C=O), 929 (C−O). H NMR spectrum, δ,
ppm (J, Hz): 2.29 (3H, s, CH3); 4.93 (1H, d, J = 9.8, H-3a); 5.68 (1H, d, J = 9.8, H-6a); 6.01 (2H, s, OCH2O);
6.84–7.35 (7H, m, H arom.). Mass spectrum, m/z: 349 [M]+. Found, %: C 65.20; H 4.03; N 8.08. C19H14N2O5.
Calculated, %: C 65.14; H 4.00; N 8.00.
5-(4-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazo-
line-4,6-dione (4c). Mp 195–197°C. IR spectrum, ν, cm−1: 1784, 1721 (>C=O), 928 (C−O). 1H NMR spectrum,
δ, ppm (J, Hz): 3.85 (3H, s, OCH3); 4.81 (1H, d, J = 9.7, H-3a); 5.59 (1H, d, J = 9.7, H-6a); 6.02 (2H, s,
OCH2O); 6.89–7.84 (7H, m, H arom.). Mass spectrum, m/z: 365 [M]+. Found, %: C 62.10; H 3.92; N 7.53.
C19H14N2O6. Calculated, %: C 62.29; H 3.82; N 7.65.
5-(4-Ethoxyphenyl)-3-(3,4-methylenedioxyphenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazo-
line-4,6-dione (4d). Mp 191–192°C. IR spectrum, ν, cm−1: 1779, 1718 (>C=O), 929 (C−O). 1H NMR spectrum,
δ, ppm (J, Hz): 1.42 (3H, t, J = 9.3, OCH2CH3); 4.05 (2H, q, J = 9.2, OCH2CH3); 4.82 (1H, d, J = 9.7, H-3a); 5.62
(1H, d, J = 9.7, H-6a); 6.02 (2H, s, OCH2O); 6.89–8.69 (7H, m, H arom.). Mass spectrum, m/z: 369 [M]+. Found,
%: C 63.21; H 4.27; N 7.21. C20H16N2O6. Calculated, %: C 63.15; H 4.21; N 7.36.
5-(4-Chlorophenyl)-3-(3,4-methylenedioxyphenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazo-
line-4,6-dione (4e). Mp 198–201°C. IR spectrum, ν, cm−1: 1780, 1720 (>C=O), 929 (C−O). 1H NMR spectrum, δ, ppm
(J, Hz): 4.89 (1H, d, J = 9.2, H-3a); 5.66 (1H, d, J = 9.2, H-6a); 6.02 (2H, s, OCH2O); 6.84–7.99 (7H, m, arom.). Mass
spectrum, m/z: 370 [M]+. Found: C 58.01; H 2.82; N 7.43. C18H11ClN2O5. Calculated, %: C 58.29; H 2.96; N 7.55.
3-(3,4-Methylenedioxyphenyl)-5-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazo-
line-4,6-dione (4f). Mp 196–199°C. IR spectrum, ν, cm−1: 1780, 1732 (>C=O), 931 (C−O). 1H NMR spectrum, δ,
ppm (J, Hz): 4.90 (1H, d, J = 9.7, H-3a); 5.68 (1H, d, J = 9.7, H-6a); 6.02 (2H, s, OCH2O); 6.85–8.01 (7H, m,
H arom.). Mass spectrum, m/z: 381 [M]+. Found, %: C 56.20; H 2.73; N 11.07. C18H11N3O7. Calculated, %:
C 56.69; H 2.88; N 11.02.
5-Benzyl-3-(3,4-methylenedioxyphenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-
1
4,6-dione (4g). Mp 186–188°C. IR spectrum, ν, cm−1: 1780, 1721 (>C=O), 929 (C−O). H NMR spectrum, δ,
ppm (J, Hz): 4.59 (2H, s, CH2 benzyl); 4.85 (1H, d, J = 9.4, H-3a); 5.66 (1H, d, J = 9.4, H-6a); 6.01 (2H, s, 2H,
OCH2O); 6.93–7.41 (8H, m, H arom.). Mass spectrum, m/z: 350 [M]+. Found, %: C 65.01; H 3.97; N 7.95.
C19H14N2O5. Calculated, %: C 65.14; H 4.00; N 8.00.
3-(3-Nitrophenyl)-5-phenyl-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-dione (5a).
Mp 240°C. IR spectrum, ν, cm−1: 1790, 1718 (>C=O). 1H NMR spectrum, δ, ppm (J, Hz): 4.81 (1H, d, J = 9.2,
H-3a); 5.67 (1H, d, J = 9.2, H-6a); 7.21–7.45 (9H, m, H arom.). Mass spectrum, m/z: 337 [M]+. Found, %:
C 60.53; H 3.10; N 12.51. C17H11N3O5. Calculated, %: C 60.21; H 3.26; N 12.46.
3-(3-Nitrophenyl)-5-(4-tolyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-dione (5b).
1
Mp 180–182°C. IR spectrum, ν, cm−1; 1795, 1717 (>C=O). H NMR spectrum, δ, ppm (J, Hz): 2.37 (3H, s,
CH3); 4.98 (1H, d, J = 9.7, H-3a); 5.72 (1H, d, J = 9.7, H-6a); 7.11–8.93 (8H, m, H arom.). Mass spectrum, m/z:
351 [M]+. Found, %: C 61.62; H 3.62; N 11.81. C18H13N3O5. Calculated, %: C 61.53; H 3.70; N 11.96.
363

5-(4-Methoxyphenyl)-3-(3-nitrophenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-
4,6-dione (5c). Mp 203–205°C. IR spectrum, ν, cm−1: 1780, 1720 (>C=O). 1H NMR spectrum, δ, ppm (J, Hz): 3.93,
(3H, s, OCH3); 5.06 (1H, d, J = 9.7, H-3a); 5.68 (1H, d, J = 9.7, H-6a); 7.01–8.27 (8H, m, H arom.). Mass spectrum,
m/z: 367 [M]+. Found, %: C 57.01; H 3.68; N 11.56.C18H13N3O6. Calculated, %: C 56.69; H 3.54; N 11.44.
5-(Ethoxyphenyl)-3-(3-nitrophenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-dione
(5d). Mp 195–198°C. IR spectrum, ν, cm−1: 1772, 1720 (>C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.41 (3H, t,
J = 9.3, OCH2CH3); 4.06 (2H, q, J = 9.3, OCH2CH3); 4.91 (1H, d, J = 9.3, H-3a); 5.67 (1H, d, J = 9.3, H-6a);
6.95–8.73 (8H, m, H arom.). Mass spectrum, m/z (Irel): 381 [M]+. Found, %: C 59.50; H 3.76; N 11.08.
C19H15N3O6. Calculated, % C 59.84; H 3.93; N 11.02.
5-(4-Chlorophenyl)-3-(3-nitrophenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-dione
(5e). Mp 207–209°C. IR spectrum, ν, cm−1: 1780, 1724 (>C=O). 1H NMR spectrum, δ, ppm (J, Hz): 4.89 (1H, d,
J = 9.4, H-3a); 5.58 (1H, d, J = 9.4, H-6a); 7.04–8.15 (8H, m, H arom.). Mass spectrum, m/z: 371 (35Cl) [M]+.
Found, %: C 54.68; H 2.81; N 11.38. C17H10ClN3O5. Calculated, %: C 54.91; H 2.69; N 11.30.
3-(3-Nitrophenyl)-5-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-dione
(5f). Mp 229–231°C. IR spectrum, ν, cm−1: 1789, 1720 (>C=O). 1H NMR spectrum, δ, ppm (J, Hz): 4.91 (1H, d,
J = 9.45, H-3a); 5.67 (1H, d, J = 9.45, H-6a); 6.91–8.02 (8H, m, H arom.). Mass spectrum, m/z: 382 [M]+. Found,
%: C 53.21; H 2.50; N 18.67. C17H10N5O7. Calculated, %: C 53.40; H 2.61; N 18.32.
5-Benzyl-3-(3-nitrophenyl)-3a,4,6,6a-tetrahydro-4H,6H-pyrrolo[3,4-d]isoxazoline-4,6-dione (5g).
Mp 203–205°C. IR spectrum, ν, cm−1: 1765, 1709 (>C=O). 1H NMR spectrum, δ, ppm (J, Hz): 4.59 (2H, s, CH2);
5.20 (1H, d, J = 9.7, H-3a); 5.66 (1H, d, J = 9.7, H-6a); 7.28–8.82 (9H, m, H arom.). Mass spectrum, m/z: 352
[M]+. Found: C 61.20; H 3.68; N 11.72. C18H13N3O5. Calculated, %: C 61.53; H 3.70; N 11.96.
The authors thank the Department of Chemistry, Punjabi University, Patiala for providing research
facilities.
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