A novel cyclization to isoxazolo[3,4-e][2,1]benzisoxazole

Article abstract of DOI:10.1016/S0040-4039(02)00496-3

Methylation of 2,1-benzisoxazole 4,5-dione 4-oxime 2 using dimethyl sulfate in DMF and in the presence of potassium carbonate gave a substantial yield of isoxazolo[3,4-e][2,1]benzisoxazole 4 by an unexpected cyclization reaction of the O-methylation product 3.

Full text of DOI:10.1016/S0040-4039(02)00496-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3449–3451
A novel cyclization to isoxazolo[3,4-e][2,1]benzisoxazole
Alan R. Katritzky,* Zuoquan Wang, C. Dennis Hall, Yu Ji and Novruz G. Akhmedov
Center for Heterocyclic Chemistry, Department of Chemistry, The University of Florida, P.O. Box 117200, Gainesville,
FL 32611-7200, USA
Received 22 January 2002; accepted 8 February 2002
Abstract—Methylation of 2,1-benzisoxazole 4,5-dione 4-oxime 2 using dimethyl sulfate in DMF and in the presence of potassium
carbonate gave a substantial yield of isoxazolo[3,4-e][2,1]benzisoxazole 4 by an unexpected cyclization reaction of the O-methyla-
tion product 3. © 2002 Elsevier Science Ltd. All rights reserved.
The Boulton–Katritzky rearrangement (BKR) general-
ized in Scheme 1 has received considerable attention
from both experimental and theoretical standpoints.1a,1b
The rearrangement occurs with a wide variety of N-, O-
and S-containing heterocycles the prototype of which is
4-nitrobenzofuroxan 1 which rearranges to an identical
molecule probably via the transition state shown in
Scheme 2 according to calculations at the MP4(SDQ)/
6-31G* level.2
alkoxy or dialkylamino group) attached to the 5-posi-
tion of 4-nitroso-2,1-benzisoxazole, such a rearrange-
ment might be energetically possible through
deprotonation of the isoxazole ring. During an experi-
mental program designed to test the theoretical predic-
tions we synthesized 2 obtained as the keto-oximino
tautomer via the route shown in Scheme 3.
It was hoped that methylation of 2 would give 5-
methoxy-4-nitroso-2,1-benzisoxazole as a suitable pre-
cursor to attempt a base-catalyzed BKR but in fact the
reaction gave a mixture of 3 (5%) and 4 (32%). The
products were readily separated by chromatography on
silica gel and characterized by MS, elemental analysis
The common feature of all these rearrangements is a
pivotal nitrogen atom that probably suffers minimal
change in geometry during the molecular transition.
Recently the possibility of using carbon as the pivotal
atom in a BKR has been considered theoretically3 and
it was concluded that with suitable substituents (e.g. an
1
and H/13C NMR.
The cyclized product 4 was particularly intriguing since
it appeared to be derived from 3 probably by the
mechanism shown in Scheme 3. Convincing evidence to
support this hypothesis was provided by heating a
sample of pure 3 in DMF at 55°C for 1 h in the
presence of anhydrous potassium carbonate. All the
starting material was consumed and compound 4 was
separated from the reaction mixture as the only isolable
product. To the best of our knowledge there is no
reported precedent for this cyclization. Apart from
B
A
F
E
F
E
N
B
N
A
A, E = N, N+-O-, N+-N-R or C-R
B, F = O, NR, S
Scheme 1.
O
O-
N+
N
O
N+
Oδ-
N+
N
O-
N+
Oδ-
N+
N
N+
O-
-O
Oδ-
δ-O
O
O
TS1
1
Scheme 2.
Keywords: 2,1-benzisoxazole; cyclization; Boulton–Katritzky rearrangement.
* Corresponding author. E-mail: katritzky@chem.ufl.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00496-3

3450
A. R. Katritzky et al. / Tetrahedron Letters 43 (2002) 3449–3451
References
1. (a) Boulton, A. J.; Ghosh, P. B.; Katritzky, A. R. Angew.
Chem., Int. Ed. Engl. 1964, 3, 693; (b) Katritzky, A. R.;
Gordeev, M. F. Heterocycles 1993, 35, 483.
2. Eckert, F.; Rauhut, G. J. Am. Chem. Soc. 1998, 120,
13478.
3. Rauhut, G. J. Org. Chem. 2001, 66, 5444.
4. Skiles, J. W.; Cava, M. P. J. Org. Chem. 1979, 44, 409.
5. Phillips, B. T.; Hartman, G. D. J. Heterocycl. Chem. 1986,
23, 897.
6. Vogel, A. Textbook of Practical Organic Chemistry, 4th
ed.; Longman: London and New York, 1978; p. 677.
7. Methyl 3-formylphenyl carbonate, methyl 3-formyl-4-
nitrophenyl carbonate, B, and 2-nitro-5-hydroxybenzalde-
hyde, C, were prepared from 3-hydroxybenzaldehyde, A,
using procedures described in Ref. 4. Methyl 3-
formylphenyl carbonate was obtained in 66% yield as color-
less crystals, mp 47–49°C; 1H NMR (300 MHz, CDCl3):
l=3.94 (s, 3H), 7.46 (dd, J=8.1, 1.0 Hz, 1H, H-6), 7.57 (t,
J=7.8 Hz, 1H, H-5), 7.72 (d, J=0.7 Hz, 1H, H-2), 7.79
(dd, J=7.7, 1.0 Hz, 1H, H-4), 10.01 (s, 1H); 13C NMR (75
MHz, CDCl3) l=55.6, 121.7, 127.1, 127.4, 130.2, 137.8,
151.6, 153.9, 190.9. Anal. Calcd for C9H8O4: C, 60.00; H,
4.48. Found: C, 59.75; H, 4.49.
Scheme 3. (i) ClCO2Me, pyridine; (ii) fuming HNO3, conc.
H2SO4; (iii) 10% aqueous NaOH; (iv) SnCl2·H2O, conc. HCl,
10–15°C; (v) NaNO2, HCl, 0–5°C; (vi) Me2SO4, DMF,
K2CO3, 55–60°C.
Methyl 3-formyl-4-nitrophenyl carbonate B, was obtained
1
in 95% yield as purple prisms, mp 76–78°C; H NMR (300
MHz, CDCl3): l=3.97 (s, 3H), 7.60 (dd, J=8.8, 2.6 Hz,
1H, H-6), 7.76 (d, J=2.6 Hz, 1H, H-2), 8.21 (d, J=8.8 Hz,
1H, H-5), 10.43 (s, 1H); 13C NMR (75 MHz, CDCl3) l,
56.1, 121.9, 125.7, 126.6, 133.2, 146.4, 152.8, 154.8, 186.9.
Anal. Calcd for C9H7NO6: C, 48.01; H, 3.13; N, 6.22.
Found: C, 48.07; H, 3.07; N, 6.09.
2-Nitro-5-hydroxybenzaldehyde C, was obtained in 92%
yield as yellow needles, mp 167–169°C, [lit. mp 167–
168°C4]; 1H NMR (300 MHz, DMSO-d6): l=5.24 (brs,
1H), 6.92 (s, 1H, H-6), 6.97 (d, J=8.9 Hz, 1H, H-4), 8.07
(d, J=8.9 Hz, 1H, H-3), 10.28 (s, 1H); 13C NMR (75
MHz, DMSO-d6) l=115.3, 119.6, 127.9, 135.7, 138.2,
166.5, 190.7.
5-Hydroxy-2,1-benzisoxazole D, was obtained in 90% yield
as colorless prisms, mp 150–152°C by the procedure
detailed in Ref. 5. 1H NMR (300 MHz, DMSO-d6): l=
6.74 (s, 1H, H-4), 7.07 (d, J=9.5 Hz, 1H, H-6), 7.57 (d,
J=9.5, Hz, 1H, H-7), 9.42 (s, 1H, H-3), 9.85 (s, 1H); 13C
NMR (75 MHz, DMSO-d6) l=96.0, 115.9, 118.5, 128.2,
153.0, 153.3, 153.4. Anal. Calcd for C7H5NO2: C, 62.22;
H, 3.73; N, 10.37. Found: C, 62.32; H, 3.73; N, 10.16.
2,1-Benzisoxazole-4,5-dione 4-oxime 2 was obtained in
100% yield as a grey-brown powder, mp 228–229°C (d) by
the method outlined in Ref. 6. 1H NMR (300 MHz,
DMSO-d6): l=6.64 (d, J=10.0 Hz, 1H, H-7), 7.89 (d,
J=10.0 Hz, 1H, H-6), 9.70 (s, 1H, H-3), 14.12 (s, 1H,
NOH); 13C NMR (75 MHz, DMSO-d6) l=108.2, 130.3,
134.8, 140.9, 154.1, 161.3, 181.7. Anal. Calcd for
C7H4N2O3: C, 51.23; H, 2.46. Found: C, 51.58; H, 2.61.
elemental analysis and HRMS, 4 was characterized by
some unusual NMR features. In CDCl3 just three pro-
ton signals with no fine structure were observed at 9.43,
8.19, and 7.65 ppm in a ratio of 1:1:2, respectively. In
toluene-d8 however, four signals were observed at 8.53
3
(d, J=1.05 Hz, 1H), 7.19 (s, 1H), 7.12 (dd, J=9.6 Hz,
4J=1.05 Hz, 1H) and 6.80 ppm (d, J=9.6 Hz, 1H),
which were assigned to protons c, b, d, and a, respec-
tively. Selective homonuclear decoupling at 6.80 ppm
collapsed proton b to a doublet (Jꢀ1 Hz) and selective
decoupling at 7.12 ppm collapsed protons a and c to
singlets consistent with the proposed structure. Pre-
sumably an intermolecular complex with the solvent
1
toluene promoted separation of the H NMR signals.
The 13C NMR in CDCl3 showed eight signals again
1
consistent with 4 and H–13C COSY correlation spectra
enabled the final carbon assignments to be made.
In conclusion, although the original objectives of the
project are still to be realized, a novel cyclization has
been established involving formation of a carbon–car-
bon bond which may well afford a new route to deriva-
tives of 2,1-benzisoxazoles through o-nitroso phenols or
their keto-oxime tautomers.
2,1-Benzisoxazole-4,5-dione-4-(O-methyloxime)
3
and
isoxazolo[3,4-e][2,1]benzisoxazole 4 were obtained as a
mixture by methylation of 2 using the procedure outlined
in Ref. 4. A mixture of 2 (1.0 g, 6.09 mmol), anhydrous
potassium carbonate (1.57 g, 11.36 mmol), dimethyl sul-
fate (1.28 g, 10.18 mmol) and dry DMF (42 mL) was
heated with stirring at 54–60°C for 3 h under argon. The
Acknowledgements
We are grateful to Dr. Guntram Rauhut for valuable
discussion on the theoretical aspects of this work.

A. R. Katritzky et al. / Tetrahedron Letters 43 (2002) 3449–3451
3451
mixture was cooled to 20°C and water (70 mL) was added
slowly with stirring. The mixture was extracted with Et2O
(3×50 ml) and the combined ether extracts dried over
anhydrous MgSO4. The solvent was evaporated and the
residue was purified by column chromatography (hexanes/
ethyl acetate, 6/1–3/1) to afford pure 3 as the first fraction
(0.05 g, 5%) and 4 as the second fraction (0.31 g, 32%).
2,1-Benzisoxazole-4,5-dione-4-(O-methyloxime) 3, color-
(s, 1H), 8.53 (d, J=1.0 Hz, 1H), which were assigned to
protons a, d, b and c, respectively (see Scheme 3). 13C
NMR (75 MHz, CDCl3): l=111.9, 113.9, 118.0, 129.7,
146.8, 152.1, 152.3, 156.2. LSIMS, Calcd for C8H5N2O2
(M+1)=161.0351. Found: 161.0360. Anal. Calcd for
C8H4N2O2: C, 60.01; H, 2.52; N, 17.49. Found: C, 59.61;
H, 2.35; N, 17.10.
Conversion of 3 to 4
1
A mixture of 2,1-benzisoxazole-4,5-dione 4-(O-methyl-
oxime) 3 (0.1 g, 0.56 mmol), anhydrous potassium carbon-
ate (0.134 g, 0.94 mmol) and dry DMF (3 mL) was stirred
at 54–57°C for 1 h under nitrogen. DMF was evaporated
under reduced pressure. The residue was purified by
column chromatography on silica gel using hexanes/ethyl
acetate (6:1, v/v) as eluent to afford isoxazolo[3,4-
e][2,1]benzisoxazole 4 (0.045 g, 0.28 mmol) as the only
isolable product in 50% yield.
less powder, mp 164–165°C; H NMR (300 MHz, CDCl3):
l=4.30 (s, 3H), 6.64 (d, J=10.4 Hz, 1H, H-7), 7.43 (d,
J=10.4 Hz, 1H, H-6), 9.31 (s, 1H, H-3); 13C NMR (75
MHz, CDCl3): l=64.5, 109.3, 131.6, 139.5, 141.6, 153.1,
161.0, 178.2. LSIMS, Calcd for C8H7N2O3 (M+1):
179.0457. Found: 179.0451.
Isoxazolo[3,4-e][2,1]benzisoxazole 4, colorless powder, mp
1
155–157°C; H NMR, (300 MHz, toluene-d8): l=6.80 (d,
J=9.6 Hz, 1H), 7.12 (dd, 3J=9.6 Hz, 4J=1.0 Hz, 1H) 7.19