Synthesis and photoreactivity of some 5-alkylidene- and 5-alkylidenamine-2,5-dihydroisoxazoles

Article abstract of DOI:10.1016/j.tetlet.2007.11.195

5-Alkylidene-2,5-dihydroisoxazoles and 5-alkylidenamine-2,5-dihydroisoxazoles were easily prepared from the corresponding 5-chloro-2-methylisoxazolium triflate and an enolizable compound or alkylamine. Their photochemical reactivity leads to photoisomers

Full text of DOI:10.1016/j.tetlet.2007.11.195

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Tetrahedron Letters 49 (2008) 764–767
Synthesis and photoreactivity of some 5-alkylidene- and
5-alkylidenamine-2,5-dihydroisoxazoles
D. Donati, S. Fusi *, F. Ponticelli, R. Rossi Paccani
`
Dipartimento di Chimica, Universita degli Studi di Siena, 53100 Siena, Italy
Received 6 November 2007; revised 27 November 2007; accepted 30 November 2007
Available online 4 December 2007
Abstract
5-Alkylidene-2,5-dihydroisoxazoles and 5-alkylidenamine-2,5-dihydroisoxazoles were easily prepared from the corresponding
5-chloro-2-methylisoxazolium triflate and an enolizable compound or alkylamine. Their photochemical reactivity leads to photoisomers
that in some cases constitute new heterocycles systems. The photorearrangement involves either triplet or singlet state depending on
substituents and experimental conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Isoxazole; Photochemistry; Singlet and triplet state; Triplet sensitizers
The isomerization of heterocycles is an important area
of organic photochemistry1 and, amongst the heterocycles,
the isoxazolic system is one of the most widely studied.2
These photoisomerizations involve different intermediates,3
which show a number of interesting reactions. The 2H-iso-
xazol-5-ylidene system is a heterocyclic ring analogous to
isoxazole but was scarcely considered. The few studies
reported in the literature on these products go back to
the early 70s4 and more recently a single example of
the reactivity of 2,5-dihydroisoxazolonic systems5 was
reported.
In recent years, we found a convenient procedure for the
synthesis of a series of 5-alkylidene-2,5-dihydroisoxazoles6
and we studied their photochemical behaviour. These com-
pounds photoisomerized to b-lactam and/or c-dihydro-
lactone systems depending on the substituents on the
exocyclic double bond. A cyclopropanone intermediate
accounted for all products so far obtained (Scheme 1).
Recently we synthetized compound 1a,7 which unex-
pectedly showed a different photoreactivity in respect to
that already known.6 Irradiation under the usual experi-
mental conditions8 gave only the spiro-photoisomer 2a8
(Scheme 2), hardly justifiable on the basis of a cyclopropa-
none intermediate.
The structure of 2a was determined by X-ray diffracto-
metric analysis (Fig. 1).
This result prompted us to carry out a wider survey on
the photoisomerization of such systems, and we planned
to extend our studies towards 2H-isoxazol-5-yliden systems
bearing an exocyclic C@N double bond.
First of all, we devised a general method for the synthe-
sis for the 2H-isoxazol-5-ylidenamine derivatives. Treat-
ment of the corresponding 5-chloro-2-methylisoxazolium
triflate6a with amines led to substitution products
which, in turn, were deprotonated in the presence of alkox-
ide yielding the (2H-isoxazol-5-ylidene)-alkylamines 1b–d9
(Scheme 3).
Irradiation of 1b–d10 in CH3CN resulted in the forma-
tion of the products reported in Scheme 4.
Irradiation of a solution of 1b in CH3CN yielded both
the imidazolonic and pyrazolonic derivatives 2b11 and
3b,12 whereas under the same experimental conditions 1c
and 1d yielded only the corresponding imidazolones 2c11
and 2d.
Following the irradiation of 1b10a in CD3CN by 1H
NMR, we noticed that the ratio 2b/3b was changing in
*
Corresponding author. Tel.: +39 0577 234273; fax: +39 0577 234254.
E-mail address: fusiste@unisi.it (S. Fusi).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.195

D. Donati et al. / Tetrahedron Letters 49 (2008) 764–767
765
R2
R1
Me
O
Ph
N
O
Ph
Ph
Me
Me
Me
Me
R1
COR2
CH CN
hν,
3
N
R1
Me N
O
R2
O
R1
Me
R2
O
O
Ph
O
N
Me
Scheme 1.
O
N
R
R'
R
R'
O
R
R'
O
Ph
Me
Me
hν
CH3CN
Me
Ph
+
hν
Me
N
N Me
Me
N
O
Me
N
N
Me
N
Me
N
O
O
CH3CN
O
Me O
O
1b-d
2b-d
3b
2a
1a
R
R'
Scheme 2.
Ph
Me
Me
Me
Ph
CO2Et
1b
1c
1d
Scheme 4.
Experiments of sensitization clarified the multiplicity of
the states involved and suggested an explanation for the
time dependent ratio of the concentrations of 2b/3b. Irradi-
ation of 1b10b in the presence of acetophenone, a typical
triplet state sensitizer, gave only pyrazolone 3b, whereas
Fig. 1. ORTEP drawing of compound 2a with 20% probability thermal
ellipsoids (CCDC 632412).
O
Ph
Me
Me
Me
Ph
CN
CN
CN
CN
CH CN
R
R'
NHMe
hν,
3
R
R'
N
CF3SO3
Me
CF3SO3
O
N
:
NH2Me
benzophenone
HCl +
Me
N
N
Cl
O
Me
2e
O
NaOEt
R'
1e
R
Scheme 5.
Me
N
N
R
R'
O
Me
1b-d
Ph
Me
Me
Me
Ph
CO2Et
1b
1c
1d
Scheme 3.
time, in particular the amount of 3b increases after a long
induction period, starting to rise when the amount of 2b
is near its maximum and reaching roughly a 1/1 ratio at
the end of the reaction. The hypothesis that 3b could derive
from 2b has been discarded: in fact the irradiation of the
imidazolonic derivative does not lead to 3b, but only to
an unidentified mixture of degradation products.
Fig. 2. ORTEP drawing of compound 2e with 20% probability thermal
ellipsoids (CCDC 632412).

766
D. Donati et al. / Tetrahedron Letters 49 (2008) 764–767
Me
Ph
Me
N
Ph
Me
Me
N
Ph
Me
Me
Ph
h
ν
N
Me
Me
N
N
N
N Me
N
O
O
Me
Me
Me
O
O
2b
1b
Scheme 6.
O
Me
Me
Ph
Ph
Me N
Me
Z
Ph
h
ν
Z
Me
N
Z
N
O
O
Me
2a,e,b
1a,e,b
O
CN
CN
1a
Z=
1e
Z=
1b
Z=
N
Me
O
Scheme 7.
irradiation in the presence of piperylene,10c a typical triplet
quencher, gave only imidazolone 2b. The induction period
is so explained supposing that 2b, initially formed via sin-
glet state, behaves as triplet sensitizer for 3b. Experimen-
tally an increase in the rate of formation of 3b was
observed when the irradiation of 1b was performed in the
presence of 2b since the beginning. But also the presence
of a pyrazolonic system itself sensitizes the reaction
towards the formation of 3b. In fact, irradiating 1b in the
presence of 1,2-hexadeuteromethyl-4-methyl-5-phenyl-1,2-
dihydro-pyrazol-3-one13 and monitoring the yield of non-
When these rearrangements are not possible, as in the
case of substrate 1e, no opening products were isolated.
On the other hand the triplet state, populated by either
intersystem crossing (cases 1a,b) or sensitization (1b,e),
evolves to new products formally derived from rotation
of the C4–C5 bond and ring closure by N–N or C–N bond
formation (Scheme 7).
In summary we have described a simple and general
method for the synthesis of a series of 2,5-dihydroisoxaz-
oles bearing a C@C or C@N exocyclic double bond in posi-
tion 5 and we have studied their photochemical reactivity.
From the mechanistic point of view, two different pathways
arising from states of different multiplicity are possible.
State-switching is attainable by changing the nature of
the substituents on the exocyclic double bond and/or by
using quenchers or sensitizers. In this way it is possible to
direct the reactions to the required products obtaining
cleanly new heterocycles from easily accessible materials.
1
deuterated 3b by H NMR, we observed the lack of the
induction period and the yield of 3b greater than 2b since
the beginning of irradiation.
Similar sensitization experiments are difficult to realize
on the alkylidene isoxazole system, owing to the overlap
of the absorption bands. However, a strong indication that
an analogous mechanism is operating was obtained by irra-
diating the dinitrile derivative 1e.7 Irradiation of 1e in
CH3CN did not yield any characterizable product, but in
the presence of benzophenone14 as sensitizer, pyrrolidone
2e14 was obtained in good yield (Scheme 5).
References and notes
1. Grunanger, P. The Chemistry of Heterocycles. In Isoxazoles; Wiley,
John & Sons: New York, 1991; Vol. 49, p 12.
The structure of 2e was determined by X-ray diffracto-
metric analysis (Fig. 2).
2. Singh, B.; Ulmann, E. F. J. Am. Chem. Soc. 1967, 89, 6911–6916.
3. (a) Ferris, J. P.; Trimmer, R. W. J. Org. Chem. 1976, 41, 13–19; (b)
Padwa, A.; Chen, E.; Ku, A. J. Am. Chem. Soc. 1975, 97, 6484–6491.
4. (a) Aurich, H. G.; Blinde, G. Chem. Ber. 1974, 107, 13–23; (b) Aurich,
H. G.; Blinde, G. Liebigs Ann. Chem. 1972, 762, 154–159.
5. Kian Ang, H.; Prager, R. H. Tetrahedron Lett. 1992, 33, 2845–2846.
6. (a) Donati, D.; Fusi, S.; Ponticelli, F. Tetrahedron Lett. 2003, 44,
9247–9250; (b) Donati, D.; Fusi, S.; Ponticelli, F.; Rossi Paccani, R.;
Adamo, M. F. A. Tetrahedron 2007, 63, 1583–1588.
The data obtained allowed us to rationalize the path-
ways of photoisomerization, both for the 5-alkylidene
and 5-alkylidenamine-2,5-dihydroisoxazole as summarized
in Schemes 6 (singlet pathway) and 7 (triplet pathway).
In the case of alkyliden amine derivatives the aziridinone
intermediate arises from a singlet state and rearranges to
the imidazolonic system (Scheme 6) in analogy to the corres-
ponding pathway reported in Scheme 1 for alkylidene-2,5-
dihydroisoxazole.
7. Synthesis of products 1a,e: To a stirred solution of compound with
easy deprotonable CH2 [malononitrile (3 mmol) or 1,3-indandione
(3 mmol)] in anhydrous benzene (15 mL) were sequentially added

D. Donati et al. / Tetrahedron Letters 49 (2008) 764–767
767
NaH 60% in oil (3 mmol) and dry Et3N (3 mmol). To this suspension
was then slowly added 5-chloro-2,4-dimethyl-3-phenylisoxazol-2-ium
trifluoromethanesulfonate (3 mmol) and the resulting yellow solution
stirred for 1 h. After this time the reaction mixture was concentrated
in vacuo and the residue treated with water (20 mL) and extracted
with CH2Cl2 (2 ꢀ 15 mL). The organic layer was dried over Na2SO4,
the solvent evaporated and the resulting oil purified by column
chromatography (eluent CH2Cl2/CH3OH 98:2 for compound 1e and
ethyl acetate/CH3OH 95:5 for compound 1a).
Experimental data: melting points were measured with a Kofler
apparatus and are uncorrected. The 1H and 13C NMR spectra were
recorded for solution in CDCl3, save otherwise stated, with a Bruker
AC200 instrument operating at 200.13 MHz for 1H and at 50.33 MHz
for 13C. ESI-MS spectra were recorded with a LCQ-DECA Thermo
Finnigan instrument, and EI-MS spectra were obtained with a VG70
250S instrument. TLC was performed on precoated 4 ꢀ 6.7 cm silica
gel 60 F254 plates silica gel (Aldrich) with detection by UV light.
Column chromatography was carried out on Silica gel (E. Merck,
0.040–0.063 mm). Irradiation was performed with a Rayonet appa-
ratus (MLU18) operating at 365 nm, with a 900 W irradiator, f/3.4
monochromator (Applied Photophysics) apparatus or with a low
pressure mercury lamp (253.7 nm). All irradiations were carried out in
CH3CN in the presence of activated molecular sieves (0.4 nm, 100–
150 mg). At the end of the irradiations the molecular sieves were
decanted and washed with a further CH3CN (10 mL).
NMR d: 2.10 (s, 3H, 3-CH3), 3.11, 3.17 (s, 3H, C@NCH3/NCH3), 7.45
(m, 5H, Ph); 13C NMR d: 11.01 (3-CH3), 33.61, 40.40 (C@NCH3/
NCH3), 109.30 (C3), 127.30, 128.28, 129.78, 131.90 (Ph), 155.89, 161.00
(C4/C5); EI-MS, m/z: 202 (M+), 185, 173. Anal. Calcd for C12H14N2O:
C, 71.26; H, 6.98; N, 13.85. Found: C, 71.41; H, 6.95; N, 13.88.
(2,3-Dimethyl-4-carbethoxy-2H-isoxazol-5-ylidene)-methylamine (1d):
oil (65% yield); 1H NMR d: 1.34 (t, 3H, J = 7.2 Hz, CH2CH3), 2.42 (s,
3H, 3-CH3), 3.05, 3.52 (s, 3H, NCH3/C@NCH3), 4.30 (q, 2H,
J = 7.2 Hz, CH2CH3); 13C NMR d: 12.23 (CH2CH3), 14.26 (3-CH3),
32.73, 36.76 (C@NCH3/NCH3), 60.58 (CH2CH3), 93.07 (C4), 159.30,
160.93, 162.76 (C@N/C@O/C3); EI-MS, m/z: 198 (M+), 184, 170, 153.
Anal. Calcd for C9H14N2O3: C, 54.53; H, 7.12; N, 14.13. Found: C,
54.30; H, 7.09; N, 14.18.
10. Procedures for the irradiation of 1b–d: (a) a solution of 1b–d (2 mmol)
in anhydrous CH3CN (10 mL) was irradiated for 3 h in a quartz tube
at 254 nm. After this time the solvent was removed in vacuo. The
crude reaction mixture obtained was purified by column chromatog-
raphy (CHCl3/CH3OH 98:2) to give pure compounds 2b–d and 3b.
1,3,4-trimethyl-5-carbethoxy-1,3-dihydro-imidazol-2-one (2d): white
solid (60% yield), mp 58–62 °C; 1H NMR d: 1.34 (t, 3H, J = 7.3 Hz,
CH2CH3), 2.38 (s, 3H, 4-CH3), 3.24, 3.47 (s, 3H, 3-NCH3/1-NCH3),
7.20-7.50 (m, 5H, Ph); 13C NMR d: 10.50 (CH2CH3), 13.69 (4-CH3),
26.81, 29.29 (3-NCH3/1-NCH3), 54.47 (CH2CH3), 109.71 (C4), 130.45
(C5), 152.31 (C2), 159.90 (CO); EI-MS, m/z: 198 (M+), 184, 170, 153.
Anal. Calcd for C9H14N2O3: C, 54.53; H, 7.12; N, 14.13. Found: C,
54.60; H, 7.14; N, 14.17.
2-(2,4-Dimethyl-3-phenylisoxazol-5(2H)-ylidene)-2H-indene-1,3-dione
(1a): yellow-orange solid (65% yield), mp 258–260 °C (ethyl acetate);
1H NMR d: 2.26 (s, 3H, 40-CH3), 3.79 (s, 3H, N–CH3), 7.34–7.56 (m,
(b) A solution of 1b (0.1 mmol) and acetophenone (10 mmol) in
anhydrous CH3CN (3 mL) (sol. a) and at the same time a solution of
1b (0.1 mmol) in anhydrous CH3CN (3 mL) (sol. b) were irradiated
for 10 h in a pyrex tube in a merry go round system, monochromatic
light (365 nm). After this time the solvent was removed in vacuo and
both spectroscopic and chromatographic analyses indicated that in
(sol. a) 3b was present, while in (sol. b) only 1b was present.
13
9H, Ph); C NMR d: 9.52 (40-CH3), 37.97 (N–CH3), 96.87 (C2),
0
108.18 (C4 ), 120.03, 124.18, 128.75, 129.41, 131.60, 131.66, 139.78
0
0
(Ph), 157.71 (C3 ), 170.79 (C5 ), 188.86 (1,3-CO); ESI-MS, m/z: 318
(MꢁH+). Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76; N, 4.41.
Found: C, 75.67; H, 4.78; N, 4.38.
2-(2,4-Dimethyl-3-phenylisoxazol-5(2H)-ylidene)malononitrile (1e):
yellow solid (60% yield), mp 205–207 °C; 1H NMR d: 2.15 (s, 3H,
4-CH3), 3.49 (s, 3H, N–CH3), 7.38–7.60 (m, 5H, Ph); 13C NMR d:
8.01 (4-CH3), 39.40 (N–CH3), 40.72 (C2), 104.37 (C4), 115.52 (CN),
124.47, 128.69, 129.59, 131.86 (Ph), 159.88 (C3), 176.11 (C5); ESI-MS,
m/z: 497 (2MꢁNa+). Anal. Calcd for C14H11N3O: C, 70.87; H, 4.67;
N, 17.71. Found: C, 71.02; H, 4.63; N, 17.79.
(c) A solution of 1b (0.1 mmol) and piperylene (10 mmol) in
anhydrous CH3CN (3 mL) (sol. a) and at the same time a solution
of 1b (0.1 mmol) in anhydrous CH3CN (3 mL) (sol. b) were irradiated
for 12 h in a quartz tube in a merry go round system, monochromatic
light (254 nm). After this time the solvent was removed in vacuo and
both spectroscopic and chromatographic analyses indicated that in
(sol. a) 2b was present, while in (sol. b) both 2b and 3b were present.
11. Holtzmann, G.; Lautenscha¨ger, B.; Konieczny, P. J. Heterocycl.
Chem. 1979, 16, 983–991.
8. 10,40-Dimethyl-50-phenylspiro[indene-2,20-pyrrole]-1,3,30(10H)-trione
(2a): A solution of 1a (1 mmol) in anhydrous CH3CN (40 mL) was
irradiated for 24 h in a pyrex tube. After this time the solvent was
removed in vacuo. The crude reaction obtained was purified by
column chromatography (eluent ethyl acetate/petroleum ether 1:1) to
give starting material (30%) and pure compound 2a, as a yellow solid
12. Adembri, G.; Camparini, A.; Ponticelli, F.; Tedeschi, P. J. Heterocycl.
Chem. 1981, 16, 957–962.
13. Synthesis 1,2-esadeuteromethyl-4-methyl-5-phenyl-1,2-dihydro-pyrazol-
3-one: Ethyl benzoyl propionate (9.0 mmol) and trideuteromethyl
hydrazine (4.5 mmol) were heated to 180 °C for 1 h. After evapora-
tion a small excess of sodium methoxide (10.0 mmol of Na in 5 mL of
CH3OH) and subsequently CD3I (11 mmol) were added, and refluxed
for 1 h. The solvent was evaporated and the resulting mixture
purified by column chromatography (eluent CH2Cl2/CH3OH 95:5) to
give 1,2-esadeuteromethyl-4-methyl-5-phenyl-1,2-dihydro-pyrazol-3-
one, white solid (50% yield), mp 136–138 °C; 1H NMR (CD3CN) d:
1.81 (s, 3H, 4-CH3), 7.20–7.38 (m, 5H, Ph); 13C NMR (CD3CN) d:
7.90 (4-CH3), 107.91 (C4), 128.67, 129.12, 129.56, 129.78 (Ph), 153.85
(C3), 165.99 (C5); EI-MS, m/z: 208 (M+), 193, 179.
14. 1,4-Dimethyl-3-oxo-5-phenyl-1H-pyrrole-2,2(3H)-dicarbonitrile (2e): a
solution of 1e (1 mmol) and benzophenone (10 mmol) in anhydrous
CH3CN (40 mL) was irradiated for 8 h in a pyrex tube at 365 nm.
After this time the solvent was removed in vacuo. The crude reaction
mixture obtained was purified by column chromatography (eluent
ethyl ether/petroleum ether 1:2) to give pure compound 2e, as a red
solid (40% yield), mp 105–107 °C; 1H NMR d: 1.67 (s, 3H, 4-CH3),
3.02 (s, 3H, N–CH3), 7.31–7.60 (m, 5H, Ph); 13C NMR d: 7.84 (4-
CH3), 15.20 (N–CH3), 57.06 (C2), 107.17 (C4), 109.51 (CN), 127.86,
129.32, 129.99, 131.66 (Ph), 177.58 (C5), 182.32 (CO); ESI-MS, m/z:
497 (2MꢁNa+). Anal. Calcd for C14H11N3O: C, 70.87; H, 4.67; N,
17.71. Found: C, 71.02; H, 4.71; N, 17.80.
1
(40% yield), mp 135–138; H NMR d: 1.57 (s, 3H, 40-CH3); 2.81 (s,
3H, N–CH3), 7.49–7.51 (m, 5H, Ph), 7.89–7.85 (m, 2H, Hm), 8.08–
13
8.03 (m, 2H, Ho); C NMR d: 7.52 (40-CH3), 32.32 (N–CH3), 87.25
0
(C2), 105.74 (C4 ), 124.38, 128.34,0 128.76, 129.45, 130.32, 136.05,
0
143.26 (Ph), 178.47 (C5 ), 189.87 (3 -CO), 190.18 (1,3-CO); ESI-MS,
m/z: 340 (MꢁNa+). Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76; N,
4.41. Found: C, 75.72; H, 4.72; N, 4.39.
9. Synthesis of products 1b–d: to a solution of CH3NH2 (2 mmol) in
anhydrous THF was added 2 mmol of the appropriate 5-chloro-2-
methylisoxazolium triflate obtaining a white precipitate. An excess of
sodium ethoxide was added. After evaporation of the solvent the
residual pale yellow solid was treated with chloroform. After filtration
of the white solid, the solvent was evaporated and the final product
purified by sublimation.
(2,4-Dimethyl-3-phenyl-2H-isoxazol-5-ylidene)-methylamine
(1b):
white solid (75% yield), mp 73–76 °C; 1H NMR d: 1.91 (s, 3H, 4-
CH3), 2.92, 3.10 (s, 3H, C@NCH3/2-NCH3), 7.45 (m, 5H, Ph); 13C
NMR d: 6.74 (4-CH3), 30.18, 40.70 (C@NCH3/2-NCH3), 99.44 (C4),
125.05, 128.68, 129.64, 131.90 (Ph), 162.68, 168.84 (C3/C5); EI-MS, m/z:
202 (M+), 185, 173. Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N,
13.85. Found: C, 71.00; H, 7.00; N, 13.91. (2,3-Dimethyl-4-phenyl-2H-
isoxazol-5-ylidene)-methylamine (1c): gummy solid (60% yield); 1H