Trapping of photochemical intermediates as a tool in organic synthesis. Preparation of spiroaziridinopyridones, a new heterocyclic system

Article abstract of DOI:10.1016/S0040-4039(02)02438-3

Whereas alkyl lithium and Grignard reagents both at rt and at -80°C thermally react with 3-methylisoxazolo[5,4-b]pyridine giving alkylation and/or isoxazole ring opening products, sodium malonate and sodium boron hydride react only under UV irradiation. Selective trappings of ketenimine or azirine intermediates give an enaminopyridone or two diasteroisomeric spiroaziridinopirydones. Regioselective opening of the aziridine ring with perchloric acid gives 3(1-amino-ethyl)-1H-pyridin-2-one.

Full text of DOI:10.1016/S0040-4039(02)02438-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9527–9530
Trapping of photochemical intermediates as a tool in organic
synthesis. Preparation of spiroaziridinopyridones, a new
heterocyclic system
Donato Donati, Stefania Fusi and Fabio Ponticelli*
Department of Chemistry, University of Siena, 53100 Siena, Italy
Received 10 October 2002; revised 23 October 2002; accepted 26 October 2002
Abstract—Whereas alkyl lithium and Grignard reagents both at rt and at −80°C thermally react with 3-methylisoxazolo[5,4-
b]pyridine giving alkylation and/or isoxazole ring opening products, sodium malonate and sodium boron hydride react only under
UV irradiation. Selective trappings of ketenimine or azirine intermediates give an enaminopyridone or two diasteroisomeric
spiroaziridinopirydones. Regioselective opening of the aziridine ring with perchloric acid gives 3(1-amino-ethyl)-1H-pyridin-2-one.
© 2002 Elsevier Science Ltd. All rights reserved.
Aromatic isoxazolopyridines are useful synthons for
photochemical access to several pyridino-condensed het-
erocycles. Isothiazolo-, pyrazolo-pyridones and pyrido-
as-triazines can be formed by intramolecular trapping of
the intermediates generated by irradiation of 4-nucle-
ophile-substituted isoxazolopyridines.1 Lifetimes of two
of these intermediates, i.e. spiroazirine and ketenimine,
measured by flash-photolysis experiments on 3-
methylisoxazolo[5,4-b]pyridine in alcohols, are in the
range of milliseconds.2 As a consequence, it is possible
to also perform intermolecular trapping experiments
with suitable nucleophiles, in order to gain more insight
into the mechanistic aspects and to ascertain the synthetic
interest of isoxazolopyridines photoreactivity. To attain
this goal the nucleophile must be thermally unreactive
towards the substrate 1 and, at the same time, good
enough to intercept the photochemical intermediates. In
this view we experimented with some reagents of different
strengths.
i. Alkyl lithium and Grignard reagents. In such a case,
compound 1 reacted in the dark giving different addition
products 2–4 (Scheme 1), depending on the amount of
organometallic compound and on the reaction tempera-
Scheme 1.
Keywords: condensed pyridines; photochemical intermediates trapping; ketenimines; aziridines.
* Corresponding author. E-mail: ponticelli@unisi.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02438-3

9528
D. Donati et al. / Tetrahedron Letters 43 (2002) 9527–9530
ture.3,4 Nucleophilic attack on pyridine ring gave the
anion A which loses a hydride ion to afford 6-
alkylpyridine 2 (path a). When this reaction was carried
out at low temperature (−80°C, path b), 6-alkyl-6,7-
dihydroisoxazolopyridine 3 was obtained by quenching
with water and extraction with ether. It is evident that
nucleophile addition occurs also at low temperature,
whereas the hydride loss is thermally activated. A dif-
ferent result was obtained using an excess of nucle-
ophile. In this case (path c) the N-alkylenamine of
dihydropyridinone 4 was formed as a consequence of
the attack of a second molecule of nucleophile on the
nitrene B, deriving from the (reversible) five-membered
ring opening in the isoxazolopyridine anion A.
tion energy higher than for the corresponding keten-
imine 9.
iii. Sodium borohydride. Also this nucleophile is ther-
mally inert towards 1 and, finally, it is able to trap the
spiroazirine intermediate giving diasteroisomeric
spiroaziridines 11a,b (Scheme 4).5 Such compounds
were the main products when the photorearrangement
was stopped at about 40% advancement. Otherwise,
increasing amounts of the pyridones 74 and 84 (Scheme
3, path c) were also formed by reductive or solvolytic
opening of the oxazole 5. The progressive loss of trap-
ping power of NaBH4 due to decomposition in iso-
propanol is probably involved.
The structure of spiroaziridines 11a,b, a new hetero-
ii. Sodium malonate. This reagent, thermally unreactive
towards the isoxazolopyridine 1, can be used as a
photochemical trapping agent. However, at room tem-
perature, irradiation of 1 in ethanol containing an
excess of sodium ethyl malonate5 gave good yields of
the imines 6a,b4 (Scheme 2, path b), due to thermal
addition6 of the solvent on C-2 of 2-methyloxazolo[5,4-
b]pyridine 5, the main photoproduct of 1 in the absence
of trapping agents.1
1
cyclic system, followed by H and 13C NMR data.4 E
configuration 11a was assigned to the diastereoisomer
which shows NOE increase of the olefin proton at 5.47
ppm by irradiation of the methyl at 1.15 ppm.
It is to be noted that when the irradiation was carried
out with the same reagents but at low temperature
(−80°C),5 formation of compounds 5 and/or 6 was not
observed. The reaction gave, with a very low quantum
yield (after 2 days of irradiation we recovered more
than 80% of the starting material) the N-methyl-
enamine 10.4 This compound was formed (Scheme 3)
by malonate addition on the ketenimine 9, which is the
minor intermediate in the photorearrangements of
isoxazolopyridines.1b
Scheme 3.
The above experiment gives more insight into the mech-
anistic aspect of the isoxazole photochemistry. The
formation of spiroazirine intermediate, the precursor of
oxazole system, is thermally activated, with an activa-
Scheme 2.
Scheme 4.

D. Donati et al. / Tetrahedron Letters 43 (2002) 9527–9530
9529
The importance of aziridines reactivity in modern
organic synthesis is well documented.7 For instance,
regioselective opening of 11a,b in the presence of
perchloric acid8 near quantitatively gave the amine 12
through the more stable carbocation intermediate.9
6-Methyl-3-(1-methylamino-ethylidene)-3,6-dihydro-1H-
pyridin-2-one 4: yield 90%; oil, H NMR (CDCl3) l: 1.19
1
(d, 3H, 6-CH3), 1.94 (s, 3H, CH3), 2.94 (d, 3H, NH-CH3),
4.25 (m, 1H, H6), 4.91 (dt, 1H, H5), 6.19 (dd, 1H, H4), 6.30
(bs, 1H, 1-NH), 9.80 (bs, 1H, NH-CH3); 13C NMR
(CDCl3) l: 13.35 (6-CH3), 24.85 (CH3), 29.99 (NHCH3),
49.83 (C6), 90.78 (C3), 114.08 (C5), 123.28 (C4), 156.90
(C7), 169.23 (C2); MS (EI), m/z: 166 (M+), 165, 151, 134,
122, 120, 106, 92, 65, 56, 42.
N-(2-Oxo-1,2-dihydro-pyridin-3-yl)-acetimidic acid ethyl
ester 6: yield 88%; mp 107–109°C; 1H NMR (CDCl3) l:
1.31 (t, 3H, OCH2 CH3), 1.88 (s, 3H, CH3), 4.26 (q, 2H,
OCH2), 6.20 (t, 1H, H5), 6.84 (dd, 1H, H4), 7.09 (dd, 1H,
H6), 12.82 (bs, 1H, NH); MS (EI), m/z: 180 (M+), 152,
135, 121, 110, 95, 82, 66, 55, 43.
In conclusion, careful choice of the nucleophilic reagent
and of the reaction conditions allowed us to trap the
photochemical intermediates to attain the goal of syn-
thesizing spiroaziridinopyridone compounds 11.
The preliminary knowledge of the properties of inter-
mediates, as lifetimes and activation energy, is manda-
tory to properly design the trapping reactions.
3-Ethylamino-1H-pyridin-2-one 7: yield 95%; mp 125–
127°C; 1H NMR (CDCl3) l: 1.28 (t, 3H, CH3), 3.11 (q,
4H, CH2), 4.75 (m, 1H, NH-CH2), 6.22 (t, 1H, H5), 6.28
(dd, 1H, H4), 6.68 (dd, 1H, H6), 12.43 (bs, 1H, NH). 13C
NMR (CDCl3) l: 14.17 (CH3), 37.61 (CH2), 108.22,
109.42 (C4 and C5), 118.99 (C6), 138.89 (C3), 159.06 (C2).
MS (EI), m/z: 138 (M+), 123, 110, 95, 81, 78, 68, 61, 54,
44.
Acknowledgements
This work was financially supported by the University
of Siena, quota Servizi per la Ricerca. The authors
thank Dr. G. L. Giorgi, Centro di Analisi e Determi-
nazioni Strutturali, Universita` di Siena, for the record-
ing of MS spectra.
N-(2-Oxo-1,2-dihydro-pyridin-3-yl)-acetimidic acid isopro-
1
pyl ester 8: yield 87%; mp 85–88°C; H NMR (CDCl3) l:
1.34 (d, 6H, CH3), 1.87 (s, 3H, CH3), 5.26 (m, 1H, OCH),
6.23 (t, 1H, H5), 6.87 (dd, 1H, H4), 7.14 (dd, 1H, H6),
12.96 (bs, 1H, NH); 13C NMR (CDCl3) l: 17.37, 21.72 (3
CH3), 68.29 (OCH), 106.81, 107.68 (C4 and C5) 114.87–
References
1. (a) Chimichi, S.; Nesi, R.; Ponticelli, F.; Tedeschi, P. J.
Chem. Soc., Perkin Trans. 1 1990, 1477–1480; (b) Donati,
D.; Fusi, S.; Ponticelli, F.; Tedeschi, P. Heterocycles 1988,
27, 1899–1905; (c) Adembri, G.; Camparini, A.; Donati,
D.; Ponticelli, F.; Tedeschi, P. Tetrahedron Lett. 1981, 22,
2121–2124.
2. Donati, D.; Ponticelli, F.; Bicchi, P.; Meucci, M. J. Phys.
Chem. 1990, 94, 5271–5274.
3. To a nitrogen flushed solution of compound 1 (1 mmol) in
ether (4 ml) ethereal alkyl lithium or methyl magnesium
bromide was added as reported in Scheme 1. The reaction
mixture was quenched with water and the organic phase
evaporated to give the reaction product.
122.06 (C6), 137.02, 139.00 (C3 and CH3C
6 ꢀN), 169.01 (C2).
MS (EI), m/z: 194 (M+), 152, 135, 111.
2 - [Methylamino - (2 - oxo - 1,2 - dihydro - pyridin - 3 - yl)-
methylene]malonic acid diethyl ester 10: advancing degree
1
20%; yield 90%; oil: H NMR (CDCl3) l: 1.25 (br t, 6H,
CH3), 2.86 (d, 3H, CH3NH), 4.24 (br q, 4H, OCH2), 6.29
(t, 1H, H5), 7.36 (dd, 1H, H4), 7.46 (dd, 1H, H6), 9.74 (bq,
1H, NHCH3), 11.26 (br s, 1H, H1); MS, m/z: 294 (M+),
249, 222, 202, 175, 135.
E,Z - 2 - Methyl - 1,5 - diaza - spiro[2,5]oct - 7 - en - 4 - one 11:
advancing degree 20%; yield 85%; oil, mixture of
diastereoisomers; NMR data were obtained from two
chromatographic fractions enriched in 11a or 11b. 11a
4. All new compounds gave satisfactory (within 0.3%) analyt-
1
1
(E-isomer): H NMR (CDCl3) l: 1.15 (d, 3H, CH3), 1.90
ical data. H and 13C NMR spectra were recorded with a
(bs, 1H, 1-NH), 2.60 (br q, 1H, H2), 4.07 (m, 2H, H6,6%),
5.47 (dt, 1H, H8), 5.95 (dt, 1H, H7), 6.75 (bs, 1H, 5-NH);
13C NMR (CDCl3) l: 14.13 (CH3), 38.49 (C3), 39.72 (C2),
43.35 (C6), 124.70, 124.91 (C7, C8), 171.37 (C4). MS, m/z:
138 (M+), 137, 123, 109, 95. 11b (Z-isomer): 1H NMR
(CDCl3) l: 1.43 (d, 3H, CH3), 1.90 (bs, 1H, 1-NH), 2.12
(q, 1H, H2), 4.07 (m, 2H, H6,6%), 5.34 (dt, 1H, H8), 5.84 (dt,
1H, H7), 6.75 (bs, 1H, 5-NH). 13C NMR (CDCl3) l: 12.90
(CH3), 39.78 (C3), 43.48 (C2 and C6), 123.03, 129.19 (C7,
C8), 169.47 (C4). MS, m/z: 138 (M+), 137, 123, 109, 95.
3-(1-Amino-ethyl)-1H-pyridin-2-one 12: yield 55%; cerous
Bruker AC 200 spectrometer at 200.13 and 50.33 MHz,
respectively. EI and FAB MS spectra were obtained with a
VG 70 250S instrument; APCI MS spectra were recorded
with a LCQ-DECA Thermo Finnigan instrument. Unless
otherwise stated, the reactions are carried out until the
starting material disappeared (TLC). The reported yields
are relative to the reacted material.
3,6-Dimethylisoxazolo[5,4-b]pyridine 2: yield 80%; mp 79–
81°C; 1H NMR (CDCl3) l: 2.60 (s, 3H, 3-CH3), 2.72 (s,
3H, 6-CH3), 7.20 (d, 1H, H4), 7.91 (d, 1H, H5); MS (EI),
m/z: 148 (M+), 133, 120, 119, 105, 92, 78, 64, 52.
3,6-Dimethyl-6,7-dihydro-isoxazolo-[5,4-b]pyridine 3: yield
92%; unstable oil which gives on standing compound 2; 1H
NMR (CDCl3) l: 1.28 (d, 3H, 6-CH3), 2.11 (s, 3H,
3-CH3), 4.54 (m, 1H, H6), 4.67 (bs, 1H, NH), 5.03 (dt, 1H,
H5), 6.04 (dd, 1H, H4); 13C NMR (CDCl3) l: 9.66 (6-
CH3), 24.35 (3-CH3), 51.70 (C6), 89.70 (C3a), 116.94 (C4),
117.69 (C5), 155.75 (C3), 166.98 (C7a); MS, m/z (FAB): 151
(M+1), 301 (M−H···M).
1
solid, mp 60°C: H NMR (CD3OD) l: 1.35 (d, 3H, CH3),
4.48 (q, 1H, H7), 6.47 (t, 1H, H5), 7.58 (dd, 1H, H4), 7.66
(dd, 1H, H6); 13C NMR (CD3OD) l: 17.64 (C8), 66.82
(C7), 108.05 (C5), 129.40 (C3), 136.64 (C6), 141.06 (C4),
163.00 (C2). MS (APCI), m/z: 139 (MH+), 122.
5. Solutions of compound 1 in a quartz tube with the suitable
solvent and nucleophile [as indicated in Scheme 2 (path c),
Schemes 3 and 4] were irradiated with a low pressure

9530
D. Donati et al. / Tetrahedron Letters 43 (2002) 9527–9530
7. McCournell, W.; Davis, F. A. Synthesis 2000, 1347–1365.
mercury lamp (253.7 nm). Chromatographic separations of
8. A solution of spiroaziridines 11 (50 mg) in THF (3 ml) was
treated with 70% perchloric acid (0.1 ml). Solvent was
neutralized with saturated sodium carbonate and evapo-
rated in vacuo. The residue was column chromatographed
with CHCl3/CH3OH 4/1 to give compound 12.
9. (a) Acar, E. A.; Glarner, F.; Burger, U. Helv. Chim. Acta
1998, 81, 1095; (b) Ling, R.; Yoshida, M.; Mariano, P. S.
J. Org. Chem. 1996, 61, 4439.
the evaporated reaction mixture gave compounds reported
in the schemes.
6. To a solution of sodium malonate (1 mmol) in ethanol (5
ml) or NaBH4 (2 mmol) in propan-2-ol (5 ml) the oxa-
zolopyridine 5 was added. Solvent was removed to give
(Scheme 2, path b) compound 6 or (Scheme 2, path c)
compounds 7 and 8 which were separated on silica gel
column with CHCl3/CH3OH 95/5 as eluent.