449
Z. T. Alkayar et al.
Letter
Synlett
(4) For intramolecular nitrone cycloadditions that give products
with an external aromatic substituent β to nitrogen, see for
example: (a) Vinick, F. J.; Fengler, I. E.; Gschwend, H. W. J. Org.
Chem. 1977, 42, 2936. (b) Black, D. S. C.; Crozier, R. F.; Rae, I. D.
Aust. J. Chem. 1978, 31, 2013. (c) Moskal, J.; Milart, P. Chem. Ber.
1985, 118, 4014. (d) Annunziata, R.; Cinquini, M.; Cozzi, F.;
Raimondi, L. Tetrahedron Lett. 1988, 29, 2881. (e) Aurich, H. G.;
Biesemeier, F.; Boutahar, M. Chem. Ber. 1991, 124, 2329.
(f) Aurich, H. G.; Biesemeier, F. Synthesis 1995, 1171.
(g) Frederickson, M.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.;
Redpath, J.; Crossley, R. Tetrahedron 1995, 51, 6835. (h) Jung, M.
E.; Vu, B. T. J. Org. Chem. 1996, 61, 4427. (i) Ferrara, M.; Cordero,
F. M.; Goti, A.; Brandi, A.; Estieu, K.; Paugam, R.; Ollivier, J.;
Salaün, J. Eur. J. Org. Chem. 1999, 2725. (j) Ishikawa, T.; Kudo, T.;
Shigemori, K.; Saito, S. J. Am. Chem. Soc. 2000, 122, 7633.
(k) Huang, K. S.-L.; Lee, E. H.; Olmstead, M. M.; Kurth, M. J. J. Org.
Chem. 2000, 65, 499. (l) Blackwell, M.; Dunn, P. J.; Graham, A. B.;
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dron 2002, 58, 7715. (m) Dunn, P. J.; Graham, A. B.; Grigg, R.;
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(n) Borsini, E.; Broggini, G.; Contini, A.; Zecchi, G. Eur. J. Org.
Chem. 2008, 2808.
(5) For intramolecular nitrone cycloadditions that give products
with a fused aromatic ring β to nitrogen, see for example
(a) Chandler, M.; Parsons, P. J. J. Chem. Soc., Chem. Commun.
1984, 322. (b) Jeong, J. H.; Weinreb, S. M. Org. Lett. 2006, 8,
2309. (c) Chua, P. J.; Tan, B.; Yang, L.; Zeng, X.; Zhu, D.; Zhong, G.
Chem. Commun. 2010, 46, 7611. (d) Xie, J.; Xue, Q.; Jin, H.; Li, H.;
Cheng, Y.; Zhu, C. Chem. Sci. 2013, 4, 1281. (e) Endoma-Arias, M.
A. A.; Hudlicky, J. R.; Simionescu, R.; Hudlicky, T. Adv. Synth.
Catal. 2014, 356, 333.
Ph
MeO2C
H
MeO2C
Ph
Me
Me
H
N
N
Zn, AcOH
70 °C, 4 h
O
O
then NaOMe
H
H
CO2Me
OH
(5:1)
14a + 14b
59% 15
Scheme 5 Breaking the N–O bond of cycloadduct 14
In conclusion, we have demonstrated that intramolecu-
lar nitrone cycloadditions are amenable to aldehydes bear-
ing α-quaternary centres in which one substituent is a
methyl ester. The regioselectivities are affected by the
length of the tether to the alkene dipolarophile and by the
nature of the dipolarophile (terminal alkene or with at-
tached electron-withdrawing group). The stereochemistry
is influenced by the α-carboxylic ester group that is
thought to interact with the proton of the CHN group in the
transition state, thereby favouring the stereoisomer with
the ester group exo to the bicyclic ring system. The chemis-
try allows the synthesis of bicyclic isoxazolidines contain-
ing a β-phenylethylamine moiety.
Acknowledgment
We are grateful for support from the Embassy of the Republic of Iraq
and the University of Sheffield. We thank Dr A. J. H. M. Meijer (Univer-
sity of Sheffield) for DFT calculations.
(6) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(7) Electrostatic interaction of a carbonyl oxygen atom with a
proton α to a nitrogen atom has been suggested to explain con-
formational preferences, see for example (a) Sandoval-Lira, J.;
Fuentes, L.; Quintero, L.; Höpfl, H.; Hernández-Pérez, J. M.;
Terán, J. L.; Sartillo-Piscil, F. J. Org. Chem. 2015, 80, 4481.
(b) Sheikh, N. S.; Leonori, D.; Barker, G.; Firth, J. D.; Campos, K.
R.; Meijer, A. J. H. M.; O’Brien, P.; Coldham, I. J. Am. Chem. Soc.
2012, 134, 5300.
Supporting Information
Supporting information for this article is available online at
spectroscopic data, including NMR spectra and X-ray crystal struc-
tures are provided .
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
(8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
References and Notes
(9) Dimethyl
1-Methyl-7-phenyloctahydrobenzo[c]isoxazole-
3,7-dicarboxylate (14a)
(1) LeBel, N. A.; Post, M. E.; Whang, J. J. J. Am. Chem. Soc. 1964, 86,
3759.
The aldehyde 13 (100 mg, 0.33 mmol), N-methylhydroxylamine
hydrochloride (30 mg, 0.36 mmol), and DIPEA (0.12 mL, 0.66
mmol) in toluene (4 mL) was heated at 110 °C. After 2 h, the
solvent was evaporated. Purification by column chromatogra-
phy, eluting with PE–EtOAc (7:2), gave the cycloadducts 14a and
14b (67 mg, 61%) as a mixture (ratio 5:1 by 1H NMR spectros-
copy) from which isomer 14a was isolated by crystallization
from CH2Cl2–hexane (1:1) as amorphous solid; mp 98–100 °C;
Rf = 0.28 [PE–EtOAc (7:2)]. IR (film): νmax = 2950, 1750, 1725,
(2) For reviews, see: (a) Jones, R. C. F.; Martin, J. N. In Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Het-
erocycles and Natural Products; Padwa, A.; Pearson, W. H., Eds.;
Wiley: New York, 2002, Chap. 1. (b) Revuelta, J.; Cicchi, S.; Goti,
A.; Brandi, A. Synthesis 2007, 485. (c) Burrell, A. J. M.; Coldham,
I. Curr. Org. Synth. 2010, 7, 312.
(3) (a) Burrell, A. J. M.; Coldham, I.; Watson, L.; Oram, N.; Pilgram, C.
D.; Martin, N. G. J. Org. Chem. 2009, 74, 2290. (b) Burrell, A. J. M.;
Coldham, I.; Oram, N. Org. Lett. 2009, 11, 1515. (c) Burrell, A. J.
M.; Watson, L.; Martin, N. G.; Oram, N.; Coldham, I. Org. Biomol.
Chem. 2010, 8, 4530. (d) Franklin, A. I.; Bensa, D.; Adams, H.;
Coldham, I. Org. Biomol. Chem. 2011, 9, 1901. (e) Coldham, I.;
Burrell, A. J. M.; Guerrand, H. D. S.; Oram, N. Org. Lett. 2011, 13,
1267. (f) Coldham, I.; Watson, L.; Adams, H.; Martin, N. G. J. Org.
Chem. 2011, 76, 2360. (g) Coldham, I.; Burrell, A. J. M.; Watson,
L.; Oram, N.; Martin, N. G. Heterocycles 2012, 84, 597.
1435 cm–1 1H NMR (400 MHz, CDCl3): δ = 7.38–7.34 (2 H, m),
.
7.31–7.26 (3 H, m), 4.13 (1 H, s), 3.79 (3 H, s), 3.67 (3 H, s), 3.57
(1 H, d, J = 4 Hz), 3.23–3.19 (1 H, m), 2.46–2.38 (1 H, m), 2.35–
2.26 (1 H, m), 1.97–1.87 (5 H, m), 1.74–1.59 (1 H, m), 1.37–1.26
(1 H, m). 13C NMR (400MHz, CDCl3): δ = 175.1, 172.9, 140.7,
128.8, 127.7, 126.3, 80.4, 70.5, 53.2, 52.4, 52.2, 48.1, 47.8, 26.9,
26.5, 22.2. HRMS (ES): m/z calcd for
C
18H23NO5 [MH+]:
334.1649; found [MH+]: 334.1646. LRMS (ES): m/z (%) = 334
(100) [MH+]. X-ray crystal structure analysis (see Supporting
Information): CCDC 1422381.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 447–449