136.8, 132.3*, 132.1, 131.9*, 130.9†, 130.6, 130.5*, 129.4*,
129.3, 128.8, 128.7†, 128.2, 128.1*, 127.5†, 126.3†, 126.2*,
105.0†, 84.8, 84.0*, 37.4*, 36.3, 25.7†, 21.2*, 21.1, 18.3*,
18.1; IR (KBr) ν/cm−1: 1747 (st), 1495 (w), 1447 (w), 1374(st),
1303 (w); HRMS (EI) found 336.1473; C20H20N2O3 requires
336.1468.
IR (KBr) ν/cm−1 1753 (st), 1480 (w), 1437 (w), 1368 (m), 1302
(w); HRMS (EI) found 398.1620, C25H22N2O3 requires
398.1625.
6-(2,4-Dichlorophenyl)-9,9-dimethyl-3-phenyl-1,8-dioxa-2,6-
diazaspiro[4.4]non-2-en-7-one, 4h
9,9-Dimethyl-6-(naphthalen-1-yl)-3-phenyl-1,8-dioxa-2,6-
diazaspiro[4.4]non-2-en-7-one, 4e
Flash column chromatography (10%–30% EtOAc in pet. ether;
Rf 0.58, 50% EtOAc in pet. ether) afforded the title compound
4h (major isomer) as a white solid (0.40 g; 51%); mp
Flash column chromatography (pet. ether to 30% EtOAc in pet.
ether; Rf 0.54, 50% EtOAc in pet. ether) afforded the title com-
pound 4 as a pink solid (0.28 g; 38%); mp 200 °C (dec); isolated
1
137.6–138.6 °C; H NMR (400 MHz, CDCl3) 7.57–7.32 (7H,
m), 7.26 (1H, dd, J = 8.5, 2.3 Hz), 3.45 (1H, d, J = 18.6 Hz),
3.21 (1H, d, J = 18.5 Hz), 1.73 (3H, s), 1.63 (3H, s); 13C NMR
(100 MHz, CDCl3) 155.9, 153.7, 136.2, 135.0, 132.3, 130.9,
130.1, 129.7, 128.9, 128.8, 127.9, 126.4, 104.7, 85.2, 36.6,
25.6, 21.0; IR(KBr) ν/cm−1 1765 (st), 1485 (m), 1397 (m), 1367
(st), 1265 (m); HRMS (EI) found 390.0519, C19H16Cl2N2O3
requires 390.0532.
1
as an inseparable 6 : 1 ratio of atropisomeric diastereomers H
NMR (400 MHz, CDCl3) * indicates minor isomer peaks, † indi-
cates major and minor isomer peaks 8.30* (0.15H, d, J = 8.8
Hz), 7.89–7.81† (3.30H, m), 7.77 (1H, dd, J = 7.4, 1.1 Hz),
7.60† (1.15H, m), 7.53† (1.15H, dt, J = 7.0, 1.2 Hz), 7.46
(1.15H, dd, J = 8.2, 7.5 Hz), 7.39* (0.15H, dd, J = 8.1, 7.3 Hz),
7.38† (3.30H, m), 7.25† (12.60H, m), 3.60* (0.15H, d, J = 17.8
Hz), 3.46* (0.15H, d, J = 17.8 Hz), 3.38 (1H, d, J = 18.4 Hz),
3.09 (1H, d, J = 18.4 Hz), 1.86 (3H, s), 1.75 (0.60H, s), 1.70
(3H, s); 13C NMR (100 MHz, CDCl3) * indicates minor isomer
peaks, † indicates major and minor isomer peaks 156.1, 155.5*,
155.0, 134.9*, 134.5*, 134.3, 131.4, 130.6, 130.5*, 130.4*,
130.3*, 129.8, 129.6, 128.9, 128.7, 128.6*, 128.1, 127.9*,
127.9, 127.7*, 127.6*, 127.5, 127.3*, 126.8*, 126.6*, 126.4,
126.3, 126.0, 125.4*, 124.7*, 124.3*, 121.6, 121.1*, 120.8*,
105.5, 105.0*, 85.0, 84.5*, 37.3*, 36.6, 26.1, 25.8*, 21.3,
14.2*; HRMS (EI) found 372.1455, C23H20N2O3 requires
372.1468.
Acknowledgements
The Authors wish to thank Dr Roger Mulder of CSIRO for
assistance with variable temperature NMR, and Dr Craig Forsyth
of Monash University for X-ray structure determinations.
References
1 D. I. Rhodes, T. S. Peat, N. Vandegraaff, D. Jeevarajah, G. Le, E.
D. Jones, J. A. Smith, J. A. V. Coates, L. J. Winfield, N. Thienthong,
J. Newman, D. Lucent, J. H. Ryan, G. P. Savage, C. L. Francis and J.
J. Deadman, Antiviral Chem. Chemother., 2011, 21, 155–168.
2 J. Clardy and C. Walsh, Nature, 2004, 432, 829–837.
3 P. J. Hajduk and J. Greer, Nat. Rev. Drug Discovery, 2007, 6, 211–219.
4 A. W. Hung, A. Ramek, Y. Wang, T. Kaya, J. A. Wilson, P. A. Clemons
and D. W. Young, Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 6799–6804.
5 S. M. Pereira, G. P. Savage, G. W. Simpson, R. J. Greenwood and M.
F. Mackay, Aust. J. Chem., 1993, 46, 1401–1412.
6 B. M. Kelly-Basetti, M. F. Mackay, S. M. Pereira, G. P. Savage and G.
W. Simpson, Heterocycles, 1994, 37, 529–539.
7 C. K. Y. Lee, C. J. Easton, G. P. Savage and G. W. Simpson, ARKIVOC,
2006, 3, 175–183.
8 R. Newton and G. P. Savage, Aust. J. Chem., 2008, 61, 432–437.
9 N. J. Beattie, C. L. Francis, A. J. Liepa and G. P. Savage, Aust. J. Chem.,
2010, 63, 445–451.
10 A. M. Said and G. P. Savage, J. Org. Chem., 2011, 76, 6946–6950.
11 P. Grunanger and P. Vita-Finzi, Isoxazoles – Part 1. Chemistry of Hetero-
cyclic Compounds, Wiley, New York, NY, 1991, vol. 49.
12 C. J. Easton, C. M. M. Hughes, G. P. Savage and G. W. Simpson, in
Cycloaddition Reactions of Nitrile Oxides with Alkenes, ed.
A. R. Katritzky, Academic Press, San Diego, CA, 1994, vol. 60, pp.
261–327.
9,9-Dimethyl-6-(2-nitrophenyl)-3-phenyl-1,8-dioxa-2,6-
diazaspiro[4.4]non-2-en-7-one, 4f
Flash column chromatography (pet. ether to EtOAc; Rf 0.49,
50% EtOAc in pet. ether) afforded the title compound 4f as a
yellow solid (0.30 g; 47%); mp 168.9–170.6 °C; 1H NMR
(400 MHz, CDCl3) 7.95 (1H, dd, J = 7.9, 1.6 Hz), 7.72 (1H, dd,
J = 8.0, 1.5 Hz), 7.62 (1H, dd, J = 7.5, 1.6 Hz), 7.57–7.31 (6H,
m), 3.57 (1H, d, J = 18.9 Hz), 3.41 (1H, d, J = 18.9 Hz), 1.73
(3H, s), 1.69 (3H, s); 13C NMR (100 MHz, CDCl3) 156.6,
153.6, 134.1, 130.9, 130.5, 129.8, 128.9, 127.9, 127.9, 127.5,
126.4, 125.3, 104.7, 85.8, 37.1, 25.4, 21.6; IR (KBr) ν/cm−1
1752 (st), 1605 (w), 1524 (st), 1393 (st), 1380 (st); HRMS (EI)
found 367.1151, C19H17N3O5 requires 367.1149.
:
13 G. P. Savage, Curr. Org. Chem., 2010, 14, 1478–1499.
14 J. Xu and A. Hamme II, Synlett, 2008, 919–923.
15 S. Dadiboyena, J. Xu and A. T. Hamme II, Tetrahedron Lett., 2007, 48,
1295–1298.
6-([1,1′-Biphenyl]-2-yl)-9,9-dimethyl-3-phenyl-1,8-dioxa-2,6-
diazaspiro[4.4]non-2-en-7-one, 4g
16 G. P. Savage and G. T. Wernert, Aust. J. Chem., 2005, 58, 877–881.
17 S. J. Barrow, C. J. Easton, G. P. Savage and G. W. Simpson, Tetrahedron
Lett., 1997, 38, 2175–2178.
18 C. J. Easton, C. M. M. Hughes, E. R. T. Tiekink, C. E. Lubin, G.
P. Savage and G. W. Simpson, Tetrahedron Lett., 1994, 35, 3589–3592.
19 J. Clayden, W. J. Moran, P. J. Edwards and S. R. LaPlante, Angew.
Chem., Int. Ed., 2009, 48, 6398–6401.
20 L. R. Domingo, M. T. Picher, P. Arroyo and J. A. Saez, J. Org. Chem.,
2006, 71, 9319–9330.
21 R. K. Howe and B. R. Shelton, J. Org. Chem., 1990, 55, 4603–4607.
Flash column chromatography (pet. ether to 15% EtOAc in pet.
ether; Rf 0.17, 20% EtOAc in pet. ether) afforded the title com-
pound 4g as a white solid (0.25 g; 45%); mp 148.5–150.6 °C;
1H NMR (400 MHz, CDCl3) 7.60 (1H, m), 7.49–7.28 (13H, m),
2.85 (1H, d, J = 18.1 Hz), 2.78 (1H, d, J = 18.1 Hz), 1.51 (3H,
s), 1.08 (3H, s); 13C NMR (100 MHz, CDCl3) 156.5, 155.5,
142.1, 139.3, 131.9, 131.1, 130.7, 130.7, 130.0, 129.4, 129.3,
128.9, 128.8, 128.4, 128.1, 126.3, 105.3, 84.1, 36.0, 24.9, 21.1;
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4759–4766 | 4765