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References
1. Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Org.
Lett. 2003, 5, 391–394.
2. The preparation of isoxazole 10 is representative: To 1,3-
diketone 9 (2.32 mmol, 1.50 equiv.) in 10 ml EtOH at rt was
added NEt3 (2.17 mmol, 1.40 equiv.) followed by nitrile oxide
8 (1.55 mmol, 1.00 equiv.). The resulting solution was
warmed to 50°C and stirred 24 h at this temperature.
Concentration under reduced pressure followed by column
chromatography on silica gel (1:1 hexanes/EtOAc) afforded
10 (1.36 mmol, 88% yield) as a white foam.
Scheme 4. Structural motifs accessible from isoxazoles.
3. Physical properties of selected, key compounds:
Further investigations and kinetic studies on catalytic
couplings are underway.
Compound 10: 1H NMR (400 MHz, CDCl3) l 7.47 (t, 1H,
J=7.4 Hz), 7.38 (dd, 1H, J=7.4, 4.8 Hz), 6.97 (dd, 1H,
J=7.4, 4.8 Hz), 5.46 (s, 1H), 4.22–4.14 (m, 1H), 4.05–3.97
(m, 1H), 3.89–3.82 (m, 1H), {3.71 (s), 3.73 (s), (3H)};
3.69–3.61 (m, 1H), 3.24–3.15 (m, 1H), 2.77–2.68 (m, 1H),
2.50–2.32 (m, 2H), 2.31–2.21 (m, 1H), 2.18–2.07 (m, 1H),
1.35–1.28 (m, 1H), {1.21 (d, J=6.4 Hz), 1.23 (d, J=6.4 Hz),
3H}; 13C NMR (100 MHz, CDCl3) l 190.5*, 190.3, 179.9*,
179.7, 157.8*, 157.6, 155.7*, 155.6, 138.7, 130.9*, 130.9,
127.2, 118.4, 118.3*, 118.2, 116.1*, 116.0, 115.1, 112.2,
111.2*, 111.1, 99.4, 99.1, 67.4*, 67.1, 67.1*, 67.0, 61.2*, 60.3,
55.9*, 55.8, 46.6*, 46.4, 31.0*, 30.9, 30.7*, 30.2, 25.7*, 25.5,
20.7*, 20.5, 15.5*, 14.1 (the compound exists as a 1:1 mixture
of atropisomers; * denotes peak doubled due to atropiso-
merism); IR (thin film) w 2964, 2884, 1694, 1599, 1479, 1446,
1272, 1075, 995 cm−1. Anal. calcd for C19H21NO5: C, 66.46;
H, 6.16; N, 4.08. Found, C, 66.16; H, 6.27; N, 4.03.
Compound 12: 1H NMR (CDCl3, 400 MHz) l 7.35 (t, 1H,
J=8.2 Hz), 7.00 (dd, 1H, J=8.2, 0.7 Hz), 6.87 (dd, 1H,
J=7.6, 0.7 Hz), 5.97 (s, 1H), 4.02–3.94 (m, 2H), 3.87 (s, 3H),
3.77 (dt, 2H, J=7.9, 2.2 Hz), 3.18 (dd, 1H, J=17.4, 5.1 Hz),
2.74–2.67 (m, 1H), 2.58–2.46 (m, 2H), 2.29–2.25 (m, 1H),
1.83–1.70 (m, 1H), 1.25–1.18 (m, 1H), 1.22 (d, 3H, J=6.6
Hz); 13C NMR (100 MHz, CDCl3) l 190.9, 178.9, 159.8,
157.0, 129.4, 128.2, 125.8, 122.9, 116.3, 112.4, 97.0, 67.1, 67.2,
56.0, 46.6, 31.0, 30.7, 25.7, 20.7; IR (thin film) w 2959, 2931,
Finally, a key feature of this methodology is the advan-
tages of the stable nitrile oxides themselves. In addition
to their inherent stability and ease of handling, they are
also easily synthesized from the corresponding oxime.
Although stable nitrile oxides have been prepared by a
two-step chlorination–base-induced elimination proce-
dure, we have found this process to be incompatible with
acid labile substrates.4 However, the nitrile oxides are
readily prepared in excellent yield from the oximes in a
single reaction step (Table 3), simply by portionwise
additionofN-chlorosuccinimidetoamixtureoftheoxime
and a slight excess of amine base. Acid labile substrates
present no complications, and nitrile oxides such as 6, 8,
and 11 are readily prepared (entries 3–5). The base effects
rapid elimination of HCl from the initially formed
C-chloro oxime and, notably, does not interfere with the
oxime chlorination nor react with the nitrile oxide itself.
These nitrile oxides are easily purified by silica-gel
chromatography, but are typically obtained in analyti-
cally pure form and can be used directly in the cyclocon-
densation reactions.
The highly functionalized isoxazole products represent a
novel entry to substituted polycyclic structures (Scheme
4) and provide access compounds including xanthones,
benzophenones and related structures.5 Coupled with the
unique chemistry of the isoxazole products, this process
offers a novel and promising route to the synthesis of
biologically active natural products including balanol6
and the coleophomones.7,8
2855, 1694, 1600, 1446, 1383, 1236, 1152, 1105, 1002 cm−1
.
Anal. calcd for C19H21NO5: C, 66.46; H, 6.16; N, 4.08.
Found: C, 66.24; H, 6.43; N, 4.09.
4. (a) For a typical procedure for the preparation of stable
nitrile oxides via this two-step protocol see: Bode, J. W.;
Carreira, E. M. J. Org. Chem. 2001, 66, 6410–6424 and
references cited therein; (b) For example, although the
C-chloro oxime corresponding to 8 could be prepared, it
rapidly decomposed upon standing or concentration due to
spontaneous elimination of HCl and subsequent destruction
of the acetal moiety.
5. For the conversion of structurally related isoxazoles to
benzophenones, xanthones and other polycyclic compounds,
see: (a) Ref. 1; (b) Bode, J. W.; Uekusa, H.; Suzuki, K. Org.
Lett. 2003, 5, 395–398.
In conclusion, we have described the efficient, amine-pro-
moted coupling of readily prepared, stable nitrile oxides
with cyclic diketones to afford functionalized isoxazole
products. These studies have established 1) the utility and
intermediacy of nitrile oxides in the cyclocondensation
process; 2) the viability of highly hindered substrates,
which give isoxazoles in high yield; and 3) a critical role
for the base in promoting the coupling reaction. Further
studies will lead to novel processes and applications based
on this technology.
6. For a leading reference to the challenges associated with the
synthesis of balanol and related compounds, see: Skrydstrup,
T.; Hazell, R.; Laursen, B.; Denieul, M.-P. J. Org. Chem.
2000, 65, 6052–6060.
7. Thismethodologyhasbeenappliedtothesynthesisandstruc-
ture confirmation of coleophomone natural products: Bode,
J. W.; Suzuki, K. Tetrahedron Lett. 2003, 44, 3559–3563.
8. For the use of acyl cyanides in the total synthesis of
coleophomone B and C, see: Nicolaou, K. C.; Vassilikogian-
nakis, G.; Montagnon, T. Angew. Chem., Int. Ed. 2002, 41,
3276–3279.
Acknowledgements
J.W.B. thanks the Japan Society for the Promotion of
Science for a postdoctoral fellowship. This research was
partially supported by the 21st Century COE Program.