References and Notes
For reviews, see:
1a
Posner GH.
Chem. Rev.
1986,
86:
831
1b
Armstrong RW.
Combs AP.
Tempest PA.
Brown SD.
Keating TA.
Acc. Chem. Res.
1996,
29:
123
1c
Tietze LF.
Modi A.
Med. Res. Rev.
2000,
20:
304
1d
Dömling A.
Ugi I.
Angew. Chem.
Int. Ed.
2000,
39:
3168
1e
Ramon DJ.
Yus M.
Angew. Chem.
Int. Ed.
2005,
44:
1602
2
Risitano F.
Grassi G.
Foti F.
Romeo R.
Synthesis
2002,
116
In contrast with previous findings,
the above spirocyclization is promoted by the regiospecific gem-C-C bond formation at the
4-position of the azolone rings. See:
3a
Tietze LF.
Hippe T.
Steinmetz A.
Synlett
1996,
1043
3b
Tietze LF.
Evers H.
Töpken E.
Angew. Chem. Int. Ed.
2001,
40:
903
4a
Risitano F.
Grassi G.
Foti F.
Moraci S.
Synlett
2005,
1633
4b
Bruno G.
Rotondo A.
Nicolò F.
Risitano F.
Grassi G.
Foti F.
Helv. Chim. Acta
2006,
89:
190
5 In comparison with our previous study,
the observed contracted ring size seems to be due to the substitution
of a 1,3-dielectrophilic compound, such as α,β-unsaturated carbonylic
compounds (ref. 4), with phenacyl chloride 3, whose
electrophilic centers are in 1,2-position.
6
Method A; Typical
Procedure: To a stirred solution of isoxazol-5-one 1 (4.2 mmol) in EtOH (20 mL), containing
4 Å molecular
sieves and an excess of AcOH-AcONH4, aldehyde 4 (8.5 mmol) and phenacyl chloride 3 (4.2 mmol) were added. The solution was
heated at reflux for 2 h. After cooling, the reaction mixture was
filtered to remove molecular sieves and the solvent was evaporated.
The resulting residue was washed with cool H2O and the
aqueous suspension was then extracted with Et2O (3 × 30
mL). The combined organic layer was washed with H2O,
dried over anhyd Na2SO4, filtered and evaporated
under reduced pressure. The crude product was purified by recrystallization from
MeOH or by column chromatography on SiO2 (CHCl3) to
afford 5. The use of pyrazolin-5-one 2 in place of isoxazol-5-one 1 provided 6 and 7.
7
Risitano F.
Grassi G.
Foti F.
Bilardo C.
Tetrahedron
2000,
56:
9669
8 Bridgehead aziridines 7 were
generated from 4 and 3 in
the presence of the AcOH-AcONH4 mixture, as
reported in ref. 4.
9
Typical Procedure:
A mixture of pyrazolin-5-one 2 (4.2 mmol),
aldehyde 4 (8.5 mmol) and phenacyl chloride 3 (4.2 mmol) in n-PrOH
(30 mL) containing an excess of AcOH-AcONH4 and
4 Å molecular sieves was heated by MW irradiation at 95 ˚C
for 5-15 min. After cooling the reaction to r.t., filtration
and evaporation of the solvent afforded a solid residue which was
worked up as mentioned above. The crude product was purified by
recrystallization from CHCl3-MeOH or by column
chromatography on neutral Al2O3 (CHCl3)
to give 8 as colorless crystals.
10
Selected Data
for 8a-h: 8a: yield: 79%;
mp 194-195 ˚C. IR (Nujol): 1716 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 5.91 (s,
1 H), 6.79-7.25 (m, arom., 10 H), 7.32 (s, 1 H), 7.34-8.24 (m,
arom., 15 H). ¹³C NMR (75 MHz, CDCl3): δ = 68.3, 119.9-142.5,
156.6, 171.7, 175. Anal. Calcd for C37H27N3O: C,
83.91; H, 5.14; N, 7.93. Found: C, 84.13; H, 5.16; N, 8.02. 8b: yield: 85%; mp 108-110 ˚C.
IR (Nujol): 1708 cm-¹. ¹H NMR
(300 MHz, CDCl3): δ = 2.14 (s, 3 H),
2.17 (s, 3 H), 5.91 (s, 1 H), 6.73-7.24 (m, arom., 10 H),
7.33 (s, 1 H), 7.35-7.95 (m, arom., 13 H). ¹³C
NMR (75 MHz, CDCl3): δ = 21.0, 21.1,
68.3, 119.8-141.7, 157.2, 171.4, 174.8. Anal. Calcd for C39H31N3O:
C, 83.99; H, 5.60; N, 7.53. Found: C, 83.81; H, 5.51; N, 7.49. 8c: yield: 84%; mp 106-108 ˚C.
IR (Nujol): 1713 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 3.65 (s,
3 H), 3.73 (s, 3 H), 5.92 (s, 1 H), 6.51-7.25 (m, arom.,
10 H), 7.30 (s, 1 H), 7.35-7.95 (m, arom., 13 H). ¹³C
NMR (75 MHz, CDCl3): δ = 55.2, 55.4,
68.6, 119.5-140.7, 157.4, 159.8, 160.0, 171.4, 174.6. Anal.
Calcd for C39H31N3O3:
C, 79.44; H, 5.30; N, 7.13. Found: C, 79.28; H, 5.20; N, 7.05. 8d: yield: 78%; mp 124-125 ˚C.
IR (Nujol): 1712 cm-¹. ¹H NMR
(300 MHz, CDCl3): δ = 5.93 (s, 1 H),
6.70-7.24 (m, arom., 10 H), 7.32 (s, 1 H), 7.35-7.96
(m, arom., 13 H).
¹³C NMR
(75 MHz, CDCl3): δ = 68.5, 119.3-143.0,
156.5, 170.5, 174.5. Anal. Calcd for C37H25N3OCl2:
C, 74.25; H, 4.21; N, 7.02. Found: C, 74.09; H, 4.16; N, 6.95. 8e: yield: 65%; mp 175-177 ˚C.
IR (Nujol): 1714 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 1.64 (s,
3 H), 2.01 (s, 3 H), 6.39 (s, 1 H), 6.72-7.25 (m, arom.,
10 H), 7.31 (s, 1 H), 7.33-7.95 (m, 13 H). ¹³C
NMR (75 MHz, CDCl3): δ = 19.4, 19.5,
67.2, 119.5-143.2, 157.2, 172.3, 174.2. Anal. Calcd for
C39H31N3O: C, 83.99; H, 5.60; N,
7.53. Found: C, 84.21; H, 5.61; N, 7.59. 8f:
yield: 63%; mp 129-130 ˚C. IR (Nujol):
1714 cm-¹. ¹H NMR
(300 MHz, CDCl3): δ = 3.21 (s, 3 H),
3.31 (s, 3 H), 6.31 (s, 1 H), 6.40-7.24 (m, arom., 10 H),
7.33 (s, 1 H), 7.35-7.99 (m, arom., 13 H). ¹³C
NMR (75 MHz, CDCl3): δ = 55.1, 55.5,
67.2, 118.3-143.2, 156.0, 157.2, 158.1, 172.5, 175.0. Anal.
Calcd for C39H31N3O3:
C, 79.44; H, 5.30; N, 7.13. Found: C, 79.32; H, 5.17; N, 7.03. 8g: yield: 84%; mp 140-141 ˚C.
IR (Nujol): 1710 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 1.95 (s,
3 H), 2.20 (s, 3 H), 5.91 (s, 1 H), 6.61-7.25 (m, arom,
10 H), 7.30 (s, 1 H), 7.34-7.96 (m, arom., 13 H). ¹³C NMR
(75 MHz, CDCl3): δ = 20.2, 20.3, 68.3,
119.6-142.4, 157.2, 171.8, 174.5. Anal. Calcd for C39H31N3O:
C, 83.99; H, 5.60; N, 7.53. Found: C, 83.85; H, 5.49; N, 7.46. 8h: yield: 81%; mp 136-138 ˚C.
IR (Nujol): 1709 cm-¹. ¹H NMR
(300 MHz, CDCl3): δ = 3.37 (s, 3 H),
3.66 (s, 3 H), 5.89 (s, 1 H), 6.64-7.25 (m, arom. 10 H),
7.32 (s, 1 H), 7.36-7.95 (m, arom., 13 H). ¹³C
NMR (75 MHz, CDCl3): δ = 55.1, 55.4,
68.5, 118.9-141.9, 156.7, 158.5, 159.1, 171.9, 174.8. Anal.
Calcd for C39H31N3O3:
C, 79.44; H, 5.30; N, 7.13. Found: C, 79.58; H, 5.31; N, 7.19.
11 X-ray data to be submitted to Acta Crystallogr.
