An improved diastereoselective synthesis of spiroazoles using multicomponent domino transformations

Article abstract of DOI:10.1055/s-0030-1258516

Spiroisoxazole and spiropyrazole derivatives were obtained in a four-component reaction of active isoxazol- or pyrazol-5-ones with aromatic aldehydes, phenacyl chloride and AcOH-AcONH₄ mixture. The reaction sequence is highly chemo- and diastereoselective affording good yields of spiroisoxazoles in refluxing ethanol, while efficient formation of spiropyrazoles is closely related to the use of a microwave-assisted protocol.

Full text of DOI:10.1055/s-0030-1258516

2106
LETTER
An Improved Diastereoselective Synthesis of Spiroazoles Using Multi-
component Domino Transformations
I
mprove
d
D
iaste
l
reosel
i
ective
S
s
ynthesis
aof Spiroazoles Altieri, Massimiliano Cordaro, Giovanni Grassi, Francesco Risitano,* Angela Scala
Dipartimento di Chimica Organica e Biologica, Università, Vill. S. Agata, 98166 Messina, Italy
Fax +39(090)393897; E-mail: frisitano@unime.it
Received 11 May 2010
No reaction occurred with enolizable aldehydes or with
phenacyl halogenides substituted on carbon bearing the
halogen or with aliphatic a-halogen ketones.
Abstract: Spiroisoxazole and spiropyrazole derivatives were ob-
tained in a four-component reaction of active isoxazol- or pyrazol-
5-ones with aromatic aldehydes, phenacyl chloride and AcOH–
AcONH4 mixture. The reaction sequence is highly chemo- and
diastereoselective affording good yields of spiroisoxazoles in re-
fluxing ethanol, while efficient formation of spiropyrazoles is close-
ly related to the use of a microwave-assisted protocol.
Conversely, analogous 1,3-diphenylpyrazolin-5-one 2 did
not give comparable results (Scheme 1, X = NPh). Under
the above conditions, in fact, bisderivatives 6 and diaza-
bicycles 7 were isolated as the only reaction products. In-
stantaneous formation of the slightly soluble 6 likely
removes azolone 2 from the reaction mixture, thus favor-
ing the formation of fused aziridines 7.8
Key words: spirans, multicomponent reactions, cyclizations,
microwave, diastereoselectivity
The isolated products were identified by direct compari-
son with authentic samples.4,7
Multicomponent reactions (MCRs) continue to emerge as
valuable tools in the development of new synthetic strate-
gies to generate in few steps highly functionalized hetero-
cyclic molecules from commercially available starting
materials.1
Recently,2 we reported the synthesis of tetrahydrospiropy-
ridines using a MCR that exploited a Michael addition of
1,2-azol-5-ones to a,b-unsaturated carbonyl compounds
in the presence of arylaldehydes and NH3, generated in
situ by the AcOH–AcONH4 mixture.3
Ph
PhCOCH2Cl
ArCHO
+
+
N
O
X
3
4
AcOH–AcONH4
1; X = O
2; X = NPh
X = O
X = NPh
Ar
In continuation of the above investigation, a concise route
to bridged aziridines was recently developed in our labo-
ratories through a multicomponent domino process in-
volving phenacyl chloride both as 1,2-dielectrophile and
as pronucleophile.4
Ar
Ph
N
Ph
Ph
Ph
Ar
+
N
N
N
O
N
N
O
Ph
O
Ph
Ar
2
7
6
5
In the present study, with the intention of further expand-
ing the scope of this methodology, we explored the use of
phenacyl chloride as selective agent for the construction
of spiroheterocycles of different ring size. Thus, the pro-
Scheme 1 Reagents and conditions: EtOH, 4 Å molecular sieves,
reflux, 2 h.
cedure involving 3 instead of a,b-unsaturated carbonylic As a result of these findings, we decided to examine the
compounds5 was applied to azolin-5-ones 1 and 2 reactivity of the pyrazolin-5-one 2 in a one-pot micro-
(Scheme 1).
wave-assisted reaction. Under these conditions, the irradi-
ation of the described mixture in n-propanol gave spiro
derivatives 8 in good yield as single diastereomers
(Scheme 2).9
Reactions of 3-phenylisoxazolin-5-ones 1 with equimolar
quantities of 3 and arylaldehyde 4 in refluxing ethanol in
the presence of AcOH–AcONH4 (method A) gave spiro
derivatives 5 (Scheme 1, X = O)6 as single diastereomers
with high yield. The efficiency of the new synthetic pro-
tocol (method A) is highly improved when compared with
our previous procedure (method B;7 Table 1).
Ar
N
Ph
Ph
2
+
3
+
4
N
O
N
Ar
Ph
8
63–85%
Scheme 2 Reagents and conditions: AcOH–AcONH4, n-PrOH, 4 Å
molecular sieves, MW, 5–15 min.
SYNLETT 2010, No. 14, pp 2106–2108
Advanced online publication: 22.07.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258516; Art ID: G12810ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Improved Diastereoselective Synthesis of Spiroazoles
2107
In the light of these results, the MCR with isoxazolin-5- In conclusion, we have devised a novel strategy for the
one 1 was repeated under the new conditions but no com- synthesis of spiroazole derivatives that proceeds with high
pound of interest was isolated.
chemo- and diastereoselectivity. The reaction process em-
ploys the AcOH–AcONH4 mixture as the basic catalyst
and nitrogen atom provider and involves a domino double
nucleophilic addition–cyclization–aldolic condensation
sequence. Further exploration of the domino strategy and
their applications in the synthesis of other types of spiro-
cycles are in progress.
The structure of spirans 8 was assigned on the basis of an-
alytical and spectroscopic data10 and by comparing the 1H
NMR spectra with the corresponding known spirans 5.
The configuration assignment was based on a NOE exper-
iment carried out on compounds 8a and 8b. As for 5, these
have E,5R*,6R* configuration, which was confirmed by
X-ray crystal structure analysis of compound 8d.11
References and Notes
Table 1 Synthesis of Spiro Derivatives 5 and 8
(1) For reviews, see: (a) Posner, G. H. Chem. Rev. 1986, 86,
831. (b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(c) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304.
(d) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (e) Ramon, D. J.; Yus, M. Angew. Chem. Int. Ed.
2005, 44, 1602.
Entry
Ar
5 (% yield)a
Method Ab Method Bc
8 (% yield)a
1
2
3
4
5
6
7
8
a
b
c
d
e
f
Ph
80
87
90
78
75
77
68
66
65
70
71
57
65
66
50
51
79
85
84
78
65
63
84
81
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-MeC6H4
2-MeOC6H4
3-MeC6H4
3-MeOC6H4
(2) Risitano, F.; Grassi, G.; Foti, F.; Romeo, R. Synthesis 2002,
116.
(3) 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:
(a) Tietze, L. F.; Hippe, T.; Steinmetz, A. Synlett 1996,
1043. (b) Tietze, L. F.; Evers, H.; Töpken, E. Angew. Chem.
Int. Ed. 2001, 40, 903.
(4) (a) Risitano, F.; Grassi, G.; Foti, F.; Moraci, S. Synlett 2005,
1633. (b) 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 a,b-unsaturated
carbonylic compounds (ref. 4), with phenacyl chloride 3,
whose electrophilic centers are in 1,2-position.
g
h
a Yield of pure isolated product.
b Conditions: EtOH, 4 Å molecular sieves, reflux, 2 h.
c Conditions: pyridine, toluene, reflux, 2 h.7
(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.
A likely mechanism for the formation of these spiroazoles
is shown in Scheme 3.
Ar
Ph
NH2
OH
AcOH–AcONH4
1 or 2
Ar
HC
NH2
4
N
9
X
10
3
Ar
N
Ar
N
N
Ph
Ph
Ph
Ph
Cl
4
5 or 8
N
(7) Risitano, F.; Grassi, G.; Foti, F.; Bilardo, C. Tetrahedron
O
X
O
X
2000, 56, 9669.
H
12
11
(8) Bridgehead aziridines 7 were generated from 4 and 3 in the
presence of the AcOH–AcONH4 mixture, as reported in ref.
4.
Scheme 3 Proposed mechanism of spiroazole formation
(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.
A Mannich reaction between the azolones 1 or 2 and the
aldimine salt 9, meanwhile formed from the aldehyde 4
and ammonium salt, seems initially to occur leading re-
giospecifically to the nonisolated Mannich base 10. This
is intercepted by phenacyl chloride 3 to give 11, which
rapidly cyclizes through 5-exo-tet process, providing 12
as a single diastereomer. Finally, immediate and inevita-
ble condensation of 12 with aldehyde 4 gives 5 or 8.
Synlett 2010, No. 14, 2106–2108 © Thieme Stuttgart · New York

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E. Altieri et al.
LETTER
(10) Selected Data for 8a–h: 8a: yield: 79%; mp 194–195 °C. IR
(Nujol): 1716 cm–1. 1H NMR (300 MHz, CDCl3): d = 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): d = 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): d = 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): d = 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): d = 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): d = 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): d = 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): d = 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): d = 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): d = 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): d = 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): d = 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):
d = 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). 13
C
NMR (75 MHz, CDCl3): d = 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): d = 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): d = 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.
Synlett 2010, No. 14, 2106–2108 © Thieme Stuttgart · New York