Multicomponent synthesis of spiroisoxazolines

Article abstract of DOI:10.1021/jo051181w

A three-component one-pot procedure (3-MCR) was developed to assemble the spiroisoxazoline nucleus from commercially available materials. This new methodology affords the title compounds in high yields and without the use of chromatography.

Full text of DOI:10.1021/jo051181w

Multicomponent Synthesis of Spiroisoxazolines
Mauro F. A. Adamo,*,† Donato Donati,‡ Eleanor F. Duffy,† and Piero Sarti-Fantoni§
Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal
Chemistry, The Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Dublin, Ireland,
Dipartimento di Chimica, Universita` di Siena, Via Aldo Moro, Siena 53100, Italy, and Dipartimento di
Chimica Organica “U. Schiff”, Universita` di Firenze, Via della Lastruccia, Sesto Fiorentino 50019, Italy
madamo@rcsi.ie
Received June 11, 2005
A three-component one-pot procedure (3-MCR) was developed to assemble the spiroisoxazoline
nucleus from commercially available materials. This new methodology affords the title compounds
in high yields and without the use of chromatography.
Introduction
such as Bacillus subtilis and Micrococcus lutens.4 Also
zamamistatin, a natural product isolated from the Oki-
nawan sponge Pseudoceratina purpurea, exhibits a sig-
nificant antibacterial activity against Rhodospirilium
salexigens.5 Aerothionin displays antimycobacterial activ-
ity.6 More recently it was found that spiroisoxazoline
containing SJ755 shows a remarkable integrin antagonist
behavior, showing a new application for spiroisoxazoline-
containing compounds.7
The discovery of new agents displaying high antimi-
crobial activity is an important topic of research in
medicinal chemistry.1 Spiroisoxazolines are heterocyclic
nuclei which have stimulated much interest in medicinal
and biological chemistry.2-7 Following the first reports
of their herbicidal and plant hormonal activity,2 some
naturally occurring spiroisoxazolines have been found
useful in other biomedical areas (Figure 1). Examples
include the naturally occurring araplysillins, which have
been found to inhibit ATP-ase enzymes,3 and naturally
occurring agelorin, a spiroisoxazoline derived from bro-
motyrosine which has proved active against pathogens
Results and Discussion
As a part of our endeavors to develop diversity-oriented
syntheses using polyfunctional scaffolds such as 3-meth-
yl-4-nitro-5-styrylisoxazole (1), we discovered a new
reaction in which 1 reacted with acetylacetone (2a), ethyl
acetoacetate (2b), and acetone (2c) (Scheme 1).8 The
reaction was completed by an acidic workup to furnish
spiroisoxazolines 5a-c in good isolated yields. In this
reaction, two Michael additions occurred consecutively
that formed the 4-nitrospiroisoxazoline core as nitronate
ammonium salts 4a-c, which gave the final product
5a-c after treatment with aqueous acid (Scheme 1). We
also established that compounds 3a-c or 5a-c could be
selectively obtained depending on the amount of base
employed.
* To whom correspondence should be addressed. Phone: +353-1-
4022208. Fax: +353-1-4022168.
† The Royal College of Surgeons in Ireland.
‡ Universita` di Siena.
§ Universita` di Firenze.
(1) Overbye, K. M.; Barrett, J. F. Drug Discovery Today 2005, 10,
45. Rogers, B. L. Curr. Opin. Drug Discovery Dev. 2004, 7, 211.
(2) Howe, R. K.; Shelton, B. R. J. Org. Chem. 1990, 55, 4603. De
Amici, M.; De Micheli, M.; Misani, V. Tetrahedron 1990, 46, 1975.
Smietana, M.; Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1999,
40, 1291.
(3) Faulkner, J. Nat. Prod. Rep. 2001, 18, 1.
(4) Wright, A. D.; King, G. M.; Sticher, O. J. Nat. Prod. 1990, 53,
1615.
(5) Takada, N.; Watanabe, R.; Suenaga, K.; Yamada, K.; Ueda, K.;
Kita, M.; Uemura, D. Tetrahedron Lett. 2001, 42, 5265.
(6) Encarnacio´n-Dimayuga, R.; Ram´ırez, M. R.; Luna-Herrera, J.
Pharm. Biol. 2003, 41, 384.
(7) Cue, D.; Southern, S. O.; Southern, P. J.; Prabhakar, J.; Lorelli,
W.; Smallheer, J. M.; Mousa, S. A.; Cleary, P. P. Proc. Natl. Acad. Sci.
U.S.A. 2000, 97, 2858.
Spiroisoxazolines 5a-c precipitated out as a single
diastereoisomer.8 Remarkably in this reaction a total of
(8) Adamo, M. F. A., Chimichi, S.; De Sio F.; Donati, D.; Sarti-
Fantoni, P. Tetrahedron Lett. 2002, 43, 4157. Adamo, M. F. A.;
Chimichi, S.; Donati, D.; Sarti-Fantoni, P. Acta Crystallogr. 2002, E58,
o-1125-o1127.
10.1021/jo051181w CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/22/2005
J. Org. Chem. 2005, 70, 8395-8399
8395

Adamo et al.
FIGURE 1. Spiroisoxazolines possessing biological activity.
SCHEME 1. Reaction of 1 with Bisenolizable
Compounds 2a-c
when 5a-p were dissolved in CD3COCD3 or CDCl3 and
the spectrum was rapidly acquired. Typically, a solution
of 8-10 mg of 5a in 0.6 mL of CD3COCD3 required 4 min
to epimerize to a 1:1 ratio of 5a and 4-epi-5a (Scheme 2).
Because of the long acquisition times required, the 13C
NMR of compounds 5a-p displayed a 1:1 mixture of 5
and 4-epi-5 diastereoisomers.11
We report now a new one-pot three-component proce-
dure (MCR-3) which allows the preparation of spiroisox-
azolines 5a-p (Scheme 3 and Table 1) in a modular
fashion and from commercially available materials. Mul-
SCHEME 3. One-Pot Procedure To Prepare
Spiroisoxazolinesa
four stereogenic centers are formed with complete control
of the relative stereochemistry. The diastereoisomer
obtained is the most thermodynamically stable, holding
the sterically demanding groups in the equatorial posi-
tions. Although 5a-c were obtained as a single diaster-
eoisomer in the solid state, when dissolved, compounds
5a-c underwent a rapid equilibration to form two
diastereoisomers in solution (Scheme 2).9
a Conditions and reagents: (a) 7, 8a-c (1 equiv), piperidine (0.1
equiv), ethanol, 60 °C, 2 h; (b) 2a-c (2 equiv), piperidine (1.9
equiv), 60 °C, 6 h; (c) HCl(dil).
SCHEME 2. Behavior of Compounds 5a in
Solution
ticomponent reactions (MCRs) are of increasing impor-
tance in organic and medicinal chemistry.12 In these
procedures a number of building blocks come together
in a single reaction vessel to form a new product in which
each individual component is contained. Therefore, in
MCRs, a high degree of molecular diversity can be
introduced by variation of a single component at a time.
Considering that rapidity and diversity are key features
in modern drug discovery, it becomes clear that MCR
strategies offer significant advantages over traditional
This behavior is usual for aliphatic nitroalkanes which
establish an equilibrium with their aci form in solution.10
Therefore, we obtained a 1H NMR spectrum of com-
pounds 5a-p (Table 1) as a single diastereoisomer only
(11) 1H NMR studies showing the epimerization of 5a to 4-epi-5a
are included in the Supporting Information.
(12) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879. Ugi, I. Pure Appl.
Chem. 2001, 73, 187. Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
2005, 44, 1602.
(9) 5a and 4-epi-5a were identified by NOE experiments. Significant
enhancement was observed between CHNO2 and OCCHaxHeqCdO in
5a.
(10) Turnbull, D.; Maron, S. H. J. Am. Chem. Soc. 1943, 65, 212.
8396 J. Org. Chem., Vol. 70, No. 21, 2005

Multicomponent Synthesis of Spiroisoxazolines
linear-type syntheses, especially when designed to rely
on readily available materials.
amount of piperidine (0.1 equiv) was required for the
condensation of components 7 and 8 and that using the
catalyst base in restricted amounts led to improved yields
and increased the purity of the products. We also
observed that secondary amines such as piperidine,
pyrrolidine, or morpholine were better catalysts than
tertiary amines for the synthesis of 6 and for the
following Michael reactions (Scheme 1). Finally, in the
reaction of 1 with 2a-c only 0.1 equiv of piperidine was
required to obtain adducts 3a-c in good yields, and just
2 equiv of piperidine was required to convert 1 to
spiroisoxazolines 5a-c.
Our approach to the development of diversity-oriented
syntheses is based on the generation of building blocks
that contain multiple functionalities which could be
selectively reacted.8,13,14 We worked on the hypothesis
that a product containing a number of functionalities m
which could be selectively reacted in a number of n
directions will generate diversity in D ) mn directions.
These findings defined a set of optimized conditions
that were used to prepare spiroisoxazolines 5a-p in one
pot and in excellent isolated yields (Scheme 3 and Table
1). Typically, (condition a, Scheme 3) equimolar amounts
TABLE 1. Yields of Spiroisoxazolines 5a-p
FIGURE 2. Polyfunctional scaffold: 5-styryl-4-nitroisoxazoles
6.
yield
(%)
entry
product
Ar
R
In this respect, 3-methyl-4-nitro-5-styrylisoxazoles 6
(Figure 2) represent a class of polyfunctional scaffolds
which hold great potential for the generation of diversity.
For example, in 6 two electrophilic centers are available
that can each be reacted independently. Enolates, which
are stabilized soft nucleophiles, react selectively at the
soft electrophilic center E2+,8 whereas hard nucleophiles
such as -OH react exclusively at the hard electrophilic
center E1+; for example, it was shown that treatment of
6 with NaOH generated cinnamic acids.15 The photo-
chemical behavior of 6 has also been studied extensively,
and it was shown that cyclobutanes could be accessed
by irradiation of 6.16 Photochemistry thus enhances the
range of directions in which diversity can be generated
from 6. Additional practical features of 6 are their
stability and their ease of generation from commercially
available materials 3,5-dimethyl-4-nitroisoxazole (7) and
an aromatic aldehyde (8) (Figure 2) by a condensation
reaction.
1
2
5a
5b
5c
5d
5e
5f
5g
5h
5i
5k
5l
5m
5n
5o
5p
Ph-
Ph-
Ph-
-COCH3
-CO2Et -
-H
-COCH3
-CO2Et
-H
-COCH3
-CO2Et
-H
-COCH3
-CO2Et
-H
83
71
84
83
71
78
80
69
86
65a
59
68
85
72
77
3
4
p-NO2Ph-
p-NO2Ph-
p-NO2Ph-
p-ClPh-
5
6
7
8
p-ClPh-
9
p-ClPh-
10
11
12
13
14
15
o-ClPh-
o-ClPh-
o-ClPh-
p-OCH3Ph-
p-OCH3Ph-
p-OCH3Ph-
-COCH3
-CO2Et
-H
a Obtained as the 8-enolic form.
of 7 and aromatic aldehyde 8a-e were reacted in the
presence of piperidine (0.1 equiv) in ethanol (2 h at 60
°C), (condition b, Scheme 3), a moderate excess (2 equiv)
of 2a-c was added to the reaction mixture together with
a further amount of piperidine (1.9 equiv) and the
reaction mixture was heated (6 h at 60 °C), and (condition
c, Scheme 3) evaporation of the solvent and workup with
aqueous dilute hydrochloric acid gave compounds 5a-p
without the need for column chromatography. This ease
of purification complements the one-pot procedure, mak-
ing this methodology facile, practical, and rapid to
execute.
Considering that tandem syntheses involving sequen-
tial Knoevenagel and Michael processes have been ex-
tensively reported,17 we anticipated that spiroisoxazolines
5 could be prepared through a multicomponent procedure
in which 6 was first generated from 7 and 8 and then
reacted in situ with 2a-c (Figure 3).
As a means of expanding the range of chemically
diverse species available from 5, we developed a similar
one-pot procedure that could be used to access adducts
3a-m (Scheme 4 and Table 2). Adducts 3a-m constitute
a class of polyfunctional scaffolds themselves. Compounds
3a-m contain a ketone, a â-diketone, or a â-ketoester
FIGURE 3. One-pot synthesis of spiroisoxazolines 5a-p.
The following findings were pivotal to the establish-
ment of a one-pot procedure. The preparation of 4-nitro-
5-styrylisoxazoles from 7 and 8 has previously been
reported using large amounts of triethylamine or piperi-
dine base.18 However, we found that only a limited
(15) Sarti-Fantoni, P.; Donati, D.; De Sio, F.; Moneti, G. J. Hetero-
cycl. Chem. 1980, 17, 1643. Baracchi, A.; Chimichi, S.; De Sio, F.;
Donati, D.; Nesi, R.; Sarti-Fantoni, P.; Torroba, T. J. Labelled Compd.
Radiopharm. 1986, 23, 487.
(16) Donati, D.; Fiorenza, M.; Moschi, E.; Sarti-Fantoni, P. J.
Heterocycl. Chem. 1977, 14, 951. Baracchi, A.; Chimichi, S.; De Sio,
F.; Donati, D.; Nesi, R.; Sarti-Fantoni, P.; Torroba, T. Heterocycles 1986,
24, 2863.
(13) Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. E.; Pritchard,
G. J.; Rathmell R. E. Tetrahedron 2003, 59, 2197.
(14) Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. Org. Chem.
2005, 70, 3307.
(17) List B. Synlett 2001, 11, 1675.
(18) Kochetkov, N. K.; Sokolov, S. D.; Luboschnikova, V. M. J. Gen.
Chem. USSR (Engl. Transl.) 1962, 32, 1763. Quilico, C.; Musante, A.
Gazz. Chim. Ital. 1942, 72, 399.
J. Org. Chem, Vol. 70, No. 21, 2005 8397

Adamo et al.
SCHEME 4. One-Pot Synthesis of Adducts 3a-pa
SCHEME 5.
a Conditions and reagents: (a) 7, 8a-e (1 equiv), piperidine (0.1
equiv), ethanol, 60 °C, 2 h; (b) 2a-c (1.2 equiv), 60 °C, 6 h.
functionality together with a 4-nitroisoxazole core. Con-
sidering that carbonyl-containing compounds19 and the
4-nitroisoxazole core20 were shown to possess a wide
range of different reactivities, it is easy to anticipate that
diversity could stem from 3a-m in a wide number of
directions.
as a type II MCR.21 In a type II MCR, a final product D
is irreversibly formed from an intermediate compound
C, which is in equilibrium with its precursors A and B,
which is analogous to our case.
In conclusion, we have developed an effective method-
ology for the assembly of title compounds from com-
mercially available materials. This new methodology is
modular, and benefits from a simple method of purifica-
tion which does not require chromatography. We also
have established a modular one-pot approach to the
preparation of heteroaryl â-diketones, heteroaryl ketones,
and heteroaryl â-ketoesters. Spiroisoxazolines are known
to possess a wide range of biological activities, and also
in 5a-p, a number of functionalities are present that will
allow a further development of chemical diversity. Simi-
lar considerations are valid for adducts 3a-m.
TABLE 2. Yields of Michael Adducts 3a-p
yield
(%)
entry
product
Ar
R
1
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph-
Ph-
Ph-
-COCH3
-CO2Et
-H
-COCH3
-CO2Et
-H
-COCH3
-CO2Et
-H
-COCH3
-CO2Et
-H
84
69
82
82
74a
80
71
78
81
62
52a
72
b
3
4
p-NO2Ph-
p-NO2Ph-
p-NO2Ph-
p-ClPh-
5
6
7
8
p-ClPh-
9
p-ClPh-
10
11
12
13
14
15
3k
3l
3m
o-ClPh-
o-ClPh-
Experimental Section
o-ClPh-
General Procedure for the Preparation of Compounds
5a-p (Table 1). To a stirred solution of 7 (426 mg, 3 mmol)
in ethanol (10 mL) were added piperidine (26 mg, 0.3 mmol,
0.1 equiv) and an aromatic aldehyde (8a-e) (3 mmol, 1 equiv).
The resulting solution was reacted at 60 °C for 2 h, before
ketone 2a-c (6 mmol, 2 equiv) was added together with a
further amount of piperidine (485 mg, 5.7 mmol, 1.9 equiv).
The reaction mixture was heated at 60 °C for 6 h and then
allowed to cool at room temperature and the solvent removed
in vacuo. The yellow oil so obtained was treated with water
(100 mL) and extracted with diethyl ether (2 × 25 mL). The
organic layer was discarded and the aqueous phase made
acidic (pH ≈ 1-2) by addition of 1 M hydrochloric acid and
extracted with diethyl ether (2 × 50 mL). This second organic
layer was dried over MgSO4, filtered, and evaporated to yield
crude spiroisoxazolines 5a-p as colorless solids, which were
recrystallized from ethanol.
p-OCH3Ph-
p-OCH3Ph-
p-OCH3Ph-
-COCH3
-CO2Et
-H
b
b
a Obtained as a a 1:1 mixture of diastereoisomers. b A 5-8%
yield of the corresponding spiroisoxazolines 5n-p was isolated
together with a 75-85% yield of 9.
Similarly, (condition a, Scheme 4) equimolar amounts
of 7 and aromatic aldehyde 8a-e were reacted in the
presence of piperidine (0.1 equiv) in ethanol (2 h at 60
°C), and (condition b, Scheme 4) a moderate excess (1.2
equiv) of 2a-c was added and the reaction mixture was
heated (6 h at 60 °C). Compounds 3a-m were isolated
in good yields; however, we could not isolate compounds
3n-p (Table 2, entries 13-15). These experiments
furnished compounds 5n-p in only 5-8% yields together
with a 70-75% yield of 3-methyl-4-nitro-5-(4-methoxy-
phenyl)ethenylisoxazole (9) (Scheme 5).
Data for 8-acetyl-3-methyl-4-nitro-9-phenyl-1-oxa-2-
azaspiro[4.5]dec-2-en-7-one (5a): colorless solid (820 mg,
83% yield); mp 170-1 °C (ethanol); νmax (film)/cm-1 1710s,
1
1702s, 1575m; H NMR (400 MHz, CD3COCD3) (5a) δ 7.41-
We explained this result as follows (Scheme 5). The
first reaction (Michael I, Scheme 5) is a reversible
process, and in the case of a less effective acceptor such
as p-OCH3-substituted styrylisoxazole 9, the equilibrium
for this step is shifted toward the reagents. On the
contrary, the second reaction (Michael II, Scheme 5) is
an irreversible process, and in the presence of a suitable
amount of piperidine base, the final products 5n-p are
formed effectively.
7.23 (5H, m), 6.02 (1H, s), 4.43 (1H, d, J ) 12 Hz), 3.79 (1H,
td, J ) 12 Hz, J ) 4 Hz), 3.24 (1H, d, J ) 14 Hz), 2.73 (1H,
dd, J ) 12 Hz, J ) 2.5 Hz), 2.63 (1H, t, J ) 12 Hz), 2.02 (3H,
s), 1.88 (3H, s), 1.89 (1H, ddd, J ) 12 Hz, J ) 4 Hz, J ) 2.5
1
Hz); H NMR (400 MHz, CD3COCD3) (4-epi-5a) δ 7.41-7.23
(5H, m), 5.88 (1H, s), 4.43 (1H, d, J ) 12 Hz), 3.79 (1H, td, J
) 12 Hz, J ) 4 Hz), 3.28 (1H, d, J ) 14 Hz), 2.52 (1H, t, J )
12 Hz), 2.37 (1H, dd, J ) 12 Hz, J ) 2.5 Hz), 2.18 (1H, ddd, J
) 12 Hz, J ) 4 Hz, J ) 2.5 Hz), 2.02 (3H, s), 1.88 (3H, s); 13
C
NMR (80 MHz, CD3COCD3) δ 202.7, 201.9, 201.8, 151.2, 151.0,
141.2, 128.3, 127.8, 126.9, 126.8, 97.8, 97.5, 88.1, 66.5, 66.4,
48.6, 44.6, 41.0, 37.5, 36.9, 35.9, 29.8, 10.7; MS m/z 331 (100,
In light of these results, the 3-MCR procedure we have
developed to prepare spiroisoxazolines could be classified
8398 J. Org. Chem., Vol. 70, No. 21, 2005

Multicomponent Synthesis of Spiroisoxazolines
MH+). Anal. Calcd for C17H18N2O5: C, 61.81; H, 5.45; N, 8.48.
Found: C, 61.77; H, 5.48; N, 8.21.
(3H, s); 13C NMR (100 MHz, CDCl3) δ 202.1, 201.7, 171.8,
155.4, 138.0, 131.0, 129.0, 128.0, 127.7, 74.7, 42.6, 32.3, 29.6,
29.4, 11.5; HRMS m/z found (MH+) 331.1295, C17H19N2O5
requires 331.1294; MS m/z 331 (100, MH+).
Data for 3-methyl-4-nitro-7-oxo-9-phenyl-1-oxa-2-aza-
spiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (5b):
colorless solid (765 mg, 71% yield); mp 148-9 °C (ethanol);
νmax (film)/cm-1 1725s, 1570s; 1H NMR (200 MHz, CDCl3) δ
7.32-7.21 (5H, m), 5.36 (1H, s), 4.05 (2H, q, J ) 7 Hz), 3.96-
3.81 (1H, m), 3.71 (1H, d, J ) 13 Hz), 2.81 (1H, d, J ) 15 Hz),
2.70 (1H, dd, J ) 15 Hz, J ) 2 Hz), 2.32-2.12 (2H, m), 2.13
(3H, s), 1.06 (3H, t, J ) 7 Hz); 13C NMR (80 MHz, CD3COCD3)
δ 199.5, 167.2, 150.4, 150.2, 140.8, 140.7, 128.2, 127.0, 126.8,
97.9, 97.6, 88.1, 61.7, 61.3, 59.7, 48.1, 43.5, 41.7, 41.5, 40.1,
35.4, 12.9, 10.7; HRMS m/z found (MH+) 361.1399, C18H21N2O6
requires 361.1400; MS m/z 361 (95, MH+).
Data for 3-methyl-4-nitro-9-phenyl-1-oxa-2-azaspiro-
[4.5]dec-2-en-7-one (5c): colorless solid (728 mg, 84% yield);
mp 141-2 °C (ethanol); νmax (film)/cm-1 1720s, 1570s; 1H NMR
(200 MHz, CD3COCD3) δ 7.15-6.99 (5H, m), 5.74 (1H, s,), 3.15
(1H, tt, J ) 14 Hz, J ) 4 Hz), 2.92-2.60 (2H, m), 2.42-2.03
(3H, m), 1.90 (3H, s), 1.83-1.61 (1H, m); 13C NMR (80 MHz,
CD3COCD3) 205.6, 204.2, 150.4, 150.1, 143.6, 142.9, 128.1,
127.6, 127.2, 126.7, 126.1, 98.4, 98.1, 89.7, 48.6, 47.1, 46.9, 43.8,
40.5, 39.0, 38.7, 35.7, 10.7; HRMS m/z found (MH+) 289.1189,
C15H17N2O4 requires 289.1188; MS m/z 289 (95, MH+).
General Procedure for the Preparation of Compounds
3a-m (Table 3). To a solution of 7 (426 mg, 3 mmol) in
ethanol (10 mL) were added piperidine (26 mg, 0.3 mmol, 0.1
equiv) and an aromatic aldehyde (8a-e) (3 mmol, 1 equiv).
The reaction mixture was reacted at 60 °C for 2 h, then ketone
2a-c (3.6 mmol, 1.2 equiv) was added, and the reaction was
further reacted for 6 h at the same temperature. After this
time, the reaction mixture was allowed to reach room tem-
perature, the solvent removed in vacuo, and the oil so obtained
purified by flash chromatography.
Data for 2-acetyl-4-(3-methyl-4-nitroisoxazol-5-yl)-3-
phenylbutyric acid ethyl ester (3b): colorless solid (745
mg, 69% yield); Rf ) 0.4 (ethyl acetate:petroleum ether ) 1:4);
mp 84-5 °C (ethanol); νmax (film)/cm-1 1726s (CdO), 1601s (Is),
1525m (NO2); 1H NMR (200 MHz, CDCl3) δ 7.18-7.02 (5H,
m), 4.01-3.90 (2H, m), 3.81 (2H, q, J ) 7 Hz), 3.55 (1H, dd, J
) 14 Hz, J ) 7 Hz), 3.38 (1H, dd, J ) 14 Hz, J ) 5 Hz), 2.36
(3H, s), 2.20 (3H, s), 0.85 (3H, t, J ) 7 Hz); 13C NMR (80 MHz,
CDCl3) δ 201.0, 172.2, 167.7, 155.3, 138.5, 130.5, 128.9, 128.6,
127.8, 65.4, 61.5, 42.6, 31.9, 30.0, 14.7, 11.4; HRMS m/z found
(MH+) 361.1398, C18H21N2O6 requires 361.1399; MS m/z 361
(100, MH+).
Data for 5-(3-methyl-4-nitroisoxazol-5-yl)-4-phenyl-
pentan-2-one (3c): colorless oil (708 mg, 82% yield); Rf )
0.4 (ethyl acetate:petroleum ether ) 1:5); νmax (film)/cm-1 1709s
1
(CdO), 1600m (Is), 1575s (NO2); H NMR (400 MHz, CDCl3)
δ 7.29-7.19 (5H, m), 3.84 (1H, quintet, J ) 7 Hz), 3.60 (1H,
dd, J ) 14 Hz, J ) 7 Hz), 3.47 (1H, dd, J ) 14 Hz, J ) 7 Hz),
2.96 (1H, dd, J ) 17 Hz, J ) 7 Hz), 2.88 (1H, dd, J ) 17 Hz,
J ) 7 Hz), 2.50 (3H, s), 2.10 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 205.6, 172.5, 154.9, 141.2, 132.6, 130.1, 128.4, 126.6,
48.7, 38.5, 33.4, 30.0, 11.2; HRMS m/z found (MH+) 289.1189,
C15H17N2O4 requires 289.1188; MS m/z 289 (100, MH+).
Acknowledgment. We acknowledge the Royal So-
ciety of Chemistry for a grant to M.F.A.A. and the RCSI
Research Committee and PTRLI cycle III for a grant to
E.F.D.
Data for 3-[2-(3-methyl-4-nitroisoxazol-5-yl)-1-phenyl-
ethyl]pentane-2,4-dione (3a): colorless solid (831 mg, 84%
yield); Rf ) 0.2 (ethyl acetate:petroleum ether ) 1:5); mp
Supporting Information Available: General experimen-
tal procedures, spectroscopic data for compounds 5d-p and
1
3d-m, H NMR spectra showing the epimerization of 5a to
1
121-2 °C (ethanol); νmax (film)/cm-1 1705s, 1600s, 1520m; H
4-epi-5a, 1H NMR spectra of compounds 5a-p and 3a-m, 1H
NMR (400 MHz, CDCl3) δ 7.16-6.98 (5H, m), 4.20 (1H, d, J )
12 Hz), 4.10 (1H, m), 3.46 (1H, dd, J ) 14 Hz, J ) 9 Hz), 3.26
(1H, dd, J ) 14 Hz, J ) 5 Hz), 2.33 (3H, s), 2.20 (3H, s), 1.75
1
and 13C NMR peak assignments for 5a and 4-epi-5a, H-1H
correlation and 1H-13C correlation spectra of compound 5a,
and NOE experiments for assigning the identity of 5a and
4-epi-5a. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Kel’in, A. V.; Maioli, A. Curr. Org. Chem. 2003, 7, 1855.
(20) Kashima, C. Heterocycles 1979, 12, 1343.
(21) Ugi, I. J. Prakt. Chem. 1997, 339, 499.
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