Investigation on the reactivity of isoxazol-5-ones towards 1,2-diaza-1,3-dienes: New entry to variously substituted (imidazol-2-yl)acetate and 1,3-oxazin-6-one derivatives

Article abstract of DOI:10.1016/j.tet.2011.10.118

1,2-Diaza-1,3-dienes (DDs) undergo, under neutral conditions, N-nucleophilic attack from a 4-ethoxycarbonylisoxazol-5-one derivative. The first aza-Michael addition is followed by an intramolecular second, affording a fused heterobicyclic system that, upo

Full text of DOI:10.1016/j.tet.2011.10.118

Tetrahedron 68 (2012) 608e613
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Tetrahedron
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Investigation on the reactivity of isoxazol-5-ones towards 1,2-diaza-1,3-dienes:
new entry to variously substituted (imidazol-2-yl)acetate and 1,3-oxazin-6-one
derivatives
Orazio A. Attanasi a, Silvia Bartoccini a, Gianfranco Favi a, Gianluca Giorgi b, Francesca R. Perrulli a,
,
Stefania Santeusanio a
*
a
ꢀ
Department DiSteVa, Organic Chemistry Section, Universita degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino, Italy
b
ꢀ
Department of Chemistry, Universita degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2011
Received in revised form 17 October 2011
Accepted 31 October 2011
Available online 6 November 2011
1,2-Diaza-1,3-dienes (DDs) undergo, under neutral conditions, N-nucleophilic attack from
a 4-
ethoxycarbonylisoxazol-5-one derivative. The first aza-Michael addition is followed by an intra-
molecular second, affording a fused heterobicyclic system that, upon ring opening and decarboxylation
processes, gives rise to novel substituted imidazoles with an acetate functionality in the 2-position. On
the contrary, under the same reaction conditions, 3-phenylisoxazol-5-one provides a double Michael
addition at two units of DD involving first the C-4 and then the N-2 of the heterocycle. The resulting
diadduct spontaneously undergoes ring-opening/ring-closing process that concludes with a ring en-
largement of the heterocycle providing the 1,3-oxazin-6-one derivative.
Dedicated to Professor Francisco Palacios on
the occasion of his 60th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazoles
Michael addition
Imidazoles
Ring-opening
Ring enlargement
1. Introduction
afford nucleophilic attack9a,c,d and to undergo ring-opening re-
action by means of bases, nucleophiles,9a,11or by rearrangement or
The development of new methods for the synthesis of N-con-
taining heterocycles from
-unsaturated carbonyls1 is of partic-
intramolecular reactions.12
a,
b
Herein, we report the results of a study on the reactivity of DDs 1
with monosubstituted isoxazol-5-one pronucleophiles as a new
route to variously functionalized 2-(2-ethoxy-2-oxoethyl)-1H-im-
idazoles and 2,2,4,5-tetrasubstituted 1,3-oxazin-6-one derivative,
respectively.
ular interest in organic chemistry since they occur in a wide variety
of natural products2 including essential amino acids and alkaloids.3
In particular, imidazoles4 are important as heterocyclic compo-
nents in highly significant bio-active molecules.5 One of our main
targets is to employ 1,2-diaza-1,3-dienes (DDs)6 as building blocks
for imidazole skeletons through a preliminary aza-Michael addition
followed by different ring closure processes.7,8 Among heterocyclic
imines, isoxazolin-5-ones have proven to be valuable intermediates
in nucleophilic addition that in turn can afford different and in-
teresting heterocyclic compounds9 including imidazoles,10 and
therefore we were interested to explore their reactivity towards
DDs. In particular, we focused our attention in the chemistry of
monosubstituted isoxazol-5-one derivatives both for their ability to
2. Results and discussion
It is well known that isoxazol-5-one derivatives can exhibit
different tautomeric forms. With exclusive reference to prototropic
annular tautomerism, for typical substituted isoxazol-5-one A three
tautomeric forms have been recognized and designated as CH-form
A0, OH-form A00 and NH-form A000, each of them can traps electro-
philes in different ways (Fig. 1).
Considering that an initial 1H NMR study on ethyl 5-oxo-4,5-
dihydroisoxazole-4-carboxylate (2) in CDCl3 solution revealed
the CH-form as predominant, whereas only the NH-form was
observed in DMSO-d6 solution, we wanted to test the
* Corresponding author. Tel.: þ39 0722 303442; fax: þ39 0722 303441; e-mail
addresses: orazio.attanasi@uniurb.it (O.A. Attanasi), stefania.santeusanio@uniurb.it
(S. Santeusanio).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.118

O.A. Attanasi et al. / Tetrahedron 68 (2012) 608e613
609
Table 1
O
O
O
O
OH
O
N
N
HN
R
Results of the synthesis of (imidazol-2-yl)acetate derivatives 5aei
Entry
DD 1
Imidazole 5
Mp (ꢀC)
R
R
R
R
R
R1
R2
R3
Yielda(%)
A' CH-form
A'' OH-form
A''' NH-form
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
CONHPh
CO2t-Bu
CO2Me
CO2Bn
CONH2
CO2t-Bu
CONHPh
CO2Bn
Me
Me
Me
Me
Me
Me
Me
Et
N(Me)2
OMe
OMe
OMe
OEt
5a
5b
5c
5d
5e
5f
5g
5h
5i
98e100
68
75
59
61
63
64
53
56
57
122e124
118e120
121e123
195e198
118e119
178e179
114e115
132e133
Fig. 1. Tautomerism of isoxazol-5-one derivatives.
nucleophilic behaviour of 2 towards DDs 1 in different solvents.
Since the aza group in the conjugated heterodiene system exalts
the electrophilic character of the terminal carbon of 1, first we
decided to investigate the reaction between DDs 1aei (1 equiv)
and 2 (1 equiv) in DMF at room temperature, to determine which
tautomeric form of 2 would attack the electrophile. After the
consumption of the reagents (4e10 h, by TLC), the removal of
DMF and the chromatographic purification of the crude prod-
ucts, interesting 2-(2-ethoxy-2-oxoethyl)-1H-imidazole de-
rivatives 5aei were obtained in good yields (53e75%) (Scheme 1,
Table 1). A plausible mechanism of the reaction is outlined in
Scheme 1. As we postulated, isoxazol-5-one 2 affords conjugate
addition at the terminal carbon of the conjugated azo-ene sys-
tem through its NH tautomeric form producing the hydrazone
intermediate 3. Subsequent internal aza-Michael reaction leads
to the heterobicyclic structure 4. Upon spontaneous ring-open-
OBn
OMe
OMe
OMe
CO2t-Bu
Et
a
Yield of pure isolated product.
When the reaction in equimolar ratio between 1b and 2 was
carried out at room temperature in CHCl3, the TLC check displayed
the formation of 5b, 6 together with not completely reacted 2. As
showed in the Scheme 2, the formation of 6 can be explained by the
nucleophilic attack of the methylene function of the 2-acetate ap-
pendage of 5b to another molecule of 1b.
1b
2
+
ing and decarboxylation,
4 gives rise to 2-(2-ethoxy-2-
CHCl3, MS 4A
r.t.
oxoethyl)-1H-imidazole derivative 5. The occasional isolation
of the heterobicyclic imidazoisoxazole system 4a from the re-
action between 1a and 2, supports the proposed reaction path-
way in which the driving force of the ring-opening is probably
due to both the aromatization of imidazole ring and the good
carboxylate leaving group.
O
O
N
R2
R2
R3
R3
R1
R1
N
N
N
N
H
R2
O
+
N
H
H
N
R2
R2
O
O
O
O
R1
O
H
N
N
H
N
+
R3
R1
R3
N
R1
N
O
R3
O
N
H
1a-i
H
H
DMF, MS 4A
r.t.
5b 25%
6 37%
H
N
Scheme 2. Results of the reaction pathway between 1b and 2 (1:1) in CHCl3.
O
3a-i
O
O
O
O
2
O
Confirmation of this reaction pathway derived from the result of
the reaction between 1b (2 equiv) and 2 (1 equiv), carried out in the
same conditions, that afforded 6 as a diastereomeric mixture in 85%
yield (Scheme 3). Contrary to what was observed from the re-
activity of 2 and propiolate esters, in any case none C-addition of
O
O
N
O
N
R2
R2
R3
R3
the isoxazol-5-one 2 to the a,b-unsaturated system of DD 1b was
- CO2
R1
R1
observed.13
N
N
N
H
N
H
O
H
O
O
H
O
O
O
CHCl3, MS 4A
r.t.
5a-i
4a-i
1b
2
3b
+
4b
Scheme 1. Proposed mechanism for the synthesis of (imidazol-2-yl)acetate derivatives
5aei.
- CO2
O
N
R2
Although N-substituted derivatives of 2 are known for their
propensity to extrude carbon dioxide by photochemical or pyrolytic
conditions giving iminocarbenes that cyclize into imidazoles10b,c
our results represent the first example in which N-substituted de-
rivatives of 2 directly affords the imidazole ring by way of two se-
quential aza-Michael reactions with carbon dioxide extrusion,
preserving the acetate functionality that can be used as a conve-
nient handle for further transformation due to the presence of ac-
tive methylene and carboxylate groups.
R3
R1
1b
N
N
5b
R1 R2
HN
H
O
N
O
O
R3
6 85%
Scheme 3. Results of the reaction pathway between 1b and 2 in 2:1 ratio.

610
O.A. Attanasi et al. / Tetrahedron 68 (2012) 608e613
R2
Next, we turned our attention to the nucleophilic behaviour of
R2
H
N
R3
3-phenylisoxazol-5-one (7a) towards DD 1b carrying out the re-
action in equimolar ratio both in DMF and in CHCl3 and obtained
the same results: unreacted 7a in spite of the complete disap-
pearance of 1b. The incomplete consumption of 7a can be
explained by a second and faster nucleophilic attack of 8a to an-
other 1b molecule as recognized by NMR spectroscopy. In fact, in
the 1H and 13C NMR spectra of 9a, a double set of signals attribut-
able to the skeleton of 1b was observed (Scheme 4).
H
N
N
H
R1
R3
H
7a-c
N
H
R1
1b,c,g
R4
O
+
1b,c,g
R4
O
O
N
O
H
N
N
8a-e
R2
R3
NH
R1
A
R2
R2
R2
R2
H
N
H
R3
R3
N
O
O
H
N
R1
R3
R3
N
N
R1
+
N
R1
H
N
H
O
N
O
HN
R4
N
R1
R4
O
O
R4
O
H
O
R3
NH
R2
O
R3
NH
R2
R2
R1 = CO2C(CH3)3
R2 = CH3
R3 = CO2CH3
HO
N
H
N
Ph
Ph
N
N
R1
N
R3
7a
1b
NH
R1
NH
R1
(79-98 %)
B
CHCl3 or DMF
9a-e
A
r. t. MS 4
Scheme 5. Proposed mechanism for the formation of the 1,3-oxazin-6-one derivatives
9aee.
R2
H
R2
R3
H
N
N
R3
N
R1
out directly in a 2:1 ratio (1:7), no trace of 7aec was observed (TLC
check) and 9aee were obtained as diastereomeric mixtures in good
yields (Scheme 5, Table 2).
N
H
R1
+
O
Ph
NH
R2
O
Ph
O
R3
O
N
Table 2
Results of the reactions between 1b,c,g and 7aec in 2:1 ratio to afford 9aee
N
60%
9a
8a10%
R1
R2
R3
R4
Yielda
NH
R1
Entry
9
1
2
3
4
5
9a
9b
9c
9d
9e
CO2t-Bu
CO2Me
CO2Me
CONHPh
CO2Me
Me
Me
Me
Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
Ph
Me
Ph
98
81
79
82
88
Scheme 4. Results of the reaction pathway between 1b and 7a in equimolar ratio.
p-NO2C6H4
a
We postulated that in this case the reaction takes place, at first,
via C-nucleophilic addition of 7a at the terminal carbon of the
heterodiene system of 1b leading to Michael monoadduct9c 8a
(10%) followed by a further nucleophilic addition of 8a to another
molecule of 1b providing 9a (60%) even in neutral conditions.
Furthermore, in a separate experiment, the isolated monoadduct 8a
has proven to react with 1b providing derivative 9a in nearly
quantitative yield (95%). The structural characterization of 8a was
based on spectral data. The presence in the 1H NMR of three ex-
changeable protons at 5.16, 9.07 and 10.52 ppm, the presence of
diagnostic doublet at 86.4 ppm and of a C-sp2 at 91.7 ppm in 13C
NMR together with a NOE experiment, confirmed the mono C-ad-
duct in E-configuration. The structure of 9a was tentatively
assigned on the base of spectroscopic evidences hypothesizing
a complete rearrangement of the starting heterocycle. In fact, the
detection of a doublet at 51.3 ppm, attributable to a CH signal, to-
gether with two singlets at 91.0 and 95.7 ppm due to sp2 and sp3
carbons in 13C NMR spectra, suggested an analogous behaviour to
that observed from the reactivity of disubstituted isoxazolin-5-one
systems on DMAD.9a
Yield of the diastereomeric mixture.
3. Conclusions
In summary, an investigation of the chemistry of mono-
substituted isoxazol-5-ones applied to conjugated azo-ene systems
under mild conditions was assessed. Under appropriate solvent
conditions, uncatalyzed reactions of DDs with isoxazol-5-one
bearing a carboxylate group in 4-position, offer a useful entry to
(imidazol-2-yl)acetate by domino sequential aza-Michael/ring-
closing/ring-opening reactions. The availability of the proton in 3-
position of the heterocycle seems to be a prerequisite for the pro-
posed mechanism and our results represent the first example in
which the decarboxylation of the isoxazol-5-one derivative 2 is
driven by the aromatization process. Moreover, this protocol con-
veniently achieves the assembly, in one-pot and under mild con-
ditions, of the imidazole skeleton bearing the acetate appendage in
2-position, as useful building block for the synthesis of biologically
active compounds14and supplements the known protocols based to
1,3-dipolar cycloaddition of 2-unsubstituted imidazole 3-oxide to
As shown in Scheme 5, the NH tautomeric form of the iso-
xazolone ring in 8 can add a second molecule of 1 to give the in-
termediate A. The shift of the acidic proton of the hydrazone chain
bonded at N-2 of the heterocycle in A allows the NeO bond
cleavage of the isoxazole ring even in neutral condition, producing
DMAD15or to condensation reaction of imidates with
a-amino
ketals.16 On the contrary, when 3-substituted isoxazol-5-one 7aec
react with DDs under neutral conditions, the active methylene of
the heterocycle affords, at first, C-Michael addition at a DD mole-
cule and then N-Michael attack to another unit of DD leading to
2,3,4-trisubstituted isoxazol-5-one derivative that upon ring-
opening/ring-closing processes affords ring enlargement of the
starting heterocycle to produce 2,2,4,5-tetrasubstituted 1,3-oxazin-
6-one derivative.
the
intramolecular nucleophilic attack by the carboxylate function at
the -carbon of the conjugated diimine framework causes an in-
a,b,g,d-unsaturated carboxylic acid derivative B. Subsequent
b
sertion of a carbon unit, which concludes with a ring enlargement
of the heterocycle providing the 1,3-oxazin-6-one derivatives 9.
Hence, when the reactions between 1b,c,g and 7aec were carried

O.A. Attanasi et al. / Tetrahedron 68 (2012) 608e613
611
4. Experimental
z (%) 373 (Mþ, 40), 345 (1), 330 (15), 302 (80), 183 (84), 168 (44), 119
(100). Anal. Calcd for C18H23N5O4 (373.41): C, 57.90; H, 6.21; N,
18.76. Found: C, 58.20; H, 6.10; N, 18.96.
4.1. General experimental section
All chemicals and solvents were purchased from commercial
suppliers and used as received. 1,2-Diaza-1,3-dienes were prepared
as reported6,17 and used as EE/EZ isomer mixtures. Melting points
were determined in open capillary tubes and are uncorrected. FTIR
spectra were obtained as Nujol mulls. Mass spectra (MS) were
carried out by electron ionization (EI, 70 eV) and electrospray. 1H
(400 MHz) and 13C (100 MHz) spectra were recorded in DMSO-d6.
Chemical shifts (dH) are reported in parts per million (ppm), relative
to TMS as internal standard. All coupling constant (J values) are
given in hertz (Hz). Chemical shifts (dC) are reported in parts per
million (ppm), relative to the central peak of DMSO-d6 as internal
standard. The abbreviations used are as follows: s, singlet; d, dou-
blet; dd, double-doublet; t, triplet; q, quartet; m, multiplet; br,
broad; ArH, aromatic hydrogen. All the NH exchanged with D2O.
Precoated silica gel plates 0.25 mm were employed for analytical
4.2.3. Methyl 1-[(tert-butoxycarbonyl)amino]-2-(2-ethoxy-2-
oxoethyl)-5-methyl-1H-imidazole-4-carboxylate (5b). Yield: 0.2560 g
(75%). White solid, mp: 122e124 ꢀC (from THF/n-pentane). IR (Nujol)
nmax 3126,1733,1685,1558,1537 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d
: 1.18 (3H, t, J¼7.2 Hz, OCH2CH3), 1.44 (9H, s, OtBu), 2.28 (3H, s, CH3),
3.61 (1H, d, J¼16.0 Hz, CHaHb), 3.71 (1H, d, J¼16.0 Hz, CHaHb), 3.74
(3H, s, OCH3), 4.07 (2H, q, J¼7.2 Hz, OCH2CH3), 10.61 (1H, s, NH). 13
C
NMR (100 MHz DMSO-d6) d: 9.0 (q), 13.9 (q), 27.7 (q), 32.4 (t), 50.9
(q), 60.8 (t), 81.5 (s), 124.8 (s), 136.9 (s), 141.5 (s), 153.6 (s), 163.2 (s),
167.8 (s). MS (EI): m/z (%) 341 (Mþ, 21), 285 (100), 253 (41), 241 (37),
209 (53), 181 (31), 153 (27), 137 (67), 121 (35). Anal. Calcd for
C15H23N3O6 (341.36): C, 52.78; H, 6.79; N, 12.31. Found: C, 52.93; H,
6.61; N, 12.28.
4.2.4. Methyl 2-(2-ethoxy-2-oxoethyl)-1-[(methoxycarbonyl)amino]-
5-methyl-1H-imidazole-4-carboxylate (5c). Yield: 0.1766 g (59%).
White solid, mp: 118e120 ꢀC (from EtOAc/light petroleum ether). IR
thin layer chromatography and silica gel 35e70
mm for column
chromatography. All new compounds showed satisfactory ele-
mental analysis (Cþ0.35; Hþ0.30; Nþ0.30). The nomenclature was
generated using ACD/IUPAC Name (version 3.50, 5 Apr. 1998), Ad-
vanced Chemistry Development Inc., Toronto, ON (Canada).
(Nujol) nmax 3065, 1752, 1735, 1723, 1594, 1555 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6)
CH3), 3.69e3.74 (8H, m, CH2 and 2 OCH3), 4.05 (2H, q, J¼7.2 Hz,
OCH2CH3), 10.85 (1H, br s, NH). 13C NMR (100 MHz, DMSO-d6)
: 9.1
d: 1.17 (3H, t, J¼7.2 Hz, OCH2CH3), 2.29 (3H, s,
d
4.2. General one-pot procedure for the synthesis of 2-(2-
ethoxy-2-oxoethyl)-1-H-imidazole derivatives 5aei
(q), 13.9 (q), 32.4 (t), 51.7 (q), 53.1 (q), 60.9 (t), 124.9 (s), 136.9 (s),
141.5 (s), 153.6 (s), 163.1 (s), 167.9 (s). MS (EI): m/z (%) 299 (Mþ, 71),
267 (100), 239 (23), 226 (44), 194 (29), 167 (15), 152 (14), 137 (20),
121 (13). Anal. Calcd for C12H17N3O6 (299.28): C, 48.16; H, 5.73; N,
14.04. Found: C, 48.27; H, 5.62; N, 13.93.
To a stirred solution of ethyl 5-oxo-4,5-dihydroisoxazole-4-
carboxylate (2) (0.157 g, 1 mmol) in DMF (2 mL) containing sus-
ꢁ
pended molecular sieves 4 A, the corresponding DD 1 (1 mmol) was
added at room temperature. After the disappearance of the re-
agents (3.5e25 h) (TLC check) and partial evaporation of DMF in
vacuo, the crude was extracted with EtOAc (20 mL) and washed
with brine (5ꢁ5 mL). The organic layer was dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo. The residue was purified
by chromatography (silica gel, cyclohexane/EtOAc or EtOAc/MeOH)
to give 5aei that were crystallized from the appropriate solvent.
4.2.5. Methyl 1-{[(benzyloxy)carbonyl]amino}-2-(2-ethoxy-2-
oxoethyl)-5-methyl-1H-imidazole-4-carboxylate
0.2289 g (61%). White solid, mp: 121e123 ꢀC (from EtOAc/n-pen-
tane). IR (Nujol) nmax 3125, 1740, 1716, 1559 cmꢂ1 1H NMR
(400 MHz, DMSO-d6)
(5d). Yield:
.
d
: 1.15 (3H, t, J¼7.2 Hz, OCH2CH3), 2.28 (3H, s,
CH3), 3.63e3.77 (5H, m, CH2 and OCH3), 4.05 (2H, q, J¼7.2 Hz,
OCH2CH3), 5.20 (2H, s, OCH2Ph), 7.40 (5H, br s, ArH), 11.08 (1H, br s,
NH). 13C NMR (100 MHz, DMSO-d6)
d: 9.1 (q), 13.9 (q), 32.4 (t), 51.0
4.2.1. Ethyl
1-[(anilinocarbonyl)amino]-3-[(dimethylamino)car-
(q), 60.9 (t), 67.2 (t),124.9 (s),128.0 (d), 128.3 (d),128.5 (d), 135.8 (s),
136.9 (s), 141.5 (s), 154.6 (s), 163.1 (s), 167.9 (s). MS (EI): m/z (%) 375
(Mþ, 100), 302 (8), 284 (17), 252 (26), 226 (18), 194 (39), 137 (6), 121
(15). Anal. Calcd for C18H21N3O6 (375.38): C, 57.59; H, 5.64; N, 11.19.
Found: C, 57.70; H, 5.51; N, 10.98.
bonyl]-2-methyl-6-oxo-1,6,7,7a-tetrahydroimidazo[1,2-b]isoxazole-
7-carboxylate (4a). Yield: 0.0125 g (3%). Beige powder; mp:
155e157 ꢀC (from THF/n-pentane). IR (Nujol) nmax 3335, 3194, 1745,
1699, 1649, 1601, 1540 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.16
(3H, t, J¼7.2 Hz, OCH2CH3), 1.83 (3H, s, CH3), 2.88 (3H, s, CH3), 3.12
(3H, s, CH3), 4.16 (2H, q, J¼7.2 Hz, OCH2CH3), 4.50 (1H, d, J¼7.2 Hz,
CH), 4.85 (1H, d, J¼7.2 Hz, CH), 7.01 (1H, t, J¼7.2 Hz, ArH), 7.30 (2H,
t, J¼7.2 Hz, ArH), 7.59 (2H, d, J¼7.2 Hz, ArH), 8.67 (1H, s, NH), 9.96
4.2.6. Ethyl 1-[(aminocarbonyl)amino]-2-(2-ethoxy-2-oxoethyl)-5-
methyl-1H-imidazole-4-carboxylate (5e). Yield: 0.1879 g (63%).
White solid, mp: 195e198 ꢀC (from EtOAc). IR (Nujol) nmax 3372,
3269, 3156, 1744, 1719, 1690, 1596, 1547 cmꢂ1. 1H NMR (400 MHz,
(1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 13.8 (q), 14.8 (q), 35.5
(q), 37.4 (q), 48.9 (d), 50.1 (d), 62.7 (t), 116.8 (s), 119.1 (d), 122.7 (d),
128.9 (d), 139.0 (s), 143.9 (s), 153.3 (s), 165.7 (s), 167.2 (s), 167.6 (s).
MS (EI): m/z (%) 373 [MþꢂCO2, (33)], 328 (31), 301 (41), 281 (24),
235 (49), 210 (80), 182 (100). Anal. Calcd for C19H23N5O6 (417.41): C,
54.67; H, 5.55; N, 16.78. Found: C, 54.49; H, 5.62; N, 16.93.
DMSO-d6)
d
: 1.17 (3H, t, J¼7.2 Hz, OCH2CH3), 1.24 (3H, t, J¼7.2 Hz,
OCH2CH3), 2.28 (3H, s, CH3), 3.57 (1H, d, J¼16.8 Hz, CHaHb), 3.71
(1H, d, J¼16.8 Hz, CHaHb), 4.08 (2H, q, J¼7.2 Hz, OCH2CH3), 4.20 (2H,
q, J¼7.2 Hz, OCH2CH3), 6.44 (2H, s, NH2), 9.45 (1H, s, NH). 13C NMR
(100 MHz, DMSO-d6) d: 9.3 (q), 14.0 (q), 14.3 (q), 32.4 (t), 59.3 (t),
60.8 (t), 124.7 (s), 137.5 (s), 142.5 (s), 156.4 (s), 162.9 (s), 168.2 (s). MS
(EI): m/z (%) 298 (Mþ, 83), 252 (100), 224 (33), 209 (44), 180 (34),
163 (25), 137 (48), 121 (27). Anal. Calcd for C12H18N4O5 (298.30): C,
48.32; H, 6.08; N, 18.78. Found: C, 48.37; H, 6.15; N, 18.65.
4.2.2. Ethyl
{1-[(anilinocarbonyl)amino]-4-[(dimethylamino)car-
bonyl]-5-methyl-1H-imidazol-2-yl}acetate (5a). Yield: 0.2539 g
(68%). Pale yellow solid, mp: 98e100 ꢀC (from EtOAc). IR (Nujol)
nmax 3276, 3220, 1742, 1700, 1618, 1602, 1546 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6)
d
: 1.14 (3H, t, J¼7.2 Hz, OCH2CH3), 2.19 (3H, s,
4.2.7. Benzyl 1-[(tert-butoxycarbonyl)amino]-2-(2-ethoxy-2-
oxoethyl)-5-methyl-1H-imidazole-4-carboxylate (5f). Yield: 0.2672 g
(64%). White solid, mp: 118e119 ꢀC (from THF/n-pentane). IR (Nujol)
nmax 3119,1735,1716,1686,1563 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
CH3), 2.92 (3H, s, CH3), 3.27 (3H, s, CH3), 3.69 (2H, s, CH2), 4.06 (2H,
q, J¼7.2 Hz, OCH2CH3), 7.00 (1H, t, J¼7.8 Hz, ArH), 7.28 (2H, t,
J¼7.8 Hz, ArH), 7.45 (2H, d, J¼7.8 Hz, ArH), 9.37 (1H, s, NH), 9.51 (1H,
s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 9.0 (q), 13.9 (q), 32.6 (t),
d
: 1.17 (3H, t, J¼7.2 Hz, OCH2CH3), 1.45 (9H, s, OtBu), 2.29 (3H, s, CH3),
35.3 (q), 38.3 (q), 60.8 (t), 118.8 (d), 122.6 (d), 128.7 (s), 128.8 (d),
133.9 (s), 139.0 (s), 139.7 (s), 153.4 (s), 164.4 (s), 168.3 (s). MS (EI): m/
3.62 (1H, d, J¼16.8 Hz, CHaHb), 3.73 (1H, d, J¼16.8 Hz, CHaHb), 4.07
(2H, q, J¼7.2 Hz, OCH2CH3), 5.25 (2H, s, OCH2Ph), 7.34e7.44 (5H, m,

612
O.A. Attanasi et al. / Tetrahedron 68 (2012) 608e613
ArH), 10.63 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 9.1 (q), 13.9
butoxycarbonyl)ethanehydrazonoyl]succinate
astereomer. Light pink solid, mp: 117e121 ꢀC (from EtOAc/Et2O). IR
(Nujol) nmax 3226, 3168, 1744, 1711, 1589, 1531 cmꢂ1 1H NMR
(6). Major
di-
(q), 27.7 (q), 32.4 (t), 60.8 (t), 65.1 (t), 81.6 (s),124.7 (s),128.0 (d),128.1
(d), 128.4 (d), 136.4 (s), 137.3 (s), 141.7 (s), 153.6 (s), 162.5 (s), 167.8 (s).
MS (EI): m/z (%) 417 (Mþ, 9), 317 (11), 311 (14), 283 (23), 255 (25), 227
(100), 211 (15), 183 (46), 168 (12). Anal. Calcd for C21H27N3O6
(417.46): C, 60.42; H, 6.52; N, 10.07. Found: C, 60.24; H, 6.67; N, 10.16.
.
(400 MHz, DMSO-d6)
d
: 1.05 (3H, t, J¼6.8 Hz, OCH2CH3), 1.45 (9H, s,
OtBu), 1.50 (9H, s, OtBu),1.80 (3H, s, CH3), 2.24 (3H, s, CH3), 3.68 (3H,
s, OCH3), 3.71 (3H, s, OCH3), 3.87e3.91 (1H, m, OCHaHbCH3),
3.99e4.07 (2H, m, OCHaHbCH3 and CH), 4.58 (1H, d, J¼11.6 Hz, CH),
4.2.8. Methyl 1-[(anilinocarbonyl)amino]-2-(2-ethoxy-2-oxoethyl)-
5-methyl-1H-imidazole-4-carboxylate (5g). Yield: 0.1910 g (53%).
White solid, mp: 178e179 ꢀC (from DCM/n-pentane). IR (Nujol)
10.12 (1H, s, NH), 10.58 (1H, s, NH). 13C NMR (100 MHz, DMSO-d6)
d:
9.0 (q), 13.6 (q), 16.8 (q), 27.7 (q), 27.8 (q), 40.4 (d), 50.9 (q), 52.7 (q),
54.6 (d), 61.1 (t), 81.0 (s), 81.2 (s), 125.0 (s), 136.9 (s), 143.7 (s), 147.2
(s), 152.9 (s), 154.9 (s), 163.0 (s), 168.6 (s), 170.1 (s). MS (EI): m/z (%)
569 (Mþ, 36), 469 (18), 397 (55), 338 (99), 306 (52), 278 (100). Anal.
Calcd for C25H39N5O10 (569.60): C, 52.72; H, 6.90; N, 12.30. Found:
C, 52.84; H, 6.69; N, 12.22.
nmax 3340, 3298, 1745, 1730, 1703, 1608, 1561 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6)
d
: 1.12 (3H, t, J¼7.2 Hz, OCH2CH3), 2.33 (3H, s,
CH3), 3.68e3.75 (5H, m, CH2 and OCH3), 4.06 (2H, q, J¼7.2 Hz,
OCH2CH3), 7.00 (1H, t, J¼7.2 Hz, ArH), 7.28 (2H, t, J¼7.2 Hz, ArH),
7.45 (2H, d, J¼7.2 Hz, ArH), 9.39 (1H, s, NH), 9.65 (1H, s, NH). 13C
NMR (100 MHz, DMSO-d6)
d
: 9.4 (q), 13.9 (q), 32.5 (t), 50.9 (q), 60.8
4.4. General one-pot procedure for the synthesis of 2,2,4,5-
(t), 118.8 (d), 122.6 (d), 124.7 (s), 128.8 (d), 137.9 (s), 138.9 (s), 142.1
(s), 153.2 (s), 163.3 (s), 168.1 (s). MS (EI): m/z (%) 360 (Mþ, 100), 328
(16), 268 (38), 241 (85), 236 (55), 209 (67), 181 (20), 137 (60), 121
(49),119 (71). Anal. Calcd for C17H20N4O5 (360.36): C, 56.66; H, 5.59;
N, 15.55. Found: C, 56.45; H, 5.77; N, 15.72.
tetrasubstituted 1,3-oxazin-6-one derivatives 9aee
To a stirred solution of DD 1b,c,g (2 mmol) in CHCl3 (4 mL)
ꢁ
containing molecular sieves 4 A, isoxazol-5-one derivative 7aec
(1 mmol) was added portionwise within 2e3 h at room tempera-
ture. After the disappearance of 7aec (2 h) the reaction mixture
was left at room temperature until the consumption of 1b,c,g was
complete (3e5 h, TLC check). The solvent was removed in vacuo
and 9aed were obtained by crystallization from appropriate sol-
vents after a chromatographic separation, whereas 9e was collected
by crystallization from the crude reaction mixture.
4.2.9. Methyl 1-{[(benzyloxy)carbonyl]amino}-2-(2-ethoxy-2-
oxoethyl)-5-ethyl-1H-imidazole-4-carboxylate (5h). Yield: 0.2180 g
(56%). White solid, mp: 115e116 ꢀC (from EtOAc/Et2O). IR (Nujol)
nmax 3153, 1751, 1714, 1564 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d:
1.02 (3H, t, J¼6.8 Hz, CH2CH3), 1.15 (3H, t, J¼7.2 Hz, OCH2CH3),
2.61e2.78 (2H, m, CH2CH3), 3.62 (1H, d, J¼16.8 Hz, CHaHb),
3.70e3.74 (4H, m, CHaHb and OCH3), 4.06 (2H, q, J¼7.2 Hz,
OCH2CH3), 5.21 (2H, br s, OCH2Ph), 7.36e7.41 (5H, m, ArH), 11.12
4.4.1. tert-Butyl 2-[(1E)-3-methoxy-1-methyl-3-oxo-2-(5-oxo-3-
phenyl-4,5-dihydroisoxazol-4-yl)prop-1-en-1-yl]hydrazinecarbox-
ylate (8a). White powder, mp: 95e98 ꢀC, (EtOAc/Et2O). IR (Nujol)
(1H, br s, NH). 13C NMR (100 MHz DMSO-d6)
d: 12.9 (q), 13.9 (q),
16.6 (t), 32.4 (t), 50.9 (q), 60.9 (t), 67.2 (t), 124.3 (s), 127.9 (d), 128.3
(d), 128.5 (d), 135.8 (s), 141.5 (s), 142.2 (s), 154.8 (s), 162.9 (s), 167.8
(s). MS (EI): m/z (%) 389 (Mþ, 83), 357 (100), 329 (9), 266 (42), 238
(10), 222 (25), 208 (29). Anal. Calcd for C19H23N3O6 (389.40): C,
58.60; H, 5.95; N, 10.79. Found: C, 58.52; H, 6.12; N, 10.90.
nmax 3257, 3195, 1755, 1720, 1707, 1701, 1656, 1596 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d
: 1.45 (9H, s, OtBu), 1.97 (3H, s CH3), 3.71 (3H,
s, OCH3), 5.16 (1H, s, CH), 7.51e7.58 (3H, m, ArH), 7.71 (2H, d,
J¼7.2 Hz, ArH), 9.03 (1H, s, NH), 10.19 (1H, s, NH). 13C NMR
(100 MHz, DMSO-d6) d: 12.4 (q), 28.0 (q), 52.9 (q), 79.9 (s), 86.3 (d),
91.8 (s), 127.3 (d), 128.8 (d), 131.7 (d), 132.0 (s), 145.3 (s), 152.6 (s),
158.7 (s), 162.2 (s), 169.1 (s). MS (EI): m/z (%) 389 (Mþ, 2), 345 (5),
289 (9), 274 (100), 229 (44), 170 (24), 103 (44). Anal. Calcd for
C19H23N3O6 (389.40): C, 58.60; H, 5.95; N, 10.79. Found: C, 58.78; H,
6.07; N, 10.62.
4.2.10. Methyl 1-[(tert-butoxycarbonyl)amino]-2-(2-ethoxy-2-
oxoethyl)-5-ethyl-1H-imidazole-4-carboxylate (5i). Yield: 0.2025 g
(57%). White solid, mp: 132e133 ꢀC (from EtOAc/n-pentane). IR
(Nujol) nmax 3116, 1737, 1715, 1685, 1545 cmꢂ1. 1H NMR (400 MHz,
DMSO-d6)
d
: 1.06 (3H, t, J¼7.2 Hz, CH2CH3), 1.18 (3H, t, J¼7.2 Hz,
OCH2CH3), 1.45 (9H, s, OtBu), 2.65e2.76 (2H, m, CH2CH3), 3.59 (1H,
d, J¼16.0 Hz, CHaHb), 3.70 (1H, d, J¼16.0 Hz, CHaHb), 3.74 (3H, s,
OCH3), 4.05e4.11 (2H, m, OCH2CH3), 10.72 (1H, s, NH). 13C NMR
4.4.2. Methyl 2-[N-(tert-butoxycarbonyl)ethanehydrazonoyl]-5-{2-
[2-(tert-butoxycarbonyl)hydrazono]-1-(methoxycarbonyl)propyl}-6-
oxo-4-phenyl-3,6-dihydro-2H-1,3-oxazine-2-carboxylate
(9a). Major diastereomer. Light yellow powder from Et2O. IR
(Nujol) nmax 3405, 3229, 3183, 1752, 1709, 1703, 1689, 1600, 1564,
(100 MHz, DMSO-d6) d: 12.9 (q), 14.0 (q), 16.6 (t), 27.7 (q), 32.4 (t),
50.9 (q), 60.8 (t), 81.5 (s),124.2 (s), 141.6 (s),142.3 (s),153.7 (s),163.0
(s), 167.7 (s). MS (EI): m/z (%) 355 (Mþ, 14), 299 (76), 267 (100), 255
(9), 223 (38), 195 (27). Anal. Calcd for C16H25N3O6 (355.39): C,
54.07; H, 7.09; N, 11.82. Found: C, 54.19; H, 6.87; N, 11.90.
1528 cmꢂ1. 1H NMR (400 MHz, DMSO-d6) : 1.37 (9H, s, OtBu), 1.45
d
(9H, s, OtBu), 1.69 (3H, s CH3), 1.95 (3H, s, CH3), 3.56 (3H, s, OCH3),
3.72 (3H, s, OCH3), 4.03 (1H, s, CH), 7.37e7.54 (5H, m, ArH), 9.24
(1H, s, NH), 9.39 (1H, s, NH), 10.16 (1H, s, NH). 13C NMR (100 MHz,
4.3. General one-pot procedure for the synthesis of 6
DMSO-d6) d: 12.4 (q), 13.7 (q), 27.9 (q), 28.0 (q), 51.3 (d), 51.9 (q),
53.0 (q), 78.9 (s), 80.0 (s), 91.0 (s), 95.7 (s), 128.8 (d), 129.3 (d), 130.7
(d), 132.0 (s), 143.6 (s), 152.5 (s), 152.8 (s), 159.1 (s), 162.5 (s), 169.3
(s), 171.5 (s). MS (ESI): m/z 618 [MþH]þ, 640 [MþNa]þ. Anal. Calcd
for C29H39N5O10 (617.64): C, 56.39; H, 6.36; N, 11.34. Found: C,
56.45; H, 6.18; N, 11.43.
To a stirred solution of DD 1b (0.456 g, 2 mmol) in CHCl3 (6 mL)
containing molecular sieves 4 A, ethyl 5-oxo-4,5-dihydroisoxazole-
ꢁ
4-carboxylate (2) (0.157 g, 1 mmol) was added portionwise within
3 h at room temperature. After the disappearance of 2 (2 h) the
reaction mixture showed the presence of predominant 5b over 6
(TLC check) and was left under magnetic stirring until 1b was
completely consumed (16 h) (TLC monitoring). Then, the solvent
was removed and the residue was chromatographed yielding 6 as
mixture of diastereoisomers in 85%. Analytically pure diastereomer
was obtained by recrystallization from EtOAc/Et2O.
4.4.3. Methyl
2-[N-(methoxycarbonyl)ethanehydrazonoyl]-5-{1-
[methoxycarbonyl]-2-[2-(methoxycarbonyl)hydrazino]-prop-1-en-1-
yl}-6-oxo-4-phenyl-3,6-dihydro-2H-1,3-oxazine-2-carboxylate
(9b). Beige powder from Et2O. IR (Nujol) nmax, 3290, 3244, 3201,
1768, 1755, 1736, 1681, 1671, 1641, 1588, 1567 cmꢂ1 1H NMR
.
(400 MHz, DMSO-d6) d: 1.36 and 1.70 (3H, 2s, CH3), 1.96 and 1.98
4.3.1. 1-Ethyl 4-methyl 2-{1-[(tert-butoxycarbonyl)amino]-4-(me-
thoxycarbonyl)-5-methyl-1H-imidazol-2-yl}-3-[N-(tert-
(3H, 2s, CH3), 3.52, 3.57, 3.69, 3.75 and 3.78 (12H, 5s, 4 OCH3),
7.35e7.43 (5H, m, ArH), 8.77 and 8.88 (1H, 2s, NH), 9.19 and 9.34

O.A. Attanasi et al. / Tetrahedron 68 (2012) 608e613
613
(1H, 2br s, NH), 9.87 and 9.92 (1H, 2s, NH), 10.42 and 10.49 (1H, 2s,
NH). 13C NMR (100 MHz, DMSO-d6)
: 12.5 (q),14.1 (q),15.5 (q), 50.3
53.0 (q), 53.1 (q), 87.6 (s), 88.4 (s), 90.9 (s), 91.3 (s), 98.0 (s), 98.3 (s),
123.0 (d), 123.3 (d), 123.6 (d), 129.5 (d), 129.6 (d), 140.1 (s), 140.5 (s),
145.0 (s), 148.0 (s), 148.1 (s), 154.3 (s), 155.9 (s), 156.5 (s), 162.0 (s),
162.1 (s), 162.4 (s), 168.5 (s), 168.9 (s), 169.2 (s), 170.1 (s). MS (ESI):
m/z 579 [MþH]þ, 601 [MþNa]þ. Anal. Calcd for C23H26N6O12
(578.48): C, 47.75; H, 4.53; N, 14.53. Found: C, 47.91; H, 4.43; N,
14.36.
d
(q), 50.6 (q), 52.1 (q), 52.2 (q), 52.9 (q), 53.0 (q), 88.3 (s), 89.0 (s),
90.7 (s), 91.1 (s), 96.5 (s), 96.9 (s), 127.9 (d), 128.0 (d), 128.1 (d), 129.9
(d), 130.2 (d), 133.9 (s), 134.2 (s), 145.3 (s), 154.2 (s), 156.6 (s), 157.7
(s), 158.5 (s), 162.0 (s), 162.4 (s), 162.6 (s), 168.9 (s), 169.3 (s), 169.7
(s), 170.4 (s). MS (ESI): m/z 534 [MþH]þ, 556 [MþNa]þ. Anal. Calcd
for C23H27N5O10 (533.48): C, 51.78; H, 5.10; N,13.13. Found: C, 51.98;
H, 5.02; N, 13.09.
Acknowledgements
4.4.4. Methyl
2-[N-(methoxycarbonyl)ethanehydrazonoyl]-5-{1-
Financial support from the Ministero dell’Istruzione,
[methoxycarbonyl]-2-[2-(methoxycarbonyl)hydrazino]-prop-1-en-1-
yl}-6-oxo-4-methyl-3,6-dihydro-2H-1,3-oxazine-2-carboxylate
(9c). White powder from DCM/n-pentane. IR (Nujol) nmax, 3470,
ꢀ
dell’Universita e della Ricerca (MIUR)-Roma and from the Univer-
sity of Urbino ‘Carlo Bo’ is gratefully acknowledged.
3267, 3206, 1751, 1721, 1674, 1605, 1586 cmꢂ1 1H NMR (400 MHz,
.
Supplementary data
DMSO-d6) d: 1.57 and 1.65 (3H, 2s, CH3), 1.75 (3H, s, CH3), 1.94 and
1.96 (3H, 2s, CH3), 3.45, 3.49, 3.61, 3.67, 3.68 and 3.71 (12H, 6s, 4
OCH3), 8.69 and 8.85 (1H, 2s, NH), 9.39 (1H, br s, NH), 10.04 and
10.07 (1H, 2s, NH), 10.42 and 10.48 (1H, 2s, NH). 13C NMR (100 MHz,
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.10.118.
DMSO-d6) d: 12.2 (q),14.2 (q),14.7 (q),17.0 (q),17.1 (q), 50.6 (q), 52.2
(q), 52.7 (q), 52.9 (q), 88.0 (s), 88.6 (s), 90.5 (s), 90.6 (s), 96.3 (s), 96.6
(s), 145.5 (s), 154.2 (s), 156.8 (s), 159.2 (s), 159.5 (s), 161.6 (s), 162.9
(s),163.5 (s),169.3 (s),169.5 (s),169.6 (s),170.4 (s). MS (ESI): m/z 472
[MþH]þ, 494 [MþNa]þ. Anal. Calcd for C18H25N5O10 (471.41): C,
45.86; H, 5.35; N, 14.86. Found: C, 45.98; H, 5.18; N, 14.65.
References and notes
1. Azaheterocycles Based on a,b-Unsaturated Carbonyls; Chebanov, A. V., Desenko,
S. M., Gurley, T. W., Eds.; Springer: Berlin Heidelberg, 2008.
2. Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931e948.
3. Jin, Z. Nat. Prod. Rep. 2009, 26, 382e445.
4. (a) Grimmet, M. R. Imidazoles In. Comprehensive Heterocyclic Chemistry II; Ka-
tritzky, A. R., Rees, C. W., Scriven, E. F. W., Eds.; Pergamon: Oxford, 1996; Vol. 3;
(b) Xi, N.; Huang, Q.; Liu, L. Imidazoles In. Comprehensive Heterocyclic Chemistry
III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. W., Taylor, R. J. K., Eds.; Elsevier:
Oxford, 2008; Vol. 4.
5. (a) De Luca, L. Curr. Med. Chem. 2006, 13, 1e23; (b) Nantermet, P.; Barrow, G.;
Lindsley, S. R.; Young, M.; Mao, S.; Carroll, S.; Bailey, C.; Bossermann, M.; Co-
lussi, D.; McMasters, D. R.; Vacca, J. P.; Selnick, H. G. Bioorg. Med. Chem. Lett.
2004, 14, 2141e2145; (c) Jyoti, P.; Vinod, T. K.; Shyam, V. S.; Vinita, C.; Bhat-
nagar, S.; Sinha, S.; Gaikwad, A. N.; Tripathi, R. P. Eur. J. Med. Chem. 2009, 44,
3350e3355; (d) Carini, D. J.; Duncia, J. V.; Johnson, A. L.; Chiu, A. T.; Price, W. A.;
Wong, P. C.; Timmermans, P. B. M. W. J. Med. Chem. 1990, 33, 1330e1336.
6. Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli,
F. R.; Santeusanio, S. Eur. J. Org. Chem. 2009, 3109e3127.
4.4.5. Methyl
2-[N-(anilinocarbonyl)ethanehydrazonoyl]-5-{2-[2-
(anilinocarbonyl)hydrazono]-1-(methoxycarbonyl)-propyl}-6-oxo-4-
phenyl-3,6-dihydro-2H-1,3-oxazine-2-carboxylate (9d). Light yellow
powder from EtOAc/Et2O. IR (Nujol) nmax 3353, 3323, 3192, 1746,
1708, 1686, 1596, 1534 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
d: 1.76
and 1.78 (3H, 2s, CH3),1.98 and 2.04 (3H, 2s, CH3), 3.57 and 3.62 (3H,
2s, OCH3), 3.73 and 3.87 (3H, 2s, OCH3), 3.96 and 4.14 (1H, 2s, CH),
6.97e7.05 (2H, m, ArH), 7.28e7.32 (4H, m, ArH), 7.43e7.60 (9H, m,
ArH), 8.16 and 8.19 (1H, 2s, NH), 8.69 (1H, s, NH), 9.24 and 9.37 (1H,
2s, NH), 9.59 and 9.65 (1H, 2s, NH), 10.22 (1H, s, NH). 13C NMR
7. (a) Preti, L.; Attanasi, O. A.; Caselli, E.; Favi, G.; Ori, C.; Davoli, P.; Felluga, F.; Prati,
F. Eur. J. Org. Chem. 2010, 4312e4320; (b) Attanasi, O. A.; Caselli, E.; Davoli, P.;
Favi, G.; Mantellini, F.; Ori, C.; Prati, F. Org. Lett. 2009, 11, 2840e2843; (c) At-
tanasi, O. A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.; Moscatelli, G.; Prati, F.
Org. Lett. 2007, 9, 3461e3464.
(100 MHz, DMSO-d6) d: 12.2 (q), 12.3 (q), 14.9 (q), 15.5 (q), 51.2 (d),
51.8 (d), 51.9 (q), 52.0 (q), 53.6 (q), 53.7 (q), 89.9 (s), 97.1 (s), 118.2
(d), 118.5 (d), 119.3 (d), 119.5 (d), 122.3 (d), 123.0 (d), 128.3 (d), 128.7
(d), 128.8 (d), 128.9 (d), 130.9 (d), 132.1 (s), 138.3 (s), 138.4 (s), 138.8
(s), 140.9 (s), 141.2 (s), 147.1 (s),147.5 (s), 152.6 (s), 153.0 (s),158.4 (s),
158.5 (s), 162.5 (s), 162.8 (s), 169.3 (s), 169.5 (s), 171.2 (s). MS (ESI):
m/z 656 [MþH]þ, 678 [MþNa]þ. Anal. Calcd for C33H33N7O8
(655.65): C, 60.45; H, 5.07; N, 14.95. Found: C, 60.62; H, 5.12; N,
14.76.
8. Attanasi, O. A.; Bartoccini, S.; Giorgi, G.; Mantellini, F.; Perrulli, F. R.; Santeu-
sanio, S. Tetrahedron 2010, 66, 5121e5129.
9. (a) Beccalli, E. M.; Marchesini, A. J. Org. Chem. 1987, 52, 1666e1669; (b) Attanasi,
O. A.; Filippone, P.; Fiorucci, C.; Mantellini, F. Chem. Lett. 2000, 984e985; (c)
ꢀ
Risitano, F.; Grassi, G.; Foti, F.; Nicolo, F.; Condello, M. Tetrahedron 2002, 58,
191e195; (d) Chande, M. S.; Verna, R. S.; Barve, P. A.; Khanwelkar, R. R.; Vaidya,
R. B.; Ajaikumar, K. B. Eur. J. Med. Chem. 2005, 40, 1143e1148.
10. (a) Beccalli, E. M.; Marchesini, A.; Pilati, T. Synthesis 1991, 127e131; (b) Prager,
R. H.; Singh, Y.; Weber, B. Aust. J. Chem. 1994, 47, 1249e1262; (c) Prager, R. H.;
Singh, Y. Tetrahedron 1993, 49, 8147e8158.
4.4.6. Methyl
2-[N-(methoxycarbonyl)ethanehydrazonoyl]-5-{1-
[methoxycarbonyl]-2-[2-(methoxycarbonyl)hydrazino]-prop-1-en-1-
yl}-4-(4-nitrophenyl)-6-oxo-3,6-dihydro-2H-1,3-oxazine-2-carboxyl-
11. (a) Zvilichovskj, G.; Gbara-Haj-Yahia, I. J. Org. Chem. 2004, 69, 4966e4973; (b)
Rao, M. H.; Reddy, A. P. R.; Veeranagaiah, V. Synthesis 1992, 446e448.
12. Beccalli, E. M.; Pocar, D.; Zoni, C. In Targets in Heterocyclic Chemistry; Attanasi,
O. A., Spinelli, D., Eds.; Italian Chemical Society: Rome, 2003; Vol. 7, pp 31e63.
13. Cox, M.; Prager, R. H.; Riessen, D. M. ARKIVOC 2001, vii, 88e103.
14. (a) Marciniak, G.; Decolin, D.; Leclerc, G.; Decker, N.; Schwartz, J. J. Med. Chem.
1988, 31, 2289e2296; (b) Kruse, L. I.; Kaiser, C.; DeWolf, W. E.; Finkelstein, J. A.;
Frazee, J. S.; Hilbert, E. L.; Ross, S. T.; Flaim, K. E.; Sawyer, J. L. J. Med. Chem. 1990,
33, 781e789.
ate (9e). Orange powder from CHCl3/n-pentane. IR (Nujol) nmax
3413, 3373, 3297, 3188, 1758, 1744, 1717, 1686, 1670, 1604,
1560 cmꢂ1. 1H NMR (400 MHz, DMSO-d6)
: 1.40 and 1.67 (3H, 2s,
,
d
CH3), 1.98 and 2.00 (3H, 2s, CH3), 3.39 and 3.51 (3H, 2s, OCH3), 3.57
(3H, s, OCH3), 3.69 and 3.70 (3H, 2s, OCH3), 3.77 and 3.80 (3H, 2s,
OCH3), 7.58e7.63 (2H, m, ArH), 8.23e8.30 (2H, m, ArH), 9.02 and
9.21 (1H, s and br s, NH), 9.16 (1H, s, NH), 9.84 and 9.91 (1H, 2s, NH),
ꢂ
ꢂ
15. Mloston, G.; Jasinski, M.; Heimgartner, H. Eur. J. Org. Chem. 2011, 2542e2547.
16. Ha, J. D.; Lee, S. J.; Nam, S. Y.; Kang, S. K.; Cho, S. Y.; Ahn, J. H.; Choi, J.-K. Tet-
rahedron Lett. 2006, 47, 6201e6204.
10.45 and 10.52 (1H, 2s, NH). 13C NMR (100 MHz, DMSO-d6)
d: 12.4
17. (a) Sommer, S. Tetrahedron Lett. 1977, 18, 117e120; (b) Attanasi, O. A.; Filippone,
(q), 14.3 (q), 15.4 (q), 50.4 (q), 50.7 (q), 52.0 (q), 52.1 (q), 52.2 (q),
P.; Mei, A.; Santeusanio, S. Synthesis 1984, 671e672.