Regioselective synthesis of spiro-cyclopropanated 1-aminopyrrol-2-ones by Bi(OTf)3-catalyzed one-pot 'Mukaiyama-Michael addition/cyclization/ring-contraction' reactions of 1,2-bis(trimethylsilyloxy)cyclobutene with 1,2-diaza-1,3-butadienes

Article abstract of DOI:10.1016/j.tet.2009.04.018

Unknown spiro-cyclopropanated 1-aminopyrrol-2-ones are regioselectively prepared in high yields by Bi(OTf)₃-catalyzed one-pot 'Mukaiyama-Michael addition/cyclization/ring-contraction' reactions of 1,2-bis(trimethylsilyloxy)cyclobutene with 1,2-

Full text of DOI:10.1016/j.tet.2009.04.018

Tetrahedron 65 (2009) 5456–5461
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective synthesis of spiro-cyclopropanated 1-aminopyrrol-2-ones by
Bi(OTf)3-catalyzed one-pot ‘Mukaiyama–Michael addition/cyclization/ring-
contraction’ reactions of 1,2-bis(trimethylsilyloxy)cyclobutene with
1,2-diaza-1,3-butadienes
,
a
b
a
c
Orazio A. Attanasi a , Gianfranco Favi , Gianluca Giorgi , Fabio Mantellini , Vahuni Karapetyan ,
*
,d,
Peter Langer c
*
a
`
Istituto di Chimica Organica, Universita degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino, Italy
b
`
Centro Interdipartimentale di Analisi e Determinazioni Strutturali, Universita degli Studi di Siena, Via Aldo Moro 53100, Italy
c Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
d Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Unknown spiro-cyclopropanated 1-aminopyrrol-2-ones are regioselectively prepared in high yields by
Bi(OTf)3-catalyzed one-pot ‘Mukaiyama–Michael addition/cyclization/ring-contraction’ reactions of 1,2-
bis(trimethylsilyloxy)cyclobutene with 1,2-diaza-1,3-butadienes at room temperature.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 20 March 2009
Received in revised form 29 March 2009
Accepted 1 April 2009
Available online 14 April 2009
1. Introduction
workers reported the preparation of spiro-cyclopropanated ana-
logues of bioactive demethoxyfumitremorgine C and tadalafil using
Spirocyclic compounds occur in diverse natural products and in
many drugs.1 Among them, the spiro-cyclopropyl moiety is present in
the skeleton of many biologically significant molecules such as highly
cytotoxic sesquiterpene illudins M and S (Chart 1), semisynthetic
derivative antitumor agent (ꢀ)-irofulven (HMAF), and the taxane-AB
fragment.2 Recently, one of us reported the synthesis of 1-hydroxy-
spiro[2.5]cyclooct-4-en-3-ones, which show a considerable anti-
proliferative activity against human HL 60 cells (leukemia) (Chart 1).3
A strong cancerostatic activity was also reported for the CC-1065 or
duocarmycin SA (Chart 2).4 In a recent paper, de Meijere and co-
methyl 2-chloro-2-cyclopropylideneacetate as a building block.5
Also, a synthesisofspiroannelated analogues of fungicide Iprodione is
reported.6 In addition, spiro[cyclopropan-1,30-oxindoles] are used as
starting materials for alkaloid synthesis of oxindoles7 as exemplified
recently in the first elegant total synthesis of strychnofoline by Car-
reira and Lerchner.8
Therefore, interest in developing new strategies that can give
rise to spiro-cyclopropane derivatives2–11 has risen considerably
due to the inherent rigidity displayed together by the spiro and
cyclopropane12 functionality.
On the other hand, pyrroles and their derivatives are important
classes of heterocycles broadly used in material science and can be
found in many natural and medicinally active compounds.13 Re-
cently, 1-aminopyrroles have been used as building blocks during
the synthesis of analgesic14 and NMDA receptor antagonists.15
Me
R
O
O
O
OH
Me
OEt
Me
HO
Me
HO
Me
O
H
1-Hydroxyspiro[2.5]-
cyclooct-4-en-3-one
Illudin M; R = Me
Illudin S; R = CH2OH
N
O
H
N
OMe
OMe
MeO2C
N
Chart 1.
OMe
Duocarmyin SA
* Corresponding authors.
E-mail address: orazio.attanasi@uniurb.it (O.A. Attanasi).
Chart 2.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.018

O.A. Attanasi et al. / Tetrahedron 65 (2009) 5456–5461
5457
R3
O
N
1) Bi(TfO)3
(20%)
CH2Cl2, r.t.
NHR3
N
O
N
NH2
NH2
TMSO
+
R2
N
1) L.A.
CH2Cl2, r.t.
O
HN
N
R2
TMSO
+
N
Me
O
Me
R1O2C
2) TFA
TMSO
R1O2C
2) TFA
TMSO
EtO2C
EtO2C
1a-n
2
3a-n
3a
1a
2
Scheme 2. Synthesis of 3a–n.
TMSOH
TFA
TMSOH
NH2
afforded, after addition of trifluoroacetic acid (TFA), removal of the
solvent, and chromatographic purification, new and unexpected
spiro-cyclopropanated pyrrol-2-one 3a in 50% yield (Scheme 1,
Table 1, entry 1).
O
O
NH2
HN
N
HN
N
O
O
H
Me
Me
To identify suitable conditions for the process, the series of
Lewis acids depicted in Table 1 was screened. Various Lewis acids
such as ZnCl2, InBr3, LiClO4, Sc(TfO)3, Y(TfO)3, In(TfO)3, Bi(TfO)3,
Sm(TfO)3, or Yb(TfO)3 were found active. Among them, the rela-
EtO2C
H
OTMS
EtO2C
OTMS
A
B
25
tively common and inexpensive Bi(TfO)3 gave the best result at
Scheme 1. Possible mechanism for the formation of 3a–n.
room temperature (Table 1, entry 8). The InCl3 catalyst was in-
effective for the reaction providing only chloro-hydrazonic adduct
(Table 1, entry 2).
Although numerous methods have been developed for the syn-
thesis of pyrroles, direct syntheses of 1-aminopyrroles are much
more rare. In contrast to this literature scenario, no structures of
spiro-cyclopropanated pyrrol-2-ones have been found.
The formation of 3a can be rationalized as shown in Scheme 1.
The Lewis acid catalyzed Mukaiyama–Michael addition of 2 at the
terminal carbon of the azo–ene system of 1a gave hydrazonic in-
termediate A. Subsequently, five-membered ring closure affords
hydroxy-1-aminopyrroline B by internal nucleophilic attack of the
nitrogen atom at the carbonyl group. In turn, the addition of TFA
results in the cleavage of the silyl groups, and cyclobutane ring
contraction with concomitant loss of a water molecule (pinacol-like
rearrangement) provided the final spiro-cyclopropanated pyrrol-2-
one (Scheme 1).
The chemistry of 1,2-diaza-1,3-butadienes16 has been exten-
sively studied by some of us. Recently, we have reported the syn-
thesis of 1-aminopyrrol-2-ones, 1-aminopyrroles and pyrazoles by
‘Mukaiyama–Michael addition/cyclization’ reactions of 1,2-diaza-
1,3-butadienes with silyl enol ethers,17 Danishefsky’s dienes,18 and
1,3-bis(silyloxy)-1,3-butadienes.19
In connection with our ongoing interest in developing new syn-
thetic strategies for the construction of heterocycle rings, herein, we
report what are, to the best of our knowledge, the first one-pot
‘Mukaiyama–Michael addition/cyclization/ring-contraction’ re-
actions of 1,2-diaza-1,3-butadienes with 1,2-bis(trimethylsilyloxy)-
cyclobutene. These reactions provide a convenient approach to
functionalized spiro-cyclopropanated 1-aminopyrrol-2-ones, which
are not readily available by other methods.
The conjugate addition of nucleophiles to a,b-unsaturated car-
bonyl compounds represents one of the most powerful methods for
the formation of carbon–carbon bonds.26 The use of silyl enol
ethers in Lewis acid catalyzed conjugate additions, introduced by
Mukaiyama and co-workers, offers a mild alternative to base-me-
diated variants.27,28
It is worthy of note that in this case the reaction proceed with
cyclobutane ring contraction in concert with cyclization and no
cyclobutane ring expansion products were isolated.23,24 The only
example of formation of spiro-cyclopropane derivatives that pro-
ceed with an analogous pinacol-like rearrangement has been pre-
viously reported by Hanna and Ricard.29
Under the optimized conditions, the cyclization of 1,2-diaza-1,3-
butadienes 1a–n with 2 afforded the spiro-cyclopropanated pyrrol-
2-ones 3a–n in 32–98% yield (Scheme 2, Table 2).
The chemistry of 1,3-bis(silyloxy)-1,3-butadienes has been
reviewed.20,21 Reactions of 1,2-bis(trimethylsilyloxy)cyclobutene,
available by the method reported by Ru¨hlmann,22 are more rare.
For example, the geminal acylation of ketones and ketals has been
studied in details. These transformations proceed by Lewis acid-
mediated reaction of 1,2-bis(trimethylsilyloxy)cyclobutene onto
the ketone and subsequent acid-mediated rearrangement with
ring-enlargement.23 Burnell and Gao reported the synthesis of
cyclopentane-1,3-diones.24
2. Results and discussion
Table 2
Synthesis of 3a–n
Exploratory reaction between 1,2-bis(trimethylsilyloxy)-
cyclobutene 2 and 1,2-diaza-1,3-butadiene 1a catalyzed by ZnCl2
3
R1
R2
R3
Yielda (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Et
Me
i-Pr
Bn
Me
Et
Et
Et
Et
allyl
Me
Et
(CH2)2OCH3
i-Pr
Me
Me
Me
Me
Et
Me
Me
Me
Pr
Me
CH2CO2Me
CH2CO2Et
Me
CONH2
CONH2
CONH2
CONH2
CONH2
CONHPh
Ph
85
79
98
81
87
64
86
32b
82
94
75
54
56
60
Table 1
Screening activity of various Lewis acids (L.A.)
Entry
Catalyst
Reaction time
Yielda (%)
1
2
3
4
5
6
7
8
9
10
ZnCl2
InCl3
InBr3
LiClO4
Sc(TfO)3
Y(TfO)3
In(TfO)3
Bi(TfO)3
Sm(TfO)3
Yb(TfO)3
10 h
d
50
d
>48 h
>48 h
0.5 h
12 h
2 h
0.01 h
6 h
0.5 h
30
34
84
67
49
85
74
80
Ts
CONH2
CONH2
CONH2
CONH2
CONHPh
CONHPh
Me
a
Isolated yields.
Compound 3h was obtained without quenching with TFA.
a
b
Isolated yields.

5458
O.A. Attanasi et al. / Tetrahedron 65 (2009) 5456–5461
Figure 1. Ortep plot of 3g (50% probability level).
TMSO
TMSO
4. Experimental section
OEt
TMSO
EtO
TMSO
TMSO
R
4.1. General
OTMS
Me
All reactions requiring anhydrous conditions were carried out
using oven-dried glassware. All the commercially available re-
agents and solvents were used without further purification. 1,2-
Diaza-1,3-butadienes 1a–n were synthesized as a mixture of E/Z
isomers as previously reported.32,33 Chromatographic purification
5
6
4a (R = H)
4b (R = Me)
Chart 3.
of compounds was carried out on silica gel (60–200 mm). TLC
A structural requirement for the success of the cyclization is the
presence of an ester group bonded to the carbon C-4 and of
a methyl, ethyl, propyl or CH2COOR group linked to the carbon C-3
of the 1,2-diaza-1,3-butadiene. An amido, phenyl or tosyl group
must be located at the nitrogen atom N1 (substituent R3).
The structure of all products (3a–n) was assigned on the basis of
the spectroscopic data. In particular 13C NMR spectra of 3a exhibit
some peculiarities: (i) the absence of CO signals of ketones; (ii) the
presence of four C-sp2 signals (175.9, 162.6, 157.2, and 103.6 ppm);
(iii) the presence of only one C-sp3 resonance at highfield
(26.8 ppm); (iv) the coupling constant value for the CH2 carbons
that resonates at 16.8 and 17.0 ppm is JCH¼165 Hz, typical for a CH2
in a cyclopropane ring.30
analysis was performed on pre-loaded (0.25 mm) glass supported
silica gel plates (Kieselgel 60); compounds were visualized by ex-
posure to UV light and by dipping the plates in 1% Ce(SO4)$4H2O,
2.5% (NH4)6Mo7O24$4H2O in 10% sulfuric acid followed by heating
on a hot plate. All 1H NMR and 13C NMR spectra were recorded at
400 and 100.56 MHz, respectively. Proton and carbon spectra were
referenced internally to solvent signals, using values of
for proton (middle peak) and
¼39.50 ppm for carbon (middle
peak) in DMSO-d6 and ¼77.00 ppm for
¼7.26 ppm for proton and
d¼2.49 ppm
d
d
d
carbon (middle peak) in CDCl3. The following abbreviations are
used to describe peak patterns where appropriate: s¼singlet,
d¼doublet, t¼triplet q¼quartet, sept¼septet, m¼multiplet and
br¼broad signal. All coupling constants (J) are given in hertz. FTIR
spectra were obtained as Nujol mulls. Low- and high-resolution
mass spectrometric data were obtained by electron ionization (EI,
70 eV). Melting points were determined in open capillary tubes and
are uncorrected.
However, the structure of 3g was unambiguously confirmed by
X-ray crystal structure analysis31 (Fig. 1).
All attempts to vary the silyl enol ether failed. The employment
of substituted 1,2-bis(silyloxy)cyclobutenes 4a,b, 1,2-bis(silyloxy)-
cyclopentene 5, and 1,2-bis(ethoxy)-1,2-bis(silyloxy)ethene
6
resulted in the formation of complex mixtures (Chart 3).
4.2. General procedure for the ‘Mukaiyama–Michael type
addition/cyclization/ring-contraction’ reaction of 1,2-diaza-
1,3-butadienes 1a–n with 1,2-bis[(trimethylsilyl)-
oxy]cyclobutene 2
Among spirocyclic compounds,1 the spiro-cyclopropane-
annelated heterocycles’ framework5–9,11 is an important motif
in biologically relevant compounds as natural products and
pharmaceuticals. Despite of their potential importance, spiro-
cyclopropanated 1-aminopyrrol-2-ones are unknown products.
Under a nitrogen atmosphere, to
a solution of 1,2-diaza-
Moreover, the presence of the spiro-cyclopropane ring in
a posi-
1,3-butadienes 1a–n (1.0 mmol) in CH2Cl2 (5 mL) 1,2-bis-
(trimethylsilyloxy)cyclobutene 2 (1.1 mmol) and Bi(TfO)3 (0.2 mmol)
were added. The mixture was stirred at room temperature until
complete disappearance of 1,2-diaza-1,3-butadienes 1a–n (TLC
check) and then the reaction was quenched with TFA to obtain 3a–n.
Products 3a–nwere purified bychromatography on silica gel column.
tion to the carbonyl group in the final azaheterocycles might open
new pathways for further and useful synthetic elaborations of the
pyrrolone skeleton.
3. Conclusion
In conclusion, we have reported a convenient regioselective
synthesis of functionalized spiro-cyclopropanated 1-aminopyrrol-
2-ones. The products are formed by a novel Bi(OTf)3-catalyzed one-
pot ‘Mukaiyama–Michael addition/cyclization/ring-contraction’
reaction from 1,2-bis(trimethylsilyloxy)cyclobutene and 1,2-diaza-
1,3-butadienes. These reactions are easy, occur under mild condi-
tions, and with excellent yields.
4.2.1. Ethyl 5-[(aminocarbonyl)amino]-6-methyl-4-oxo-5-
azaspiro[2,4]hept-6-ene-7-carboxylate (3a)
Spirocompound 3a was isolated by column chromatography
(ethyl acetate) in 85% yield as a white solid; mp 216–218 ꢁC; IR
(Nujol) nmax 3440, 3338, 3287, 3211, 1744, 1683, 1270, 1235, 1133,
1082 cmꢀ1
;
1H NMR (DMSO-d6)
d
1.16–1.26 (m, 5H), 1.70–1.85 (m,
2H), 2.27 (s, 3H), 4.08 (q, J¼7.0 Hz, 2H), 6.32 (br, 2H), 8.62 (br, 1H);

O.A. Attanasi et al. / Tetrahedron 65 (2009) 5456–5461
5459
13C NMR (DMSO-d6)
d
11.7, 14.0, 16.8, 17.0, 26.8, 59.1, 103.6, 153.8,
59.3, 103.8, 118.6, 122.4, 128.7, 139.1, 153.7, 154.0, 162.6, 176.0; EIMS
m/z (%) 329 (Mþ, 16), 284 (3), 210 (100), 194 (51), 181 (38), 166 (32),
149 (10), 137 (15), 119 (35), 109 (15). Anal. Calcd for C17H19N3O4: C,
62.00; H, 5.81; N, 12.76. Found: C, 61.84; H, 5.98; N, 12.54.
157.2, 162.6, 175.9; EIMS m/z (%) 253 (Mþ, 45), 210 (51), 194 (100),
181 (67), 166 (56), 148 (20), 136 (35), 121 (29), 109 (39); Anal. Calcd
for C11H15N3O4: C, 52.17; H, 5.97; N, 16.59. Found: C, 52.02; H, 6.09;
N, 16.44.
4.2.7. Ethyl 5-anilino-6-methyl-4-oxo-5-azaspiro[2.4]hept-6-ene-
7-carboxylate (3g)
Spirocompound 3g was isolated by column chromatography
(cyclohexane/ethyl acetate 80:20) in 86% yield as a white solid; mp
116–118 ꢁC; IR (Nujol) nmax 3291, 1721, 1701, 1623, 1450, 1386, 1233,
4.2.2. Methyl 5-[(aminocarbonyl)amino]-6-methyl-4-oxo-5-
azaspiro[2,4]hept-6-ene-7-carboxylate (3b)
Spirocompound 3b was isolated by column chromatography
(ethyl acetate) in 79% yield as a white solid; mp 213–215 ꢁC; IR
(Nujol) nmax 3444, 3337, 3211, 1734, 1685, 1447, 1384 cmꢀ1; 1H NMR
1128, 1067 cmꢀ1; 1H NMR (CDCl3)
d
1.31 (t, J¼7.2 Hz, 3H), 1.47–1.53
(DMSO-d6)
d
1.18–1.28 (m, 2H), 1.70–1.83 (m, 2H), 2.26 (s, 3H), 3.62
11.8, 16.8,
(m, 2H), 1.95–2.05 (m, 2H), 2.47 (s, 3H), 4.20 (q, J¼7.2 Hz, 2H), 6.47
(s, 3H), 6.32 (br, 2H), 8.62 (br, 1H); 13C NMR (DMSO-d6)
d
(s, 1H), 6.67 (d, J¼7.6 Hz, 2H), 6.93 (t, J¼7.6 Hz, 1H), 7.23 (t, J¼7.6 Hz,
17.0, 26.8, 50.6, 103.5, 153.9, 157.2, 163.1, 175.9; EIMS m/z (%) 239
(Mþ, 32), 222 (3), 208 (12), 196 (42), 180 (100), 164 (30), 148 (30),
135 (29), 120 (26), 109 (30). Anal. Calcd for C10H13N3O4: C, 50.21; H,
5.48; N, 17.56. Found: C, 50.34; H, 5.37; N, 17.51.
2H); 13C NMR (CDCl3)
d 12.0, 14.2, 18.3, 27.8, 59.7, 105.3, 112.8, 121.5,
129.3, 146.4, 153.6, 163.3, 177.3; EIMS m/z (%) 286 (Mþ, 100), 271 (3),
257 (5), 241 (9), 211 (9), 194 (38), 166 (32), 148 (15), 138 (14), 122
(13). Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C,
67.33; H, 6.17; N, 9.97.
4.2.3. Isopropyl 5-[(aminocarbonyl)amino]-6-methyl-4-oxo-5-
azaspiro[2.4]hept-6-ene-7-carboxylate (3c)
Spirocompound 3c was isolated by column chromatography
(ethyl acetate) in 98% yield as a white solid; mp 190–192 ꢁC; IR
(Nujol) nmax 3428, 3335, 3269, 3196, 1740, 1692, 1622, 1537, 1261,
4.2.8. Ethyl 6-methyl-5-{[(4-methylphenyl)sulfonyl]amino}-4-oxo-
5-azaspiro[2.4]hept-6-ene-7-carboxylate (3h)
Spirocompound 3h was isolated by column chromatography
(cyclohexane/ethyl acetate 80:20) in 32% yield as a white solid; mp
1231 cmꢀ1
;
1H NMR (DMSO-d6)
d
1.19 (d, J¼6.0 Hz, 6H), 1.19–1.28
150–154 ꢁC; IR (Nujol) nmax 3231, 1740, 1696, 1343, 1167, 1102 cmꢀ1
;
(m, 2H), 1.70–1.85 (m, 2H), 2.26 (s, 3H), 4.92 (sept, J¼6.0 Hz, 1H),
1H NMR (CDCl3)
d
1.09–1.39 (m, 2H), 1.31 (t, J¼7.2 Hz, 3H), 1.81–1.95
6.31 (br, 2H), 8.61 (br,1H); 13C NMR (DMSO-d6)
d
11.7, 16.9,17.1, 21.6,
(m, 2H), 2.41 (s, 3H), 2.57 (s, 3H), 4.18 (q, J¼7.2 Hz, 2H), 7.24 (d,
26.8, 66.5, 103.8, 153.8, 157.3, 162.2, 175.9; EIMS m/z (%) 267 (Mþ,
10), 225 (17), 208 (11), 182 (49), 166 (100), 149 (80), 136 (12), 109
(19). Anal. Calcd for C12H17N3O4: C, 53.92; H, 6.41; N, 15.72. Found:
C, 53.79; H, 6.25; N, 15.51.
J¼8.4 Hz, 2H), 7.64 (d, J¼8.4 Hz, 2H), 7.71 (s, 1H); 13C NMR (CDCl3)
d
12.6, 14.2, 18.0, 19.1, 21.7, 26.8, 59.9, 106.3, 128.4, 129.6, 134.2,
145.2, 151.7, 163.0, 175.7; EIMS m/z (%) 364 (Mþ, 11), 319 (4), 209
(39), 181 (100), 163 (8), 135 (10). Anal. Calcd for C17H20N2O5S: C,
56.03; H, 5.53; N, 7.69; S, 8.80. Found: C, 56.16; H, 5.37; N, 7.51; S,
8.99.
4.2.4. Benzyl 5-[(aminocarbonyl)amino]-6-methyl-4-oxo-5-
azaspiro[2.4]hept-6-ene-7-carboxylate (3d)
Spirocompound 3d was isolated by column chromatography
(ethyl acetate) in 81% yield as a white solid; mp 187–189 ꢁC; IR
(Nujol) nmax 3338, 3238, 3043, 1739, 1705, 1688, 1363, 1267,
4.2.9. Ethyl 5-[(aminocarbonyl)amino]-4-oxo-6-propyl-5-
azaspiro[2.4]hept-6-ene-7-carboxylate (3i)
Spirocompound 3i was isolated by column chromatography
(ethyl acetate) in 82% yield as a white solid; mp 201–203 ꢁC; IR
(Nujol) nmax 3432, 3337, 3238, 1736, 1700, 1689, 1619, 1546, 1269,
1236 cmꢀ1
;
1H NMR (DMSO-d6)
d
1.18–1.29 (m, 2H), 1.70–1.82 (m,
2H), 2.27 (s, 3H), 5.12 (s, 2H), 6.33 (br, 2H), 7.30–7.40 (m, 5H, Ar),
8.62 (br, 1H); 13C NMR (DMSO-d6)
11.8, 16.9, 17.1, 26.9, 64.9, 103.3,
d
1239 cmꢀ1
;
1H NMR (DMSO-d6)
d
0.90 (t, J¼7.2 Hz, 3H), 1.19 (t,
127.9, 128.0, 128.5, 136.3, 154.6, 157.2, 162.4, 175.9; EIMS m/z (%) 315
(Mþ, 3), 272 (4), 257 (5), 185 (392), 181 (100), 166 (35), 149 (18), 139
(23),125 (26),111 (50). Anal. Calcd for C16H17N3O4: C, 60.94; H, 5.43;
N, 13.33. Found: C, 60.71; H, 5.32; N, 13.48.
J¼7.2 Hz, 3H), 1.19–1.28 (m, 2H), 1.45–1.55 (m, 2H), 1.72–1.90 (m,
2H), 2.45–2.55 (m, 1H), 2.78–2.90 (m, 1H), 4.07 (q, J¼7.2 Hz, 2H),
6.29 (br, 2H), 8.66 (br, 1H); 13C NMR (DMSO-d6)
d 13.9, 14.0, 17.1,
17.3, 20.9, 26.9, 27.1, 59.2, 103.6, 157.2, 157.3, 162.4, 176.2; EIMS m/z
(%) 281 (Mþ, 46), 252 (9), 238 (68), 222 (100), 209 (59), 193 (46), 176
(30), 165 (25), 148 (35), 136 (35), 120 (27). Anal. Calcd for
C13H19N3O4: C, 55.50; H, 6.81; N, 14.94. Found: C, 55.72; H, 6.63; N,
15.02.
4.2.5. Methyl 5-[(aminocarbonyl)amino]-6-ethyl-4-oxo-5-
azaspiro[2.4]hept-6-ene-7-carboxylate (3e)
Spirocompound 3e was isolated by column chromatography
(ethyl acetate) in 87% yield as a white solid; mp 195–197 ꢁC; IR
(Nujol) nmax 3345, 3202, 3040, 1738, 1701, 1694, 1617, 1545, 1295,
4.2.10. Allyl 5-[(aminocarbonyl)amino]-6-methyl-4-oxo-5-
azaspiro[2.4]hept-6-ene-7-carboxylate (3j)
Spirocompound 3j was isolated by column chromatography
(ethyl acetate) in 94% yield as a white solid; mp 195–197 ꢁC; IR
(Nujol) nmax 3448, 3339, 3252,1740,1686,1544,1261,1123 cmꢀ1; 1H
1240, 1054 cmꢀ1; 1H NMR (DMSO-d6)
d
1.07 (d, J¼7.6 Hz, 3H), 1.18–
1.25 (m, 2H), 1.70–1.85 (m, 2H), 2.45–2.58 (m, 1H), 2.78–2.90 (m,
1H), 3.62 (s, 3H), 6.31 (br, 2H), 8.66 (br, 1H); 13C NMR (DMSO-d6)
d
12.2,17.1,17.3, 18.8, 26.8, 50.7,102.8,157.2,159.0, 162.9, 176.1; EIMS
m/z (%) 253 (Mþ, 30), 210 (45), 194 (100), 178 (17), 162 (33), 149 (17),
134 (25), 123 (15), 106 (18). Anal. Calcd for C11H15N3O4: C, 52.17; H,
5.97; N, 16.59. Found: C, 52.02; H, 6.05; N, 16.37.
NMR (DMSO-d6)
4.56–4.61 (m, 2H), 5.19–5.23 (m, 1H), 5.25–5.31 (m, 1H), 5.89–6.01
(m, 1H), 6.34 (br, 2H), 8.63 (br, 1H); 13C NMR (DMSO-d6)
11.9, 16.9,
d 1.19–1.29 (m, 2H), 1.72–1.85 (m, 2H), 2.28 (s, 3H),
d
17.2, 26.9, 63.8, 103.3, 117.7, 132.9, 154.4, 157.3, 162.3, 175.9; EIMS
m/z (%) 265 (Mþ, 8), 236 (3), 222 (7), 208 (6), 181 (100), 166 (10), 151
(5),137 (8),123 (5),109 (14). Anal. Calcd for C12H15N3O4: C, 54.33; H,
5.70; N, 15.84. Found: C, 54.16; H, 5.89; N, 16.04.
4.2.6. Ethyl 5-[(anilinocarbonyl)amino]-6-methyl-4-oxo-5-
azaspiro[2.4]hept-6-ene-7-carboxylate (3f)
Spirocompound 3f was isolated by column chromatography
(cyclohexane/ethyl acetate 50:50) in 64% yield as a white solid; mp
179–180 ꢁC; IR (Nujol) nmax 3321, 1711, 1698, 1563, 1411, 1256, 1131,
4.2.11. Methyl 5-[(aminocarbonyl)amino]-6-(2-methoxy-2-
oxoethyl)-4-oxo-5-azaspiro[2.4]hept-6-ene-7-carboxylate (3k)
Spirocompound 3k was isolated by column chromatography
(ethyl acetate) in 75% yield as a white solid; mp 172–174 ꢁC; IR
(Nujol) nmax 3317, 3280, 3194, 1749, 1732, 1693, 1688, 1356, 1253,
1073 cmꢀ1
;
1H NMR (DMSO-d6)
d
1.20 (t, J¼7.2 Hz, 3H), 1.22–1.32
(m, 2H), 1.77–1.88 (m, 2H), 2.32 (s, 3H), 4.11 (q, J¼7.2 Hz, 2H), 6.97
(t, J¼7.6 Hz, 1H), 7.25 (t, J¼7.6 Hz, 2H), 7.42 (d, J¼7.6 Hz, 2H), 8.84 (s,
1H), 9.31 (br, 1H); 13C NMR (DMSO-d6)
d 11.8, 14.1, 16.9, 17.2, 26.9,

5460
O.A. Attanasi et al. / Tetrahedron 65 (2009) 5456–5461
2. (a) Primke, H.; Sarin, G. S.; Kohlstruk, S.; Adiwidjaja, G.; de Meijere, A. Chem.
1123 cmꢀ1; 1H NMR (DMSO-d6)
d
1.29–1.35 (m, 2H), 1.78–1.88 (m,
Ber. 1994, 127, 1051; (b) Tokuzaki, K.; Kanemitu, Y.; Yoshimitsu, T.; Nagaoka, H.
Tetrahedron Lett. 2000, 41, 5923; (c) Friese, J. C.; Scha¨fer, H. J. Synlett 2002, 814;
(d) Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetra-
hedron Lett. 2002, 43, 3633; (e) Movassaghi, M.; Piizzi, G.; Siegel, D. S.; Piersanti,
G. Angew. Chem., Int. Ed. 2006, 45, 5959; For the synthesis of an illudinoid li-
brary, see: (f) Pirrung, M. C.; Liu, H. Org. Lett. 2003, 5, 1983.
2H), 3.50 (d, J¼16.4 Hz, 1H), 3.61 (s, 3H), 3.62 (s, 3H), 4.21 (d,
J¼16.4 Hz, 1H), 6.29 (br, 2H), 8.74 (br, 1H); 13C NMR (DMSO-d6)
d
17.6, 17.8, 27.3, 31.1, 51.0, 52.2, 106.2, 149.5, 157.2, 162.6, 168.2,
175.5; EIMS m/z (%) 297 (Mþ, 15), 280 (2), 254 (69), 238 (39), 222
(51), 206 (100), 194 (41), 179 (21), 163 (25), 135 (28). Anal. Calcd
for C12H15N3O6: C, 48.48; H, 5.09; N, 14.14. Found: C, 48.67; H,
5.34; N, 14.03.
3. Bose, G.; Bracht, K.; Bednarski, P. J.; Lalk, M.; Langer, P. Bioorg. Med. Chem. 2006,
14, 4694.
4. (a) Bryson, T. A.; Roth, G. A. Tetrahedron Lett. 1988, 29, 2167; (b) Boger, D. L.;
Johnson, D. S. J. Am. Chem. Soc. 1990, 112, 5832; (c) Tietze, L. F.; Hannemann, R.;
Buhr, W.; Lo¨gers, M.; Menningen, P.; Lieb, M.; Starck, D.; Grote, T.; Do¨ring, A.;
Schuberth, I. Angew. Chem., Int. Ed. 1996, 35, 2674; (d) Boger, D. L.; Garbaccio, R.
M.; Jin, Q. J. Org. Chem. 1997, 62, 8875; (e) Boger, D. L.; Boyce, C. W.; Carpaccio,
R. M.; Goldberg, J. A. Chem. Rev. 1997, 97, 787; (f) Tietze, L. F.; Buhr, W.; Looft, J.;
Grote, T. Chem.dEur. J. 1998, 4, 1554.
4.2.12. Ethyl 5-[(aminocarbonyl)amino]-6-(2-ethoxy-2-oxoethyl)-
4-oxo-5-azaspiro[2.4]hept-6-ene-7-carboxylate (3l)
Spirocompound 3l was isolated by column chromatography
(ethyl acetate) in 54% yield as a white solid; mp 182–184 ꢁC; IR
(Nujol) nmax 3423, 3320, 3277, 3191, 1747, 1735, 1692, 1416, 1353,
5. Limbach, M.; Dalai, S.; Janssen, A.; Es-Sayed, M.; Magull, J.; de Meijere, A. Eur. J.
Org. Chem. 2005, 610.
6. Brackmann, F.; Es-Sayed, M.; de Meijere, A. Eur. J. Org. Chem. 2005, 2250.
7. (a) Robertson, D. W.; Krushinski, J. H.; Pollock, G. D.; Wilson, H.; Kauffman, R. F.
J. Med. Chem. 1987, 30, 824; (b) Beckwith, A. L. J.; Storey, J. M. D. J. Chem. Soc.,
Chem. Commun. 1995, 977; (c) Shanmugam, P.; Vaithiyanathan, V.; Viswamb-
haran, B. Tetrahedron 2006, 62, 4342; (d) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.;
Bieza, K.; Caldwell, J.; Bursulaya, B.; Tuntland, T.; Zhang, K.; Karanewsky, D.; He,
Y. Bioorg. Med. Chem. Lett. 2006, 16, 2109; (e) Jiang, T.; Kuhen, K. L.; Wolff, K.;
Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu, T. Y.-H.; He, Y. Biorg. Med. Chem.
Lett. 2006, 16, 2105.
1255, 1196, 1125 cmꢀ1; 1H NMR (DMSO-d6)
d
1.18 (t, J¼7.2 Hz, 6H),
1.29–1.35 (m, 2H), 1.80–1.90 (m, 2H), 3.47 (d, J¼16.4 Hz, 1H), 4.00–
4.12 (m, 4H), 4.18 (d, J¼16.4 Hz, 1H), 6.28 (br, 2H), 8.73 (br, 1H); 13C
NMR (DMSO-d6)
d 13.9, 14.0, 17.6, 17.8, 27.3, 31.2, 59.6, 60.9, 106.3,
149.4, 157.2, 162.1, 167.8, 175.6; EIMS m/z (%) 325 (Mþ, 18), 308 (3),
282 (100), 266 (22), 236 (78), 220 (44), 208 (65), 192 (50), 179 (39),
166 (32), 151 (22), 136 (33). Anal. Calcd for C14H19N3O6: C, 51.69; H,
5.89; N, 12.92. Found: C, 51.86; H, 5.58; N, 13.12.
8. Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002, 124, 14826.
9. For reviews on cyclopropane-annelated carbo- and heterocycles, see: (a) de
Meijere, A.; Wessjohann, L. Synlett 1990, 20; (b) de Meijere, A.; Kozhushkov, S.
I.; Khlebnikov, A. F. Top. Curr. Chem. 2000, 207, 89.
10. For examples on cyclopropane-annelated carbocycles, see: (a) Langer, P.; Bose,
G. Angew. Chem., Int. Ed. 2003, 42, 4033; (b) Bose, G.; Nguyen, V. T. H.; Ullah, E.;
Lahiri, S.; Go¨rls, H.; Langer, P. J. Org. Chem. 2004, 69, 9128; (c) Bose, G.; Langer, P.
Tetrahedron Lett. 2004, 45, 3861; (d) Barbero, A.; Castren˜o, P.; Pulido, F. J. J. Am.
Chem. Soc. 2005, 127, 8022; (e) Rasool, N.; Rashid, M. A.; Reinke, H.; Fischer, C.;
Langer, P. Tetrahedron 2008, 64, 3246.
4.2.13. 2-Methoxyethyl 5-[(anilinocarbonyl)amino]-6-methyl-4-
oxo-5-azaspiro[2.4]hept-6-ene-7-carboxylate (3m)
Spirocompound 3m was isolated by column chromatography
(cyclohexane/ethyl acetate 50:50) in 56% yield as a white solid; mp
166–168 ꢁC; IR (Nujol) nmax 3348, 1693, 1633,1602, 1551, 1281, 1240,
1147, 1082 cmꢀ1; 1H NMR (DMSO-d6)
d 1.25–1.31 (m, 2H), 1.75–1.91
11. For examples on cyclopropane-annelated heterocycles, see: (a) Anichini, B.;
Goti, A.; Brandi, A.; Kozhushkov, S. I.; de Meijere, A. Chem. Commun. 1997, 261;
(b) de Meijere, A.; Von Seebach, M.; Kozhushkov, S. I.; Boese, R.; Blaser, D.;
Cicchi, S.; Dimoulas, T.; Brandi, A. Eur. J. Org. Chem. 2001, 20, 3789; (c) Marti, C.;
Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505; (d) Storey, J. M. D.; Ladwa, M.
M. Tetrahedron Lett. 2006, 47, 381; (e) Zheng, X.; Kerr, M. A. Org. Lett. 2006, 8,
3777; (f) Zanobini, A.; Brandi, A.; de Meijere, A. Eur. J. Org. Chem. 2006, 5, 1251;
(g) Hamaguchi, M.; Nakaishi, M.; Nagai, T.; Nakamura, T.; Abe, M. J. Am. Chem.
Soc. 2007, 129, 12981; (h) Rotzoll, S.; Reinke, H.; Langer, P. Tetrahedron Lett.
2008, 49, 675; (i) Method, J. L.; Dunstan, T. A.; Mampreian, D. M.; Adams, B.;
Altman, M. D. Tetrahedron Lett. 2008, 49, 1155.
(m, 2H), 2.33 (s, 3H), 3.26 (s, 3H), 3.53 (t, J¼4.8 Hz, 2H), 4.17 (t,
J¼4.8 Hz, 2H), 6.97 (t, J¼7.6 Hz, 1H), 7.26 (t, J¼7.6 Hz, 2H), 7.42 (d,
J¼7.6 Hz, 2H), 8.84 (s, 1H), 9.32 (br, 1H); 13C NMR (DMSO-d6)
d 11.8,
17.0, 17.2, 26.9, 58.0, 62.1, 69.8, 103.7, 118.6, 122.4, 128.7, 139.1, 154.0,
154.1, 162.5, 175.9; EIMS m/z (%) 359 (Mþ, 16), 284 (6), 240 (66), 182
(36), 164 (100), 148 (12), 136 (22), 119 (23). Anal. Calcd for
C18H21N3O5: C, 60.16; H, 5.89; N, 11.69. Found: C, 60.04; H, 5.99; N,
12.82.
12. Cyclopropanes and related rings: de Meijere, A. Chem. Rev. 2003, 103, 931.
13. (a) Joule, J. A.; Mills, K. Heterocyclic chemistry, 4th ed.; Blackwell: Oxford, 2000;
(b) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Heterocycles, 2nd ed.;
Wiley-VCH: Weinheim, Germany, 2003; p 97.
14. Effland, R.C.; Klein, J.T. U.S. Patent 4,546,105, 1985; Chem. Abstr. 1986, 104,
186307.
4.2.14. Isopropyl 5-[(anilinocarbonyl)amino]-6-methyl-4-oxo-5-
azaspiro[2.4]hept-6-ene-7-carboxylate (3n)
Spirocompound 3n was isolated by column chromatography
(cyclohexane/ethyl acetate 60:40) in 60% yield as a white solid; mp
153–155 ꢁC; IR (Nujol) nmax 3302, 1699, 1554, 1409, 1238, 1117,
15. Kulagowski, J.; Janusz, J.; Leeson, P.D. UK Patent 2,265,372, 1993; Chem. Abstr.
1993, 120, 134504.
16. For a review on 1,2-diaza-1,3-butadienes, see: Attanasi, O. A.; De Crescentini, L.;
Filippone, P.; Mantellini, F.; Santeusanio, S. ARKIVOC 2002, xi, 274; For recent
developments on the chemistry of 1,2-diaza-1,3-butadienes, see: (a) Boeckman,
R. K., Jr.; Ge, P.; Reed, J. E. Org. Lett. 2001, 3, 3651; (b) Rossi, E.; Arcadi, A.; Ab-
biati, G.; Attanasi, O. A.; De Crescentini, L. Angew. Chem., Int. Ed. 2002, 41, 1400;
(c) Kramp, G. J.; Kim, M.; Gais, H.-J.; Vermeeren, C. J. Am. Chem. Soc. 2005, 127,
17910; (d) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Lillini, S.;
Mantellini, F.; Santeusanio, S. Org. Lett. 2005, 7, 2469; (e) Palacios, F.; Aparicio,
D.; Lo´pez, Y.; de los Santos, J. M. Tetrahedron 2005, 61, 2815; (f) Yang, H.-T.;
Wang, G.-W.; Xu, Y.; Huang, J.-C. Tetrahedron Lett. 2006, 47, 4129; (g) Attanasi,
O. A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.; Moscatelli, G.; Prati, F. Org. Lett.
2007, 9, 3461; (h) Attanasi, O. A.; Favi, G.; Filippone, P.; Perrulli, F. R.; Santeu-
sanio, S. Org. Lett. 2009, 11, 309.
1066 cmꢀ1
;
1H NMR (DMSO-d6)
d
1.20 (d, J¼6.0 Hz, 6H), 1.20–1.30
(m, 2H), 1.75–1.88 (m, 2H), 2.32 (s, 3H), 4.93 (sept, J¼6.0 Hz, 1H),
6.97 (t, J¼7.6 Hz, 1H), 7.25 (t, J¼7.6 Hz, 2H), 7.42 (d, J¼7.6 Hz, 2H),
8.84 (s, 1H), 9.31 (br, 1H); 13C NMR (DMSO-d6)
d 11.8, 17.0, 17.2, 21.7,
26.9, 66.6, 104.0, 118.6, 122.4, 128.7, 139.1, 153.6, 154.0, 162.1, 175.9;
EIMS m/z (%) 343 (Mþ, 12), 301 (7), 284 (6), 224 (39), 208 (6), 182
(75), 166 (100), 153 (9), 137 (17), 119 (23), 111 (27). Anal. Calcd for
C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 63.08; H, 6.29; N,
12.07.
17. Attanasi, O. A.; Favi, G.; Filippone, P.; Lillini, S.; Mantellini, F.; Spinelli, D.; Stenta,
M. Adv. Synth. Catal. 2007, 349, 207.
18. Attanasi, O. A.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Spinelli, D. Org.
Lett. 2008, 10, 1983.
19. Karapetyan, V.; Mkrtchyan, S.; Schmidt, A.; Attanasi, O. A.; Favi, G.; Mantellini,
F.; Villinger, A.; Fischer, C.; Langer, P. Adv. Synth. Catal. 2008, 350, 1331.
20. For a review on 1,3-bis(silyloxy)-1,3-butadienes, see: Langer, P. Synthesis 2002, 441.
21. For a review on [3þ3] cyclizations of 1,3-bis(silyloxy)-1,3-butadienes, see: Feist,
H.; Langer, P. Synthesis 2007, 327.
Acknowledgements
`
Financial support from the Ministero dell’Universita, dell’Is-
truzione e della Ricerca (MIUR)dRome, Universita degli Studi di
Urbino ‘Carlo Bo’, and by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
`
22. (a) Ru¨ hlmann, K. Synthesis 1971, 236; (b) Bisel, P.; Breitling, E.; Frahm, A. W. Eur.
J. Org. Chem. 1998, 729.
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