Synthesis of new cycloalkenyliden-pyrroles by domino reaction

Article abstract of DOI:10.1016/j.tet.2009.01.040

Easily accessible cycloalkenyl-1-diazenes and β-dicarbonyl compounds are converted in one-pot into previously unknown functionalized fused cycloalkenyliden-pyrroles of different sizes. The domino reaction proceeds through a base-catalyzed conjugate additi

Full text of DOI:10.1016/j.tet.2009.01.040

Tetrahedron 65 (2009) 2290–2297
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new cycloalkenyliden-pyrroles by domino reaction
Orazio A. Attanasi a, Stefano Berretta a, Lucia De Crescentini a, Gianfranco Favi a,
a
,
ˇ b
*
Amalija Golobic , Fabio Mantellini
a
`
Istituto di Chimica Organica, Universita degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino, Italy
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva, Ljubljana, Slovenia
b
ˇ
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
Easily accessible cycloalkenyl-1-diazenes and b-dicarbonyl compounds are converted in one-pot into
Received 16 October 2008
Received in revised form 17 December 2008
Accepted 9 January 2009
previously unknown functionalized fused cycloalkenyliden-pyrroles of different sizes. The domino re-
action proceeds through a base-catalyzed conjugate addition/cyclization/elimination sequence.
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 15 January 2009
Dedicated to Professor Branko Stanovnik on
the occasion of his 70th birthday
1. Introduction
O
O
EWG
R1
N
+
H
N
H
R2
Recently, 1,2-diaza-1,3-butadienes have been intensively stud-
ied by several authors and they have been demonstrated to be in-
teresting products and powerful intermediates in organic
synthesis.1 In our investigations, these compounds have manifested
the aptitude to furnish polyfunctionalized five-,2 six-3 and seven-
membered4 heterocycles containing nitrogen, sulfur and
phosphorus.
II
I
Michael addition
H
H
H
N
EWG
R2
N
N
R1
N
R1
EWG
R2
In the course of our activity in this field, we have detected that
O
O
the reaction between 1,2-diaza-1,3-butadienes I and b-dicarbonyl
O
O
compounds containing activated methylene groups II always gen-
erates pyrrole derivatives IV rather than dihydropyridazines V, as
erroneously reported by previous authors (Scheme 1).5 This be-
haviour is a consequence of initial 1,4-Michael-type addition that
III
III
[3+2] type
[4+2] type
cyclization
cyclization
leads to
internal ring closure. In particular, when the nucleophilic reagent
bears a ketonic function in the -position with respect to the
attacking carbon atom, the ring annulation occurs via a [3þ2] in-
stead of a [4þ2] cyclization process.6 This ring closure is promoted
in the intermediates III by the presence of an acidic hydrogen
originally placed in position 4 of the azo-ene system I (Scheme 1).
In an attempt to promote the [4þ2] cyclization, we have pre-
viously investigated the reactions of cyclopentenyl- and cyclo-
hexenyl-1-diazenes, which lack the above-mentioned hydrogen,
a-substituted hydrazone intermediates III, and subsequent
O
O
R2
EWG
H
H
EWG
N
R2
a
N
N
N
R1
R1
IV
V
Scheme 1.
with b-ketoamide derivatives. Surprisingly, we synthesized tetra-
hydro-1H-indoles from cyclohexenyl-1-diazenes by means of an
‘uncommon’ [3þ2] cyclization and no formation of dihydropyr-
idazines was observed.7
Herein, we report full details of these studies. With regard to
our preliminary communication, the scope considerably extends
the applicability of this protocol, involving cycloheptenyl- or
* Corresponding author. Tel.: þ39 0722 303442; fax: þ39 0722 303441.
E-mail address: fabio.mantellini@uniurb.it (F. Mantellini).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.040

O.A. Attanasi et al. / Tetrahedron 65 (2009) 2290–2297
2291
O
O
R3O
O
OR3
N
R4
O
O
+
( )n
R4
COR2
R1
N
R1
N
2a−j
1a−f
N
COR2
4a−h
n=2
O
THF,
H
MeONa
O
[4+2]
cyclization
R4
O
O
O
O
O
R4
O
R3O
O
R4
R3O
( )n
O
R4
R3O
R4
R3O
R1
R3O
R1
n=1
n=3
( )n
( )n
N
N
R1
N
O
COR2
R1
O
N
N
N
N
COR2
3
R1
HN
COR2
N
N
H
COR2
H
COR2
H
H
5
3a−d
4i−s
n=4
R3O
[3+2]
O
O
cyclization
R4
R4
H
O
O
O
O
R4
N
R3O
( )n
R3O
( )n
R1
N COR2
OH
-H2O
COR2
R1
H
N
N
4t−ab
Scheme 3.
R1
N
COR2
N
H
H
A
4a−ab
Scheme 2.
tetrahydro-1H-indoles 4a–i during the chromatographic processes
(Scheme 2, Table 1). The ring closure process that transforms
the hydrazones 3 into the corresponding tetrahydro-1H-indoles
4a–i happens by means of an uncommon [3þ2] cyclization.
Usually, in the reaction that involves 1,2-diaza-1,3-butadienes I
cyclooctenyl-1-diazenes and different
b
-dicarbonyl compounds
-ketoamides.7 The
such as 2,4-pentandione, -ketoesters and
b
b
here reported 2-cycloalkenylpyrrole derivatives of different sizes
are unknown and not readily available by other methods, have
potential usefulness in medicinal8 and technological fields.9
Moreover, the flexibility in the introduction of different groups in
these systems confers an interesting contribution to this work,
making them suitable as intermediates for more complex
compounds.
and
b
-dicarbonyl derivatives II (Scheme 1), the [3þ2] annulation
starts by deprotonation of a hydrogen activated by two electron
withdrawing substituents (i.e., carbonyl groups) yielding aromatic
pyrrole derivatives.6 In this case, the regioselective conjugate nu-
cleophilic attack of the hydrazonic nitrogen at the ketonic function
is promoted by the loss of a hydrogen in the a-position to only one
hydrazone moiety. This occurrence produces the hexahydro-1H-
2-indolol intermediate A that spontaneously furnishes the final
tetrahydro-1H-indoles 4a–i by elimination of a water molecule. It
is noteworthy that although the final products 4 are not stabilized
by aromaticity, no [4þ2] ring closure occurred and pyridazine
derivatives 5 were not found (Scheme 2). The X-ray diffraction
study of 4f confirms unequivocally the structure assigned to these
compounds (Fig. 1).11
2. Results and discussion
Cycloalkenyl-1-diazenes 1a–f of different sizes were easily
prepared starting from the corresponding cycloketone derivatives
as previously reported.7,10 The fast reaction of 1a–f with
b-
dicarbonyl compounds 2a–j confirms their good electrophilic
character (Scheme 2). However, we have observed some differ-
ences in the final products obtained, depending on the ring-sizes
of the starting cycloalkenyl-1-diazenes 1 (Scheme 3). In fact, the
The 1H NMR and 13C NMR spectroscopic analysis of 4f,g,i
revealed that these compounds were obtained exclusively as a sole
couple of enantiomers that corresponds to racemic forms R,R/S,S as
evinced by X-ray of 4f. Compound 4h was isolated as a mixture of
R,R/S,S and R,S/S,R forms in 80:20 ratio.
reaction of cyclopentenyl-1-diazenes 1a,b (n¼1) with
b-keto-
amides 2a,b or ketoester 2d in tetrahydrofuran at room tem-
perature in the presence of catalytic sodium methoxide led to the
exclusive formation of the hydrazonic derivatives 3a–c in good
yields (Scheme 2, Table 1). The reaction takes place by means of
conjugated addition (Michael-type) of the nucleophiles 2 to the
terminal carbon atom of the 1,2-diaza-1,3-diene system. All at-
tempts to convert 3a–c into the corresponding cyclo-
pentenyliden-pyrroles 4 failed either by means of heat or under
basic or acid conditions.
Then, we have extended our investigations employing cyclo-
heptenyl-1-diazene 1e (n¼3) or cycloctenyl-1-diazene 1f (n¼4) as
starting materials. They easily reacted with
b-dicarbonyl com-
pounds 2a–j in tetrahydrofuran at room temperature in the pres-
ence of catalytic sodium methoxide. At the disappearance of the
typical red colour of the 1,2-diaza-1,3-dienes, a TLC analysis of the
crude mixture showed the presence of only one product that was
isolated and identified as 2-methyl-1,3a,4,5,6,7-hexahydro
cyclohepta[b]pyrroles 4j–s (n¼3) or 2-methyl-3a,4,5,6,7,8-hexahy-
dro-1H-cycloocta[b]pyrroles 4t–ab (n¼4), respectively (Scheme 3,
Table 1). In these cases, no hydrazone intermediate was observed in
the reaction mixture. The ring strain due to the presence of the
carbon–carbon double bonds in the fused bicyclic ring systems of 4
can explain these experimental results (Scheme 3, Table 1). In
particular, due to an increment in the dimension of the cycloalkyl
portion, a lower ring strain results. Thus, in the case of cyclo-
heptenyl-1-diazene 1e (n¼3) or cycloctenyl-1-diazene 1f (n¼4)
only cycloalkenyliden-pyrroles 4j–s and 4t–ab were produced,
Under the same conditions for the synthesis of 3a–c, the re-
action between cyclohexenyl-1-diazenes 1c,d (n¼2) and 2a–e
revealed the presence of two major products by TLC analysis.
However, it was possible to isolate by flash chromatography only
the most non-polar ones that were identified as 3-substituted
tetrahydro-1H-indoles 4a–i. Only in the case of the reaction be-
tween 1d and 2a we have isolated a small amount of the more
polar
ethyl
3-[2-(aminocarbonyl)hydrazono]-1-[1-(anilino-
carbonyl)-2-oxopropyl]-1-cyclohexanecarboxylate 3d. In the
other cases, hydrazones 3 were converted into the corresponding

2292
O.A. Attanasi et al. / Tetrahedron 65 (2009) 2290–2297
Table 1
Yields and reaction times of a-substituted hydrazones 3a–c and cycloalkenyliden-pyrroles 4a–ab
1
n
R1
R2
R3
2
R4
3
Yielda
%
Time (h)
4
Yielda
%
Time (h)
1a
1b
1b
1c
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1f
1
1
1
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
H
H
H
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ot-Bu
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
2a
2b
2d
2a
2b
2c
2d
2e
2a
2b
2c
2d
2a
2b
2c
2d
2e
2f
NHPh
NHC6H4-4-OMe
OMe
3a
3b
3c
79
84
68
0.5
0.5
0.5
NHPh
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
63
59
62
51
54
61
57
66
58
68
71
83
74
51
76
63
56
59
81
63
71
65
86
95
64
73
78
92
3.5
5.0
3.0
4.0
4.5
3.5
3.0
3.5
4.5
1.0
1.0
1.5
0.5
1.0
2.0
1.0
1.5
2.0
2.0
1.5
1.5
2.5
2.0
1.5
1.5
1.5
2.0
1.0
NHC6H4-4-OMe
NHC6H4-4-Cl
OMe
OEt
NHPh
NHC6H4-4-OMe
NHC6H4-4-Cl
OMe
3d
7
3.5
NHPh
NHC6H4-4-OMe
NHC6H4-4-Cl
OMe
OEt
Oi-Pr
Ot-Bu
OAllyl
OBn
Me
2g
2h
2i
2j
4s
4t
2a
2b
2c
2d
2e
2f
2g
2h
2i
NHPh
1f
1f
1f
1f
1f
1f
1f
1f
NHC6H4-4-OMe
NHC6H4-4-Cl
OMe
OEt
Oi-Pr
Ot-Bu
OAllyl
OBn
4u
4v
4w
4x
4y
4z
4aa
4ab
a
Yield of pure isolated products 3a–d and 4a–ab based on starting 1,2-diaza-1,3-dienes 1a–f.
while cyclohexenyl-1-diazenes (n¼2) furnish a mixture of tetra-
hydro-1H-indoles 4a–i and hydrazones 3. Only in the case of
cyclopentenyl-1-diazenes (n¼1) hydrazones 3a–c were formed
exclusively (Scheme 3, Table 1).
cyclization/elimination reactions of b-dicarbonyl derivatives with
cycloalkenyl-1-diazenes. The advantage of this type of synthesis is
the accessibility of the starting materials and the simplicity of the
experimental procedures. It is noteworthy that the 1-amino
cycloalkenyliden-pyrroles are not easily available from other
methods and they represent new classes of polyheterocycles of
interest as targets in organic,12 biological,13 medicinal14 and agri-
cultural chemistry.15
4. Experimental
4.1. General
Methyl, ethyl, iso-propyl, tert-butyl, allyl, benzyl acetoacetates,
acetoacetanilide, 40-methoxyacetanilide, 40-chloroacetoacetanilide,
2,4-pentandione, sodium methoxide were commercial materials
and were used without further purification. Solvents were pur-
chased and used without further purification with the exception of
THF, which was distilled over sodium hydroxide. Melting points
were determined on open capillary tubes. FTIR spectra were
obtained as Nujol mulls. Mass spectra (EI) were made at an ionizing
voltage of 70 eV. 1H NMR and 13C NMR spectra were recorded at
400 and 100.32 MHz, respectively. All NMR spectra were recorded
in CDCl3 or in DMSO-d6, as specified below. Chemical shifts (dH) are
reported in parts per million (ppm), relative to TMS as internal
standard. All coupling constants (J) values are given in hertz.
Chemical shifts (dC) are reported in parts per million (ppm), relative
to CDCl3 or DMSO-d6 as internal standard in a broad band decou-
pled mode; the multiplicities were obtained using 135ꢀ and 90ꢀ
DEPT experiments to aid in assignment (CH3¼methyl,
CH2¼methylene, CH¼methine, C¼quaternary). The abbreviations
used are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
Figure 1. A view of the asymmetric unit of 4f, showing the labelling of the non-
hydrogen atoms.
3. Conclusion
In conclusion, this paper describes the convenient regioselective
synthesis of functionalized fused cycloalkenyliden-pyrroles of dif-
ferent sizes through base-catalyzed one-pot conjugate addition/

O.A. Attanasi et al. / Tetrahedron 65 (2009) 2290–2297
2293
multiplet; br, broad. All the NH and NH2 exchanged with D2O.
Precoated silica gel plates 0.25 mm were employed for analytical
C20H26N4O6: C, 57.41; H, 6.26; N, 13.39. Found: C, 57.55; H, 6.29; N,
13.44.
thin layer chromatography and silica gel 35–70
chromatography.
m for column
4.1.4. Ethyl 2-[2-(aminocarbonyl)hydrazono]-1-{1-[(methyloxy)-
carbonyl]-2-oxopropyl]-1-cyclopentanecarboxylate 3c
4.1.1. General procedure for the synthesis of
hydrazones 3a–d and cycloalkenyliden-pyrroles 4a–ab
To a magnetically stirred solution of -dicarbonyl compounds
a-substituted
Yield 222 mg, 68%, white powder; mp 136–138 ꢀC; IR (Nujol):
nmax¼3320, 3232, 1781, 1701 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
b
d
1.13 (t, 3H, 3J¼7.2 Hz), 1.79–1.93 (m, 2H), 2.04–2.23 (m, 3H), 2.27
2a–j (1.0 mmol) and cycloalkenyl-1-diazenes 1a–f (1.0 mmol) in
tetrahydrofuran (30 mL) catalytic sodium methoxide (0.1 equiv)
was added. The reaction was allowed to stand at room temperature
until the disappearance of the reagents (TLC analysis, 0.5–5 h) and
then the solvent was evaporated under reduced pressure. Starting
(s, 3H), 2.33–2.41 (m, 1H), 3.61–3.64 (m, 3H), 3.98–4.08 (m, 2H),
4.81 and 4.92 (2s, 1H), 6.23 and 6.34 (2br s, 2H), 9.13 and 9.16 (2s,
1H); 13C NMR (100 MHz, DMSO-d6)
d 14.4 (CH3), 22.9 (CH3), 28.3
(CH2), 31.6 (CH2), 32.5 (CH2), 52.9 (CH3), 57.8 (CH), 61.6 (CH2), 62.2
(C), 155.5 (C), 156.4 (C), 157.6 (C), 169.1 (C), 169.8 (C), 172.5 (C), 172.7
(C), 203.5 (C), 203.6 (C); MS: m/z (%)¼327 (Mþ, 1), 282 (17), 253
(100), 223 (61), 193 (17), 139 (61), 123 (78). Anal. Calcd for
C14H21N3O6: C, 51.37; H, 6.47; N, 12.84. Found: C, 51.45; H, 6.39; N,
12.87.
from cyclopentenyl-1-diazenes 1a,b, only
a-substituted cyclo-
pentanone hydrazones 3a–c were obtained by crystallization from
ethyl acetate–light petroleum ether (40–60 ꢀC). Instead, in the case
of cyclohexenyl-1-diazenes 1c,d, the TLC check revealed the for-
mation of two major products. The crudes were chromatographed
on silica column (elution mixtures: ethyl acetate–cyclohexane).
Only in the case of the reaction between 1d and 2a, ethyl 3-[2-
(aminocarbonyl)hydrazono]-1-[1-(anilinocarbonyl)-2-oxopropyl]-
1-cyclohexanecarboxylate 3d was isolated together with the
corresponding tetrahydro-1H-indole 4f. In the other cases, the
chromatographic processes furnished only tetrahydro-1H-indoles
4a–e,g–i. Compounds 3d and 4a–i were crystallized from ethyl
acetate–light petroleum ether (40–60 ꢀC). Starting from
cycloheptenyl-1-diazene 1e or from cyclooctenyl-1-diazene 1f only
2-methyl-1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrroles 4j–s (n¼3)
or 2-methyl-3a,4,5,6,7,8-hexahydro-1H-cycloocta[b]pyrroles 4t–ab
were formed. Products 4j–s and 4t–ab were purified by silica gel
flash chromatography (elution mixtures: ethyl acetate–
cyclohexane) and were crystallized from diethyl ether–
cyclohexane.
4.1.5. Ethyl 2-[2-(aminocarbonyl)hydrazono]-1-(anilinocarbonyl)-
2-oxopropyl]-4-methyl-1-cyclohexanecarboxylate 3d
Yield 29 mg, 7%, white powder; mp 132–134 ꢀC; IR (Nujol):
nmax¼3482, 3310, 3207,1720,1684 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
0.90 (d, 3H, 3J¼6.4 Hz), 1.04–1.08 (m, 1H), 1.16 (t, 3H, 3J¼7.2 Hz),
1.27–1.31 (m, 1H), 1.73–1.76 (m, 2H), 1.96–2.07 (m, 1H), 2.09 (s, 3H),
2.60–2.64 (m, 1H), 3.33–3.39 (m, 1H), 4.06 (q, 2H, 3J¼7.2 Hz), 4.36
(s, 1H), 5.91 and 6.12 (2br s, 2H), 7.07 (t, 1H, 3J¼7.2 Hz), 7.30 (t, 2H,
3J¼7.6 Hz), 7.53 (d, 2H, 3J¼8.0 Hz), 9.47 (s, 1H), 10.24 (s, 1H); 13C
NMR (100 MHz, CDCl3)
d 14.5 (CH3), 15.9 (CH3), 21.1 (CH2), 29.5
(CH3), 30.3 (CH), 32.1 (CH2), 56.9 (CH2), 61.2 (CH), 62.0 (CH2), 65.6
(C), 120.1 (CH), 124.4 (CH), 129.5 (CH), 139.2 (C), 149.9 (C), 157.8 (C),
167.4 (C), 172.2 (C), 203.8 (C); MS: m/z (%)¼416 (Mþ, 1), 398 (8), 355
(7), 342 (13), 325 (100). Anal. Calcd for C21H28N4O5: C, 60.56; H,
6.78; N, 13.45. Found: C, 60.51; H, 6.83; N, 13.52.
4.1.2. tert-Butyl 2-(2-[(ethyloxy)carbonyl]-2-{2-oxo-1-
[(phenylamino)carbonyl]propyl}cyclopentyliden)-1-
hydrazinecarboxylate 3a
4.1.6. Ethyl 1-[(aminocarbonyl)amino]-3-(anilinocarbonyl)-2-
methyl-3a,4,5,6-tetrahydro-1H-3a-indolecarboxylate 4a
Yield 242 mg, 63%, white powder; mp 189–191 ꢀC; IR (Nujol):
Yield 352 mg, 79%, white powder, mp 116–118 ꢀC; IR (Nujol):
nmax¼3431, 3327, 3187, 1739, 1724 cmꢁ1
;
1H NMR (400 MHz,
nmax¼3307, 3243, 1776, 1704 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
DMSO-d6) d 1.11–1.15 (m, 3H), 1.36–1.48 (m, 3H), 1.63–1.79 (m,
d
1.16 (t, 3H, 3J¼7.2 Hz), 1.25 (s, 9H), 1.61–1.69 (m, 1H), 1.71–1.86 (m,
1H), 1.98–2.13 (m, 1H), 2.11 (s, 3H), 2.67–2.71 (m, 1H), 4.10–4.21
(m, 2H), 4.88–4.90 (m, 1H), 6.02 (br s, 2H), 7.02 (t, 1H, 3J¼8.0 Hz),
7.28 (m, 2H), 7.56 (d, 2H, 3J¼8.0 Hz), 8.41 and 8.54 (2br s, 1H),
1H), 2.00–2.31 (m, 3H), 2.26 (s, 3H), 2.80–2.89 (m, 1H), 4.04–4.18
(m, 2H), 4.68 (br s,1H), 7.06 (t,1H, 3J¼7.2 Hz), 7.20 (t, 2H, 3J¼8.0 Hz),
7.58–7.67 (m, 2H), 7.70 (br s, 1H), 9.17 (br s, 1H); 13C NMR (100 MHz,
8.99 and 9.08 (2br s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 11.6
DMSO-d6)
d
13.8 (CH3), 13.9 (CH3), 19.6 (CH3), 21.0 (CH2), 21.6 (CH2),
(CH3), 13.8 (CH3), 18.7 (CH2), 21.4 (CH2), 28.4 (CH2), 52.8 (C), 61.7
(CH2), 96.2 (CH), 106.7 (C), 119.2 (CH), 122.9 (CH), 128.7 (CH),
139.2 (C), 144.1 (C), 155.7 (C), 158.6 (C), 162.5 (C), 172.8 (C); MS:
m/z (%)¼384 (Mþ, 7), 325 (1), 311 (100), 264 (6), 192 (5). Anal.
Calcd for C20H24N4O4: C, 62.49; H, 6.29; N, 14.57. Found: C, 62.44;
H, 6.31; N, 14.71.
26.7 (CH2), 26.8 (CH2), 28.0 (CH3), 28.1 (CH3), 32.8 (CH2), 33.7 (CH2),
57.9 (CH), 61.3 (CH2), 61.6 (CH2), 65.0 (C), 119.8 (CH), 124.2 (CH),
128.6 (CH), 138.0 (C), 152.7 (C), 159.9 (C), 166.0 (C), 168.9 (C), 171.2
(C), 171.8 (C), 201.9 (C); MS: m/z (%)¼445 (Mþ, 1), 368 (12), 314 (14),
295 (12), 249 (18), 214 (93), 168 (43), 124 (100). Anal. Calcd for
C23H31N3O6: C, 62.01; H, 7.01; N, 9.43. Found: C, 62.12; H, 7.06; N,
9.42.
4.1.7. Ethyl 1-[(aminocarbonyl)amino]-3-[(4-methoxyanilino)-
carbonyl]-2-methyl-3a,4,5,6-tetrahydro-1H-3a-indole-
carboxylate 4b
4.1.3. Ethyl 2-[2-(aminocarbonyl)hydrazono]-1-[1-({[4-
(methoxy)phenyl]amino}carbonyl)-2-oxopropyl]-1-
cyclopentanecarboxylate 3b
Yield 244 mg, 59%, white powder; mp 167–170 ꢀC; IR (Nujol):
nmax¼3426, 3346, 3259, 1784, 1742 cmꢁ1
;
1H NMR (400 MHz,
DMSO-d6) d 1.13–1.16 (m, 3H), 1.39–1.52 (m, 2H), 1.65–1.79 (m, 2H),
Yield 351 mg, 84%, white powder; mp 142–143 ꢀC; IR (Nujol):
nmax¼3374, 3258, 1762, 1735 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
1.91–2.12 (m, 1H), 2.10 (s, 3H), 2.66–2.69 (m, 1H), 3.71 (s, 3H), 4.10–
4.19 (m, 2H), 4.72–4.88 (m, 1H), 5.99 (br s, 2H), 6.86 (d, 2H,
3J¼9.2 Hz), 7.47 (d, 2H, 3J¼9.2 Hz), 8.36 and 8.50 (2br s, 1H), 8.83
d
1.12 (t, 3H, 3J¼7.2 Hz),1.70–1.82 (m, 1H), 2.00–2.21 (m, 2H), 2.17 (s,
3H), 2.35–2.50 (m, 2H), 2.63–2.72 (m, 1H), 3.69 (s, 3H), 3.96–4.11
(m, 2H), 4.79 (s, 1H), 6.53 (br s, 2H), 6.85 (d, 2H, 3J¼7.2 Hz), 7.37 (d,
2H, 3J¼7.2 Hz), 9.01 (s, 1H), 10.03 (s, 1H); 13C NMR (100 MHz,
and 8.92 (2br s,1H); 13C NMR (100 MHz, DMSO-d6)
d 11.5 (CH3),13.7
(CH3), 18.7 (CH2), 21.4 (CH2), 28.3 (CH2), 52.8 (C), 55.1 (CH3), 61.5
(CH2), 96.0 (CH), 106.9 (C), 113.8 (CH), 120.7 (CH), 132.2 (C), 144.2
(C), 154.9 (C), 155.0 (C), 158.5 (C), 162.2 (C), 172.7 (C); MS: m/z
(%)¼414 (Mþ, 11), 356 (3), 341 (100), 324 (6), 298 (6), 282 (7), 264
(18). Anal. Calcd for C21H26N4O5: C, 60.86; H, 6.32; N, 13.52. Found:
C, 60.84; H, 6.28; N, 13.61.
DMSO-d6)
d 14.6 (CH3), 22.9 (CH3), 28.3 (CH2), 29.4 (CH2), 31.4
(CH2), 55.9 (CH3), 57.7 (CH), 61.5 (CH2), 64.2 (C), 114.5 (CH), 121.8
(CH), 132.2 (C), 155.6 (C), 156.4 (C), 157.7 (C), 166.0 (C), 173.0 (C),
203.0 (C); MS: m/z (%)¼418 (Mþ, 2), 372 (2), 344 (100), 329 (14), 298
(10), 270 (27), 228 (48), 179 (24), 137 (40), 123 (93). Anal. Calcd for

2294
O.A. Attanasi et al. / Tetrahedron 65 (2009) 2290–2297
4.1.8. Ethyl 1-[(aminocarbonyl)amino]-3-[(4-
chloroanilino)carbonyl]-2-methyl-3a,4,5,6-tetrahydro-1H-3a-
indolecarboxylate 4c
DMSO-d6)
d
0.95 (d, 3H, 3J¼7.6 Hz), 1.14 (t, 3H, 3J¼7.2 Hz), 1.21–1.39
(m, 1H), 1.43–1.51 (m, 1H), 1.62–1.76 (m, 1H), 2.08 (s, 3H), 2.23–2.37
(m, 1H), 2.49–2.55 (m, 1H), 3.69 (s, 3H), 4.07–4.15 (m, 2H), 4.77 (d,
1H, 3J¼3.2 Hz), 5.99 (br s, 2H), 6.84 (d, 2H, 3J¼8.8 Hz), 7.45 (d, 2H,
3J¼8.8 Hz), 8.57 (br s, 1H), 8.90 (br s, 1H); 13C NMR (100 MHz,
Yield 259 mg, 62%, white powder; mp 178–180 ꢀC; IR (Nujol):
nmax¼3412, 3385, 3231, 1745, 1723 cmꢁ1
;
1H NMR (400 MHz,
DMSO-d6)
d
1.11–1.15 (m, 3H), 1.36–1.54 (m, 2H), 1.62–1.79 (m, 2H),
DMSO-d6) d 11.5 (CH3),13.7 (CH3), 22.3 (CH3), 22.6 (CH2), 24.7 (CH2),
1.91–2.08 (m, 1H), 2.10 (s, 3H), 2.66–2.69 (m, 1H), 4.08–4.17 (m, 2H),
4.77–4.89 (m, 1H), 6.01 (br s, 2H), 7.33 (d, 2H, 3J¼8.4 Hz), 7.60 (d,
2H, 3J¼8.4 Hz), 8.42 and 8.55 (2br s, 1H), 9.12 and 9.23 (2br s, 1H);
25.9 (CH2), 26.3 (CH), 53.4 (C), 55.1 (CH3), 61.5 (CH2), 102.2 (CH),
107.1 (C), 113.8 (CH), 120.6 (CH), 132.3 (C), 143.8 (C), 154.9 (C), 158.5
(C), 162.2 (C), 172.5 (C); MS: m/z (%)¼428 (Mþ, 12), 369 (1), 355
(100), 278 (21), 206 (29), 146 (33). Anal. Calcd for C22H28N4O5: C,
61.67; H, 6.59; N, 13.08. Found: C, 61.81; H, 6.48; N, 13.11.
13C NMR (100 MHz, DMSO-d6)
d 11.6 (CH3), 13.7 (CH3), 16.6 (CH2),
21.4 (CH2), 28.3 (CH2), 52.8 (C), 61.6 (CH2), 96.3 (CH),106.7 (C),120.7
(CH), 126.4 (C), 128.5 (CH), 138.2 (C), 144.0 (C), 155.4 (C), 158.5 (C),
162.7 (C), 172.6 (C); MS: m/z (%)¼420 (Mþþ2, 2), 418 (Mþ, 7), 390
(12), 388 (38), 374 (21), 372 (56), 346 (32), 344 (100), 218 (26), 202
(67). Anal. Calcd for C20H23ClN4O4: C, 57.35; H, 5.53; N, 13.38.
Found: C, 57.34; H, 5.32; N, 13.51.
4.1.13. Ethyl 1-[(aminocarbonyl)amino]-3-[(4-chloroanilino)-
carbonyl]-2,6-dimethyl-3a,4,5,6-tetrahydro-1H-3a-
indolecarboxylate 4h
Yield 285 mg, 66%, white powder; mp 183–184 ꢀC; IR (Nujol):
nmax¼3465, 3376, 3265, 1758, 1737 cmꢁ1
;
1H NMR (400 MHz,
4.1.9. 3a-Ethyl 3-methyl 1-[(aminocarbonyl)amino]-2-methyl-
3a,4,5,6-tetrahydro-1H-3-3a-indoledicarboxylate 4d
DMSO-d6)
d
0.95 (d, 3H, 3J¼6.8 Hz), 1.09–1.15 (m, 3H), 1.35–1.39 (m,
1H), 1.44–1.53 (m, 1H), 1.66–1.74 (m, 1H), 2.09 (s, 3H), 2.28–2.36 (m,
1H), 2.48–2.56 (m, 1H), 4.05–4.17 (m, 2H), 4.62 (d, 0.2H, 3J¼3.2 Hz),
4.79 (d, 0.8H, 3J¼3.2 Hz), 5.99 (br s, 2H), 7.31 (d, 2H, 3J¼8.8 Hz), 7.59
(d, 2H, 3J¼8.8 Hz), 8.41 and 8.54 (2br s, 1H), 9.08 and 9.21 (2br s,
Yield 165 mg, 51%, white powder; mp 173–176 ꢀC; IR (Nujol):
nmax¼3423, 3362, 3158, 1748, 1693 cmꢁ1
;
1H NMR (400 MHz,
DMSO-d6) d 1.13–1.28 (m, 3H), 1.34–1.68 (m, 3H), 1.87–2.19 (m, 2H),
2.28 (s, 3H), 2.69–2.75 (m,1H), 3.69 (s, 3H), 4.14–4.28 (m, 2H), 5.06–
1H); 13C NMR (100 MHz, DMSO-d6)
d 11.6 (CH3), 13.7 (CH3), 13.9
5.12 (m, 1H), 5.27 and 6.13 (2br s, 2H), 7.52 and 9.00 (2br s, 1H); 13C
(CH3), 22.3 (CH3), 22.5 (CH2), 24.7 (CH2), 25.9 (CH2), 26.1 (CH2), 26.2
(CH), 53.1 (C), 61.1 (CH2), 61.6 (CH2), 102.5 (CH), 106.9 (C), 120.6
(CH), 120.7 (CH), 126.4 (C), 128.5 (CH), 138.1 (C), 138.4 (C), 143.6 (C),
155.5 (C), 158.4 (C), 162.7 (C), 172.4 (C); MS: m/z (%)¼434 (Mþþ2, 2),
432 (Mþ, 9), 361 (35), 359 (100), 264 (96), 219 (26), 189 (36). Anal.
Calcd for C21H25ClN4O4: C, 58.26; H, 5.82; N, 12.94. Found: C, 58.24;
H, 5.69; N, 13.01.
NMR (100 MHz, DMSO-d6) d 11.5 (CH3), 14.0 (CH3), 20.4 (CH2), 23.7
(CH2), 29.6 (CH2), 50.5 (CH3), 52.7 (C), 61.5 (CH2), 94.9 (CH), 98.3 (C),
143.7 (C), 148.7 (C), 159.9 (C), 165.2 (C), 172.6 (C); MS: m/z (%)¼323
(Mþ, 7), 294 (16), 278 (83), 249 (100), 235 (26), 191 (33), 132 (52).
Anal. Calcd for C15H21N3O5: C, 55.72; H, 6.55; N, 13.00. Found: C,
55.64; H, 6.42; N, 13.08.
4.1.10. Diethyl 1-[(aminocarbonyl)amino]-2-methyl-3a,4,5,6-
tetrahydro-1H-3a-indoledicarboxylate 4e
4.1.14. 3a-Ethyl 3-methyl 1-[(aminocarbonyl)amino]-2,6-dimethyl-
3a,4,5,6-tetrahydro-1H-3-3a-indoledicarboxylate 4i
Yield 182 mg, 54%, white powder; mp 154–156 ꢀC; IR (Nujol):
nmax¼3410, 3342, 3218, 1782, 1737 cmꢁ1; 1H NMR (400 MHz, CDCl3)
Yield 195 mg, 58%, white powder; mp 177–178 ꢀC; IR (Nujol):
nmax¼3295, 3232, 1776, 1727 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
1.14–1.34 (m, 6H), 1.39–1.58 (m, 3H), 1.87–2.04 (m, 2H), 2.23 (s,
d
0.98 (d, 3H, 3J¼6.8 Hz), 1.19 (t, 3H, 3J¼7.2 Hz), 1.21–1.35 (m, 2H),
3H), 2.69–2.77 (m, 1H), 4.11–4.25 (m, 4H), 5.01–5.08 (m, 1H), 5.42
1.42–1.57 (m, 1H), 1.74–1.98 (m, 1H), 2.26 (s, 3H), 2.73–2.85 (m, 1H),
and 6.20 (2br s, 2H), 7.05 (br s, 1H); 13C NMR (100 MHz, CDCl3)
3.66 (s, 3H), 4.12 (q, 2H, 3J¼7.2 Hz), 4.93 (d, 1H, 3J¼3.2 Hz), 6.14 (br s,
d
11.5 (CH3), 14.1 (CH3),14.3 (CH3),19.0 (CH2), 26.7 (CH2), 29.3 (CH2),
2H), 7.45 (s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 11.7 (CH3), 14.3
56.2 (C), 61.3 (CH2), 62.6 (CH2), 98.3 (CH), 105.0 (C), 143.9 (C), 150.4
(C),159.5 (C),164.8 (C),172.7 (C); MS: m/z (%)¼337 (Mþ,19), 308 (4),
292 (70), 264 (100), 235 (29), 219 (21), 190 (100), 175 (56), 132 (63).
Anal. Calcd for C16H23N3O5: C, 56.96; H, 6.87; N, 12.46. Found: C,
56.91; H, 6.95; N, 12.39.
(CH3), 22.6(CH), 24.5 (CH2), 26.8(CH2), 27.1 (CH2), 50.8(CH3), 53.2(C),
61.6(CH2),104.7(CH),105.0(C),143.7(C),158.4(C),160.1(C),165.4(C),
172.5 (C); MS: m/z (%)¼337 (Mþ, 6), 306 (1), 278 (10), 264 (100), 247
(30), 232 (13), 205 (17),189 (20),172 (38). Anal. Calcd for C16H23N3O5:
C, 56.96; H, 6.87; N, 12.46. Found: C, 56.91; H, 6.94; N, 12.41.
4.1.11. Ethyl 1-[(aminocarbonyl)amino]-3-(anilinocarbonyl)-2,6-
dimethyl-3a,4,5,6-tetrahydro-1H-3a-indolecarboxylate 4f
4.1.15. Methyl 1-[(aminocarbonyl)amino]-3-(anilinocarbonyl)-2-
methyl-1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrrole-3a-
dicarboxylate 4j
Yield 243 mg, 61%, white powder; mp 201–203 ꢀC; IR (Nujol):
nmax¼3465, 3353, 3196, 1719, 1709, 1647 cmꢁ1; 1H NMR (400 MHz,
Yield 261 mg, 68%, pale-pink powder; mp 189–191 ꢀC; IR (Nujol):
nmax¼3379, 3316, 3128,1783,1745 cmꢁ1; 1H NMR (400 MHz, DMSO-
CDCl3)
d
0.98 (d, 3H, 3J¼6.0 Hz), 1.13 (t, 3H, 3J¼7.2 Hz), 1.36–1.43 (m,
1H), 1.51 (dt, 1H, 2J¼12.8 Hz, 3J¼4.0 Hz), 1.66–1.74 (m, 1H), 2.11 (s,
3H), 2.21–2.33 (m, 1H), 2.52–2.58 (m, 1H), 4.14 (q, 2H, 3J¼7.2 Hz),
4.80 (d, 1H, 3J¼3.6 Hz), 6.07 (br s, 2H), 7.02 (t, 1H, 3J¼7.2 Hz), 7.29 (t,
2H, 3J¼8.4 Hz), 7.56 (dd, 2H, 3J¼8.4 Hz, 4J¼0.8 Hz), 8.41 and 8.58 (2br
d6) d 1.24–1.31 (m, 1H), 1.40–1.47 (m, 1H), 1.61–1.67 (m, 1H), 1.88–
2.01 (m, 4H), 2.06 (s, 3H), 2.38–2.52 (m, 1H), 3.68 (s, 3H), 4.91–5.05
(m,1H), 6.06 (br s, 2H), 6.89–7.01 (m,1H), 7.26 (d, 2H, 3J¼8.0 Hz), 7.53
(d, 2H, 3J¼8.0 Hz), 8.44 and 8.50 (2br s,1H), 9.12 and 9.32 (2br s,1H);
s, 1H), 8.91 and 9.09 (2br s, 1H); 13C NMR (100 MHz, CDCl3)
d
11.5
13C NMR (100 MHz, DMSO-d6)
d 12.5 (CH3), 25.4 (CH2), 28.5 (CH2),
(CH3), 13.7 (CH3), 22.2 (CH2), 24.8 (CH3), 25.9 (CH2), 26.1 (CH), 53.1
(C), 61.6 (CH2), 102.4 (CH), 106.9 (C), 119.0 (CH), 122.9 (CH), 128.7
(CH),139.1 (C),143.7 (C),155.5 (C),158.4 (C),162.5 (C),172.5 (C); MS:
m/z (%)¼398 (Mþ, 7), 340 (5), 325 (100). Anal. Calcd for C21H26N4O4:
C, 63.30; H, 6.58; N, 14.06. Found: C, 63.21; H, 6.63; N, 14.01.
28.7 (CH2), 32.6 (CH2), 53.2 (CH3), 58.9 (C),100.8 (CH),105.1 (C),119.9
(CH), 123.3 (CH), 129.3 (CH), 140.1 (C), 140.2 (C), 148.1 (C), 158.8 (C),
163.3 (C),173.0 (C); MS: m/z (%)¼384 (Mþ,14), 369 (5), 325 (78), 206
(36),119 (100). Anal. Calcd for C20H24N4O4: C, 62.49; H, 6.29; N,14.57.
Found: C, 62.44; H, 6.21; N, 14.71.
4.1.12. Ethyl 1-[(aminocarbonyl)amino]-3-[(4-methoxyanilino)-
carbonyl]-2,6-dimethyl-3a,4,5,6-tetrahydro-1H-3a-
indolecarboxylate 4g
4.1.16. Methyl 1-[(aminocarbonyl)amino]-3-[(4-methoxy-
anilino)carbonyl]-2-methyl-1,3a,4,5,6,7-hexahydro-
cyclohepta[b]pyrrole-3a-dicarboxylate 4k
Yield 244 mg, 57%, white powder; mp 158–160 ꢀC; IR (Nujol):
Yield 294 mg, 71%, white powder; mp 202–204 ꢀC; IR (Nujol):
nmax¼3395, 3364, 3218, 1773, 1721 cmꢁ1
;
1H NMR (400 MHz,
nmax¼3440, 3364, 3303, 1784, 1762 cmꢁ1
;
1H NMR (400 MHz,

O.A. Attanasi et al. / Tetrahedron 65 (2009) 2290–2297
2295
DMSO-d6)
d
1.07–1.33 (m, 2H), 1.41–1.73 (m, 2H), 1.89–2.20 (m, 4H),
(100), 264 (8), 250 (17), 234 (15), 206 (30). Anal. Calcd for C17H25N3O5:
C, 58.11; H, 7.17; N, 11.96. Found: C, 57.98; H, 7.21; N, 12.01.
2.02 (s, 3H), 3.69 (s, 3H), 3.71 (s, 3H), 4.91–5.06 (m, 1H), 6.04 (br s,
2H), 6.84 (d, 2H, 3J¼8.8 Hz), 7.45 (d, 2H, 3J¼8.8 Hz), 8.42 and 8.48
(2br s, 1H), 8.98 and 9.19 (2br s, 1H); 13C NMR (100 MHz, DMSO-d6)
4.1.21. 3-(tert-Butyl) 3a-methyl 1-[(aminocarbonyl)amino]-2-
methyl-1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrrole-3,3a-
dicarboxylate 4p
d
11.7 (CH3), 24.6 (CH2), 24.9 (CH2), 28.0 (CH2), 31.8 (CH2), 52.4
(CH3), 55.1 (CH3), 58.2 (C), 99.9 (CH), 104.5 (C), 113.7 (CH), 120.6
(CH), 132.4 (C), 132.6 (C), 147.4 (C), 154.9 (C), 158.2 (C), 162.3 (C),
172.3 (C); MS: m/z (%)¼414 (Mþ, 7), 382 (2), 357 (39), 323 (7), 234
(16), 123 (100). Anal. Calcd for C21H26N4O5: C, 60.86; H, 6.32; N,
13.52. Found: C, 60.74; H, 6.24; N, 13.70.
Yield 230 mg, 63%, white powder; mp 125–129 ꢀC; IR (Nujol):
nmax¼3386, 3253, 3167,1735,1697 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.31 (s, 9H), 1.54–1.67 (m, 2H), 1.80–1.91 (m, 2H), 1.93–2.11 (m,
2H), 2.13–2.21 (m, 1H), 2.19 (s, 3H), 2.69–2.74 (m, 1H), 3.67 (s, 3H),
5.14 and 5.16 (2d, 1H, 3J¼4.8 Hz), 5.85 (br s, 2H), 8.05 (s, 1H); 13C
4.1.17. Methyl 1-[(aminocarbonyl)amino]-3-[(4-chloroanilino)-
carbonyl]-2-methyl-1,3a,4,5,6,7-hexahydrocyclo-
hepta[b]pyrrole-3a-dicarboxylate 4l
NMR (100 MHz, CDCl3) d 11.5 (CH3), 25.0 (CH2), 27.8 (CH2), 27.9
(CH2), 28.2 (CH3), 30.3 (CH2), 52.1 (CH3), 57.6 (C), 79.6 (C), 102.0
(CH), 105.0 (C), 146.5 (C), 156.3 (C), 160.0 (C), 163.6 (C), 172.6 (C);
MS: m/z (%)¼365 (Mþ, 11), 306 (58), 292 (2), 264 (7), 250 (100), 233
(9), 206 (28),189 (17),146 (24). Anal. Calcd for C18H27N3O5: C, 59.16;
H, 7.45; N, 11.50. Found: C, 59.11; H, 7.48; N, 11.65.
Yield 347 mg, 83%, pale-yellow powder; mp 178–180 ꢀC; IR
(Nujol): nmax¼3378, 3326, 3241, 1790, 1686 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6) d 1.18–1.71 (m, 3H), 1.83–2.16 (m, 4H), 2.05 (s,
3H), 2.45–2.52 (m, 1H), 3.67 (s, 3H), 4.98–5.06 (m, 1H), 6.02 (br s,
2H), 7.29 (d, 2H, 3J¼8.8 Hz), 7.57 (d, 2H, 3J¼8.8 Hz), 8.43 and 8.48
(2br s, 1H), 9.23 and 9.42 (2br s, 1H); 13C NMR (100 MHz, DMSO-d6)
4.1.22. 3-Allyl 3a-methyl 1-[(aminocarbonyl)amino]-2-methyl-
1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrrole-3,3a-dicarboxylate 4q
Yield 195 mg, 56%, pale-yellow powder; mp 68–71 ꢀC; IR (Nujol):
nmax¼3413, 3317, 3105, 1769, 1719 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
11.8 (CH3), 24.6 (CH2), 27.8 (CH2), 28.0 (CH2), 31.8 (CH2), 52.4
(CH3), 58.1 (C), 100.3 (CH), 104.4 (C), 120.6 (CH), 126.2 (C), 128.4
(CH), 138.3 (C), 138.5 (C), 147.2 (C), 158.1 (C), 162.6 (C), 172.3 (C); MS:
m/z (%)¼420 (Mþþ2, 6), 418 (Mþ, 20), 405 (2), 403 (5), 361 (26), 359
(80), 265 (17), 234 (44), 206 (100). Anal. Calcd for C20H23ClN4O4: C,
57.35; H, 5.53; N, 13.38. Found: C, 57.44; H, 5.51; N, 13.31.
d
1.30–1.44 (m, 2H), 1.65–1.70 (m, 2H), 1.85–2.15 (m, 3H), 2.23 (s,
3H), 2.79–2.83 (m,1H), 3.70 (s, 3H), 4.50–4.61 (m, 2H), 5.14–5.30 (m,
3H), 5.63 and 5.88 (2br s, 2H), 5.83–5.93 (m, 1H), 8.01 (s, 1H); 13C
NMR (100 MHz, CDCl3)
d 11.8 (CH3), 25.3 (CH2), 27.8 (CH2), 28.1
(CH2), 30.2 (CH2), 52.3 (CH3), 57.6 (C), 64.1 (CH2), 102.8 (CH), 103.2
(C), 117.3 (CH2), 132.6 (CH), 146.4 (C), 157.9 (C), 159.7 (C), 163.9 (C),
172.7 (C); MS: m/z (%)¼349 (Mþ, 11), 306 (4), 292 (19), 290 (100),
264 (7), 249 (14), 232 (16), 205 (30). Anal. Calcd for C17H23N3O5: C,
58.44; H, 6.64; N, 12.03. Found: C, 58.55; H, 6.66; N, 11.92.
4.1.18. Dimethyl 1-[(aminocarbonyl)amino]-2-methyl-1,3a,4,5,6,7-
hexahydrocyclohepta[b]pyrrole-3,3a-dicarboxylate 4m
Yield 239 mg, 74%, beige powder; mp 139–142 ꢀC; IR (Nujol):
nmax¼3378, 3312, 3186, 1756, 1711 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.19–1.39 (m, 2H), 1.58–1.91 (m, 2H), 2.01–2.30 (m, 3H), 2.18 (s,
3H), 2.69–2.81 (m, 1H), 3.58 (s, 3H), 3.65 (s, 3H), 5.14–5.29 (m, 1H),
4.1.23. 3-Benzyl 3a-methyl 1-[(aminocarbonyl)amino]-2-methyl-
1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrrole-3,3a-dicarboxylate 4r
Yield 235 mg, 59%, pale-yellow powder; mp 136–138 ꢀC; IR
5.83 (br s, 2H), 8.19 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
11.6 (CH3),
25.1 (CH2), 27.7 (CH2), 29.7 (CH2), 30.1 (CH2), 50.3 (CH3), 52.2 (CH3),
57.4 (C),102.5 (CH),102.9 (C),146.3 (C), 157.5 (C),159.7 (C),164.6 (C),
172.3 (C); MS: m/z (%)¼323 (Mþ, 9), 308 (1), 264 (100), 205 (14), 150
(30). Anal. Calcd for C15H21N3O5: C, 55.72; H, 6.55; N, 13.00. Found:
C, 55.84; H, 6.49; N, 13.03.
(Nujol): nmax¼3402, 3315, 3174, 1819, 1745 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 1.20–1.42 (m, 2H), 1.55–1.68 (m, 2H), 2.05–2.21
(m, 3H), 2.19 (s, 3H), 2.70–2.84 (m, 1H), 3.56 (s, 3H), 5.01 (d, 1H,
2J¼12.4 Hz), 5.13 (d, 1H, 2J¼12.4 Hz), 5.15–5.20 (m, 1H), 5.42 and
5.91 (2br s, 2H), 6.85–7.58 (m, 5H), 7.86 (s, 1H); 13C NMR (100 MHz,
4.1.19. 3-Ethyl 3a-methyl 1-[(aminocarbonyl)amino]-2-methyl-
1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrrole-3,3a-dicarboxylate 4n
Yield 172 mg, 51%, white powder; mp 149–152 ꢀC; IR (Nujol):
nmax¼3426, 3387, 3265,1801,1739 cmꢁ1; 1H NMR (400 MHz, CDCl3)
CDCl3) d 11.8 (CH3), 25.3 (CH2), 27.8 (CH2), 28.1 (CH2), 30.3 (CH2),
52.2 (CH3), 57.6 (C), 65.1 (CH2), 102.8 (CH), 103.2 (C), 127.8 (CH),
128.4 (CH), 128.8 (CH), 136.4 (C), 146.4 (C), 158.0 (C), 159.5 (C), 163.9
(C), 172.7 (C); MS: m/z (%)¼399 (Mþ, 7), 340 (100), 249 (28), 193
(28). Anal. Calcd for C21H25N3O5: C, 63.15; H, 6.31; N, 10.52. Found:
C, 63.09; H, 6.39; N, 10.47.
d
1.15–1.23 (m, 3H), 1.24–1.54 (m, 2H), 1.60–1.74 (m, 2H), 1.80–2.14
(m, 3H), 2.19 (s, 3H), 2.73–2.77 (m, 1H), 3.67 (s, 3H), 4.01–4.06 (m,
2H), 5.16–5.20 (m, 1H), 5.85 (br s, 2H), 8.15 (s, 1H); 13C NMR
(100 MHz, CDCl3)
d
11.6 (CH3), 13.7 (CH3), 24.5 (CH2), 25.1 (CH2),
4.1.24. Methyl 3-acetyl-1-[(aminocarbonyl)amino]-2-methyl-
1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrrole-3a-carboxylate 4s
Yield 249 mg, 81%, pale-yellow powder; mp 189–191 ꢀC; IR
27.8 (CH3), 30.1 (CH2), 52.1 (CH3), 57.5 (C), 59.1 (CH2), 102.4 (CH),
103.3 (C), 146.3 (C), 157.3 (C), 159.8 (C), 164.2 (C), 172.6 (C); MS: m/z
(%)¼337 (Mþ, 9), 293 (4), 278 (100), 232 (13), 205 (24), 191 (26).
Anal. Calcd for C16H23N3O5: C, 56.96; H, 6.87; N, 12.46. Found: C,
57.05; H, 6.99; N, 12.34.
(Nujol): nmax¼3389, 3306, 3268, 1756, 1713 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6)
d 1.06–1.46 (m, 3H), 1.58–1.84 (m, 2H), 1.91–
2.06 (m, 1H), 2.12 (s, 3H), 2.16 (s, 3H), 2.28–2.49 (m, 1H), 2.61–2.74
(m, 1H), 3.57 (s, 3H), 4.96–5.11 (m, 1H), 5.75 and 6.14 (2br s, 2H),
4.1.20. 3a-Methyl 3-iso-propyl 1-[(aminocarbonyl)amino]-2-
methyl-1,3a,4,5,6,7-hexahydrocyclohepta[b]pyrrole-3,3a-
dicarboxylate 4o
8.59 and 8.66 (2br s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 12.4
(CH3), 12.6 (CH3), 23.5 (CH2), 24.2 (CH2), 27.5 (CH2), 29.7 (CH2), 51.6
(CH3), 56.2 (C), 101.2 (CH), 114.4 (C), 146.9 (C), 156.7 (C), 157.5 (C),
170.8 (C), 189.0 (C); MS: m/z (%)¼307 (Mþ, 6), 276 (45), 248 (100),
203 (43), 161 (49). Anal. Calcd for C15H21N3O4: C, 58.62; H, 6.89; N,
13.67. Found: C, 58.51; H, 7.00; N, 13.65.
Yield 267 mg, 76%, white powder; mp 133–136 ꢀC; IR (Nujol):
nmax¼3249, 3218, 3056, 1784, 1738 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
1.17 (d, 3H, 3J¼6.4 Hz), 1.21 (d, 3H, 3J¼6.4 Hz), 1.24–1.35 (m, 2H),
1.61–1.79 (m, 2H), 1.83–2.18 (m, 3H), 2.21 (s, 3H), 2.74–2.81 (m, 1H),
3.74 (s, 3H), 4.99 (q, 1H, 3J¼6.4 Hz), 5.18–5.24 (m, 1H), 5.71 and 5.93
4.1.25. Ethyl 1-[(aminocarbonyl)amino]-3-(anilinocarbonyl)-2-
methyl-3a,4,5,6,7,8-hexahydro-1H-cycloocta[b]pyrrole-3a-
dicarboxylate 4t
(2br s, 2H), 7.98 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 11.6 (CH3), 21.8
(CH3), 21.9 (CH3), 25.2 (CH2), 27.9 (CH2), 28.1 (CH2), 30.2 (CH2), 52.2
(CH3), 57.7 (C), 66.5 (CH), 102.5 (CH), 104.0 (C), 146.5 (C), 157.1 (C),
159.8 (C), 163.8 (C), 172.9 (C); MS: m/z (%)¼351 (Mþ, 10), 308 (2), 292
Yield 260 mg, 63%, white powder; mp 139–141 ꢀC; IR (Nujol):
nmax¼3354, 3278, 3127, 1784, 1728 cmꢁ1
;
1H NMR (400 MHz,

2296
O.A. Attanasi et al. / Tetrahedron 65 (2009) 2290–2297
DMSO-d6)
d
0.98–1.19 (m, 2H), 1.13 (t, 3H, 3J¼7.2 Hz), 1.23–1.51 (m,
d
1.12–1.37 (m, 8H), 1.39–1.55 (m, 2H), 1.62–1.83 (m, 2H), 1.96–2.14 (m,
3H), 1.61–1.94 (m, 3H), 1.98–2.11 (m, 2H), 2.05 (s, 3H), 3.98–4.19
(m, 2H), 4.59–4.77 (m, 1H), 6.08 (br s, 2H), 6.94–7.01 (m, 1H),
7.24–7.31 (m, 2H), 7.54 (t, 2H, 3J¼7.2 Hz), 8.43 and 8.70 (2br s, 1H),
3H), 2.25 (s, 3H), 2.63–2.81 (m, 1H), 3.99–4.24 (m, 4H), 4.78–5.01 (m,
1H), 5.51 (s, 2H), 7.82 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 11.5 (CH3),
13.9 (CH3),14.2 (CH3), 22.1 (CH2), 22.8 (CH2), 25.1 (CH2), 28.6 (CH2), 36.9
(CH2), 56.0 (C), 61.0 (CH2), 61.2 (CH2), 100.5 (CH), 107.1 (C), 144.5 (C),
155.4(C),159.3(C),164.3(C),172.5(C);MS:m/z(%)¼365(Mþ,8),336(1),
320 (5), 292 (100), 246 (36), 203 (12). Anal. Calcd for C18H27N3O5: C,
59.16; H, 7.45; N, 11.50. Found: C, 59.19; H, 7.43; N, 11.39.
8.90 and 9.31 (2br s, 1H); 13C NMR (100 MHz, DMSO-d6)
d 11.9
(CH3), 13.9 (CH3), 21.8 (CH2), 22.8 (CH2), 24.9 (CH2), 29.5 (CH2),
37.4 (CH2), 56.3 (CH2), 60.6 (C), 96.3 (CH), 108.5 (C), 119.3 (CH),
122.7 (CH), 128.4 (CH), 139.5 (C), 146.2 (C), 150.2 (C), 158.0 (C),
162.7 (C), 172.3 (C); MS: m/z (%)¼412 (Mþ, 23), 383 (26), 367
(100), 339 (65), 319 (100), 291 (31), 247 (39), 203 (48). Anal. Calcd
for C22H28N4O4: C, 64.06; H, 6.84; N, 13.58. Found: C, 64.14; H,
6.81; N, 13.50.
4.1.30. 3a-Ethyl 3-iso-propyl 1-[(aminocarbonyl)amino]-2-methyl-
3a,4,5,6,7,8-hexahydro-1H-cycloocta[b]pyrrole-3,3a-
dicarboxylate 4y
Yield 242 mg, 64%, pale-yellow powder; mp 136–138 ꢀC; IR
4.1.26. Ethyl 1-[(aminocarbonyl)amino]-3-[(4-methoxyanilino)-
carbonyl]-2-methyl-3a,4,5,6,7,8-hexahydro-1H-
(Nujol): nmax¼3256, 3157, 3086, 1812, 1789 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d 1.11–1.48 (m, 9H), 1.16–1.27 (m, 3H), 1.40–1.52
cycloocta[b]pyrrole-3a-dicarboxylate 4u
(m, 2H), 1.58–1.85 (m, 3H), 1.92–2.05 (m, 2H), 2.14 (s, 3H), 4.00–4.10
(m, 2H), 4.61–4.71 (m, 1H), 4.74–4.89 (m, 1H), 6.14 (br s, 2H), 8.45
Yield 314 mg, 71%, white powder; mp 173–176 ꢀC; IR (Nujol):
nmax¼3425, 3352, 3263, 1792, 1710 cmꢁ1
;
1H NMR (400 MHz,
(br s, 1H); 13C NMR (100 MHz, CDCl3)
d 11.5 (CH3), 13.9 (CH3), 20.7
DMSO-d6)
d
1.11–1.19 (m, 3H), 1.13 (t, 3H, 3J¼7.2 Hz), 1.27–1.78 (m,
(CH3), 21.8 (CH2), 23.1 (CH2), 24.9 (CH2), 26.3 (CH2), 29.6 (CH2), 55.2
(C), 59.9 (CH2), 65.2 (CH), 97.7 (CH), 104.1 (C), 146.0 (C), 156.7 (C),
157.5 (C), 163.2 (C), 171.6 (C); MS: m/z (%)¼379 (Mþ, 16), 350 (11),
336 (21), 320 (45), 320 (65), 292 (100), 247 (38), 219 (64), 175 (69).
Anal. Calcd for C19H29N3O5: C, 60.14; H, 7.70; N, 11.07. Found: C,
60.03; H, 7.63; N, 10.96.
4H), 1.95–2.19 (m, 3H), 2.08 (s, 3H), 3.70 (s, 3H), 4.01–4.15 (m, 2H),
4.58–4.79 (m, 1H), 6.06 (br s, 2H), 6.83 (d, 2H, 3J¼6.8 Hz), 7.45 (d,
2H, 3J¼6.8 Hz), 8.40 and 8.63 (2br s, 1H), 8.76 and 9.21 (2br s, 1H);
13C NMR (100 MHz, DMSO-d6)
d 11.9 (CH3), 13.9 (CH3), 21.9 (CH2),
22.4 (CH2), 24.9 (CH2), 28.9 (CH2), 37.4 (CH2), 55.1 (CH3), 56.3 (CH3),
60.6 (C), 96.2 (CH), 108.3 (C), 113.6 (CH), 120.9 (CH), 132.5 (C), 132.7
(C), 146.4 (C), 154.9 (C), 157.2 (C), 162.4 (C), 172.3 (C); MS: m/z
(%)¼442 (Mþ, 5), 397 (71), 369 (100), 335 (61), 319 (16), 292 (8), 262
(82), 219 (45), 174 (27). Anal. Calcd for C23H30N4O5: C, 62.43; H,
6.85; N, 12.66. Found: C, 64.34; H, 6.81; N, 12.70.
4.1.31. 3-(tert-Butyl) 3a-ethyl 1-[(aminocarbonyl)amino]-2-
methyl-3a,4,5,6,7,8-hexahydro-1H-cycloocta[b]pyrrole-3,3a-
dicarboxylate 4z
Yield 287 mg, 73%, beige powder; mp 110–112 ꢀC; IR (Nujol):
nmax¼3417, 3354, 3156, 1784, 1743 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.1.27. Ethyl 1-[(aminocarbonyl)amino]-3-[(4-chloroanilino)
carbonyl]-2-methyl-3a,4,5,6,7-hexahydro-1H-
d
1.03–1.54 (m, 4H),1.21 (t, 3H, 3J¼7.2 Hz),1.43 (s, 9H),1.53–2.06 (m,
5H), 2.23 (s, 3H), 2.67–2.76 (m, 1H), 4.15 (q, 2H, 3J¼7.2 Hz), 4.93 (t,
cycloocta[b]pyrrole-3a-dicarboxylate 4v
1H, 3J¼8.2 Hz), 5.49 (br s, 2H), 7.67 (s, 1H); 13C NMR (100 MHz,
Yield 290 mg, 65%, white powder; mp 156–158 ꢀC; IR (Nujol):
CDCl3) d 11.4 (CH3), 14.1 (CH3), 22.1 (CH2), 22.9 (CH2), 25.2 (CH2),
nmax¼3289, 3216, 3164, 1745, 1723 cmꢁ1
;
1H NMR (400 MHz,
28.3 (CH3), 28.7 (CH2), 37.0 (CH2), 56.0 (C), 61.0 (CH2), 80.0 (C),100.2
(CH),108.5 (C),144.5 (C),154.4 (C),159.4 (C),163.7 (C),172.1 (C); MS:
m/z (%)¼393 (Mþ, 12), 336 (3), 320 (100), 264 (100), 247 (10), 220
(89). Anal. Calcd for C20H31N3O5: C, 61.05; H, 7.94; N, 10.68. Found:
C, 60.99; H, 7.88; N, 10.81.
DMSO-d6)
d
1.01–1.20 (m, 2H), 1.13 (t, 3H, 3J¼7.2 Hz), 1.28–1.49 (m,
4H), 1.55–1.76 (m, 2H), 1.86–2.15 (m, 2H), 2.08 (s, 3H), 3.99–4.18 (m,
2H), 4.59–4.81 (m, 1H), 6.07 (br s, 2H), 7.29 (d, 2H, 3J¼8.8 Hz), 7.58
(d, 2H, 3J¼8.8 Hz), 8.45 and 8.71 (2br s, 1H), 9.08 and 9.43 (2br s,
1H); 13C NMR (100 MHz, DMSO-d6)
d 12.0 (CH3), 13.9 (CH3), 21.8
(CH2), 22.8 (CH2), 24.7 (CH2), 28.9 (CH2), 37.4 (CH2), 56.3 (CH2), 60.2
(C), 96.5 (CH), 108.5 (C), 120.7 (CH), 125.9 (C), 128.3 (CH), 138.6 (C),
146.2 (C), 150.3 (C), 158.0 (C), 162.8 (C), 172.1 (C); MS: m/z (%)¼448
(Mþþ2, 3), 446 (Mþ, 8), 421 (15), 419 (42), 377 (35), 375 (100), 322
(73), 293 (36), 249 (43), 205 (17). Anal. Calcd for C22H27N4O4: C,
59.12; H, 6.09; N, 12.54. Found: C, 59.14; H, 6.21; N, 12.50.
4.1.32. 3-Allyl 3a-ethyl 1-[(aminocarbonyl)amino]-2-methyl-
3a,4,5,6,7,8-hexahydro-1H-cycloocta[b]pyrrole-3,3a-
dicarboxylate 4aa
Yield 294 mg, 78%, pale-yellow powder; mp 149–153 ꢀC; IR
(Nujol): nmax¼3386, 3265, 3218, 1793, 1742 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
1.18 (t, 3H, 3J¼7.2 Hz), 1.33–1.51 (m, 2H), 1.67–
2.02 (m, 2H), 2.04–2.17 (m, 5H), 2.26 (s, 3H), 2.73–2.86 (m, 1H), 4.12
(q, 2H, 3J¼7.2 Hz), 4.51–4.57 (m, 1H), 4.79–4.96 (m, 2H), 5.12–5.27
(m, 2H), 5.81–5.92 (m, 1H), 6.02 and 6.13 (2br s, 2H), 7.92 (br s, 1H);
4.1.28. 3a-Ethyl 3-methyl 1-[(aminocarbonyl)amino]-2-methyl-
3a,4,5,6,7,8-hexahydro-1H-cycloocta[b]pyrrole-3,3a-
dicarboxylate 4w
13C NMR (100 MHz, CDCl3)
d 11.6 (CH3), 13.9 (CH3), 22.8 (CH2), 25.1
Yield 302 mg, 86%, beige powder; mp 149–151 ꢀC; IR (Nujol):
nmax¼3347, 3318, 3216, 1768, 1752 cmꢁ1; 1H NMR (400 MHz, CDCl3)
(CH2), 28.7 (CH2), 30.2 (CH2), 37.0 (CH2), 56.0 (C), 61.2 (CH2), 64.2
(CH2), 100.7 (CH), 101.6 (C), 117.5 (CH2), 132.5 (CH), 146.1 (C), 156.3
(C), 158.2 (C), 162.9 (C), 170.9 (C); MS: m/z (%)¼377 (Mþ, 14), 336
(23), 320 (58), 304 (67), 292 (79), 247 (100), 219 (38),175 (28). Anal.
Calcd for C19H27N3O5: C, 60.46; H, 7.21; N, 11.13. Found: C, 60.52; H,
7.34; N, 11.21.
d
1.02–1.26 (m, 2H), 1.17 (t, 3H, 3J¼7.2 Hz), 1.30–1.47 (m, 2H), 1.65–
2.00 (m, 5H), 2.21 (s, 3H), 2.58–2.71 (m, 1H), 3.58 (s, 3H), 4.02–4.17
(m, 2H), 4.72–4.95 (m,1H), 5.41 and 5.78 (2br s, 2H), 8.12 (s,1H); 13C
NMR (100 MHz, CDCl3)
d 11.5 (CH3), 13.8 (CH3), 22.1 (CH2), 22.7
(CH2), 24.9 (CH2), 28.6 (CH2), 37.5 (CH2), 50.4 (CH3), 55.8 (C), 60.9
(CH2), 100.3 (CH), 106.6 (C), 144.3 (C), 155.7 (C), 159.5 (C), 164.6 (C),
172.3 (C); MS: m/z (%)¼351 (Mþ, 3), 322 (1), 278 (24), 246 (9), 203
(3), 149 (100). Anal. Calcd for C17H25N3O5: C, 58.11; H, 7.17; N, 11.96.
Found: C, 58.04; H, 7.21; N, 12.01.
4.1.33. 3-Benzyl 3a-ethyl 1-[(aminocarbonyl)amino]-2-methyl-
3a,4,5,6,7,8-hexahydro-1H-cycloocta[b]pyrrole-3,3a-
dicarboxylate 4ab
Yield 393 mg, 92%, yellow powder; mp 142–147 ꢀC; IR (Nujol):
nmax¼3422, 3276, 3179, 1786, 1740 cmꢁ1; 1H NMR (400 MHz, CDCl3)
4.1.29. Diethyl 1-[(aminocarbonyl)amino]-2-methyl-3a,4,5,6,7,8-
hexahydro-1H-cycloocta[b]pyrrole-3,3a-dicarboxylate 4x
Yield 347 mg, 95%, pale-yellow powder; mp 152–154 ꢀC; IR (Nujol):
d 0.96–1.13 (m, 3H), 1.18–1.46 (m, 4H), 1.67–2.01 (m, 5H), 2.22 (s,
3H), 2.70–2.82 (m, 1H), 3.98 (q, 2H, 3J¼7.2 Hz), 4.79–4.99 (m, 1H),
5.02 (d, 1H, 2J¼8.4 Hz), 5.09 (d, 1H, 2J¼8.4 Hz), 5.30 (br s, 2H), 7.07–
nmax¼3427, 3372, 3117, 1742, 1688 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
7.39 (m, 5H), 7.41 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 11.7 (CH3),

O.A. Attanasi et al. / Tetrahedron 65 (2009) 2290–2297
2297
3. (a) Attanasi, O. A.; Filippone, P.; Fiorucci, C.; Foresti, E.; Mantellini, F. J. Org.
Chem. 1998, 63, 9880–9887; (b) Attanasi, O. A.; Ballini, R.; De Crescentini, L.;
Filippone, P.; Mantellini, F. J. Org. Chem. 1999, 64, 9653–9657; (c) Attanasi, O. A.;
De Crescentini, L.; Filippone, P.; Foresti, E.; Mantellini, F. J. Org. Chem. 2000, 65,
2820–2823; (d) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Fringuelli, F.;
Mantellini, F.; Matteucci, M.; Piermatti, O.; Pizzo, F. Helv. Chim. Acta 2001, 84,
513–525; (e) Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.;
Santeusanio, S. Helv. Chim. Acta 2001, 84, 2379–2386; (f) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Lillini, S.; Mantellini, F.; Santeusanio, S.
Synlett 2005, 1474–1476; (g) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio,
R.; Lillini, S.; Mantellini, F.; Palacios, F.; de los Santos, J. M. J. Org. Chem. 2006, 71,
5897–5905.
13.9 (CH3), 22.2 (CH2), 22.9 (CH2), 25.1 (CH2), 28.6 (CH3), 37.0 (CH2),
56.1 (C), 61.3 (CH2), 65.3 (CH2), 100.7 (CH), 106.9 (C), 127.9 (CH),
128.1 (CH), 128.4 (CH), 136.4 (C), 144.5 (C), 156.1 (C), 158.9 (C), 164.1
(C),172.6 (C); MS: m/z (%)¼427 (Mþ,11), 398 (1), 354 (100), 310 (13).
Anal. Calcd for C23H29N3O5: C, 64.62; H, 6.84; N, 9.83. Found: C,
64.69; H, 6.97; N, 9.71.
Acknowledgements
This work was supported by the financial assistance from the
4. Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Giorgi, G.; Mantellini, F.; Maz-
zanti, A. Synlett 2006, 2403–2406.
`
Ministero dell’Universita, dell’Istruzione e della Ricerca (MIUR)-
5. (a) Brodka, S.; Simon, H. Justus Liebigs Ann. Chem. 1971, 745, 193–203; (b) At-
tanasi, O. A.; Bonifazi, P.; Foresti, E.; Pradella, G. J. Org. Chem. 1982, 47, 684–687.
6. (a) Attanasi, O. A.; Filippone, P. Synlett 1997, 1128–1140; (b) Attanasi, O. A.; De
Crescentini, L.; Filippone, P.; Mantellini, F.; Santeusanio, S. ARKIVOC 2002, xi,
274–292.
PRIN and the Universita` degli Studi di Urbino ‘Carlo Bo’.
References and notes
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7. Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Lillini, S.; Golobic, A.;
Mantellini, F. Synlett 2006, 2735–2738.
1. For recent developments on the chemistry of 1,2-diaza-1,3-butadienes, see: (a)
Figuereido, L. J. O.; Kascheres, C. J. Org. Chem. 1997, 62, 1164–1167; (b) Capo-
scialli, N.; Dell’Erba, C.; Novi, M.; Petrillo, G.; Tavani, C. Tetrahedron 1998, 54,
8. (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2, pp 119–
206; (b) Gribble, G. W. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon–Elsevier
Science: Amsterdam, 1996; Vol. 2, pp 207–257; (c) Effland, R. C.; Klein, J. T.
U.S. Patent 4,546,105, 1985; Chem. Abstr. 1986, 104, 186307; (d) Kulagowski,
J.; Janusz, J.; Leeson, P. D. UK Patent 2,265,372, 1993; Chem. Abstr. 1993,
120, 134504.
9. Goller, M. I.; Barthet, C.; McCarthy, G. P.; Corradi, R.; Newby, B. P.; Wilson, S. A.;
Armes, S. P.; Luk, S. Y. Colloid Polym. Sci. 1998, 276, 1010–1018.
10. Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.;
Perrulli, F. R.; Spinelli, D. Tetrahedron 2008, 64, 3837–3858.
11. The final atomic and geometrical parameters, crystal data and details con-
cerning data collection and refinement have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary material with the
deposition number: CCDC 614163. Copies of the data can be obtained, free of
charge via www.ccdc.cam.ac.uk/const/retrieving.html. ORTEP-3 was used to
produce the drawing of molecule, which is shown in Figure 1.
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5315–5324; (c) Schantl, J. G.; Nadenık, P. Synlett 1998, 786–788; (d) South, M. S.
J. Heterocycl. Chem. 1999, 36, 301–319; (e) Boeckman, R. K., Jr.; Ge, P.; Reed, J. E.
Org. Lett. 2001, 3, 3651–3653; (f) Avalos, M.; Babiano, R.; Cintas, P.; Clemente, F.
´
R.; Gordillo, R.; Jimenez, J. L.; Palacios, J. C. J. Org. Chem. 2002, 67, 2241–2251;
(g) Rossi, E.; Arcadi, A.; Abbiati, G.; Attanasi, O. A.; De Crescentini, L. Angew.
Chem., Int. Ed. 2002, 41, 1400–1402; (h) Kramp, G. J.; Kim, M.; Gais, H.-J.; Ver-
meeren, C. J. Am. Chem. Soc. 2005, 71, 17910–17920; (i) Palacios, F.; Aparicio, D.;
Lo´pez, Y.; de los Santos, J. M. Tetrahedron 2005, 61, 2815–2830; (j) Yang, H.-T.;
Wang, G.-W.; Xu, Y.; Huang, J.-C. Tetrahedron Lett. 2006, 47, 4129–4231; (k) Kim,
M.; Gais, H.-J. J. Org. Chem. 2006, 71, 4642–4650.
2. For recent developments on the synthesis of five-membered heterocycles
starting from 1,2-diaza-1,3-butadienes, see: (a) Attanasi, O. A.; Filippone, P.;
Mei, A. Tetrahedron 1992, 48, 1707–1714; (b) Attanasi, O. A.; Filippone, P.;
Fiorucci, C.; Mantellini, F. Tetrahedron Lett. 1999, 40, 3891–3894; (c) Attanasi, O.
A.; De Crescentini, L.; Filippone, P.; Mantellini, F. Synlett 2001, 557–559; (d)
Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; San-
teusanio, S. J. Org. Chem. 2002, 67, 8178–8181; (e) Attanasi, O. A.; De Crescentini,
L.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Santeusanio, S. J. Org. Chem.
2003, 68, 1947–1953; (f) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Filippone, P.;
Mantellini, F.; Santeusanio, S. Synlett 2001, 549–551; (g) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.; Santeusanio, S.
J. Org. Chem. 2004, 69, 2686–2692; (h) Attanasi, O. A.; Baccolini, G.; Boga, C.; De
Crescentini, L.; Filippone, P.; Mantellini, F. J. Org. Chem. 2005, 70, 4033–4037; (i)
12. (a) Schmuck, C.; Rupprecht, D. Synthesis 2007, 20, 3095–3110; (b) Roman, G.
Mini-Rev. Org. Chem. 2006, 3, 167–184.
13. (a) Antunes, E. M.; Copp, B. R.; Davies-Coleman, M. T.; Samaai, T. Nat. Prod. Rep.
2005, 22, 62–72; (b) Liu, Y.; Zhang, S.; Abreu, P. Nat. Prod. Rep. 2006, 23, 2735–
2738; (c) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Nat. Prod. Rep.
2006, 23, 517–531; (d) Bando, T.; Sugiyama, H. Acc. Chem. Res. 2006, 39, 935–
944.
ˇ
Attanasi, O. A.; Favi, G.; Filippone, P.; Golobic, A.; Stanovnik, B.; Svete, J. J. Org.
14. (a) Huffman, J. W.; Padgett, L. W. Curr. Med. Chem. 2005, 12, 1395–1411; (b)
Henry, M.; Alibert, S.; Orlandi-Pradines, E.; Bogreau, H.; Fusai, T.; Rogier, C.;
Barbe, J.; Pradines, B. Curr. Drug Targets 2006, 7, 935–948; (c) Costantino, L.;
Barlocco, D. Curr. Med. Chem. 2006, 13, 65–85.
15. (a) Ligon, J. M.; Hill, D. S.; Hammer, P. E.; Torkewitz, N. R.; Hofman, D.; Kempf,
H. J.; Van Pee, K. H. Pest Manag. Sci. 2000, 56, 688–695; (b) Pedersen, J. A.;
Yeager, M.; Suffet, I. H. J. Agric. Food Chem. 2003, 51, 1360–1372; (c) N’Guessan,
R.; Boko, P.; Odjo, A.; Akogbeto, M.; Yates, A.; Rowland, M. Acta Trop. 2007, 102,
69–78.
Chem. 2005, 70, 4307–4313; (j) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Fil-
ippone, P.; Lillini, S.; Mantellini, F.; Santeusanio, S. Org. Lett. 2005, 7, 2469–2471;
(k) Attanasi, O. A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.; Moscatelli, G.;
Prati, F. Org. Lett. 2007, 9, 3461–3464; (l) Attanasi, O. A.; Favi, G.; Filippone, P.;
Lillini, S.; Mantellini, F.; Spinelli, D.; Stenta, M. Adv. Synth. Catal. 2007, 349, 907–
915; (m) Karapetyan, V.; Mkrtchyan, S.; Schmidt, A.; Attanasi, O. A.; Favi, G.;
Mantellini, F.; Villinger, A.; Fischer, C.; Langer, P. Adv. Synth. Catal. 2008, 350,
1331–1336; (n) Attanasi, O. A.; Favi, G.; Filippone, P.; Giorgi, G.; Mantellini, F.;
Spinelli, D. Org. Lett. 2008, 10, 1983–1986.