Access to original spirocyclic derivatives via inter- or intramolecular reaction mediated by manganese(III) acetate

Article abstract of DOI:10.1016/j.tet.2012.03.004

An easily reproducible protocol allowing inter- or intramolecular spirocyclization on β-dicarbonyl structures is described. This methodology could afford a wide variety of spirocyclic pharmacophores. As examples, highly substituted spirobenzophenanthridin

Full text of DOI:10.1016/j.tet.2012.03.004

Tetrahedron 68 (2012) 3596e3604
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Access to original spirocyclic derivatives via inter- or intramolecular reaction
mediated by manganese(III) acetate
a
a
b
a,
*
ꢀ
Ahlem Bouhlel , Christophe Curti , Michele P. Bertrand , Patrice Vanelle
a
ꢁ
Aix-Marseille Univ, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculte de Pharmacie, 27 Bd Jean Moulin, CS 30064,
13385 Marseille Cedex 05, France
ˇ
b
ꢁ
ꢁ
ꢁ
Aix-Marseille Univ, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Chimie Moleculaire Organique, Faculte des Sciences et Techniques de Saint Jerome,
Avenue Normandie-Niemen, 13397 Marseille Cedex 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An easily reproducible protocol allowing inter- or intramolecular spirocyclization on
b-dicarbonyl
Received 10 November 2011
Received in revised form 17 February 2012
Accepted 1 March 2012
structures is described. This methodology could afford a wide variety of spirocyclic pharmacophores. As
examples, highly substituted spirobenzophenanthridin-6(5H)-ones and spirolactones were synthesized.
These scaffolds could be used for the design of many compounds exhibiting biological activities.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 8 March 2012
Keywords:
Manganese(III) acetate
Spirocyclic derivatives
Benzophenanthridinone
Spirolactones
1. Introduction
compounds exhibiting a wide range of biological activities (i.e., anti-
tumor15 or antiviral16 activities).
Mn(III)-based oxidative free-radical cyclizations have been ex-
tensively explored over the past 40 years. Indeed, Mn(OAc)3 is an
important tool in CeC bond formation in organic synthesis.1 Several
Our study establishes an easily reproducible protocol allowing
inter- or intramolecular spirocyclization of b-dicarbonyl structures.
reactions have been conducted on
1,3-diketones,2 -nitro ketones,4 malonates,2,5
ketosulfones,7 -ketonitriles,8 and -ketoamides.9
b
-ketoesters2 like acetoacetate,3
-ketoenamines,6
b-
2. Results and discussion
a
b
b
b
2.1. Intermolecular Mn(OAc)3-mediated reaction
For instance, Citterio and co-workers have explored additions to
aromatic rings10 and the subsequent formation of substituted tet-
ralin. Snider and co-workers have also reported spirocyclic scaffold
synthesis with this methodology.11
Intermolecular Mn(OAc)3-mediated reaction between benzyl-
malonate and alkene was first reported by Citterio and co-workers
in several studies.10 With
a 1,1-disubstituted alkene, 2,4,4-
Despite the existence of several synthetic methodologies to
obtain spirocyclic compounds12 the last decade has seen a large
number of patents on spirocyclic scaffold synthesis and applica-
tions13 illustrating the high level of interest in the unique spatial
arrangement of spirocyclic rings in medicinal chemistry.14
We report herein the synthesis of spirocyclic compounds via in-
termolecular radical addition mediated by Mn(OAc)3 under mild con-
ditions. This protocol was extended to the intramolecular Mn(OAc)3
promoted multistep synthesis of substituted spirobenzophenan-
thridin-6(5H)-ones, spirolactones, and tetrahydroquinolinones. These
scaffolds have been extensively used for the design of many
trimethylpent-1-ene, they described tetralin (63%) as the major
product. Their reaction was conducted in acetic acid, at 60 ꢀC, using
a 1:1.5:2 molar ratio, corresponding, respectively, to substrate/al-
kene/Mn(III).10a
The use of a methylenecycloalkane as a 1,1-disubstituted alkene
allowed efficient spirocyclization under mild conditions. Thus, the
reaction yielded three different products, in proportions, which
varied with the reaction conditions: the elimination product 1,
spirocyclic tetralin 2, and spirolactone 3 (Scheme 1).
As shown in Table 1, three products were formed in nearly equal
yields in our first attempt (entry 1). Microwave irradiation at 80 ꢀC
improved slightly tetralin 2 and spirolactone 3 yields (entry 2), and
at rt, none of these products was observed (entry 4). To investigate
conditions that might favor spirocyclic tetralin formation, Mn(OAc)3
* Corresponding author. Tel.: þ33 4 91 83 55 80; fax: þ33 4 91 79 46 77; e-mail
address: patrice.vanelle@univ-amu.fr (P. Vanelle).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.004

A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
3597
O
O
O
O
O
O
O
Mn(OAc)3
Cu(OAc)2
O
O
O
O
O
O
O
+
+
+
O
O
AcOH
Spirolactone
Spirocyclic tetralin
Elimination product
1
2
3
Scheme 1. Radical oxidative cyclization via manganese acetate between benzyldiethylmalonate and methylenecyclohexane.
The formation of elimination product 1 and spirolactone 3
could be promoted under strong oxidative conditions. Adding
copper acetate17 (entries 7 and 8) led to an increase in elimination
product 1 and spirolactone 3 yields, while these conditions dras-
tically decreased the yield of compound 2. Replacing Mn(OAc)3 by
CAN also resulted in a decrease of product 2 yield (entry 9). These
results can be explained by the reaction mechanism proposed in
Scheme 2.18
According to this mechanism, the reaction of Mn(OAc)3 with
diethylbenzylmalonate yields manganese(III)-enolate A. Then,
radical B is formed. Addition of B to the alkene forms a carbon-
carbon bond and radical C is obtained. There are two possible
pathways. Under strong oxidative conditions, oxidation to carbo-
cation D is promoted. This carbocation leads to product 1 via proton
elimination or to spirolactone 3 via intramolecular cyclization-
lactonization.19 Under mild oxidation conditions, radical C is more
slowly oxidized, which promotes the formation of tetralin 2.18
Table 1
Survey of manganese acetate reaction conditions
Entry Alkene Mn(OAc)3 Oxidant Heating
Yield
Yield
Yield
(equiv) (equiv)
(equiv)
0
of 1 (%) of 2 (%) of 3 (%)
1
2
2.1
Classical,
60 ꢀC
22
17
13
2
3
4
5
2
2
2.1
2.1a
2.1
2.1
0
0
0
0
MW, 80 ꢀ
MW, 80 ꢀ
None
C
C
28
11
0
22
52
0
20
2
0
2
2a
Classical,
20
20
14
60 ꢀC
6
7
2
2
3
3
0
MW, 80 ꢀ
C
C
26
31
18
17
23
22
Cu(OAc)2 MW, 80 ꢀ
(1)
8
2
2
6
0
Cu(OAc)2 MW, 80 ꢀ
(2)
C
28
27
8
0
23
19
9
CAN (2)b None
a
Reactant fractioned in five portions added successively.
Reaction conducted in ethyl alcohol for 72 h.
b
2.2. Intramolecular Mn(OAc)3-mediated reactions
was divided in five portions that were added successively (entry 3)
in order to ensure, according to Snider, moderate oxidizing condi-
tions.11 Tetralin 2 was effectively obtained as the major product
(52%) via radical aromatic substitution. Alkene fractioning had al-
most no effect on reaction yields (entry 5).
We propose a multistep synthesis leading in parallel to three
types of products: (i) spirobenzophenanthridin-6(5H)-one series
8aec, (ii) tetrahydroquinolinone series 9aec, (iii) and spirolactone
attached to tetrahydroquinolinone, series 10aec.
Mn2+
Mn3+
O
O
O
O
O
O
O
O
B
A
Mn(OAc)3
O
O
O
O
O
O
O
O
Mn(OAc)3
or other oxidant
C
O
O
O
O
O
O
O
O
D
O
O
O
O
O
O
O
O
O
O
O
O
3
2
1
Scheme 2. Mechanism for formation of elimination product 1, spirocyclic tetralin 2, and spirolactone 3.

3598
A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
The required starting materials, ethyl 2-benzyl-3-(2-(cyclo-
alkylidenemethyl)phenylamino)-3-oxopropanoates 7aec, were
synthesized in four steps as shown in Scheme 3.
We postulate that when the carbon centered radical and the aro-
matic ring are cis (radical B), their proximity allows addition to the
aromatic ring, and thus the formation of 8a. In contrast, when the
Scheme 3. Synthesis of starting materials 7aec.
First, we synthesized 1-nitro-2-[(1-nitrocycloalkyl)methyl]ben-
zenes 4aec via the SRN1 process.20 This radical chain reaction is
particularly efficient when p-nitrobenzylchloride reacts with ali-
phatic and cyclic nitronate anions. Indeed, in the presence of 2-
nitropropane anions, p-nitrobenzylchloride led to 83e95% of C-al-
kylation. In contrast, o-nitrobenzylchloride led to only 46% of C-
alkylation product.21 Here, the SRN1 reaction conditions had to
change to ensure the reaction of o-nitrobenzylchloride with various
nitrocycloalkanes. The synthesis was performed in two steps. First,
nitrocycloalkane reacted with sodium hydride, under inert atmo-
sphere and in DMSO20a to give the corresponding nitronate anion.
Then, 1-(chloromethyl)-2-nitrobenzene was added under light ir-
radiation. Corresponding C-alkylation products were obtained in
moderate to good yields (55e79%). Elimination products were also
observed in very low yields (0e7%).
Compounds 4aec were then converted into the desired elimi-
nation products 1-(cycloalkylidenemethyl)-2-nitrobenzenes 5aec,
as a result of loss of nitrous acid from the C-alkylation products.
Reaction led to good yields (61e94%).
The third step was nitro group reduction conducted with iron in
acetic acid at 70 ꢀC.22 The 2-(cycloalkylidenemethyl)benzenamines
6aec were obtained in good yields (75e80%).
carbon centered radical and the aromatic ring are trans (radical C),
distance and steric hindrance slow down the rate of the aromatic
substitution leading to trans-fused products. The proximity of the
cylohexyl radical and the ester group promotes the formation of lactone
10a. Lactonization is likely to originate from the oxidation of the tertiary
alkyl radical. The absence of any alkene resulting from oxidative
elimination of radical C is very surprising, since the diastereomeric
radical Bwas shown to lead to alkene 9a according to a similar pathway.
Under experimental conditions, which promoted radical addi-
tion to the aromatic ring in the previously described intermolecular
reactions (entry 2, Table 1), we observed only 19% of lactone 10a
from radical C, and an overall 40% yield of products originating from
radical B (Table 2). In the case of b-diesters, Bertrand and co-workers
reported that in the cyclization of 5-hexenyl radical, the di-
astereomer analogous to C was clearly preferred over radical B
analogous, and that steric bulk of the substituents on the double
bond enhanced this preference. The dramatic influence of the sub-
stituents on the double bond was demonstrated by recent mecha-
nistic studies on Mn(OAc)3-mediated cyclization of substituted allyl
a-methyl-
b
-ketoesters.24
Mn(III)-mediated oxidative cyclization was extended to cyclo-
pentylidene and cycloheptylidene derivatives, 7b and 7c, re-
spectively. Products such as spirobenzophenanthridin-6(5H)-ones
8b,c, 1,2,3,4-tetrahydroquinolinones 9b,c, and spirolactones 10b,c
were obtained in moderate yields (11e29%). These results are
reported in Table 2.
Finally, the formation of amide linkage was carried out by
reacting compounds 6aec with ethyl 2-(chlorocarbonyl)-3-
phenylpropanoate. The reaction, conducted in 5 min at rt, led to
ethyl 2-benzyl-3-(2-(cycloalkylidenemethyl)phenylamino)-3-oxop
ropanoates 7aec in good yields (69e73%).
b
-Ketoamides 7aec,
In the case of amides 7aec bearing a disubstituted cycloalkyl
scaffold the diastereoselectivity between radicals B and C was re-
versed as compared to that reported in the case of diesters. These
differences probably result from the nature of the unsaturated
tether, i.e., 5-hexenyl or 6-heptenyl radical intermediates (the latter
being rigidified by the conjugate aromatic system). The fate of the
6-heptenyl radicals, formed from 7aec was clearly probed, by the
stereochemical assignment of products 8a, 9c, and 10a.
The structure of compounds 8a, 9c, and 10a was established by
X-ray diffraction analysis (Figs. 1e3). Product 9a is an oil and NOE
analysis was unsuccessful. Its structure was deduced from the X-ray
analysis of its cycloheptyl- analogous 9c. This crystal structure
contains four conformers and an acetonitrile molecule in the
asymmetric unit. Fig. 2 represents the ORTEP view of only one of
the four conformers, ORTEP views of all the asymmetric units of 9c
are provided as Supplementary data.
bearing a CeC double bond, were used as key substrates for
intramolecular oxidative cyclization mediated by Mn(OAc)3.
In acetic acid at 80 ꢀC and under microwave irradiation, the first
synthesis was conducted from ethyl 2-benzyl-3-[2-(cyclo-
hexylidenemethyl)phenylamino]-3-oxopropanoate 7a. Mn(OAc)3,
separated into five fractions, was added slowly every 20 min. The
reaction led to three compounds: spirocyclic benzophenanthridin-
6(5H)-one 8a (17%), 1,2,3,4-tetrahydroquinolinone 9a (23%), and
spirolactone 10a (19%) (Scheme 4, Table 2).
As shown in Scheme 4, the reaction of
b-ketoamide 7a and
Mn(OAc)3 affords radical A. Then, intramolecular radical addition to the
double bond allows cyclization, and a new radical is formed as a mixture
of two diastereomers (B and C). Bertrand and co-workers previously
worked on Mn(III)-mediated oxidative cyclizations of
b-diesters bear-
ing a benzyl side chain.23 Different mechanistic pathways may occur.

A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
3599
O
O
O
N
H
7a
O
O
O
O
O
O
O
NH
O
N
H
NH
O
( ) B
A
( ) C
O
O
O
O
O
O
O
O
O
NH
NH
NH
H
H
( ) 9a
( ) 8a
( ) 10a
Scheme 4. Hypothesis of spirobenzophenanthridin-6(5H)-one 8a, tetrahydroquinoline 9a, and spirolactone 10a formation.
Table 2
Intramolecular oxidative radical cyclization of 7a, 7b, 7c via manganese acetate
Spirobenzophenanthridin-6(5H)-one 8
1,2,3,4-Tetrahydroquinolinone 9
Spirolactone 10
O
O
O
O
O
O
O
O
NH
NH
NH
O
n
n
n
7a (n¼2)
7b (n¼1)
8a (17%)
8b (22%)
8c (20%)
9a (23%)
10a (19%)
10b (29%)
10c (20%)
9b (11%)
9c (28%)
7c (n¼3)
3. Conclusion
4. Experimental section
4.1. General
An efficient and convenient radical oxidative cyclization initi-
ated by manganese acetate between diethylmalonate and methyl-
enecyclohexane was performed in this study. This reaction afforded
three different types of products: an elimination product, a spi-
rocyclic tetralin, and spirolactone. By modifying the conditions, the
spirocyclic compound could be obtained as the major product.
Microwave-assisted reactions were performed in a multimode
microwave oven (ETHOS Synth Lab Station, Ethos start, Milestone
€
Inc.). Melting points were determined with a B-540 Buchi melting
point apparatus. 1H NMR (200 MHz) and 13C NMR (50 MHz) spectra
Then, extension to b-ketoamide bearing a CeC double bond allowed
were recorded on a Bruker ARX 200 spectrometer in CDCl3 or
ꢁ
us to obtain spirobenzophenanthridin-6(5H)-ones 8aec, 1,2,3,4-
tetrahydroquinolinone derivatives 9aec and spirolactones 10aec.
Stereocontrol should make it possible for this synthesis to serve as a key
step in accessing various molecules with potential biological activities.
To further define the scope and limitations of our reaction and to
extend our chemical library, applications of this reaction to other
starting materials are in progress.
DMSO-d6 at the Service Interuniversitaire de RMN de la Faculte de
Pharmacie de Marseille. The 1H chemical shifts are reported as
parts per million downfield from tetramethylsilane (Me4Si), and
the 13C chemical shifts were referenced to the solvent peaks: CDCl3
(76.9 ppm) or DMSO-d6 (39.6 ppm). Absorptions are reported with
the following notations: s, singlet; br s, broad singlet; d, doublet; t,
triplet; q, quartet; m, a more complex multiplet or overlapping

3600
A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
Fig. 3. ORTEP view of one enantiomer of (ꢂ)10a.
irradiation (200 W, 80 ꢀC) for 15 min, until dissolution. Then, the
reaction mixture was cooled down to 60 ꢀC, and a solution of
diethylbenzylmalonate
(3.99 mmol,
1.0 g)
and
methyl-
enecyclohexane (7.98 mmol, 0.767 g) in 5 mL of glacial acetic acid
was added. The mixture was heated under microwave irradiation
(200 W, 80 ꢀC) for 20 min. Then, the reaction mixture was cooled
down to 60 ꢀC once more, and a second quantity of manganese(III)
acetate dihydrate (1.68 mmol, 0.449 g) was added. The mixture was
heated under microwave irradiation (200 W, 80 ꢀC) for 20 min. The
addition of manganese(III) acetate dihydrate (1.68 mmol, 0.449 g)
was repeated three times in the same conditions every 20 min
successively. The reaction mixture was poured into 100 mL of cold
water, and extracted with chloroform (3ꢁ70 mL). The organic ex-
tracts were collected, washed with saturated aqueous NaHCO3
(3ꢁ50 mL) and brine (3ꢁ50 mL), dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by
silica gel chromatography with ethyl acetate/petroleum ether
(0.5:9.5) to give compounds 1, 2, and 3.
Fig. 1. ORTEP view of one enantiomer of (ꢂ)8a.
4.2.1. Diethyl 2-benzyl-2-(cyclohexenylmethyl)malonate 1. Colorless
oil; 1H NMR (200 MHz, CDCl3) dH 1.20 (t, J¼7.1 Hz, 6H, 2CH3),
1.55e1.59 (m, 4H, 2CH2), 1.90e2.00 (m, 4H, 2CH2), 2.58 (s, 2H, CH2),
3.26 (s, 2H, CH2), 4.12 (q, J¼7.1 Hz, 4H, 2CH2), 5.52 (s, 1H, 1CH),
7.11e7.24 (m, 5H, 5CH). 13C NMR (50 MHz, CDCl3) dC 13.9 (2CH3),
22.1 (CH2), 23.0 (CH2), 25.5 (CH2), 29.2 (CH2), 39.0 (CH2), 41.4 (CH2),
58.7 (C), 61.0 (2CH2), 126.4 (CH), 126.7 (CH), 128.0 (2CH), 130.1
(2CH), 133.1 (C), 136.7 (C), 171.4 (2C). Anal. Calcd for C21H28O4: C,
73.23; H, 8.19. Found: C, 72.95; H, 8.35.
4.2.2. Diethyl 20H-spiro[cyclohexane-1,10-naphtalene]-30,30(40H)-di-
carboxylate 2. Colorless oil; 1H NMR (200 MHz, CDCl3) dH 1.22 (t,
J¼7.1 Hz, 6H, 2CH3), 1.47e1.80 (m, 10H, 5CH2), 2.46 (s, 2H, CH2), 3.19
(s, 2H, CH2), 4.14 (q, J¼7.1 Hz, 2H, CH2), 4.15 (q, J¼7.1 Hz, 2H, CH2),
7.10e7.23 (m, 3H, 3CH), 7.35e7.39 (m, 1H, 1CH). 13C NMR (50 MHz,
CDCl3) dC 13.9 (2CH3), 21.9 (2CH2), 25.9 (CH2), 34.9 (CH2), 35.6
(CH2), 36.8 (C), 39.6 (2CH2), 52.4 (C), 61.26 (2CH2), 125.8 (CH), 126.1
(CH), 126.5 (CH), 128.7 (CH), 133.4 (C), 144.0 (C), 171.8 (2C). Anal.
Calcd for C21H28O4: C, 73.23; H, 8.19. Found: C, 73.40; H, 8.50.
Fig. 2. ORTEP view of one enantiomer of (ꢂ)9c.
multiplets. Elemental analysis and mass spectra, which were run on
an API-QqToF mass spectrometer were carried out at the Spectro-
ˇ
ꢁ
ꢁ
pole de la Faculte des Sciences et Techniques de Saint-Jerome. The
following adsorbent was used for flash column chromatography:
Silica Gel 60 (Merck, particle size 0.040e0.063 nm, 70e230 mesh
ASTM). TLC was performed on 5 cmꢁ10 cm aluminum plates
coated with silica gel 60 F-254 (Merck) in an appropriate solvent.
4.2.3. Ethyl 3-benzyl-5-cyclohexyl-2-oxo-tetrahydrofuran-3-
carboxylate 3. Colorless oil; 1H NMR (200 MHz, CDCl3) dH 1.30 (t,
J¼7.2 Hz, 3H, CH3), 1.36e1.79 (m, 10H, 5CH2), 2.03 (d, J¼13.7 Hz, 1H,
CH2), 2.48 (d, J¼13.7 Hz, 1H, CH2), 3.14 (d, J¼13.7 Hz, 1H, CH2), 3.42
(d, J¼13.7 Hz,1H, CH2), 4.25 (q, J¼7.2 Hz, 2H, CH2), 7.16e7.30 (m, 5H,
5CH). 13C NMR (50 MHz, CDCl3) dC 13.9 (CH3), 22.4 (CH2), 22.5 (CH2),
24.6 (CH2), 37.4 (CH2), 37.7 (CH2), 39.8 (CH2), 40.2 (CH2), 57.4 (C),
62.3 (CH2), 84.1 (C), 127.3 (CH), 128.5 (2CH), 130.3 (2CH), 135.6 (C),
4.2. Protocol for Mn(OAc)3-mediated reaction leading to
compounds 1e3 following conditions in entry 2 of Table 1
A solution of manganese(III) acetate dihydrate (1.68 mmol,
0.449 g) in 55 mL of glacial acetic acid was heated under microwave

A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
3601
170.6 (2C). HMRS (ESI): m/z calcd for C19H24O4 MþHþ: 317.1747,
2H, 2CH), 7.35e7.57 (m, 1H, CH), 7.91e7.95 (m, 1H, CH). 13C NMR
(50 MHz, CDCl3) dC 26.5 (CH2), 27.9 (CH2), 28.4 (CH2), 29.9 (CH2),
37.2 (CH2), 117.6 (CH), 124.2 (CH), 127.0 (CH), 132.3 (CH), 132.4 (CH),
133.4 (C), 145.6 (C), 148.8 (C).
found: 317.1746.
4.3. General procedure for the synthesis of C-alkylation
products 4aec
4.4.2. 1-(Cyclopentylidenemethyl)-2-nitrobenzene 5b.26 Yellow oil;
1H NMR (200 MHz, CDCl3) dH 1.67e1.75 (m, 4H, 2CH2), 2.34e2.41
(m, 2H, CH2), 2.47e2.53 (m, 2H, CH2), 6.61e6.63 (m, 1H, CH),
7.29e7.34 (m, 1H, CH), 7.45e7.56 (m, 2H, 2CH), 7.86 (d, J¼8.6 Hz,1H,
CH). 13C NMR (50 MHz, CDCl3) dC 25.5 (CH2), 26.7 (CH2), 30.9 (CH2),
35.0 (CH2), 115.7 (CH), 124.1 (CH), 126.5 (CH), 130.7 (CH), 132.2 (CH),
133.7 (C), 148.2 (C), 151.1 (C).
Into a two-necked flask containing 70 mL of DMSO, sodium
hydride (0.372, 15.5 mmol) was added under inert atmosphere and
at rt. Then, nitrocycloalkane (15.5 mmol) was added and the solu-
tion was stirred for 2e3 h. Under light stimulation, 1-(chlor-
omethyl)-2-nitrobenzene (0.892 mg, 5.20 mmol) was added. The
reaction mixture, maintained under inert atmosphere, was stirred
at rt and monitored by TLC. When the starting material dis-
appeared, the reaction was quenched with 50 mL of water at 0 ꢀC.
The reaction mixture was extracted with ethyl acetate (5ꢁ100 mL).
The combined organic layers were washed with a solution of brine
(5ꢁ200 mL), dried over MgSO4, filtered, and concentrated under
vacuum. The crude product was purified by silica gel chromatog-
raphy with dichloromethane/petroleum ether/diethyl ether
(1:8.5:0.5) to give the corresponding C-alkylation products 4aec.
These products were recrystallized in isopropanol.
4.4.3. (2-Nitrobenzylidene)cycloheptane 5c. Yellow oil; 1H NMR
(200 MHz, CDCl3) dH 1.53e1.72 (m, 8H, 4CH2), 2.21e2.26 (m, 2H,
CH2), 2.39e2.45 (m, 2H, CH2), 6.46 (s, 1H, CH), 7.30e7.39 (m, 2H,
2CH), 7.53 (td, J¼7.5, 1.2 Hz, 1H, CH), 7.92 (d, J¼8.2 Hz, 1H, CH). 13C
NMR (50 MHz, CDCl3) dC 27.1 (CH2), 28.8 (CH2), 28.9 (CH2), 29.6
(CH2), 31.1 (CH2), 37.7 (CH2), 121.0 (CH), 124.1 (CH), 127.0 (CH), 132.1
(CH),132.3 (CH),133.8 (C),147.1 (C),148.6 (C). HMRS (ESI): m/z calcd
for C14H17NO2 MþHþ: 249.1598, found: 249.1589.
4.3.1. 1-Nitro-2-((1-nitrocyclohexyl)methyl)benzene
4a.25 White
4.5. General procedure for the synthesis of 2-
solid; mp 94 ꢀC; 1H NMR (200 MHz, CDCl3) dH 1.22e1.61 (m, 8H,
4CH2), 2.34e2.41 (m, 2H, CH2), 3.58 (s, 2H, CH2), 7.08 (dd, J¼7.4 Hz,
J¼1.6 Hz,1H, CH), 7.39e7.55 (m, 2H, 2CH), 7.89 (dd, J¼7.7, 1.6 Hz,1H,
CH). 13C NMR (50 MHz, CDCl3) dC 22.1 (2CH2), 24.4 (CH2), 33.6
(2CH2), 42.3 (CH2), 92.5 (C), 124.9 (CH), 128.7 (CH), 128.8 (C), 132.5
(CH), 133.0 (CH), 150.2 (C).
(cycloalkylidenemethyl)benzenamines 6aec
To
a solution of 1-(cycloalkylidenemethyl)-2-nitrobenzene
5aec (4 mmol) in 60 mL of acetic acid at 70 ꢀC, Fe (5.58 g,
100 mmol) was added. The resulting suspension was refluxed for
2e3 h. Then, the mixture was filtered on Celite to remove Fe. The
filtrate was extracted with dichloromethane (3ꢁ80 mL). The com-
bined organic layers were washed with a solution of brine
(2ꢁ80 mL), dried over MgSO4, filtered, and concentrated under
vacuum. The crude product was purified by silica gel chromatog-
raphy with dichloromethane/petroleum ether (3L7) to give the
corresponding 2-(cycloalkylidenemethyl)benzenamine 6aec.
4.3.2. 1-Nitro-2-((1-nitrocyclopentyl)methyl)benzene
4b. White
solid; mp 51 ꢀC; 1H NMR (200 MHz, CDCl3) dH 1.70e1.87 (m, 6H,
3CH2), 2.47e2.55 (m, 2H, CH2), 3.78 (s, 2H, CH2), 7.15 (dd, J¼7.4,
1.6 Hz, 1H, CH), 7.37e7.55 (m, 2H, 2CH), 7.88 (dd, J¼7.8, 1.6 Hz, 1H,
CH). 13C NMR (50 MHz, CDCl3) dC 23.2 (2CH2), 36.5 (2CH2), 39.2
(CH2), 100.7 (C), 125.0 (CH), 128.5 (CH), 130.1 (C), 132.0 (CH), 133.1
(CH), 150.0(C). HMRS (ESI): m/z calcd for C12H14N2O4 MþHþ:
268.1292, found: 268.1293.
4.5.1. 2-(Cyclohexylidenemethyl)benzenamine 6a.27 Yellow oil; 1H
NMR (200 MHz, CDCl3) dH 1.52e1.64 (m, 6H, 3CH2), 2.17e2.32 (m,
4H, 2CH2), 3.69 (br s, 2H, NH2), 6.01 (s, 1H, CH), 6.68e6.76 (m, 2H,
2CH), 6.98e7.10 (m, 2H, 2CH). 13C NMR (50 MHz, CDCl3) dC 26.6
(CH2), 28.0 (CH2), 28.8 (CH2), 29.9 (CH2), 37.1 (CH2), 114.9 (CH), 117.6
(CH),118.0 (CH),124.0 (C),127.4 (CH),130.2 (CH),144.1 (C),145.4 (C).
4.3.3. 1-Nitro-1-(2-nitrobenzyl)cycloheptane 4c. White solid; mp
75 ꢀC; 1H NMR (200 MHz, CDCl3) dH 1.46 (s, 8H, 4CH2),1.74e1.82 (m,
2H, CH2), 2.20e2.27 (m, 2H, CH2), 3.59 (s, 2H, CH2), 7.01 (d,
J¼6.7 Hz,1H, CH), 7.34e7.42 (m, 2H, 2CH), 7.79 (d, J¼7.2 Hz,1H, CH).
13C NMR (50 MHz, CDCl3) dC 22.4 (2CH2), 29.4 (2CH2), 36.2 (2CH2),
41.1 (CH2), 96.3 (C), 124.5 (CH), 128.3 (CH), 129.1 (C), 131.9 (CH),
132.7(CH), 150.1 (C). HMRS (ESI): m/z calcd for C14H18N2O4 MþHþ:
296.1605, found: 296.1608.
4.5.2. 2-(Cyclopentylidenemethyl)benzenamine 6b.27 Yellow oil; 1H
NMR (200 MHz, CDCl3) dH 1.67e1.74 (m, 4H, 2CH2), 2.38e2.48 (m,
4H, 2CH2), 3.68 (s, 2H, NH2), 6.22 (s, 1H, CH), 6.67e6.78 (m, 2H,
2CH), 7.00e7.07 (m, 1H, CH), 7.14 (d, J¼7.5 Hz, 1H, CH). 13C NMR
(50 MHz, CDCl3) dC 25.7 (CH2), 26.6 (CH2), 30.6 (CH2), 34.5 (CH2),
115.1 (CH), 115.7 (CH), 118.2 (CH), 124.9 (C), 127.2 (CH), 129.0 (CH),
143.6 (C), 148.6 (C).
4.4. General procedure for the synthesis of elimination
products 5aec
To a solution of sodium hydride (0.202 g, 8.40 mmol) in 25 mL of
DMSO, C-alkylation product 4 (2.80 mmol) was added under inert
atmosphere. The reaction mixture was stirred at rt and monitored
by TLC. When the starting material disappeared, the reaction was
quenched with 25 mL of water at 0 ꢀC. The reaction mixture was
extracted with ethyl acetate (5ꢁ50 mL). The combined organic
layers were washed with a solution of brine (5ꢁ100 mL), dried over
MgSO4, filtered, and concentrated under vacuum. The crude prod-
uct was purified by silica gel chromatography with dichloro-
methane/petroleum ether/diethyl ether (1.5:8:0.5) to give the
corresponding elimination products 5aec.
4.5.3. 2-(Cycloheptylidenemethyl)benzenamine 6c.27 Yellow oil; 1H
NMR (200 MHz, CDCl3) dH 1.56e1.69 (m, 8H, 4CH2), 2.29e2.31 (m,
2H, CH2), 2.40e2.46 (m, 2H, CH2), 3.67 (s, 2H, NH2), 6.09 (s, 1H, CH),
6.68e6.77 (m, 2H, 2CH), 7.00e7.09 (m, 2H, 2CH). 13C NMR (50 MHz,
CDCl3) dC 27.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.7 (CH2), 31.1 (CH2),
37.8 (CH2), 114.8 (CH), 118.0 (CH), 121.0 (CH), 124.5 (C), 127.4 (CH),
129.9 (CH), 143.9 (C), 147 (C).
4.6. General procedure for the synthesis of b-ketoamides
7aec
To a solution of ethyl 2-(chlorocarbonyl)-3-phenylpropanoate
(0.520 mg, 2.16 mmol) in 10 mL of toluene were added 2-(cyclo-
alkylidenemethyl)benzenamine 6aec (1.44 mmol) and dimethyla-
minopyridine (0.352 mg, 2.88 mmol). The reaction mixture was
4.4.1. 1-(Cyclohexylidenemethyl)-2-nitrobenzene 5a.26 Yellow oil;
1H NMR (200 MHz, CDCl3) dH 1.50e1.70 (m, 6H, 3CH2), 2.09e2.15
(m, 2H, CH2), 2.26e2.32 (m, 2H, CH2), 6.43 (s, 1H, CH), 7.24e7.39 (m,

3602
A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
stirred at rt for 5 min. Evaporation of the solvent left a yellow oil as
crude product. Purification with dichloromethane by silica gel
chromatography gave the corresponding b-ketoamide 7aec.
give the corresponding products 8aec, 9aec, 10aec. For solid
products, a recrystallization was conducted in the appropriate
solvent.
4.6.1. Ethyl 2-benzyl-3-(2-(cyclohexylidenemethyl)phenylamino)-3-
oxopropanoate 7a. Yellow oil; 1H NMR (200 MHz, CDCl3) dH 1.17
(t, J¼7.1 Hz, 3H, CH3), 1.46e1.70 (m, 6H, 3CH2), 1.99e2.05 (m, 2H,
CH2), 2.29e2.34 (m, 2H, CH2), 3.26 (dd, J¼13.7, 8.7 Hz,1H, CH2), 3.38
(dd, J¼13.7, 6.3 Hz, 1H, CH2), 3.62 (dd, J¼8.7, 6.3 Hz, 1H, CH), 4.14 (q,
J¼7.1 Hz, 2H, CH2), 5.94 (s, 1H, CH), 7.07e7.09 (m, 2H, 2CH),
7.21e7.32 (m, 6H, 6CH), 8.24 (d, J¼8.1 Hz, 1H, CH), 8.46 (s, 1H, NH).
13C NMR (50 MHz, CDCl3) dC 13.9 (CH3), 26.4 (CH2), 27.7 (CH2), 28.4
(CH2), 29.7 (CH2), 36.8 (CH2), 36.9 (CH2), 55.9 (CH), 61.5 (CH2), 116.4
(CH), 120.3 (CH), 123.8 (CH), 126.8 (CH), 127.2 (CH), 128.4 (C), 128.5
(2CH), 128.8 (2CH), 129.7 (CH), 135.4 (C), 137.6 (C), 147.8 (C), 165.4
(C), 171.2 (C). HMRS (ESI): m/z calcd for C25H29NO3 MþHþ:
392.2220, found: 392.2221.
4.7.1. Ethyl 6-oxo-5,12a-dihydro-6H-spiro[benzo[j]phenanthridine-
12,10-cyclohexane]-6a(7H)-carboxylate 8a. White solid; recrystal-
lized in diethyl ether; mp 255 ꢀC; 1H NMR (200 MHz, DMSO-d6) dH
0.82 (t, J¼7.0 Hz, 3H, CH3), 1.12e1.33 (m, 2H, CH2), 1.47e1.74 (m, 4H,
2CH2), 1.88e2.10 (m, 4H, 2CH2), 3.02e3.11 (m, 2H, CH2), 3.79e3.98
(m, 3H, CH, CH2), 6.93e6.98 (m, 2H, 2CH), 7.11e7.26 (m, 5H, 5CH),
7.60e7.63 (m, 1H, CH), 10.51 (s, 1H, NH). 13C NMR (50 MHz, DMSO-
d6) dC 13.7 (CH3), 22.3 (CH2), 24.1 (CH2), 25.4 (CH2), 30.1 (CH2), 33.0
(CH2), 33.4 (CH2), 42.2 (C), 51.2 (C), 53.3 (CH), 61.2 (CH2), 115.7 (CH),
120.8 (C), 121.6 (CH), 125.7 (CH), 126.3 (CH), 126.4 (CH), 128.5 (CH),
129.3 (CH), 132.9 (CH), 134.6 (C), 137.8 (C), 144.9 (C), 169.7 (C), 172.9
(C). HMRS (ESI): m/z calcd for C25H27NO3 MþHþ: 390.2064, found:
390.2068.
4.6.2. Ethyl 2-benzyl-3-(2-(cyclopentylidenemethyl)phenylamino)-3-
oxopropanoate 7b. Yellow oil; 1H NMR (200 MHz, CDCl3) dH 1.17 (t,
J¼7.1 Hz, 3H, CH3), 1.64e1.75 (m, 4H, 2CH2), 2.13e2.30 (m, 2H, CH2),
2.41e2.57 (m, 2H, CH2), 3.25 (dd, J¼13.6, 8.5 Hz, 1H, CH2), 3.37 (dd,
J¼13.6, 6.3 Hz, 1H, CH2), 3.62 (dd, J¼8.5, 6.3 Hz, 1H, CH), 4.14 (q,
J¼7.1 Hz, 2H, CH2), 6.10 (s, 1H, CH), 7.08e7.28 (m, 8H, 8CH), 8.13 (d,
J¼8.0 Hz, 1H, CH), 8.48 (s, 1H, NH). 13C NMR (50 MHz, CDCl3) dC 13.9
(CH3), 25.7 (CH2), 26.5 (CH2), 30.5 (CH2), 34.4 (CH2), 37.0 (CH2), 55.8
(CH), 61.6 (CH2), 114.8 (CH), 121.1 (CH), 124.1 (CH), 126.9 (CH), 127.0
(CH), 128.5 (2CH), 128.8 (CH), 128.9 (2CH), 134.6 (C), 137.6 (C), 151.4
(C),165.5 (C),171.4 (C). HMRS (ESI): m/z calcd for C24H27NO3 MþHþ:
378.2064, found: 378.2066.
4.7.2. Ethyl 6-oxo-5,12a-dihydro-6H-spiro[benzo[j]phenanthridine-
12,10-cyclopentane]-6a(7H)-carboxylate 8b. White solid; recrystal-
lized in diethyl ether/petroleum ether (5:5); mp 167 ꢀC; 1H NMR
(200 MHz, CDCl3) dH 0.95 (t, J¼7.1 Hz, 3H, CH3), 1.40e1.65 (m, 5H,
1CH, 2CH2), 1.69e2.11 (m, 3H, 1CH, 1CH2), 3.19 (d, J¼17.4 Hz, 1H,
CH2), 3.59 (s, 1H, CH), 3.90e4.12 (m, 3H, CH, CH2), 6.76 (d, J¼6.8 Hz,
1H, CH), 6.98e7.06 (m, 1H, CH), 7.17e7.23 (m, 6H, 6CH), 7.89 (s, 1H,
NH). 13C NMR (50 MHz, CDCl3) dC 13.7 (CH3), 24.5 (CH2), 24.8 (CH2),
32.5 (CH2), 34.9 (CH2), 37.1 (CH2), 48.9 (CH), 49.6 (C), 52.9 (C), 61.7
(CH2), 115.6 (CH), 122.8 (CH), 123.3 (C), 125.9 (CH), 126.0 (CH), 126.3
(CH), 128.4 (CH), 128.6 (CH), 132.1 (CH), 132.5 (C), 136.9 (C), 145.0
(C), 169.9 (C), 172.5 (C). HMRS (ESI): m/z calcd for C24H25NO3
MþHþ: 376.1907, found: 376.1908.
4.6.3. Ethyl 2-benzyl-3-(2-(cycloheptylidenemethyl)phenylamino)-3-
oxopropanoate 7c. Yellow oil; 1H NMR (200 MHz, CDCl3) dH 1.15 (t,
J¼7.1 Hz, 3H, CH3), 1.52e1.72 (m, 8H, 4CH2), 2.15e2.17 (m, 2H, CH2),
2.42e2.47 (m, 2H, CH2), 3.23 (dd, J¼13.7, 8.9 Hz, 1H, CH2), 3.35 (dd,
J¼13.7, 6.1 Hz, 1H, CH2), 3.59 (dd, J¼8.9, 6.1 Hz, 1H, CH), 4.14 (q,
J¼7.1 Hz, 2H, CH2), 6.00 (s, 1H, CH), 7.06e7.09 (m, 2H, 2CH),
7.22e7.25 (m, 6H, 6CH), 8.23 (d, J¼8.0 Hz, 1H, CH), 8.48 (s, 1H, NH).
13C NMR (50 MHz, CDCl3) dC 13.9 (CH3), 27.1 (CH2), 28.9 (CH2), 29.3
(CH2), 29.6 (CH2), 31.0 (CH2), 37.1 (CH2), 37.6 (CH2), 56.0 (CH), 61.6
(CH2), 119.8 (CH), 120.3 (CH), 123.9 (CH), 126.9 (CH), 127.3 (CH),
128.5 (2CH), 128.8 (C), 128.9 (2CH), 129.6 (CH), 135.3 (C), 137.6 (C),
149.9 (C), 165.4 (C), 171.3 (C). HMRS (ESI): m/z calcd for C26H31NO3
MþHþ: 406.2377, found: 406.2370.
4.7.3. Ethyl 6-oxo-5,12a-dihydro-6H-spiro[benzo[j]phenanthridine-
12,10-cycloheptane]-6a(7H)-carboxylate 8c. Colorless oil; 1H NMR
(200 MHz, CDCl3) dH 0.92 (t, J¼7.1 Hz, 3H, CH3), 1.38e2.36 (m, 12H,
6CH2), 3.19 (d, J¼17.7 Hz, 1H, CH2), 3.38 (s, 1H, CH), 3.89e4.15 (m,
3H, CH, CH2), 6.78 (d, J¼7.8 Hz, 1H, CH), 6.96e7.03 (m, 1H, CH),
7.20e7.25 (m, 5H, 5CH), 7.47e7.52 (m, 1H, CH), 7.94 (s, 1H, NH). 13C
NMR (50 MHz, CDCl3) dC 13.7 (CH3), 23.4 (CH2), 24.8 (CH2), 31.2
(CH2), 32.2 (CH2), 33.0 (CH2), 34.0 (CH2), 37.4 (CH2), 45.5 (CH2), 52.4
(C), 52.7 (CH), 61.7 (CH2), 115.3 (CH), 123.0 (CH), 123.3 (C), 124.9
(CH),125.8 (CH), 126.3 (CH),128.4 (CH), 129.4 (CH),131.9 (CH), 133.8
(C), 136.8 (C), 145.8 (C), 170.8 (C), 172.7 (C). HMRS (ESI): m/z calcd
for C24H25NO3 MþHþ: 404.2220, found: 404.2212.
4.7. General procedure for Mn(OAc)3-mediated reaction
4.7.4. Ethyl 3-benzyl-4-cyclohex-1-en-1-yl-2-oxo-1,2,3,4-
tetrahydroquinoline-3-carboxylate 9a. Colorless oil; 1H NMR
(200 MHz, CDCl3) dH 0.79 (t, J¼7.1 Hz, 3H, CH3), 1.39e1.83 (m, 6H,
3CH2), 2.05e2.11 (m, 2H, CH2), 2.99 (d, J¼13.9 Hz, 1H, CH2), 3.60 (d,
J¼13.9 Hz,1H, CH2), 3.73 (q, J¼7.1 Hz, 2H, CH2), 3.99 (s, 1H, CH), 5.85
(s, 1H, CH), 6.72 (d, J¼7.5 Hz, 1H, CH), 6.92e6.99 (m, 1H, CH),
7.10e7.19 (m, 5H, 5CH), 7.33e7.37 (m, 2H, 2CH), 8.25 (s, 1H, NH). 13C
NMR (50 MHz, CDCl3) dC 13.5 (CH3), 22.0 (CH2), 22.7 (CH2), 25.1
(CH2), 25.5 (CH2), 37.3 (CH2), 53.4 (CH), 57.2 (C), 61.4 (CH2), 115.2
(CH), 123.4 (CH), 126.3 (C), 126.6 (CH), 127.1 (CH), 127.7 (CH), 127.8
(2CH), 128.8 (CH), 130.8 (2CH), 135.5 (C), 135.7 (C), 137.0 (C), 169.8
(C), 170.0 (C). HMRS (ESI): m/z calcd for C25H27NO3 MþHþ:
390.2064, found: 390.2065.
A solution of manganese(III) acetate dihydrate (1.56 mmol,
0.418 g) in 55 mL of glacial acetic acid was heated under microwave
irradiation (200 W, 80 ꢀC) for 15 min, until dissolution. Then, the
reaction mixture was cooled down to 60 ꢀC, and the corresponding
b-ketoamide 7aec (3.71 mmol) in 5 mL of glacial acetic acid was
added. The mixture was heated under microwave irradiation
(200 W, 80 ꢀC) for 20 min. Then, the reaction mixture was cooled
down to 60 ꢀC once more, and a second quantity of manganese(III)
acetate dihydrate (1.56 mmol, 0.418 g) was added. The mixture was
heated under microwave irradiation (200 W, 80 ꢀC) for 20 min. The
addition of manganese(III) acetate dihydrate (1.56 mmol, 0.418 g)
was repeated three times in the same conditions every 20 min
successively. The reaction mixture was poured into 100 mL of cold
water, and extracted with chloroform (3ꢁ70 mL). The organic ex-
tracts were collected, washed with saturated aqueous NaHCO3
(3ꢁ50 mL) and brine (3ꢁ50 mL), dried over MgSO4, filtered, and
concentrated under vacuum. The crude product was purified by
silica gel chromatography with a gradient from ethyl acetate/pe-
troleum ether (0.2:9.8) to ethyl acetate/petroleum ether (1:9) to
4.7.5. Ethyl 3-benzyl-4-cyclopent-1-en-1-yl-2-oxo-1,2,3,4-
tetrahydroquinoline-3-carboxylate 9b. Colorless oil; 1H NMR
(200 MHz, CDCl3) dH 0.84 (t, J¼7.1 Hz, 3H, CH3), 1.75e2.36 (m, 6H,
3CH2), 3.03 (d, J¼13.9 Hz,1H, CH2), 3.61 (d, J¼13.9 Hz,1H, CH2), 3.78
(q, J¼7.1 Hz, 2H, CH2), 4.20 (s, 1H, CH), 5.79 (s, 1H, CH), 6.71 (d,
J¼7.7 Hz, 1H, CH), 6.91e6.99 (m, 1H, CH), 7.09e7.13 (m, 2H, 2CH),
7.22e7.28 (m, 5H, 5CH), 7.78 (s, 1H, NH). 13C NMR (50 MHz, CDCl3)

A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
3603
dC 13.5 (CH3), 23.1 (CH2), 32.2 (CH2), 32.7 (CH2), 37.1 (CH2), 46.4
(CH), 57.4 (C), 61.3 (CH2), 115.2 (CH), 123.5 (CH), 126.2 (C), 126.7
(CH), 127.7 (CH), 127.9 (2CH), 128.6 (CH), 129.1 (CH), 130.6 (2CH),
135.3 (C), 136.7 (C), 140.5 (C), 169.4 (C), 169.5 (C). HMRS (ESI): m/z
calcd for C24H25NO3 MþHþ: 376.1907, found: 376.1908.
Crystal data for compound 9c: C106H119N5O12, colorless prism
(0.4ꢁ0.3ꢁ0.2 mm3), MW¼1655.06, triclinic, space group P-1
ꢂ
ꢂ
ꢂ
(T¼293 K), a¼12.6276(2) A, b¼17.7477(4) A, c¼22.0139(7) A,
3
ꢀ
a
¼81.9686(6)ꢀ,
b
¼78.1177(6)ꢀ,
g
¼72.946(10) , V¼4598.94(1) A ,
ꢂ
Z¼2, Dcalcd¼11.95 g cmꢃ1
,
m
¼0.077 mmꢃ1
F(000)¼1772, index
,
ranges 0ꢄhꢄ16, ꢃ21ꢄkꢄ23, ꢃ27ꢄlꢄ28,
q
range¼0.95e27.44ꢀ, 1135
4.7.6. Ethyl 3-benzyl-4-cyclohept-1-en-1-yl-2-oxo-1,2,3,4-
tetrahydroquinoline-3-carboxylate 9c. White solid; recrystallized
in diethyl ether; mp 136 ꢀC; 1H NMR (200 MHz, CDCl3) dH 0.81 (t,
J¼7.0 Hz, 3H, CH3), 1.34e1.85 (m, 6H, 3CH2), 2.03e2.23 (m, 4H,
2CH2), 3.04 (d, J¼13.7 Hz,1H, CH2), 3.52 (d, J¼13.7 Hz,1H, CH2), 3.74
(q, J¼7.0 Hz, 2H, CH2), 4.09 (s, 1H, CH), 5.95e6.01 (m, 1H, CH), 6.72
(d, J¼7.8 Hz, 1H, CH), 6.96e7.38 (m, 7H, 7CH), 7.97 (s, 1H, NH). 13C
NMR (50 MHz, CDCl3) dC 13.5 (CH3), 26.4 (CH2), 26.5 (CH2), 28.3
(CH2), 30.1 (CH2), 32.0 (CH2), 37.4 (CH2), 54.6 (CH), 58.0 (C), 61.4
(CH2), 115.4 (CH), 123.4 (CH), 125.9 (C), 126.6 (CH), 127.7 (3CH),
128.9 (CH), 130.8 (2CH), 132.4 (CH), 135.7 (C), 137.2 (C), 141.4 (C),
169.6 (C), 170.0 (C). HMRS (ESI): m/z calcd for C26H29NO3 MþHþ:
421.2486, found: 421.2481.
variables and 2 restraints, were refined for 13,655 reflections with
lꢅ2sl to R¼0.0783, GoF¼1.087.
Crystal data for compound 10a: C23H23NO3, colorless prism
(0.4ꢁ0.4ꢁ0.3 mm3), MW¼361.42, monoclinic, space group C2/c
ꢂ
ꢂ
ꢂ
(T¼293 K), a¼26.8219(4) A, b¼10.9244(2) A, c¼14.1090(3) A,
3
ꢂ
a
¼90ꢀ,
b
¼115.984(1)ꢀ,
g
¼90ꢀ,
V¼3716.23(12) A ,
Z¼8,
Dcalcd¼12.92 g cmꢃ1
,
m
¼0.085 mmꢃ1, F(000)¼1536, index ranges
0ꢄhꢄ35, 0ꢄkꢄ14, ꢃ19ꢄlꢄ17,
q
range¼1.69e28.69ꢀ, 244 variables
and 0 restraint, were refined for 3727 reflections with lꢅ2sl to
R¼0.055, GoF¼1.115.
Crystallographic data for the structure 8a, 9c, and 10a have been
deposited with the Cambridge Crystallographic Data Centre (CCDC)
under the numbers 852539 for 8a, 864201 for 9c and 852540 for
10a. Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44
(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.7.7. 3a0-Benzyl-50,9b0-dihydro-30H-spiro[cyclohexane-1,10-furo[3,4-
c]quinoline]-30,40(3a0H)-dione 10a. White solid; recrystallized in
acetone; mp 255 ꢀC; 1H NMR (200 MHz, CDCl3) dH 1.32e1.75 (m,
10H, 5CH2), 3.05 (d, J¼13.6 Hz, 1H, CH2), 3.14 (s, 1H, CH), 3.54 (d,
J¼13.6 Hz, 1H, CH2), 6.82 (d, J¼7.8 Hz, 1H, CH), 7.03e7.07 (m, 4H,
4CH), 7.14e7.29 (m, 4H, 4CH), 8.92 (s, 1H, NH). 13C NMR (50 MHz,
CDCl3) dC 21.0 (CH2), 22.4 (CH2), 24.6 (CH2), 31.1 (CH2), 36.6 (CH2),
40.9 (CH2), 52.1 (CH), 54.3 (C), 86.5 (C), 116.0 (CH), 117.9 (C), 124.0
(CH), 127.5 (CH), 128.3 (2CH), 128.8 (CH), 129.1 (CH), 130.2 (2CH),
134.1 (C), 136.1 (C), 167.0 (C), 171.8 (C). HMRS (ESI): m/z calcd for
C23H23NO3 MþHþ: 362.1751, found: 362.1752.
Acknowledgements
This work was supported by the Centre National de la Recherche
ꢁ
ꢁ
ꢁ
Scientifique and the Universite de la Mediterranee. We would like
to express our thanks to V. Remusat for NMR spectra recording, M.
Giorgi for X-ray diffraction and structure analysis, V. Monnier for
mass spectra recording and M. Kaafarani and reviewers for useful
discussions and advices.
4.7.8. 3a0-Benzyl-50,9b0-dihydro-30H-spiro[cyclopentane-1,10-furo
[3,4-c]quinoline]-30,40(3a0H)-dione 10b. White solid; recrystallized
in diethyl ether; mp 232 ꢀC; 1H NMR (200 MHz, CDCl3) dH 1.59e1.84
(m, 8H, 4CH2), 3.04 (d, J¼13.7 Hz, 1H, CH2), 3.47e3.53 (m, 2H, 2CH),
6.75 (d, J¼7.9 Hz, 1H, CH), 6.99e7.20 (m, 8H, 8CH), 8.29 (s, 1H, NH).
13C NMR (50 MHz, CDCl3) dC 22.4 (CH2), 23.8 (CH2), 32.7 (CH2), 37.4
(CH2), 39.9 (CH2), 48.2 (CH), 55.3 (C), 95.2 (C), 115.7 (CH), 118.1 (C),
124.0 (CH), 127.4 (CH), 128.3 (2CH), 128.9 (CH), 129.2 (CH), 130.3
(2CH), 134.0 (C), 136.2 (C), 166.4 (C), 171.7 (C). HMRS (ESI): m/z calcd
for C22H21NO3 MþHþ: 348.1594, found: 348.1589.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.03.004.
References and notes
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[3,4-c]quinoline]-30,40(3a0H)-dione 10c. White solid; recrystallized
in diethyl ether; mp 211 ꢀC; 1H NMR (200 MHz, CDCl3) dH 1.10e1.72
(m, 12H, 6CH2), 3.03 (d, J¼13.3 Hz,1H, CH2), 3.24 (s, 1H, CH), 3.53 (d,
J¼13.3 Hz, 1H, CH2), 6.77 (d, J¼7.8 Hz, 1H, CH), 7.04e7.20 (m, 8H,
8CH), 8.40 (s, 1H, NH). 13C NMR (50 MHz, CDCl3) dC 21.4 (CH2), 22.6
(CH2), 28.8 (CH2), 29.2 (CH2), 34.4 (CH2), 41.1 (CH2), 42.3 (CH2), 52.5
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128.4 (2CH), 129.1 (2CH), 130.2 (2CH), 134.1 (C), 136.0 (C), 166.6 (C),
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found: 376.1910.
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10a
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Crystal data for compound 8a: C25H27NO3, colorless prism
(0.25ꢁ0.2ꢁ0.06 mm3), MW¼389.48, monoclinic, space group P21/c
¼90ꢀ,
ꢂ
ꢂ
ꢂ
a
(T¼293 K), a¼14.2821(3) A, b¼8.9954(3) A, c¼16.9435(4) A,
3
ꢀ
ꢂ
b
m
¼112.176(2)ꢀ,
g
¼90 , V¼2015.77(9) A , Z¼4, Dcalcd¼12.83 g cmꢃ1
,
¼0.084 mmꢃ1
F(000)¼832, index ranges 0ꢄhꢄ19, 0ꢄkꢄ12,
,
ꢃ21ꢄlꢄ20,
q
range¼1.54e28.65ꢀ, 258 variables and 1 restraint,
were refined for 3750 reflections with lꢅ2sl to R¼0.0605,
GoF¼1.128.

3604
A. Bouhlel et al. / Tetrahedron 68 (2012) 3596e3604
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~ꢁ~
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