Synthesis of benzo- and naphtho-fused bicyclo[n.3.1]alkane frameworks with a bridgehead nitrogen function by palladium-catalyzed intramolecular α′-arylation of α-nitroketones

Article abstract of DOI:10.1039/c0ob00526f

The C-alkylation of cyclic α-nitroketones with α-halobenzyl halides in the presence of DBU followed by a Pd-catalyzed intramolecular C-arylation afforded benzo-and naphtho-fused bicyclo[n.3.1]alkane derivatives (n = 3, 4, 5) in excellent overall yields for the two-step sequence. In some of the reactions starting from α-nitrocyclooctanone, the major products were fused indane derivatives arising from an intramolecular attack of an intermediate Pd species onto the carbonyl group, followed by elimination.

Full text of DOI:10.1039/c0ob00526f

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PAPER
Synthesis of benzo- and naphtho-fused bicyclo[n.3.1]alkane frameworks with a
bridgehead nitrogen function by palladium-catalyzed intramolecular
a¢-arylation of a-nitroketones†
Giorgio Giorgi, Swarupananda Maiti, Pilar Lo´pez-Alvarado and J. Carlos Mene´ndez*
Received 1st August 2010, Accepted 6th January 2011
DOI: 10.1039/c0ob00526f
The C-alkylation of cyclic a-nitroketones with a-halobenzyl halides in the presence of DBU followed
by a Pd-catalyzed intramolecular C-arylation afforded benzo-and naphtho-fused bicyclo[n.3.1]alkane
derivatives (n = 3, 4, 5) in excellent overall yields for the two-step sequence. In some of the reactions
starting from a-nitrocyclooctanone, the major products were fused indane derivatives arising from an
intramolecular attack of an intermediate Pd species onto the carbonyl group, followed by elimination.
Introduction
Areno-fused derivatives of bicyclo[n.3.1]alkane systems (Fig. 1)
are present in a variety of bioactive natural and unnatural
compounds. Thus, compounds of structure 1 represent a new class
of opioid analgesics, designed as analogues of the benzomorphans
having an exocyclic rather than endocyclic nitrogen atom.1 The
structurally related dezocine is a well-established analgesic drug,
with a potency comparable to that of meperidine, but which
produces dysphoria and hallucinations at high doses due to inter-
action with k-opioid receptors.2 One example of a natural product
with a benzo-fused bicyclo[n.3.1]alkane framework is obtusanal B,
a diterpene recently isolated from the heartwood of the Taiwanian
tree Chamaecyparis obtusa.3 N-Methylwelwistatin (also known as
N-methylwelwitindolinone C isothiocyanate) can be considered as
the biologically most relevant of the welwitindolinones, a family
of structurally unusual oxindole alkaloids isolated from marine
cyanobacteria.4 It inhibits the glycoprotein P-170-mediated resis-
tance of MCF-7/ADR tumor cells to commonly used anticancer
drugs such as vinblastine, taxol, actinomycin D and daunomycin
at 10-7 M concentrations,5 representing a potency 20- to 100-fold
that of verapamil, the reference MDR reversor.6 Furthermore,
welwistatin also behaves as an antimicrotubule agent that inhibits
the polymerization of tubulin.7 Since this is the main mechanism
of action of antitumor drugs such as vincristine and vinblastine,
and because P-gp-overexpressing cells show virtually no resistance
to welwistatin due to its MDR reversal properties, this natural
product can be considered as a good lead compound in the
chemotherapy of drug-resistant tumors. Finally, huperzine A,
isolated from the firmoss Huperzia serrata, is a centrally-acting
acetylcholinesterase inhibitor that is sold as a dietary supplement
Fig. 1 Some bioactive compounds and natural products containing fused
bicyclo[n.3.1]alkane frameworks.
for memory support in some countries and has been clinically
evaluated as an anti-Alzheimer drug.8 It is noteworthy that both
N-methylwelwistatin and huperzine A bear nitrogen functions at
a bridgehead position, which so far have been installed through a
multistep approach involving a Curtius rearrangement.9
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farma-
cia, Universidad Complutense, 28040 Madrid, Spain. E-mail: josecm@
farm.ucm.es; Fax: +34 91 3941823; Tel: +34 913941840
† Electronic supplementary information (ESI) available: Copies of spectra
of representative compounds. See DOI: 10.1039/c0ob00526f
2722 | Org. Biomol. Chem., 2011, 9, 2722–2730
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We present in this paper our findings related to the development
of a new route to bicyclo[n.3.1]alkane systems from cyclic a-
nitroketones, which leads to the presence of bridgehead nitrogen
functions in a natural, straightforward fashion. Retrosynthetically,
our plan involved an a-alkylation/a¢-arylation sequence, as
summarized in Scheme 1. The preparation of bicyclic compounds
with a bridgehead nitro group by this strategy is unprecedented
although there is mention in the literature of the synthesis of one
example of a benzo-fused bicyclo[3.3.1]decane and another of a
benzo-fused bicyclo[4.3.1]undecane using a similar method but
starting from 6- and 7-membered cyclic a-ketoesters.10 In spite of
its straightforward appearance, our strategy involved some novel
aspects that were a cause for concern in the planning stage. Thus,
the intermolecular C-alkylation of a nitronate required for the first
step can be considered problematic and indeed this type of reaction
has found little application in synthesis owing to the existence of a
competing O-alkylation process.11 Furthermore, the direct carbon-
carbon bond formation between an arene and the carbon adjacent
to a carbonyl group is quite challenging, since enolate nucleophiles
and aromatic halides are not good reaction partners, and it has
been only recently that methods allowing this transformation have
been developed, mostly based on nickel12 or (specially) palladium-
catalyzed13 cross-coupling reactions. Nevertheless, there was no
precedent for such an arylation starting from an a-nitroketone
derivative.
Scheme 2 Synthesis of compounds 4 through a palladium-catalyzed
a¢-intramolecular C-arylation reaction.
functional groups that can be used as synthetic handles, including
halogen and nitro groups and oxygenated functions. The latter are
particularly important because of the presence of oxygen functions
in many of the natural and unnatural bioactive derivatives of
the bicyclo[n.3.1]alkane system. On the other hand, the presence
of an ester group precluded the intramolecular C-arylation step,
and the only observed products in these cases were compounds 5
(Fig. 2), arising from the elimination of a molecule of nitrous
acid from the starting materials. For some of the reactions
starting from a-nitrocycloheptanone and a-nitrocyclooctanone
(n = 2, 3), an additional product containing an indane or
indene structural fragment was observed (see compounds 6
below).
Scheme 1 Retrosynthetic analysis of our target molecules.
Results and discussion
The C-alkylation of a-nitroketones 1 with dihalides 2 was assayed
under a variety of conditions, and we eventually identified DBU as
base and tetrahydrofuran as solvent, at room temperature, as the
optimal combination. In these conditions, and contrary to litera-
ture precedent with other nitroalkanes,11 the desired compounds
3 were the only reaction products and no trace of O-alkylated
derivatives was observed (see the ESI for further details†).
Furthermore, compounds 3 were sufficiently pure to be used for
the next step without further treatment. Thus, treatment of crude
3 with dichloro-bis(diphenylphosphino)palladium in toluene, in
the presence of caesium carbonate, gave the desired compounds 4,
generally in good to excellent overall yields for the C-alkylation/C-
arylation sequence (Scheme 2 and Table 1). The reaction tolerates
a wide range of substituents in the aromatic region, with either
electron-releasing or electron-withdrawing character, and several
Fig. 2 Elimination products isolated from starting materials containing
an ester function.
The formation of compounds 4 can be explained by the catalytic
cycle summarized in Scheme 3, involving the palladation of the
caesium enolate of the starting ketone, followed by an insertion
step and reductive elimination of Pd leading to formation of
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Table 1 Scope and yields obtained in the synthesis of benzo- and naphtho-fused bicyclo[n.3.1]alkane derivatives 4 (overall yields for the full a-
alkylation/a¢-arylation reaction sequence are given)
Cmpd
n
R3
R4
R5
Time/h
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
1
1
1
2
2
2
2
2
2
2
3
3
3
3
3
3
3
H
H
H
CH3
H
H
H
H
4
95
98
92
80
72a
57
0b
26
17
5
24
9
26
28
29
16
5
45
3
–CH CH–CH CH–
–CH CH–CH CH–
–CH CH–CH CH–
H
H
H
H
H
H
H
H
H
H
Cl
NO2
CO2CH3
H
CH3
78
40c
68
0d
–O–CH2–O–
H
H
Cl
NO2
CO2CH3
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
CH3
H
85a
0e
21
48
24
22
0f
58g
80
88
a Stoichiometric amounts of the Pd reagent were needed. b Compound 5g was obtained instead. c Together with compound 6h. d Compound 6j was
obtained instead. e Compound 6l was obtained instead. f Compound 5n was obtained instead. g Together with compound 6n.
Scheme
4
Isolation of cyclohepta[a]indene and cycloocta[a]indene
derivatives 6 from the Pd-catalyzed cyclization of some compounds 3
derived from a-nitroheptanone and a-nitrocyclooctanone.
Intramolecular additions of Pd complexes onto ketones leading
to fused cyclopentanol derivatives have been described by Ya-
mamoto, who carried out these transformations in the presence
of Pd(OAc)2, PCy3 (PPh3 was ineffective) and sodium carbonate,
in DMF solution, and noticed that the addition of 1-hexanol was
crucial for the success of the reaction,15 which contrasts with our
results using an a-nitroketone as a starting material.
Scheme 3 Mechanism proposed for the transformation of 3 into 4.
the final product 4, with concomitant regeneration of the Pd(0)
catalyst.
As previously mentioned, some of the reactions starting
from compounds 3 derived from a-nitrocycloheptanone or a-
nitrocyclooctanone led to products additional or alternative
to the expected bridged systems 4, which were identified as
cycloocta[a]indane derivatives 6 (Scheme 4 and Table 2). Their
formation involves the arylation of the carbonyl group of 3
by intramolecular nucleophilic attack of a palladium species
generated from the starting halide. Such nucleophilic “Grignard-
type”14 additions of Pd species are unusual, since aryl and
vinyl palladium complexes normally behave as electrophiles.15
Table 2 Yields of cycloocta[a]indene derivatives
Cmpd.
R4
R5
Time/h
Yield (%)
6i
O–CH2–O
H
H
CH3
29
5
3
30a
82
6k
6m
6o
H
NO2
H
85
48
41b
a Together with compound 4i. b Together with compound 4o.
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A plausible mechanism that explains the generation of com-
pounds 6 is shown in Scheme 5, and starts by the formation of
7, a common intermediate for both mechanisms, followed by an
insertion reaction involving an intramolecular nucleophilic attack
of the palladated aromatic position onto the carbonyl group to give
8. A final reaction with the carbonate base furnishes compound
9 and regenerates the reactive Pd(0) species. While for the few
previous literature examples of this reaction the product is an
alcohol arising from protonation of an intermediate similar to 9,14
in our case only the seven-membered system 6i showed the same
behaviour. In all other cases, the final products (6k,m,o) contain a
double bond that arises by elimination of a molecule of caesium
nitrate from 9. Although still preliminary in this regard, our results
are significant in that they offer some insights on the possibility to
control the competition between the Pd-catalyzed arylation a to
the carbonyl and the nucleophilic attack onto the carbonyl, which
so far has not been systematically studied.16 First, our results show
that the ring size of the starting ketone has an influence on the
outcome of the reaction, since the competing carbonyl insertion
was generally observed only for eight-membered rings. This can be
ascribed to the less rigid nature of the corresponding enolate, where
the conformational flexibility of the cyclooctene ring may hinder
the insertion step shown in Scheme 3, as reflected in the longer
reaction times found for the formation of the bicyclic products
(see Table 1). Furthermore, our results also suggest that the
electron density on the aromatic ring does not greatly influence the
success of the nucleophilic Pd addition, in agreement with previous
observations related to the palladium-catalyzed intramolecular
nucleophilic substitution at the alkoxycarbonyl group.15b However,
the presence of two strongly electron-releasing groups favours the
formation of compounds 6, as observed for the case of 6i, partially
overcoming the tendency of seven-membered systems to afford
compounds 4 exclusively.
Conclusions
In summary, we have developed the first synthesis of benzo- and
naphtho-fused bicyclo[n.3.1]alkane systems (n = 1–3) bearing a
bridgehead nitrogen function from cyclic a-nitroketones. Our
study proves that it is possible to selectively carry out the C-
benzylation of the starting a-nitroketones in the presence of
DBU in THF, without any competing O-alkylation. The C-
alkylated materials, without the need for purification, were suitable
substrates for Pd-catalyzed intramolecular C-arylation reactions,
that afforded the dersired bicyclic products, normally in excellent
overall yields for the alkylation–arylation sequence. The reaction
showed good tolerance for functional groups, including halogen
and nitro groups and oxygen functions, and the only limitation
found was the absence of intramolecular cyclization when ester
substituents were present in the aromatic moiety. In some of the
reactions starting from a-nitrocyclooctanone, the Pd-catalyzed
reaction afforded cycloocta[a]indene derivatives instead of the
expected bicyclic compounds. Their formation can be explained
by an unusual intramolecular nucleophilic attack of a palladium
species onto a ketone carbonyl group, followed by elimination of
a molecule of caesium nitrate.
Experimental section
General experimental information
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
were of commercial quality and were used as received. Reactions
were monitored by thin layer chromatography on aluminium
plates coated with silica gel with fluorescent indicator (SDS
CCM221254). Separations by flash chromatography were per-
formed on silica gel (SDS 60 ACC 40–63 mm) or neutral alumina
(Merck S22). Melting points were measured on a Reichert 723
hot stage microscope, and are uncorrected. Infrared spectra were
recorded on a Perkin Elmer Paragon 1000 FT-IR spectropho-
tometer, with all compounds examined as KBr pellets or as thin
films on NaCl disks. NMR spectra were obtained on Bruker
1
Avance spectrometers operating at 250 or 300 MHz for H and
63 or 75 MHz for 13C (CAI de Resonancia Magne´tica Nuclear,
Universidad Complutense). Mass spectra were obtained by the
CAI de Espectrometr´ıa de Masas, Universidad Complutense.
Elemental analyses were determined by the CAI de Microana´lisis
Elemental, Universidad Complutense, using a Leco 932 CHNS
combustion microanalyzer.
Scheme 5 Mechanism proposed to explain the isolation of compounds
6.
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General procedure for the C-alkylation of a-nitroketones.
Synthesis of compounds 3
7.20–7.03 (m, 2H, H-4¢, H-5¢); 6.94 (dd, 1H, J = 7.5 and 1.9 Hz,
H-6¢); 3.64 (s, 2H, H-a); 2.60–2.51 (m, 2H, H-7); 2.11–2.02 (m,
2H, H-3); 1.70–1.40 (m, 6H, H-4,5,6) ppm. 13C NMR (CDCl3, 63
MHz) d 201.6 (C-1); 133.5 (C-1¢); 133.1 (C-3¢); 131.3 (C-6¢); 129.3
(C-4¢); 127.8 (C-5¢); 126.2 (C-2¢); 100.2 (C-2); 40.5 (C-7); 39.5 (C-
a); 31.2 (C-3); 29.4 (C-5); 26.1 (C-6); 24.3 (C-4) ppm. Anal. Calcd
for C14H16NO3Br: C, 51.53; H, 4.90; N, 4.29. Found: C, 51.55; H,
5.09; N, 4.25.
To a solution of the suitable 2-nitrocycloalkanone 1 (0.64–3.50
mmol) in dry tetrahydrofuran (5–10 ml) was added DBU (0.13–
0.65 ml, 0.83–4.15 mmol). After stirring for 5 min at room
temperature and under an argon atmosphere, a solution of the
suitable benzylic halide (0.83–4.55 mmol) in dry THF was added,
and stirring at room temperature was maintained for 2–24 h. The
reaction mixture was diluted with dichloromethane (15 ml) and 2
M aqueous HCl was added until the aqueous layer was acidic. The
aqueous solution was extracted with dichloromethane (3 ¥ 10 mL),
and the combined organic layers were dried over anhydrous
sodium sulfate and evaporated. The residue was identified as
the essentially pure compounds 3, which were employed for
the next step without further purification. Analytical samples
were obtained by chromatography on silica gel using a gradient
from petroleum ether to dichloromethane, and the corresponding
characterization data are given below.
2-(2-Bromo-5-chlorobenzyl)-2-nitrocycloheptanone (3e). Pale
yellow oil. IR (NaCl): 2976; 1728 (CO), 1543 (NO2); 1463; 1348
(NO2) cm-1. 1H NMR (CDCl3, 250 MHz) d 7.53 (d, 1H, J = 8.5 Hz,
H-3¢); 7.15 (dd, 1H, J = 8.5 and 2.4 Hz, H-4¢); 7.05 (d, 1H, J =
2.4 Hz, H-6¢); 3.69 (br s, 2H, H-a); 2.77–2.58 (m, 2H, H-7); 2.29–
2.02 (m, 2H, H-3); 1.86–1.49 (m, 6H, H-4,5,6) ppm. 13C NMR
(CDCl3, 63 MHz) d 201.8 (C-1); 135.9 (C-1¢); 134.6 (C-3¢); 134.3
(C-5¢); 131.7 (C-6¢); 130.0 (C-4¢); 124.5 (C-2¢); 100.2 (C-2); 41.0
(C-7); 39.9 (C-a); 31.9 (C-3); 29.8 (C-5); 26.5 (C-6); 24.8 (C-4)
ppm. Anal. Calcd for C14H15NO3ClBr: C, 46.63; H, 4.19; N, 3.88.
Found: C, 46.66; H, 4.25; N, 3.74.
2-(2-Bromo-4-methylbenzyl)-2-nitrocyclohexanone (3a). Pale
yellow oil. IR (NaCl): 1733 (CO), 1542 and 1386 (NO2) cm-1.
1H NMR (CDCl3, 250 MHz) d 7.57 (dd, 1H, J = 7.9 and 1.2 Hz,
H-3¢); 7.29–7.15 (m, 2H, H-4¢, H-5¢); 7.03 (dd, 1H, J = 7.5 and
1.7 Hz, H-6¢); 3.71 (d, 1H, J = 14.9 Hz, H-a); 3.56 (d, 1H, J =
14.9 Hz, H-a); 2.70–2.42 (m, 2H, H-6); 2.23–1.32 (m, 6H, H-3,4,5)
ppm. 13C NMR (CDCl3, 63 MHz) d 199.6 (C-1); 133.6 (C-1¢); 133.1
(C-3¢); 131.5 (C-6¢); 129.2 (C-4¢); 127.6 (C-5¢); 125.9 (C-2¢); 96.9
(C-2); 39.5 (C-a); 39.5 (C-6); 34.8 (C-3); 26.6 (C-5); 21.0 (C-4)
ppm. Anal. Calcd for C13H14NO3Br: C, 50.00; H, 4.48; N, 4.48.
Found: C, 49.62; H, 4.13; N, 4.39.
2-(2-Bromo-5-nitrobenzyl)-2-nitrocycloheptanone
(3f). Pale
yellow oil. 1H NMR (CDCl3, 250 MHz): d 8.03 (dd, 1H, J = 8.7
and 2.7 Hz, H-4¢); 7.97 (d, 1H, J = 2.7 Hz, H-6¢); 7.81 (d, 1H, J =
8.7 Hz, H-3¢); 3.84 (d, 1H, J = 14.9 Hz, H-a); 3.76 (d, 1H, J =
14.9 Hz, H-a); 2.77–2.58 (m, 2H, H-7); 2.27–2.04 (m, 2H, H-3);
1.91–1.53 (m, 6H, H-4, 5, 6) ppm. 13C NMR (CDCl3, 63 MHz): d
201.3 (C-1); 147.1 (C-5¢); 135.9 (C-1¢); 134.1 (C-3¢); 133.4 (C-2¢);
126.1 (C-6¢); 123.8 (C-4¢); 99.0 (C-2); 40.6 (C-7); 39.7 (C-a); 32.0
(C-3); 29.1 (C-5); 25.7 (C-6); 24.2 (C-4) ppm. Anal. Calcd for
C14H16N2O5Br: C, 45.28; H, 4.04; N, 7.54. Found: C, 45.16; H,
4.10; N, 7.49.
2-(2-Bromobenzyl)-2-nitrocyclohexanone (3b). Pale yellow oil.
IR (NaCl): 2943, 1732 (CO), 1543 and 1435 (NO2), 1041; 825 cm-1.
1H NMR (CDCl3, 250 MHz) d 7.43 (d, 1H, J = 1.0 Hz, H-3¢); 7.06
(dd, 1H, J = 7.8 and 1.0 Hz, H-5¢); 6.90 (d, 1H, J = 7.8 Hz, H-6¢);
3.66 (d, 1H, J = 14.9 Hz, H-a); 3.52 (d, 1H, J = 14.9 Hz, H-a);
2.72–2.49 (m, 3H, H-3,6); 2.33 (s, 3H, CH3); 2.10–1.55 (m, 5H,
H-3,4,5) ppm. 13C NMR (CDCl3, 63 MHz) d 199.7 (C-1); 139.5
(C-4¢); 133.5 (C-3¢); 131.1 (C-6¢); 130.3 (C-1¢); 128.4 (C-5¢); 125.6
(C-2¢); 97.0 (C-2); 39.5 (C-a); 39.2 (C-6); 34.8 (C-3); 26.6 (C-5);
21.0 (C-4); 20.6 (CH3) ppm. Anal. Calcd for C14H16NO3Br: C,
51.53; H, 4.91; N, 4.29. Found: C, 51.67; H, 5.27; N, 3.91.
2-(2-Bromo-5-methoxycarbonylbenzyl)-2-nitrocycloheptanone
(3g). Colourless liquid. IR (neat) 2934, 2858, 1728 (2 C O),
1548 and 1345 (NO2), 1435, 1289 (C–O), 1261, 1118, 764 cm-1.
1H-NMR (CDCl3, 250 MHz) d 8.25 (d, J = 1.7 Hz, 1H, H-6¢);
7.87 (dd, J = 1.7 and 8.1 Hz, 1H, H-4¢); 7.12 (d, J = 8.1 Hz, 1H,
H-3¢); 3.93 (s, 3H, OMe); 3.77 (s, 2H, H-a); 2.60–2.74 (m, 2H, H-
7); 2.02–2.26 (m, 2H, H-2); 1.53–1.85 (m, 6H, H-3,4,5). 13C-NMR
(CDCl3, 62.9 MHz) d 201.7 (C-1); 165.7 (CO2Me); 139.2 (C-1¢);
134.6 (H-6¢); 131.8 (H-3¢); 131.7 (H-3¢); 129.1 (C-2¢); 126.7 (C-5¢);
100.3 (C-2); 52.9 (CO2Me); 41.0 (C-7); 40.1 (C-a); 31.9 (C-3); 29.8
(C-5); 26.5 (C-4); 24.8 (C-6). Anal. Calcd for C16H18BrNO5: C,
50.02; H, 4.72, N, 3.65. Found: C, 49.83; H, 4.56; N, 3.42.
2-(1-Bromonaphth-2-ylmethyl)-2-nitrocyclohexanone
(3c).
Pale yellow solid; mp 99–100 ◦C (EtOH). IR (KBr) 2947; 1731
1
(CO); 1542 and 1355 (NO2) cm-1. H NMR (CDCl3, 250 MHz)
2-(2-Bromo-4-methylbenzyl)-2-nitrocycloheptanone (3h). Pale
d 8.35 (dd, 1H, J = 8.4 and 0.6 Hz, H-8¢); 7.84 (dd, 1H, J = 7.8
and 1.3 Hz, H-5¢); 7.76 (d, 1H, J = 8.4 Hz, H-4¢); 7.68–7.52 (m,
2H, H-6¢,7¢); 7.13 (d, 1H, J = 8.5 Hz, H-3¢); 4.03 (d, 1H, J =
14.8 Hz, H-a); 3.82 (d, 1H, J = 14.8 Hz, H-a); 2.75–2.52 (m, 3H,
H-3, 6); 2.17–1.91 (m, 2H, H-3, 5); 1.83–1.45 (m, 3H, H-4, 5)
ppm. 13C NMR (CDCl3, 63 MHz) d 199.6 (C-1); 133.7 (C-8a¢);
132.3 (C-4a¢); 131.8 (C-2¢); 128.0; 127.9; 127.8; 127.8; 127.6; 126.7
(C-3¢-8¢); 126.2 (C-1¢); 96.9 (C-2); 40.8 (C-a); 39.4 (C-6); 34.9
(C-3); 26.6 (C-5); 21.0 (C-4) ppm. Anal. Calcd for C17H16NO3Br:
C, 56.35; H, 4.42; N, 3.87. Found: C, 56.00; H, 4.13; N, 3.70.
yellow oil. IR (NaCl): 2952, 1731 (CO), 1543 and 1350 (NO2),
1
862, 830, 674 cm-1. H NMR (CDCl3, 250 MHz): d 7.44 (d, 1H,
J = 1.0 Hz, H-3¢); 7.05 (dd, 1H, J = 7.8 and 1.0 Hz, H-5¢); 6.92
(d, 1H, J = 7.8 Hz, H-6¢); 3.67 (br s, 2H, H-a); 2.75–2.56 (m, 2H,
H-7); 2.33 (s, 3H, CH3); 2.28–2.05 (m, 2H, H-3); 1.84–1.49 (m,
6H, H-4,5,6) ppm. 13C NMR (CDCl3, 63 MHz): d 201.7 (C-1);
139.5 (C-4¢); 133.4 (C-3¢); 130.8 (C-6¢); 130.1 (C-1¢); 128.6 (C-5¢);
125.8 (C-2¢); 100.2 (C-2); 40.5 (C-7); 39.1 (C-a); 31.1 (C-3); 29.3
(C-5); 26.1 (C-6); 24.2 (C-4); 20.5 (CH3) ppm. Anal. Calcd for
C15H18NO3Br: C, 52.94; H, 5.29; N, 4.11. Found: C, 53.02; H,
5.22; N, 4.22.
2-(2-Bromobenzyl)-2-nitrocycloheptanone (3d). Pale yellow oil.
IR (NaCl): 1731 (CO), 1548 and 1331 (NO2) cm-1. 1H NMR
(CDCl3, 250 MHz) d 7.50 (dd, 1H, J = 7.5 and 1.4 Hz, H-3¢);
2-(6-Bromobenzo[1,3]dioxol-5-ylmethyl)-2-nitrocycloheptanone
(3i). White solid, mp 96 ◦C. IR (neat) 2934, 1731 (CO), 1542 and
2726 | Org. Biomol. Chem., 2011, 9, 2722–2730
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1342 cm-1. 1H NMR (CDCl3, 250 MHz) d 7.02 (s, 1H, H-5); 6.53
(s, 1H, H-8); 5.99 (s, 2H, H-2); 3.64 (s, 2H, H-a); 2.59–2.77 (m,
2H, H-3¢); 2.05–2.29 (m, 2H, H-7¢); 1.56–1.83 (m, 6H, H-4¢,5¢,6¢)
ppm. 13C NMR (CDCl3, 62.9 MHz) d 202.2 (C-2¢); 148.5 and
148.2 (C-3a, 8a); 126.7 (C-6);117.1 (C-5); 113.3 (C-7); 110.9 (C-4);
102.5 (C-1¢); 100.8 (C-2); 41.1 (C-3¢); 40.1 (C-a); 31.8 (C-7¢); 29.9
(C-5¢), 26.7 (C-4¢), 24.9 (C-6¢). Anal. Calcd for C15H16BrNO5: C,
48.67; H, 4.36, N, 3.78. Found: C, 48.42; H, 4.14; N, 3.56.
2-(2-Bromo-5-methoxycarbonylbenzyl)-2-nitrocyclooctanone
(3n). Colourless oil. IR (neat) 2934.0; 1728.2 (2 CO), 1547.8 and
1345 (NO2); 1435.2, 1289.5, 1260.8, 1118.1, 764.4 cm-1. 1H NMR
(CDCl3, 250 MHz) d 8.25 (d, J = 1.7 Hz, 1H, H-6¢); 7.87 (dd, J =
1.7 and 8.1 Hz, 1H, H-4¢); 7.12 (d, J = 8.1 Hz, 1H, H-3¢); 3.93 (s,
3H, OMe); 3.90 (d, 1H, J = 14.9 Hz, H-a); 3.67 (d, 1H, J = 14.9 Hz,
H-a); 2.60–2.74 (m, 2H, H-8); 2.02–2.26 (m, 2H, H-2); 1.15–1.90
(m, 8H, H-3,4,5,6) ppm. 13C NMR (CDCl3, 62.9 MHz) d 204.6
(C-1); 165.8 (CO2Me); 139.4 (C-1¢); 134.6 (C-6¢); 131.5 (C-3¢ and
C-4¢); 129.0 (C-2¢); 126.9 (C-5¢); 100.2 (C-2); 52.9 (OMe); 41.0 (C-
8); 39.5 (C-a); 38.8 (C-3); 27.4 (C-6); 26.6 (C-5); 25.5 (C-7); 22.7
(C-4) ppm. Anal. Calcd for C17H20BrNO5: C, 51.27; H, 5.06; Br,
N, 3.52;. Found: C, 51.02; H, 4.87; N, 3.23.
2-(1-Bromonaphth-2-ylmethyl)-2-nitrocycloheptanone
(3j).
Pale yellow solid. IR (NaCl): 2950; 1723 (CO), 1545 and 1329
1
(NO2) cm-1. H NMR (CDCl3, 250 MHz) d 8.31 (d, 1H, J =
8.5 Hz, H-8¢); 7.88–7.42 (m, 4H, H-4¢,5¢,6¢,7¢); 7.07 (d, 1H, J =
8.5 Hz, H-3¢); 4.03 (d, 1H, J = 14.7 Hz, H-a); 3.94 (d, 1H,
J = 14.7 Hz, H-a); 2.71–2.56 (m, 2H, H-7); 2.18–2.03 (m, 2H,
H-3);1.74–1.10 (m, 6H, H-4,5,6) ppm. 13C NMR (CDCl3, 63
MHz) d 201.5 (C-1); 139.5 (C-4a¢); 132.1 (C-8a¢); 131.5 (C-2¢);
127.8; 127.6; 127.5; 127.3; 126.6 (C-4¢-8¢); 126.3 (C-1¢); 100.0
(C-2); 40.7 (C-7); 40.4 (C-a); 31.1 (C-3); 29.2 (C-5); 26.1 (C-6);
24.1 (C-4) ppm. Anal. Calcd for C18H18NO3Br, M = 376: C, 57.44;
H, 4.78; N, 3.72. Found: C, 57.36; H, 4.40; N, 3.68.
2-(2-Bromo-4-methylbenzyl)-2-nitrocyclooctanone (3o). Pale
yellow oil. IR (NaCl): 2947; 1726 (CO), 1543 and 1345 (NO2);
1041 cm-1. 1H NMR (CDCl3, 250 MHz) d: 7.38 (d, 1H, J = 0.8 Hz,
H-3¢); 7.01 (dd, 1H, J = 7.9 and 1.1 Hz, H-5¢); 6.88 (d, 1H, J =
7.9 Hz, H-6¢); 3.74 (d, 1H, J = 14.9 Hz, H-a); 3.55 (d, 1H, J =
14.9 Hz, H-a); 2.73–2.47 (m, 2H, H-3); 2.42–2.12 (m, 5H, H-8,
CH3); 1.94–1.16 (m, 8H, H-4–7) ppm. 13C NMR (CDCl3, 63 MHz)
d: 204.4 (C-1); 139.3 (C-4¢); 133.4 (C-3¢); 130.5 (C-6¢); 130.3 (C-1¢);
128.4 (C-5¢); 125.6 (C-2¢); 99.9 (C-2); 38.6 (C-a); 38.2 (C-8); 30.9
(C-3); 26.7 (C-7); 26.1 (C-6); 25.0 (C-5); 22.1 (C-4); 20.4 (CH3)
ppm. Anal. Calcd for C16H20NO3Br: C, 54.23; H, 5.65; N, 3.95.
Found: C, 53.99; H, 5.50; N, 3.90.
2-(2-Bromobenzyl)-2-nitrocyclooctanone (3k). Pale yellow oil.
IR (NaCl): 2972, 1724 (CO), 1543 and 1346 (NO2) cm-1. 1H NMR
(CDCl3, 250 MHz): d 7.59 (dd, 1H, J = 7.8 and 1.3 Hz, H-3¢);
7.28–7.11 (m, 2H, H-4¢, H-5¢); 7.03 (dd, 1H, J = 7.5 and 1.8 Hz,
H-6¢); 3.82 (d, 1H, J = 14.9 Hz, H-a); 3.63 (d, 1H, J = 14.9 Hz,
H-a); 2.78–2.64 (m, 1H, H-8); 2.62–2.49 (m, 1H, H-8); 2.47–2.33
(ddd, 1H, J = 15.4, 8.5 and 2.8 Hz, H-3); 2.27–2.13 (ddd, 1H, J =
15.2, 8.3 and 3.2 Hz, H-3); 2.07–1.13 (m, 8H, H-4–7) ppm. 13C
NMR (CDCl3, 63 MHz) d 205.0 (C-1); 134.2 (C-1¢); 133.6 (C-3¢);
131.5 (C-6¢); 129.7 (C-4¢); 128.2 (C-5¢); 126.5 (C-2¢); 100.5 (C-2);
39.7 (C-a); 38.9 (C-8); 31.7 (C-3); 27.3 (C-7); 26.7 (C-6); 25.6 (C-
5); 22.7 (C-4) ppm. Anal. Calcd for C15H18NO3Br: C, 52.94; H,
5,29; N, 4.11. Found: C, 53.26; H, 5.28; N, 4.15.
2-(2-Bromo-5-methoxybenzyl)-2-nitrocyclooctanone
(3p).
Colourless liquid. IR (neat) 2936.2, 1724.9 (CO), 1543 and 1347
(NO2), 1473, 1241, 1165, 1018 cm-1. 1H NMR (CDCl3, 250 MHz)
d 7.45 (d, J = 8.8 Hz, 1H, H-3¢); 6.71 (dd, J = 2.9 and 8.8 Hz, 1H,
H-4¢); 6.56 (d, J = 2.9 Hz, 1H, H-6¢); 3.75 (s, 3H, OMe), 3.78 (d,
J = 14.6 Hz, 1H, H-a); 3.58 (d, J = 14.9 Hz, 1H, H-a); 2.64–2.75
(m, 1H, H-8), 2.50–2.60 (m, 1H, H-8); 2.35–2.45 (m, 1H, H-3);
2.16–2.27 (m, 1H, H-3); 1.22–1.94 (m, 8H, H-4,5,6,7). 13C NMR
(CDCl3, 62.9 MHz) d 204.9 (CO); 159.4 (C-5¢); 134.5 (C-1¢); 134.1
(C-3¢); 116.8 (C-2¢); 116.7 (C-6¢); 115.8 (C-4¢); 100.6 (C-2); 55.8
(OMe); 39.9 (C-8); 38.8 (C-3); 31.7 (C-5); 27.4 (C-6); 26.7 (C-5);
25.6 (C-7); 22.9 (C-4). Anal. Calcd for C16H20BrNO4: C, 51.90; H,
5.44, N, 3.78. Found: C, 51.67; H, 5.32; N, 3.65.
2-(2-Bromo-5-chlorobenzyl)-2-nitrocyclooctanone
(3l). Pale
yellow solid; mp 96–98 ◦C. IR (KBr): 2934, 1725 (CO), 1543 and
1
1345 (NO2), 1102, 1028 cm-1. H NMR (CDCl3, 250 MHz): d
7.51 (d, 1H, J = 8.5 Hz, H-3¢); 7.14 (dd, 1H, J = 8.5 and 2.5 Hz,
H-4¢); 7.05 (d, 1H, J = 2.5 Hz, H-6¢); 3.74 (d, 1H, J = 14.9 Hz,
H-a); 3.62 (d, 1H, J = 14.9 Hz, H-a); 2.77–2.66 (m, 1H, H-8);
2.60–2.39 (m, 2H, H-3,8); 2.24–2.13 (m, 1H, H-3); 1.99–1.15 (m,
8H, H-4–7) ppm. 13C NMR (CDCl3, 63 MHz) d 204.8 (C-1);
136.0 (C-1¢); 134.6 (C-3¢); 134.1 (C-4¢); 131.5 (C-6¢); 129.8 (C-5¢);
124.4 (C-2¢); 100.0 (C-2); 39.4 (C-a); 38.8 (C-8); 31.8 (C-3); 27.4
(C-7); 26.6 (C-6); 25.5 (C-5); 22.7 (C-4) ppm. Anal. Calcd for
C15H17NO3ClBr: C, 48.06; H, 4.53; N, 3.74. Found: C, 48.43; H,
4.74; N, 3.77.
2-(1-Bromonaphth-2-ylmethyl)-2-nitrocyclooctanone
(3q).
Pale yellow solid; mp 103–105 ◦C. IR (KBr): 2934, 1724 (CO),
1542 and 1330 (NO2) cm-1. 1H NMR (CDCl3, 250 MHz) d: 8.35
(d, 1H, J = 8.2 Hz, H-8¢); 7.,83 (d, 1H, J = 7.7 Hz, H-5¢); 7.75 (d,
1H, J = 8.5 Hz, H-4¢); 7.67–7.51 (m, 2H, H-6¢,7¢); 7.12 (d, 1H, J =
8.5 Hz, H-3¢); 4.17 (d, 1H, J = 14.7 Hz, H-a); 3.87 (d, 1H, J =
14.7 Hz, H-a); 2.79–2.55 (m, 2H, H-8); 2.48–2.20 (m, 2H, H-3);
2.02–1.22 (m, 8H, H-4–7) ppm. 13C NMR (CDCl3, 63 MHz)
d: 204.6 (C-1); 133.7 (C-4a¢); 132.4 (C-8a¢); 132.0 (C-2¢); 128.0
(C-4¢,5¢,8¢); 127.7 (C-7¢); 127.4 (C-3¢); 126.7 (C-6¢); 126.5 (C-1¢);
100.1 (C-2); 40.7 (C-a); 38.4 (C-8); 31.4 (C-3); 26.8 (C-7); 26.3
(C-6); 25.2 (C-5); 22.3 (C-4) ppm. Anal. Calcd for C19H20NO3Br:
C, 58.40; H, 5.10; N, 3.50. Found: C, 58.32; H, 5.08; N, 3.43.
2-(2-Bromo-5-nitrobenzyl)-2-nitrocyclooctanone
(3m). Pale
yellow oil. IR (NaCl): 2934, 1722 (CO), 1544, 1527 and 1345
(NO2), 1031, 740 cm-1. 1H NMR (CDCl3, 300 MHz) d: 8.00–7.97
(m, 2H, H-4¢,6¢); 7.77 (d, 1H, J = 9.2 Hz, H-3¢); 3.81 (d, 1H, J =
15.0 Hz, H-a); 3.73 (d, 1H, J = 15.0 Hz, H-a); 2.76–2.47 (m,
3H, H-3,8); 2.24–2.15 (m, 1H, H-3); 1.98–1.15 (m, 8H, H-4,5,6,7)
ppm. 13C NMR (CDCl3, 75 MHz) d: 204.4 (C-1); 147.5 (C-5¢);
136.5 (C-1¢); 134.6 (C-3¢); 133.7 (C-2¢); 126.5 (C-6¢); 124.1 (C-4¢);
99.2 (C-2); 39.2 (C-a); 38.9 (C-8); 32.2 (C-3); 27.1 (C-7); 26.3
(C-6); 24.9 (C-5); 22.1 (C-4) ppm. Anal. Calcd for C15H17N2O5Br:
C, 46.75; H, 4.41; N, 7.27. Found: C, 46.52; H, 4.09; N, 7.25.
Pd-catalyzed cross-coupling reactions of compounds 3. General
procedure
To a solution of the suitable crude compound 3 (1 mmol) in
10 ml of anhydrous toluene (previously deoxygenated by running
an argon stream through the solvent while irradiating in an
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ultrasound cleaning bath) was added Cs2CO3 (3 eq., 6 eq. for the
reactions starting from 3e and 3j) and PdCl2(PPh3)2 (0.3 eq., 3 eq.
for the reactions starting from 3e and 3j). The reaction mixture was
refluxed under an argon atmosphere for the times specified in Table
2. It was then diluted with ethyl acetate (20 ml) and the solution
was washed with saturated aqueous NH4Cl solution (3 ¥ 10 ml).
The organic layer was dried over anhydrous sodium sulphate and
evaporated, and the residue was chromatographed on silica gel,
eluting with a gradient from petroleum ether to dichloromethane,
to give compounds 4 or 5.
NMR (CDCl3, 63 MHz) d: 201.7 (C-12); 135.0 (C-1); 132.0; 129.2;
127.8; 127.5; 127.0; 97.5 (C-10); 52.1 (C-5); 40.5 (C-11); 33.9 (C-9);
33.4 (C-6); 25.7 (C-7); 25.6 (C-8) ppm. MS (ESI), m/z: 246 (M+ +
1). Anal. Calcd for C14H15NO3: C, 68.57; H, 6.12; N, 5.71. Found:
C, 68.20; H, 6.07; N, 5.35.
( )-cis-2-Chloro-6,7,8,9,10,11-hexahydro-5H -10-nitro-5,10-
methanobenzocyclononen-12-one (4e). Pale yellow oil. IR (NaCl):
1
2961, 1732 (CO), 1551 and 1350 (NO2) cm-1. H NMR (CDCl3,
250 MHz) d: 7.47–7.21 (m, 3H, H-Ar); 4.08 (d, 1H, J = 16.0 Hz,
H-11); 3.99 (t, 1H, J = 4.1 Hz, H-5); 3.32 (d, 1H, J = 16.0 Hz,
H-11); 2.77 (dd, 1H, J = 15.0 and 7.2 Hz, H-9); 2.41–2.23 (m,
1H, H-6); 2.05–1.45 (m, 5H, H-6,7,8,9); 1.01–0.80 (m, 1H, H-7)
ppm. 13C NMR (CDCl3, 63 MHz) d: 200.9 (C-12); 133.9 (C-11a);
133.5 (C-4a); 133.3 (C-2); 129.1 (C-4); 128.4 (C-1); 128.1 (C-3);
97.0 (C-10); 51.7 (C-5); 40.1 (C-11); 33.8 (C-9); 33.3 (C-6); 25.6
(C-7); 25.6 (C-8) ppm. MS (ESI), m/z: 282 (M+ + 3), 280 (M+ + 1).
Anal. Calcd for C14H14NO3Cl: C, 60.10; H, 5.00; N, 5.00. Found:
C, 59.90; H, 5.21; N, 5,33.
( ) - cis - 5,6,7,8,9,10 - Hexahydro - 5,9 - methano - 9 - nitrobenzo-
cycloocten-11-one (4a). Pale yellow oil. IR (NaCl): 2941, 1741
(CO), 1546 and 1453 (NO2) cm-1. 1H NMR (CDCl3, 250 MHz) d:
7.35–7.24 (m, 3H, H-Ar); 7.06–7.00 (m, 1H, H-Ar); 4.57 (dd, 1H,
J = 17.2 and 1.7 Hz, H-10); 3.83 (t, 1H, J = 3.3 Hz, H-5); 3.63 (d,
1H, J = 17.3 Hz, H-10); 2.95 (ddt, 1H, J = 13.1, 5.8 and 2.4 Hz,
H-8); 2.55–2.44 (m, 1H, H-8); 2.28–2.21 (m, 1H, H-6); 2.18–2.02
(m, 1H, H-6); 1.85–1.62 (m, 2H, H-7) ppm. 13C NMR (CDCl3, 63
MHz) d: 201.7 (C-11); 135.6 (C-4a); 132.5 (C-10a); 128.0; 127.8;
127.7; 126.9; 95.6 (C-9); 52.5 (C-5); 41.7 (C-10); 40.4 (C-8); 36.6
(C-6); 17.8 (C-7) ppm. Anal. Calcd for C13H13NO3: C, 67.53; H,
5.63; N, 6.06. Found: C, 67.20; H, 5.45; N, 5.89.
( )-cis-6,7,8,9,10,11-Hexahydro-5H-2,10-dinitro-5,10-methano-
benzocyclononen-12-one (4f). Pale yellow solid; mp 175–176 ◦C.
IR (NaCl): 2937, 1734 (CO), 1552, 1522, 1436 and 1348 (NO2)
1
cm-1. H-NMR (CDCl3, 250 MHz) d: 8.23 (dd, 1H, J = 8.6 and
( )-cis-5,6,7,8,9,10-Hexahydro-6,10-methano-2-methyl-6-nitro-
benzocycloocten-11-one (4b). Colourless oil. IR (NaCl): 2947,
1.8 Hz, H-3); 8.16 (s, 1H, H-1); 7.47 (d, 1H, J = 8.7 Hz, H-4); 4.19
(d, 1H, J = 16.1 Hz, H-11); 4.11 (t, 1H, J = 4.6 Hz, H-5); 3.51
(d, 1H, J = 16.2 Hz, H-11); 2.83 (dd, 1H, J = 14.2 and 7.0 Hz);
2.48–2.40 (m, 1H); 2.08–1.84 (m, 3H); 1.68–1.40 (m, 3H) ppm.
13C NMR (CDCl3, 63 MHz) d: 199.6 (C-12); 144.5 (C-2); 142.7
(C-4a); 134.0 (C-11a); 128.3 (C-4); 124.3 (C-1); 122.8 (C-3); 96.6
(C-10); 52.2 (C-5); 40.2 (C-11); 33.8 (C-6); 33.5 (C-9); 25.8 (C-8);
25.5 (C-7) ppm. Anal. Calcd for C14H14N2O5: C, 57.93; H, 4.82;
N, 9.65. Found: C, 57.52; H, 5.03; N, 9.29.
1
1744 (CO), 1546 and 1353 (NO2) cm-1. H NMR (CDCl3, 250
MHz) d: 7.11 (br s, 2H, H-3,4); 6.84 (s, 1H, H-1); 4.51 (d, 1H,
J = 17.1 Hz, H-5); 3.77 (t, 1H, J = 3.1 Hz, H-10); 3.58 (d, 1H,
J = 17.1 Hz, H-5); 2.91 (ddt, 1H, J = 12.9, 6.9 and 1.8 Hz, H-7);
2.54–2.40 (m, 1H, H-7); 2.39 (s, 3H, CH3); 2.30–2.17 (m, 1H, H-9);
2.15–2.02 (m, 1H, H-9); 1.83–1.60 (m, 2H, H-8) ppm. 13C NMR
(CDCl3, 63 MHz) d: 202.2 (C-11); 137.9 (C-2); 135.9 (C-10a);
129.7 (C-4a); 129.1 (C-4); 128.8 (C-3); 127.2 (C-1); 96.1 (C-6);
53.0 (C-10); 41.9 (C-5); 40.9 (C-7); 37.0 (C-9); 21.3 (CH3); 18.3
(C-8) ppm. Anal. Calcd for C14H15NO3: C, 68.57; H, 6.12; N, 5.71.
Found: C, 68.19; H, 6.01; N, 5.51.
( )-cis-6,7,8,9,10,11-Hexahydro-5H -6,11-methano-3-methyl-
10-nitrobenzocyclononen-12-one (4h). Colourless oil. IR (NaCl):
1
2959, 1735 (CO), 1553 and 1355 (NO2) cm-1. H NMR (CDCl3,
250 MHz) d: 7.10 (br s, 2H, H-1,2); 7.04 (s, 1H, H-4); 4.04 (d, 1H,
J = 15.8 Hz, H-11); 3.98 (t, 1H, J = 4.2 Hz, H-5); 3.30 (d, 1H, J =
15.7 Hz, H-11); 2.73 (dd, 1H, J = 15.1 and 7.1 Hz, H-9); 2.47–2.32
(m, 4H, H-6, CH3); 2.09–1.48 (m, 5H, H-6,7,8,9); 1.28–1.11 (m,
1H, H-7) ppm. 13C NMR (CDCl3, 63 MHz) d: 202.0 (C-12); 137.5
(C-3); 134.8 (C-4a); 129.1 (C-1); 128.9 (C-11a); 128.4 (C-2); 127.4
(C-4); 97.6 (C-10); 52.1 (C-5); 40.1 (C-11); 33.8 (C-6); 33.4 (C-9);
25.8 (C-8); 25.7 (C-7); 21.1 (CH3) ppm. MS (ESI), m/z: 260 (M+ +
1). Anal. Calcd for C15H17NO3: C, 69.49; H, 6.56; N, 5.40. Found:
C, 69.20; H, 6.41; N, 5.32.
( )-cis-7,8,9,10,11,12-Hexahydro-8,12-methano-8-nitrocyclo-
octa[a]naphthalen-13-one (4c). Pale yellow solid; mp 171–172 ◦C.
IR (KBr): 1743 (CO), 1547 and 1365 (NO2) cm-1. 1H NMR
(CDCl3, 250 MHz) d: 7.81–7.69 (m, 3H, H-Ar); 7.53–7.41 (m,
2H, H-Ar); 7.20 (d, 1H, J = 8.6 Hz, H-Ar); 4.64 (dd, 1H, J =
15.6 and 2.2 Hz, H-7); 4.48 (t, 1H, J = 3.2 Hz, H-12); 3.64 (d,
1H, J = 17.6 Hz, H-7); 2.91 (ddt, 1H, J = 13.5, 5.5 and 2.3 Hz,
H-9); 2.47–2.40 (m, 1H, H-9); 2.26–2.16 (m, 2H, H-11); 1.80–1.54
(m, 2H, H-10) ppm. 13C NMR (CDCl3, 63 MHz) d: 201.7 (C-13);
132.7 (C-12a); 130.2 (C-6a); 130.1 (C-12b); 129.4 (C-4a); 128.9
(C-4); 128.3 (C-5); 127.2 (C-6); 125.9 (C-3); 124.7 (C-2); 121.9
(C-1); 95.3 (C-8); 48.2 (C-12); 42.3 (C-7); 40.3 (C-9); 33.7 (C-11);
18.6 (C-10) ppm. MS (ESI), m/z: 282 (M+ + 1). Anal. Calcd for
C17H15NO3: C, 72.59; H, 5.34; N, 4.98. Found: C, 72.70; H, 5.25;
N, 4.65.
( )-cis-6,7,8,9,10,11,5H-5,11-Methano-2,3-methylenedioxy-10-
nitrobenzocyclononen-12-one (4i). Colourless viscous liquid. IR
(neat) 2936, 1728 (CO), 1547.7 and 1345 (NO2), 1504, 1480, 1234,
1
1120, 1038, 932 cm-1. H NMR (CDCl3, 250 MHz) d 6.67 (s,
1H); 6.65 (s, 1H); 6.01 (dd, J = 1.3 and 4.5 Hz, 2H); 3.97 (d,
J = 15.7 Hz, 1H); 3.89–3.92 (m, 1H); 3.21 (d, J = 15.7 Hz, 1H);
2.74 (dd, J = 6.7 and 15.2 Hz, 1H); 2.26–2.36 (m, 1H); 1.89–2.03
(m, 2H); 1.78–1.86 (m, 2H); 1.63–1.73 (m, 1H); 1.53–1.59 (m,
1H). 13C NMR (CDCl3, 62.9 MHz) d 201.9 (C-12); 148.1 (C-2);
147.7 (C-3); 128.5 (C-4a); 125.5 (C-11a); 109.4 (C-1); 107.0 (C-4);
101.9 (OCH2O); 97.9 (C-10); 52.6 (C-5); 40.8 (C-11); 34.3 (C-6);
33.9 (C-9); 26.3 (C-8), 26.1 (C-7). Anal. Calcd for C15H15NO5: C,
62.28; H, 5.23, N, 4.84 Found: C, 61.95; H, 5.01; N, 4.65.
( )-cis-6,7,8,9,10,11-Hexahydro-10-nitro-5H -5,10-methano-
benzocyclononen-12-one (4d). Colourless oil. IR (NaCl): 2947,
1
1731 (CO), 1548 and 1348 (NO2) cm-1. H NMR (CDCl3, 250
MHz) d: 7.28–7.11 (m, 4H, H-Ar); 4.08 (d, 1H, J = 15,8 Hz, H-
11); 4.03 (t, 1H, J = 4.4 Hz, H-5); 3.34 (d, 1H, J = 15.8 Hz, H-11);
2.73 (dd, 1H, J = 15.1 and 7.1 Hz, H-9); 2.47–2.36 (m, 1H, H-
6); 2.03–1.48 (m, 5H, H-6,7,8,9); 1.17–1.05 (m, 1H, H-7) ppm. 13
C
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( )-cis-8,9,10,11,12,13-Hexahydro-8-nitro-7H-8,13-methano-
cyclonona[a]naphthalen-14-one (4j). Pale yellow oil. 1H NMR
(CDCl3, 250 MHz) d: 7.86–7.79 (m, 2H, H-1,4); 7.71 (d, 1H, J =
8.4 Hz, H-5); 7.51–7.40 (m, 2H, H-2,3); 7.19 (d, 1H, J = 8.4 Hz,
H-6); 4.58 (t, 1H, J = 4.9 Hz, H-13); 4.10 (d, 1H, J = 16.0 Hz,
H-7); 3.47 (d, 1H, J = 16.0 Hz, H-7); 2.79–2.60 (m, 2H, H-9,12);
2.10–1.74 (m, 3H, H-9,11,12); 1.68–1.56 (m, 2H, H-10); 1.18–0.95
(m, 1H, H-11) ppm. 13C NMR (CDCl3, 63 MHz) d: 201.4 (C-14);
133.6 (C-13a); 131.2 (C-6a); 130.4 (C-13b); 130.1 (C-4a); 129.5 (C-
4); 129.0 (C-5); 127.2 (C-6); 127.1 (C-3); 126.3 (C-2); 123.6 (C-1),
97.9 (C-8); 51.3 (C-13); 42.1 (C-7); 35.9 (C-9); 33.3 (C-12); 26.2
(C-11); 25.8 (C-10) ppm. MS (ESI), m/z: 296 (M+ + 1). Anal.
Calcd for C18H17NO3: C, 73.22; H, 5.76; N, 4.74. Found: C, 72.95;
H, 5.80; N, 4.65.
171 ◦C. IR (KBr): 2935, 1722 (CO), 1547 and 1329 (NO2) cm-1. 1H
NMR (CDCl3, 250 MHz) d: 7.91 (m, 2H, H-1,4); 7.79 (d, 1H, J =
8.4 Hz, H-5); 7.61–7.49 (m, 2H, H-2,3); 7.30 (d, 1H, J = 8.4 Hz,
H-6); 4.51 (dd, 1H, J = 10.6 and 7.3 Hz, H-14); 3.91 (s, 2H, H-7);
2.85–2.73 (m, 1H, H-9); 2.52–2.34 (m, 2H, H-9, 13); 2.18–2.04 (m,
1H, H-13); 1.94–1.82 (m, 2H, H-10); 1.79–1.57 (m, 4H, H-11, 12)
ppm. 13C NMR (CDCl3, 63 MHz) d: 204.8 (C-15); 132.9 (C-4a);
131.2 (C-14a); 130.3 (C-14b); 128.8 (C-4; C-6a); 128.0 (C-5); 126.7
(C-2); 126.2 (C-6); 125.7 (C-1); 122.2 (C-3); 95.7 (C-8); 49.6 (C-
14); 40.7 (C-7); 34.2 (C-9); 32.3 (C-13); 25.9 (C-11); 23.5 (C-12);
21.1 (C-10) ppm. Anal. Calcd for C19H19NO3: C, 73.78; H, 6.15;
N, 4.53. Found: C, 73.61; H, 6.11; N, 4.67.
(E)-2-(2¢-Bromo-4¢-methoxycarbonylbenzylidene)cycloheptanone
(5g). Colourless oil. IR (neat) 2934, 1728 (CO), 1548, 1435,
1289, 1260, 1118, 764 cm-1. 1H NMR (CDCl3, 250 MHz) d: 8.08
(d, 1H, J = 8.3 Hz, H-4¢); 7.54–7.40 (m, 2H, H-2¢,5¢); 7.29 (s, 1H,
H-a); 3.96 (s, 3H, OMe); 2.74–2.68 (m, 2H, H-7); 1.94–1.65 (m,
4H, H-3,6); 1.60–1.45 (m, 4H, H-4,5) ppm. 13C NMR (CDCl3, 63
MHz) d: 204.9 (C-1); 167.1 (CO2Me); 142.8 (C-2); 141.1 (C-1¢);
134.8 (C-a); 130.3 (C-5¢); 130.02 (C-3¢); 129.9 (C-2¢); 129.6 (C-4¢);
128.1 (C-6¢); 52.6 (CO2Me); 43.8 (C-7); 31.6 (C-5); 30.3 (C-4);
28.2 (C-3); 25.8 (C-6) ppm. Anal. Calcd. for C16H17BrO3: C,
56.99; H, 5.08. Found: C, 56.72; H, 4.89.
( )-cis-2-Chloro-5,6,7,8,9,10,11,12-octahydro-11-nitro-5,11-
methanobenzocyclodecen-13-one (4l). Pale yellow oil. IR (NaCl):
1
2936, 1725 (CO), 1548 and 1352 (NO2) cm-1. H NMR (CDCl3,
300 MHz) d: 7.22 (dd, 1H, J = 8.3 and 1.9 Hz, H-3); 7.13 (s, 1H,
H-1); 7.07 (d, 1H, J = 8.3 Hz, H-4); 3.89 (d, 1H, J = 16.4 Hz, H-12);
3.76 (dd, 1H, J = 7.1 and 4.9 Hz, H-5); 3.29 (d, 1H, J = 16.5 Hz,
H-12); 2.44–2.27 (m, 2H, H-6, 10); 2.20–2.02 (m, 2H, H-6,10);
1.84–1.70 (m, 1H, H-9); 1.68–1.49 (m, 3H, H-7,8,9); 1.43–1.11 (m,
2H, H-7,8) ppm. 13C NMR (CDCl3, 75 MHz) d: 204.7 (C-13);
134.2 (C-4a); 134.0 (C-12a); 133.2 (C-2); 128.7 (C-1); 128.6 (C-
4); 128.0 (C-3); 96.4 (C-11); 50.7 (C-5); 40.1 (C-12); 34.1 (C-6);
31.4 (C-10); 25.0 (C-8); 21.3 (C-9); 20.9 (C-7) ppm. Anal. Calcd
for C15H16NO3Cl: C, 61.33; H, 5.45; N, 4.77. Found: C, 61.16; H,
5.25; N, 4.64.
(E)-2-(2¢-Bromo-4¢-methoxycarbonylbenzylidene)cyclooctanone
(5n). Colourless oil. IR (neat) 2934, 1729, 1693, 1288, 1255, 1112,
761 cm-1. 1H NMR (CDCl3, 250 MHz) d 8.25 (d, J = 1.6 Hz, 1H,
H-6¢); 7.86 (dd, J = 1.6 and 8.0 Hz, 1H, H-4¢); 7.23 (d, J = 8.0 Hz,
1H, H-3¢); 6.62 (s, 1H, H-a); 3.93 (s, 3H, CO2Me); 2.55–2.60 (t,
J = 6.0 Hz, 2H, H-8); 2.05–2.09 (m, 2H, H-3); 1.71–1.73 (m, 4H,
H-4,7); 1.54–1.55 (m, 4H, H-5,6). 13C NMR (CDCl3, 62.9 MHz) d
215.3 (C-1); 165.9 (CO2Me); 148.7 (C-2); 141.4 (C-1¢); 134.1 (C-a);
131.2 (C-5¢); 130.4 (C-3¢); 128.9 (C-4¢); 125.9 (C-6¢); 123.4 (C-2¢);
52.8 (CO2Me); 43.8 (C-8); 38.7 (C-3), 28.6 (C-7), 26.7 (C-4), 25.9
(C-5), 23.6 (C-6) ppm. Anal. Calcd for C17H19BrO3: C, C, 58.13;
H, 5.45. Found: C, 57.82; H, 5.31.
( )-cis-5,6,7,8,9,10,11,12-Octahydro-3-methyl-11-nitro-5,11-
methanobenzocyclodecen-13-one (4o). Colourless oil. IR (NaCl):
1
2933, 1723 (CO), 1548 and 1335 (NO2) cm-1. H NMR (CDCl3,
300 MHz) d: 7.02 (s, 2H, H-3, 4); 6.99 (s, 1H, H-4); 3.95 (d, 1H,
J = 16.2 Hz, H-12); 3.82 (dd, 1H, J = 7.1 and 4.9 Hz, H-5); 3.36
(d, 1H, J = 16.2 Hz, H-12); 2.46–2.25 (m, 6H, H-7,11, CH3); 2.18–
2.14 (m, 1H, H-11); 1.88–1.60 (m, 5H, H-8–10); 1.58–1.41 (m, 1H,
H-10) ppm. 13C NMR (CDCl3, 75 MHz) d: 206.3 (C-13); 137.9
(C-3); 135.7 (C-4a); 129.8 (C-12a); 129.1 (C-1); 128.7 (C-2); 128.1
(C-4); 97.6 (C-11); 51.5 (C-5); 40.7 (C-12); 34.6 (C-6); 31.6 (C-10);
25.6 (C-8); 21.9 (C-9); 21.6 (CH3); 21.3 (C-7) ppm. Anal. Calcd for
C16H19NO3: C, 70.32; H, 6.96; N, 5.13. Found: C, 69.99; H, 6.81;
N, 5.08.
2,3 - Methylenedioxy - 9a - nitro - 4b,5,6,7,8,9,9a,10 - octahydro-
benzo[a]azulen-4b-ol (6i). Colourless liquid. IR (neat) 3508.2,
2927, 1538 and 1376 (NO2), 1505, 1479, 1263, 1249, 1037, 937,
1
864 cm-1. H NMR (CDCl3, 250 MHz) d 6.74 (s, 1H, H-1); 6.67
(s, 1H, H-4); 5.98–6.01 (m, 2H, OCH2O); 3.88 (d, J = 17.1 Hz,
1H, H-10); 3.09 (d, J = 17.1 Hz, 1H, H-10); 2.64–2.72 (m, 1H,
H-9); 2.27–2.37 (m, 2H, H-9 and OH); 2.04–2.19 (m, 2H, H-5);
1.73–1.96 (m, 2H, H-6); 1.49–1.66 (m, 4H, H-7,8) ppm. 13C NMR
(CDCl3, 62.9 MHz) d 149.4 (C-2); 148.2 (C-3); 137.6 (C-4a); 132.1
(C-104); 104.7 (C-2); 104.4 (C-4); 103.7 (OCH2O); 101.8 (C-9a);
86.7 (C-4b); 43.1 (C-10); 38.3 (C-5); 37.7 (C-9); 30.1 (C-7); 23.6
(C-8); 23.3 (C-6). Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88,
N, 4.81. Found:C, 61.69; H, 5.65; N, 4–58.
( )-cis-2-Methoxy-5,6,7,8,9,10,11,12-octahydro-11-nitro-5,11-
methanobenzocyclodecen-13-one (4p). White solid, mp 155 ◦C.
IR (neat) 2935, 1723 (CO), 1611, 1548 and 1350 (NO2), 1504,
1465, 1246, 1136, 10360 cm-1. 1H NMR (CDCl3, 250 MHz) d 7.14
(d, J = 8.6 Hz, 1H, H-4); 6.88 (dd, J = 2.4 and 8.6 Hz, 1H, H-3);
6.74 (s, 1H, H-1); 3.99 (d, J = 17.1 Hz, 1H, H-12); 3.85 (s, 3H,
OMe); 3.78–3.87 (m, 1H, H-5); 3.35 (d, J = 17.1 Hz, 1H, H-12);
2.26–2.45 and 2.07–2.20 (m, 3+1H, H-7,11); 1.63–1.88 (m, 4H, H-
8,9); 1.28–1.42 (m, 2H, H-10) ppm. 13C NMR (CDCl3, 62.9 MHz)
d 206.3 (C-13); 159.2 (C-2); 134.2 (C-12a); 128.8 (C-4); 127.7 (C-
4a); 114.2 (C-2); 114.1 (C-3); 97.5 (C-11); 55.7 (OMe); 50.9 (C-5);
41.2 (C-12); 34.7 (C-6); 31.6 (C-10); 25.6 (C-8); 21.9 (C-7); 21.2
(C-9) ppm. Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62, N, 4.84.
Found: C, 66.21; H, 6.42; N, 4.63.
6,7,8,9,10,11-Hexahydro-5H-cycloocta[a]indene (6k). Colour-
less oil. IR (NaCl): 2907, 1467, 1260, 1020 cm-1. 1H NMR (CDCl3,
250 MHz) d: 7.39 (d, 1H, J = 7.2 Hz, H-4); 7.32–7.23 (m, 2H, H-
1,2); 7.12 (td, 1H, J = 7.1 and 2.0 Hz, H-3); 3.32 (s, 2H, H-11);
2.64–2.55 (m, 4H, H-5,10); 1.88–1.71 (m, 6H); 1.40–1.15 (m, 2H)
ppm. 13C NMR (CDCl3, 63 MHz) d: 147.5 (C-4a); 145.1 (C-4b);
142.3 (C-11a); 138.8 (C-10a); 125.9 (C-3); 123.3 (C-2); 123.1 (C-1);
117.5 (C-4); 42.9 (C-11); 31.4 (C-9); 30.5 (C-10), 29.6; 27.5; 27.3
( )-cis-7,8,9,10,11,12,13,14-Octahydro-8-nitro-8,14-methano-
cyclodeca[a]naphthalen-15-one (4q). Pale yellow solid; mp 170–
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(C-6,7,8); 26.0 (C-5) ppm. MS (ESI), m/z: 199 (M+ + 1). Anal.
Calcd for C15H18: C, 90.90; H, 9.10. Found: C, 90.80; H, 9.25.
4 For reviews of the chemistry of the welwitindolinones, see: (a) C.
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Moore, Mol. Pharmacol., 1995, 47, 241–247.
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S. Scapecchi and F. Gualtieri, Farmaco, 2002, 57, 385–415; (c) C.
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Avendan˜o and J. C. Mene´ndez, Med. Chem. Rev.–Online, 2004, 1, 419–
444; (f) A. Seelig and E. Gatlik-Landwojtowicz, Mini-Rev. Med. Chem.,
2005, 5, 135–151; (g) K. Pleban and E. F. Ecker, Mini-Rev. Med.
Chem., 2005, 5, 153–163; (h) A. Boumendjel, H. Baubichon-Cortay,
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Kozikowskia, Tetrahedron Lett., 2001, 42, 5359–5361; (b) J. A. MacKay,
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10 M. Hideaki, N. Mitsutaka and N. Hiroshi, Tetrahedron, 2004, 60,
11783–11803.
11 (a) N. Kornblum and R. A. Brown, J. Am. Chem. Soc., 1963, 85, 1359;
(b) R. Gree and R. Carrie, Bull. Soc. Chim Fr., 1975, 1314; (c) Y. A.
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2-Nitro-6,7,8,9,10,11-hexahydro-5H-cycloocta[a]indene (6m).
Pale yellow oil. IR (NaCl): 2918, 1699, 1558 and 1337 (NO2)
1
cm-1. H NMR (CDCl3, 250 MHz) d: 8.25–8.21 (m, 2H, H-Ar);
7.35–7.20 (m, 1H, H-Ar); 3.44 (s, 2H, H-11); 2.77–2.63 (m, 4H,
H-5,10); 1.99–1.52 (m, 6H); 1.38–1.21 (m, 2H) ppm. 13C NMR
(CDCl3, 63 MHz) d: 160.2 (C-4a); 154.3 (C-2); 153.0 (C-11a);
135.5 (C-4b); 122.8 (C-10a); 120.0 (C-1); 118.3 (C-4); 117.4 (C-3);
43.0 (C-11); 31.1 (C-9); 30.9 (C-10); 30.9; 27.1; 27.0 (C-6,7,8);
26.0 (C-5) ppm. Anal. Calcd for C15H17NO2: C, 74.07; H, 6.99; N,
5.76. Found: C, 73.81; H, 6.76; N, 5.68.
3-Methyl-6,7,8,9,10,11-hexahydro-5H-cycloocta[a]indene (6o).
Colourless oil. IR (NaCl): 2920, 1612, 1444 cm-1. 1H NMR
(CDCl3, 300 MHz) d: 7.25 (d, 1H, J = 7.6 Hz, H-1); 7.05 (s,
1H, H-4); 6.93 (dd, 1H, J = 7.4 and 0.6 Hz, H-2); 3.26 (s, 2H, H-
11); 2.60–2.52 (m, 4H, H-5,10); 2.40 (s, 3H, CH3); 1.87–1.81 (m,
2H); 1.75–1.65 (m, 4H); 1.27 (s, 2H) ppm. 13C NMR (CDCl3, 75
MHz) d: 148.0 (C-4a); 145.4 (C-4b); 139.3 (C-11a); 138.8 (C-10a);
135.4 (C-3); 124.0 (C-2); 122.8 (C-1); 118.4 (C-4); 42.5 (C-11); 31.4
(C-9); 30.5 (C-10); 29.6; 27.6; 27.3 (C-6–8); 26.0 (C-5); 21.3 (CH3)
ppm. Anal. Calcd for C16H20: C, 90.56; H, 9.44. Found: C, 90.34;
H-9.53.
12 G. Chen, F. Y. Kwong, H. O. Chan, W.-Y. Yu and A. S. C. Chan, Chem.
Commun., 2006, 1413–1415.
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Res., 2003, 36, 234–245; (e) J. Tsuji, Palladium Reagents and Catalysts.
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Acknowledgements
Financial support from MICINN (grant CTQ2009-12320-BQU)
and UCM (Grupos de Investigacio´n, grant 920234) is gratefully
acknowledged.
Notes and references
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2730 | Org. Biomol. Chem., 2011, 9, 2722–2730
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©