Medium-sized and strained heterocycles from non-catalysed and gold-catalysed conversions of β-carbolines

Article abstract of DOI:10.1039/c2ob25755f

2-Allyl-1-vinyl-β-carbolines and dihydropyrrolo-β-carbolines react with activated internal alkynes through novel rearrangement reactions leading to complex polycyclic structures. Favored reaction pathways depend on reaction conditions and on the presence

Full text of DOI:10.1039/c2ob25755f

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PAPER
Medium-sized and strained heterocycles from non-catalysed and
gold-catalysed conversions of β-carbolines†
Sandra Medina, Álvaro González-Gómez, Gema Domínguez and Javier Pérez-Castells*
Received 19th April 2012, Accepted 17th July 2012
DOI: 10.1039/c2ob25755f
2-Allyl-1-vinyl-β-carbolines and dihydropyrrolo-β-carbolines react with activated internal alkynes through
novel rearrangement reactions leading to complex polycyclic structures. Favored reaction pathways
depend on reaction conditions and on the presence of gold catalysts. In particular, upon reaction with
2 equiv. of the alkyne, new hexacyclic structures 10 are formed with total stereocontrol.
Introduction
The β-carboline structure is present in numerous natural products
like the harman family and more complex systems like eburna-
mine, vincamine, and alkaloids from Schizozygia species, which
often exhibit biological activity.1 In addition, some β-carbolines
have gained use as synthetic intermediates and chiral ligands for
certain catalytic processes. Alkaloids with a β-carboline nucleus
possess widespread and potent biological activities and this has
prompted many groups to design new derivatives as potential
drugs for the treatment of various diseases. Some natural β-car-
boline alkaloids display antineoplastic activity,2 anticonvulsant/
anxiolytic activity,3 or antimalarial activity.4 Certain β-carbolines
have been designed successfully as anti-thrombosis agents5 or
neurotoxic agents.6 The importance of these compounds is the
cause of the great efforts devoted to their synthesis and further
transformations.7
Scheme 1 Preliminary reaction of vinyl-β-carboline 1a.
to one unsaturated carbon which leads to new polycycles with a
substantial increase in skeletal complexity (Scheme 1).9
We were intrigued by the possibility of catalyzing these pro-
cesses with metal salts hopefully providing a way to control the
different reaction pathways and improving conversions. We show
herein the influence of gold salts in the results of these kinds of
reactions. Novel divergent reaction pathways are shown.
Tandem reactions and molecular rearrangements are a power-
ful building tool to rapidly increase the complexity of a substrate
starting from relatively simple precursors. Nitrogen containing
heterocycles are known to give Michael reactions with activated
alkynes that lead to further molecular rearrangements giving
complex polycycles.8 Thus, we9 and others10 have described
reactions of tetrahydro-β-carbolines and other tetrahydropyridine
containing substrates with alkynes to give novel tandem trans-
formations into complex products. In particular, we have shown
the transformation of pyrrolo-β-carbolines and vinyl-β-carbo-
lines, upon reaction with acetylenedicarboxylates or propyolates
through a Michael type addition followed by nucleophilic attack
Results and discussion
The behavior of compounds 1a–c in their reaction with alkynes
was studied first. Synthesis of 1b was carried out following
similar procedures to those for 1a, already published.9 The reac-
tion of these three substrates with dimethyl acetylenedicarboxy-
late (DMAD) was studied under different conditions and the
results are summarized in Table 1, Scheme 2.
The preliminary result,9 in which 1a gave a mixture of 2a and
3a in low yields (entry 1), was improved in terms of selectivity
and efficiency by selecting suitable reaction conditions. Thus,
increasing the amount of DMAD from 2 to 5 equiv. and prolong-
ing the reaction time to 48 h provided 2a in good yield (68%),
with no presence of 3a in the crude mixture. When separating
the mixture through column chromatography in silica, an
additional new product was isolated and assigned to structure 4a
(entry 2). A higher excess of DMAD gave, upon chromato-
graphy, higher yields of 4a, a compound that could be formed
upon evolution of 2a (entry 3) in the presence of water. For the
Universidad San Pablo-CEU, Departamento de Química, Facultad de
Farmacia, Urb. Montepríncipe, 28668 Boadilla del Monte (Madrid),
Spain. E-mail: jpercas@ceu.es
†Electronic supplementary information (ESI) available: Spectra for new
products. A cif file with details on the X-ray analysis of compound 10a
is also included. CCDC XXXXXX. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob25755f
This journal is © The Royal Society of Chemistry 2012
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Table 1 Reaction of 2-allyl-1-vinyl-β-carbolines with DMAD
Yielda (%)
No.
Subs.
AuCl3
DMADb
Temp.
Time (h)
Ratio crude (2 : 3 : 5)
2
3
4
5
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
No
No
No
No
0.05
0.05
No
2
5
10
10
5
5
5
10
5
5
10
5
Rt
rt
rt
16
48
48
2.5
0.5
3
20
48
2
1 : 3 : 0
1 : 0 : 0
1 : 0 : 0
1 : 0 : 0c
1 : 0 : 3
4 : 0 : 1
4 : 1 : 0
4 : 1 : 0
2 : 1 : 1
3 : 0 : 1
1 : 0 : 0
1 : 0 : 0
10
68
50
41
20
55
55
25
30
20
11
35
24
—
—
—
—
16
42
—
—
5
—
—
—
55
10
Δ (DCM)
rt
0° (2 h)–rt
rt
rt
rt
0°–rt
rt
Rt
15
20
14
5
—
No
40
—
20
9
0.05
0.05
No
15d
10
11
12
18
18
No
—
a In pure product. b Equivalents. c 21% of the starting material was recovered. d Not characterized.
rest of the reactions, short pads of silica were used for separation
which reduced or avoided the formation of this compound.
Change of the solvent to DCM at reflux precluded total conver-
sion with recovery of the starting material (21%) and formation
of 2a as the only reaction product (41%, entry 4). Gold salts are
well known alkynophilic catalysts that favour many interesting
synthetic processes including cyclizations and intramolecular
rearrangements.11 We studied the possible effect of a 5% of gold
trichloride in the reaction.12 These new conditions (entry 5) pro-
vided a mixture of 2a and a new structure, 5a which is a result
of a deallylation process.13 These deallylation reactions have
been observed with various metals, and can be minimized if
adding the catalysts at 0 °C (entry 6).14 In entries 7–10, results
of the parent reactions of substrate 1b are recorded. The behavior
of this substrate is similar to 1a, observing products 2b, 3b and
4b. The use of gold catalysis produced small amounts of 5b
along with moderate yields of 2b. Entries 11–12 show the results
of the reaction of 1c which is prone to decomposition and only
gave poor yields of 2c under the conditions tested.
intermediate B. This route is only observed in the presence of
gold salts and is apparently favored by higher temperatures
(entry 5).15 The formation of 4 was presumed to start from
product 2. This was checked by reacting 2b with 3 equiv. of
DMAD in the presence of silica gel. This reaction gave 4b in
95% yield after 6 h. The same mixture in the absence of silica
gel did not produce any observable transformation. We propose
in Scheme 2 a possible pathway for the transformation of 2 into
4. The reaction would start with a hydrolysis of the enamine cat-
alysed by the silica gel and Michael attack of the resulting sec-
ondary amine C to a molecule of DMAD and subsequent
protonation to give 4.
The structure of this product was established by 2D-NMR
experiments. Isolation of DMAD tetramer 6 in these reactions
may be related with the formation of 4. This DMAD derivative
has been previously described to be formed under harsh reaction
conditions like high pressures or temperatures.16 In addition we
treated 4a with a 1 N solution of sodium hydroxide which gave
7 upon a retro Claisen process.
In Scheme 2 we show the possible reaction pathways leading
from compounds 1a–c to the different products. The processes
would start with a Michael type attack onto common intermedi-
ate A. The anionic centre in A may attack two possible positions,
namely the vinyl group attached to C1 or to C6a. These attacks
would lead respectively to products 2 and 3. Alternatively if the
anion traps a proton the reaction may follow a deallylation
Our next target was to study the behavior of pyrrolotetra-
hydro-β-carboline 8 in the reaction with triple bonded dienophiles.
These reactions gave unexpected products due to the Michael
type attack of the β-carboline nitrogen to the dienophile and skel-
etal rearrangement (Table 2, Scheme 3). The reaction of 7 with
DMAD at rt (entry 1) gave us a mixture of two reaction pro-
ducts, the minor product, 9a, being the result of a Michael-type
attack and further skeletal rearrangement upon reaction with C7a
pathway which gives product
5 through the enamine
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Table 2 Reaction of pyrrolo-β-carbolines with acetylenedicarboxylates
Yielda (%)
No.
AuCl3
R (equiv.)
Temp.
Time
9
10
1
2
3
4
5
6
7
8
No
No
0.05
0.05
No
0.05
No
Me (3)
Me (5)
Me (5)
Me (5)
Et (5)
rt
rt
0 °C
0 °C
rt
0 °C
rt
48 h
48 h
20 min
80 min
48 h
2 h
6
30
65
—
—
60
—
42
—
<5
58
11
<5
49
10
39
Et (5)
tBu (5)
tBu (5)
48 h
2 h
0.05
0 °C
a In pure product.
Scheme 3 Electrophilic aromatic substitution of 11 with DMAD.
Scheme 2 Possible reaction pathways for the formation of products
3–7 from 1.
of the pyrrolo-β-carboline system. This compound was expected
as it implies a similar reactivity to that for substrate 1a. Interest-
ingly another compound which incorporated two molecules of
DMAD was the major product albeit isolated in low yield. The
structure of this new product was assigned as 10a using several
NMR techniques and finally established by an X-ray diffraction
analysis (Fig. 1). The strained structure of this compound is
really unusual as it bears two small rings including a cyclobutene
being a compound with high connectivity. In the next reaction
we increased the amount of DMAD which gave 10a as the only
reaction product in 65% yield. The effect of a gold salt was
studied next. In the presence of 5% of AuCl3 the reaction only
gave compound 9a in 58% yield. Temperature was lowered to
avoid decomposition of 9 in the presence of the gold salt. There-
fore the reaction pathway is easily controlled by just switching
the reaction conditions (Table 2).
Fig. 1 ORTEP drawing for 10a.
similar behaviour. Thus, in the absence of gold catalysts these
reactions produced products 10b and 10c in 60% and 42%
yields as the major products along with small amounts of com-
pounds 9b and 9c (entries 5 and 7), whereas in the presence of
AuCl3 the only reaction products were 9b and 9c in moderate
yields (entries 6 and 8). The hexacyclic compounds 10 are
formed in a totally stereoselective manner in the five new stereo-
genic centers created. On the other hand non-activated alkynes
Reactions with the parent diethoxycarbonylacetylene and di-
tert-butoxycarbonyl acetylene were next studied and followed
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such as 3-hexyne did not react with 8 and the starting material
was recovered after 48 h. The reactivity of this substrate with
terminal alkynes like ethylpropyolate resulted in different re-
organization processes and will be published elsewhere.
One interesting observation with these substrates was that if
performing the reaction under air we observed the formation of
small amounts of a mixture of two isomeric products, 12. We
assumed that a partial oxidation to the pyrrole in the starting
material 8 had occurred and that a further electrophilic aromatic
substitution reaction with DMAD had produced these products.
To check this we oxidised 7 by stirring a solution in acetonitrile
under air, and when t.l.c. analysis showed total conversion into
indole 11 (12 h) we added 5 equiv. of DMAD. After 3 h we iso-
lated a 48% yield of E-12 and 13% of Z-12. The two isomers
were separated and characterized. Stereochemistry was assigned
according to chemical shift of the olefinic proton (Scheme 3).12
The plausible reaction pathway that explains the formation of
9 and 10 is depicted in Scheme 4. After Michael type attack to
the acetylenedicarboxylate reagent and formation of D, reaction
of the anionic carbon with position C6a of the heterocycle gives
product 9. Alternatively, a proton exchange with C11b produces
E, an ylide-type intermediate that appears in the Stevens
rearrangement reaction. This species rearranges onto F and a
nucleophilic attack gives cyclobutane derivative G. The reaction
of this intermediate with a second molecule of acetylenedicar-
boxylate has to be very favorable as we have not detected this
compound. The new Michael attack of G gives H which cyclizes
finally into 10.
The role of gold catalysis is not very clear. As it favours
pathway (a) leading to 9, it may be assumed that gold salts pre-
clude proton abstraction from C11b possibly by coordination
with E. This disfavors the formation of F and the pathway to 10.
To have some more information on this we performed a reaction
using 30 mol% of AuCl3 and 5 equiv. of diethyl acetylene dicar-
boxylate. These conditions allowed the formation of 9b (25%)
and the isolation of a new compound which was identified as 13
(42%), a salt that arises from intermediate D which is possibly
formed during the isolation procedure.14
Conclusions
In conclusion, new cascade reactions from β-carboline substrates
have produced novel polycyclic structures upon Michael attack
to activated alkynes and rearrangements. Several reaction path-
ways arise and may be controlled by simple selection of con-
ditions including the use of gold catalysis. Synthetic applications
to natural or biologically active compounds as well as more
mechanistic studies are underway.
Scheme 4 Possible reaction pathways for the formation of products
9–10 from 8.
chromatography. Medium pressure liquid chromatography
(MPLC) was performed using Si 25+M 2593-2 compact
columns. Elemental analyses were carried out using CHN equip-
ment. All solvents were distilled just before their use. THF and
benzene were refluxed over Na–benzophenone; DCM was
refluxed over calcium hydride. All reactions were conducted
under an argon atmosphere and in flame-dried flasks. Com-
pounds 1a, 2a, 3a, 8 were previously described.9
Experimental section
General procedures
1H NMR and 13C NMR spectra were taken on a 300 MHz spec-
trometer. Chemical shifts™ are in parts per million relative to
tetramethylsilane at 0.00 ppm. IR spectra were determined by an
FT-IR spectrometer. TLC analyses were performed on commer-
cial aluminium sheets bearing a 0.25 mm layer of silica gel.
Silica gel 0.035–0.070 mm, 60 Å was used for column
Starting materials
Preparation of 2-allyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-
bromide. To a solution of 4,9-dihydro-3H-pyrido[3,4-b]indole
7170 | Org. Biomol. Chem., 2012, 10, 7167–7176
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(1.0 g, 5.86 mmol) in anhydrous THF (8.5 mL mmol−1) was
added allyl bromide (1.3 mL, 14.69 mmol) under an argon
atmosphere. After 16 h of stirring at room temperature, the pre-
cipitate was collected obtaining 1.5 g (88%) of salt, as an orange
110.6, 117.6, 117.9, 118.7, 118.9, 121.1, 127.1, 132.5, 135.2,
135.8, 137.8. IR (NaCl) 1650, 1600 cm−1. Anal. Calcd for
C16H18N2: C, 80.63; H, 7.61; N, 11.75. Found: C, 81.90; H,
7.73; N, 11.35. ESI-MS: m/z = 239 [M + H]+.
1
solid (mp = 181–183 °C). H-NMR (DMSO) δ 3.36 (t, 2H, J =
Preparation of 11-tosyl-6,11-dihydro-5H-indolizino[8,7-b]-
indole, 11. To a solution of 11-tosyl-5,6,11,11b-tetrahydro-3H-
indolizino[8,7-b]indole, 7 (100.0 mg, 0.27 mmol) in AcOEt
(5 mL), Pd/C was added (10% weight) and the resulting mixture
was stirred for 30 min at room temperature. After that, the crude
mixture was filtered through Celite and the solvent was elimi-
nated under reduced pressure. Compound 10 was obtained ana-
9.4 Hz, CH2CH2N), 4.06 (t, 2H, J = 8.9 Hz, CH2CH2N), 4.66
(d, 2H, J = 6.2 Hz, CH2CHvCH2), 5.49 (dd, 1H, J1 = 10.1 Hz,
J2 = 1.2 Hz, CHvCH2), 5.60 (dd, 1H, J1 = 1.7 Hz, J2 = 1.2 Hz,
CHvCH2), 6.03–6.17 (m, 1H, CHvCH2), 7.20–7.25 (m, 1H,
Ar), 7.46–7.51 (m, 1H, Ar), 7.61 (d, 1H, J = 8.5 Hz, Ar), 7.80
(d, 1H, J = 8.4 Hz, Ar), 9.16 (s, 1H, H1), 12.33 (bs, 1H, H9).
13C-NMR (CDCl3) δ 20.1, 49.4, 61.7, 114.5, 122.5, 122.8,
123.1, 124.1, 124.5, 126.4, 129.7, 131.4, 142.4, 156.4. IR (KBr)
3036, 1646, 1538 cm−1. Anal. Calcd for C14H15BrN2: C, 57.75;
H, 5.19; N, 9.62. Found: C, 57.80; H, 5.23; N, 9.70.
1
lytically pure, 99 mg (100%) as a yellow oil. H NMR (CDCl3)
δ (ppm): 2.28 (s, 3H, CH3), 2.92 (t, 2H, J = 6.9 Hz, CH2CH2N),
4.06 (t, 2H, J = 6.9 Hz, CH2CH2N), 6.25 (dd, 1H, J1 = 3.8 Hz,
J2 = 2.8 Hz, H2), 6.77 (bs, 1H, H1), 7.05–7.08 (m, 3H, Ar),
7.25–7.34 (m, 3H, Ar and H3), 7.48 (dd, 2H, J1 = 6.6 Hz, J2 =
1.6 Hz, Ar), 8.27 (dd, 1H, J1 = 6.6 Hz, J2 = 1.6 Hz, Ar). 13C
NMR (CDCl3) δ (ppm): 21.5, 21.7, 44.3, 108.0, 110.4, 115.7,
116.5, 117.7, 122.5, 122.6, 124.2, 124.3, 126.7, 129.5, 129.9,
130.9, 134.4, 137.7, 144.4. IR (NaCl) ν 1620 cm−1. Anal. Calcd
for C21H18N2O2S: C, 69.59; H, 5.01; N, 7.73. Found: C, 69.67;
H, 5.12; N, 7.81. ESI-MS: m/z = 363 [M + H]+.
Preparation of tert-butyl 2-allyl-1-vinyl-3,4-dihydro-1H-pyrido-
[3,4-b]indole-9(2H)-carboxylate, 1b. To a solution of 2-allyl-1-
vinyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, 1c (1.0 g,
4.20 mmol) in anhydrous THF (21 mL) at −40 °C was added
via a syringe LiHDMS (12.6 mL, 12.6 mmol). The reaction
mixture was stirred for 1 h. Then, di-tert-butyl dicarbonate
(1.8 g, 8.4 mmol) was added, stirring for 30 min. The reaction
was extracted with 1 N HCl (20 mL), washed with NaHCO3
(15 mL), and dried over MgSO4. After filtration, the solvent was
eliminated under reduced pressure, and the resulting mixture was
purified by flash chromatography on silica gel (Hex–EtOAc
General procedure A for the reaction of 2-allyl-1-vinyl-2,3,4,9-
tetrahydro-1H-β-carbolines 1a–c with internal alkynes
1
9 : 1), obtaining 911 mg (75%) of 1b as an orange oil. H-NMR
To a solution of 1a–c (1.0 mmol) in anhydrous DCM (16 mL
mmol−1) was added the alkyne (5.0 mmol) via a syringe at room
temperature. The reaction was stirred for 48 h. The solvent was
eliminated under reduced pressure. The resulting mixture was
purified by flash chromatography on silica gel.
(CDCl3) δ 1.61 (s, 9H, C(CH3)3), 2.52 (dd, 1H, J1 = 16.2 Hz,
J2 = 4.4 Hz, CH2), 2.78–2.99 (m, 2H, CH2), 3.09–3.39 (m, 3H,
CH2), 4.76 (dt, 1H, J1 = 17.3 Hz, J2 = 1.5 Hz, CHvCH2),
4.99–5.00 (d, 1H, J = 4.4 Hz, H1), 5.15–5.23 (m, 3H,
CHvCH2), 6.91–6.14 (m, 2H, 2 × CHvCH2), 7.20–7.31
(m, 2H, Ar), 7.44 (d, 1H, J = 7.0 Hz, Ar), 8.20 (d, 1H, J =
7.5 Hz, Ar). 13C-NMR (CDCl3) δ 18.0, 28.1, 42.2, 56.2, 58.3,
83.6, 115.6, 115.7, 117.4, 117.6, 117.9, 122.5, 124.0, 129.2,
133.2, 136.3, 136.4, 137.9, 150.1. IR (NaCl) 1722, 1650,
1600 cm−1. Anal. Calcd for C21H26N2O2: C, 74.52; H, 7.74;
N, 8.28. Found: C, 74.60; H, 7.79; N, 8.35. ESI-MS: m/z = 339
[M + H]+.
General procedure B for the reaction of 2-allyl-1-vinyl-2,3,4,9-
tetrahydro-1H-β-carbolines 1a–c and internal alkynes
To a solution of the alkyne (5 mmol) and gold trichloride
(0.05 mmol) in anhydrous DCM (8 mL) at 0 °C was added via a
syringe 1a–c in 8 mL of DCM. The reaction was controlled by
t.l.c., and upon disappearance of the starting materials it was
filtered through Celite and extracted with water (15 mL), brine
(15 mL) and dried over MgSO4. The solvent was eliminated
under reduced pressure. The resulting mixture was purified by
flash chromatography on silica gel.
Preparation of 2-allyl-1-vinyl-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indole, 1c. To a suspension of 2-allyl-4,9-dihydro-3H-
pyrido[3,4-b]indol-2-ium bromide (1.2 g, 3.82 mmol) in anhy-
drous THF (36 mL) at 0 °C, vinyl magnesium bromide was
added slowly. The reaction mixture was then allowed to come to
room temperature. After 2.5 h the reaction mixture was again
cooled at 0 °C and quenched by the addition of NH4Cl (50 mL)
and extracted with AcOEt (3×). The organic layer was washed
with water (25 mL), brine and dried over MgSO4. Solvent was
eliminated under reduced pressure and after flash chromato-
graphy in Hex–AcOEt 9 : 1 we obtained 833.7 mg (97%) of 1c
Preparation of dimethyl (4E,7E)-3-allyl-9-tosyl-2,3,6,9-tetra-
hydro-1H-azecino[5,4-b]indole-4,5-dicarboxylate, 2a. Following
general procedure A the reaction of 2-allyl-9-tosyl-1-vinyl-
2,3,4,9-tetrahydro-1H-β-carboline, 1a (100.0 mg, 0.26 mmol)
and DMAD (184.7 mg, 1.13 mmol) in DCM (4.2 mL) at 0 °C
afforded after flash chromatography (Hex–AcOEt 20 : 1 to 9 : 1)
98.6 mg (68%) of 2a as a yellow oil and 29.4 mg (16%) of 4a as
a yellow oil.
1
as a yellow oil. H NMR (CDCl3) δ 2.79–2.87 (m, 1H, CH2),
2.98 (bs, 1H, CH2), 3.26 (dd, 1H, J1 = 13.7 Hz J2 = 7.4 Hz,
CH2), 3.38–3.45 (m, 1H, CH2), 3.66 (dd, 1H, J1 = 13.7 Hz, J2 =
4.9 Hz, CH2), 4.21 (d, 1H, J = 7.8 Hz, CH2), 5.40–5.51 (m, 5H,
2 × CHvCH2 and H1), 6.01–6.24 (m, 2H, 2 × CHvCH2),
7.29–7.39 (m, 3H, Ar), 7.71 (d, 1H, J = 6.3 Hz, Ar), 7.97 (s,
1H, NH). 13C NMR (CDCl3) δ 20.4, 46.8, 56.7, 62.0, 108.1,
Preparation of dimethyl (4E,7E)-3-allyl-9-(4-(tert-butoxy-
carbonyl)-2,3,6,9-tetrahydro-1H-azecino[5,4-b]indole-4,5-dicarboxy-
late, 2b. Following general procedure A the reaction of 2-allyl-
9-(tert-butoxycarbonyl)-1-vinyl-2,3,4,9-tetrahydro-1H-β-carboline,
1b (123.6 mg, 0.37 mmol) and DMAD (259.5 mg, 1.83 mmol)
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in DCM (6.0 mL) at room temperature afforded after flash
chromatography (Hex–AcOEt 20 : 1 to 9 : 1) 100.0 mg (55%) of
2b as a light yellow oil, 22.8 mg (15%) of 3b as a yellow oil and
4.9 mg (5%) of 4b as an orange oil. 1H NMR (CDCl3) δ 1.69 (s,
9H, C(CH3)3), 2.67–3.08 (m, 4H, CH2), 3.22–3.59 (m, 3H,
CH2), 3.73 (s, 3H, OCH3), 3.80–3.97 (m, 1H, CH2), 3.84 (s, 3H,
OCH3), 5.06 (dd, 1H, J1 = 10.1 Hz, J2 = 1.2 Hz, CHvCH2),
5.16 (dd, 1H, J1 = 17.1 Hz, J2 = 1.3 Hz, CHvCH2), 5.31–5.41
(m, 1H, H7), 5.70–5.83 (m, 1H, CHvCH2), 6.62 (d, 1H, J =
16.3 Hz, H8), 7.20–7.31 (m, 2H, Ar), 7.41 (d, 1H, J = 7.9 Hz,
Ar), 8.09 (d, 1H, J = 7.6 Hz, Ar). 13C NMR (CDCl3) δ 24.7,
28.7, 33.0, 51.9, 52.5, 52.9, 60.7, 84.5, 116.0, 116.5, 117.7,
118.5, 121.5, 123.0, 124.8, 124.9, 126.1, 130.9, 135.1, 135.3,
J2 = 2.1 Hz, CH2CHvCH2), 5.10 (dd, 1H, J1 = 16.2 Hz, J2 =
1.9 Hz, CH2CHvCH2), 5.26–5.32 (m, 2H,vCH–CHvCH2),
5.82–5.95 (m, 1H, CH2CHvCH2), 6.73–6.85 (m, 1H,vCH–
CHvCH2), 6.97–7.01 (m, 3H, Ar), 7.16–7.22 (m, 1H,vCH–
CHvCH2), 7.74 (d, 1H, J = 8.2 Hz, Ar). 13C NMR (CDCl3) δ
28.4, 35.5, 43.1, 46.3, 50.9, 52.8, 55.7, 82.7, 98.1, 111.6, 115.7,
116.0, 119.1, 122.6, 122.9, 127.5, 131.4, 132.7, 138.7, 140.7,
147.1, 148.9, 151.8, 166.0, 166.1. IR (NaCl): 1731, 1702 cm−1
.
Anal. Calcd for C27H32N2O6: C, 67.48; H, 6.71; N, 5.83. Found:
C, 67.29; H, 6.90; N, 5.77. ESI-MS: m/z = 481 [M + H]+.
Preparation of dimethyl 2-(allyl(2-(2-((E)-6-methoxy-4-(methoxy-
carbonyl)-5,6-dioxohex-1-enyl)-1-tosyl-1H-indol-3-yl)ethyl)amino)-
maleate, 4a. Following general procedure A the reaction of
2-allyl-9-tosyl-1-vinyl-2,3,4,9-tetrahydro-1H-β-carboline, 1a
(100.0 mg, 0.26 mmol) and DMAD (177.6 mg, 2.5 mmol) in
DCM (4.2 mL) at room temperature afforded after flash chrom-
atography (Hex–AcOEt 9 : 1 to 4 : 1) 70.3 mg (50%) of 2a as a
135.6, 150.9, 150.9, 167.4, 169.4. IR (NaCl): 1723, 1558 cm−1
.
Anal. Calcd for C27H32N2O6: C, 67.48; H, 6.71; N, 5.83. Found:
C, 67.56; H, 6.79; N, 5.88. ESI-MS: m/z = 481 [M + H]+.
Preparation of dimethyl (4E,7E)-3-allyl-2,3,6,9-tetrahydro-1H-
azecino[5,4-b]indole-4,5-dicarboxylate, 2c. Following general
procedure A the reaction of 5,6,11,11b-tetrahydro-3H-indolizino-
[8,7-b]indole, 1c (200.0 mg, 0.84 mmol) and DMAD (596.5 mg,
4.2 mmol) in DCM (13.4 mL) at room temperature afforded
after flash chromatography (Hex–AcOEt 9 : 1 to 4 : 1) 116.5 mg
(35%) of 2c as a light yellow oil. 1H NMR (CDCl3) δ 2.85–2.94
(m, 4H, CH2), 3.28–3.32 (m, 3H, CH2), 3.72–3.88 (m, 1H,
CH2), 3.73 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 5.07 (d, 1H, J =
10.1 Hz, CHvCH2), 5.14 (d, 1H, J = 17.1 Hz, CHvCH2),
5.53–5.63 (m, 1H, H7), 5.66–5.80 (m, 1H, CHvCH2), 6.26 (d,
1H, J = 15.0 Hz, H8), 6.29 (s, 1H, H9), 7.11–7.24 (m, 2H, Ar),
7.37 (d, 1H, J = 7.4 Hz, Ar), 7.45 (d, 1H, J = 7.0 Hz, Ar). 13C
NMR (CDCl3) δ 24.9, 32.9, 52.2, 52.9, 53.5, 60.5, 115.5, 117.9,
118.2, 119.1, 119.7, 121.4, 122.1, 124.1, 130.1, 131.3, 134.7,
136.0, 136.2, 151.2, 167.3, 169.2. IR (NaCl): 1735, 1694,
1576 cm−1. Anal. Calcd for C22H24N2O4: C, 69.46; H, 6.36; N,
7.36. Found: C, 69.58; H, 6.47; N, 7.42. ESI-MS: m/z = 381
[M + H]+.
1
yellow oil and 75.6 mg (42%) of 4a as a yellow oil. H NMR
(CDCl3) δ 2.29 (s, 3H, Ts–CH3), 2.91–3.03 (m, 4H, 2 × CH2),
3.22–3.32 (m, 4H, 2 × CH2), 3.64 (s, 3H, OCH3), 3.78, (s, 3H,
OCH3), 3.89 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.39 (t, 1H,
J = 6.9 Hz, CO–CH–COOMe), 4.68 (s, 1H, H3), 4.91 (d, 1H,
J = 17.1 Hz, CH2CHvCH2), 5.10 (d, 1H, J = 10.7 Hz,
CH2CHvCH2), 5.51–5.65 (m, 1H, CH2CHvCH2), 5.84 (dt,
1H, J1 = 16.2 Hz, J2 = 6.7 Hz, Indole–CHvCH–CH2), 6.79 (d,
1H, J = 16.2 Hz, Indole–CHvCH–CH2), 7.14 (d, 2H, J =
8.2 Hz, Ar), 7.23–7.36 (m, 2H, Ar), 7.40 (d, 1H, J = 8.0 Hz, Ar),
7.55 (d, 2H, J = 8.3 Hz, Ar), 8.19 (d, 1H, J = 8.2 Hz, Ar). 13C
NMR (CDCl3) δ 21.5 (Ts–CH3), 23.2 (br, Indole–CH2), 30.8
(CH2–CH–CO2Me), 49.9 (br, CH2–CH2–N), 50.8 (OCH3), 52.9
(OCH3), 53.0 (OCH3), 53.4 (OCH3), 53.5 (CH2–CH–CO2Me),
53.7 (br, N–CH2–CHv), 84.8 (HC(3)), 115.5 (Indole CH),
118.2 (vCH2), 118.9 (Indole CH), 119.0 (Indole C), 123.0
(Indole-CHvCH), 124.0 (Indole CH), 125.3 (Indole CH), 126.8
(Ts 2 × CH), 129.6 (Ts 2 × CH), 130.5 (Indole C), 131.5
(Indole–CHvCH), 131.6 (CHvCH2), 135.1 (Indole C), 135.3
(Ts C), 136.2 (Indole C), 144.7 (Ts C), 153.7 (C2), 160.6
(COOMe), 165.9 (COOMe), 168.0 (COOMe), 168.8 (COOMe),
188.2 (CvO). IR (NaCl): 1735, 1576 cm−1. Anal. Calcd for
C35H38N2O11S: C, 60.51; H, 5.51; N, 4.03. Found: C, 60.95; H,
5.70; N, 4.19. ESI-MS: m/z = 695 [M + H]+.
Preparation of dimethyl 1-tosyl-1′-allyl-2-(prop-2-en-1-ylidene)-
1,2,5′,6′-tetrahydro-1′H-spiro[indole-3,4′-pyridine]-2′,3′-dicarboxy-
late, 3a. Following general procedure A the reaction of 2-allyl-
9-tosyl-1-vinyl-2,3,4,9-tetrahydro-1H-β-carboline, 1a (250.0 mg,
0.64 mmol) and DMAD (0.16 mL, 1.28 mmol) in DCM
(10 mL) at room temperature afforded after flash chromatography
(Hex–AcOEt 9 : 1 to 4 : 1) 33 mg (10%) of 2a as a yellow oil
and 83 mg (24%) of 3a as a yellow oil.9
Preparation of dimethyl 2-(allyl(2-(1-(tert-butoxycarbonyl)-2-
((E)-6-methoxy-4-(methoxycarbonyl)-5,6-dioxohex-1-enyl)-1H-
indol-3-yl)ethyl)amino)maleate, 4b. A solution of dimethyl
(4E,7E)-3-allyl-9-(4-(tert-butoxycarbonyl)-2,3,6,9-tetrahydro-
1H-azecino[5,4-b]indole-4,5-dicarboxylate, 2b (31.0 mg,
0.064 mmol) in anhydrous DCM (16 mL mmol−1), DMAD
(45.8 mg, 0.323 mmol) and silica gel (35 mg) were added at
room temperature. After 6 h stirring the reaction mixture was
filtered and the solvent was eliminated under reduced pressure.
The resulting mixture was purified by flash chromatography on
silica gel (Hex–AcOEt 2 : 1), obtaining 39.1 mg (95%) of 4b as
a yellow oil. 1H NMR (CDCl3) δ 1.69 (s, 9H, C(CH3)3),
2.91–2.98 (m, 2H, CH2), 2.99–3.06 (m, 2H, CH2), 3.34–3.38
(m, 2H, CH2), 3.67 (s, 3H, OCH3), 3.71 (bs, 2H, CH2), 3.78 (s,
3H, OCH3), 3.93 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.36 (t,
1H, J = 4.3 Hz, CO–CH–COOMe), 4.76 (s, 1H, H1), 5.16 (d,
Preparation of (Z)-dimethyl 1′-allyl-2-allylidene-1-(4-tert-
butoxycarbonyl)-2′,3′-dihydro-1′H-spiro[indoline-3,4′-pyridine]-
5′,6′-dicarboxylate, 3b. Following general procedure A the reac-
tion of 2-allyl-9-(tert-butoxycarbonyl)-1-vinyl-2,3,4,9-tetrahy-
dro-1H-β-carboline, 1b (110.0 mg, 0.30 mmol) and DMAD
(426.3 mg, 3.00 mmol) in DCM (4.6 mL) at room temperature
afforded after flash chromatography (Hex–AcOEt 9 : 1 to 4 : 1)
39.5 mg (25%) of 2b as a yellow oil, 33.8 mg (20%) of 3b as a
1
yellow oil and 82.5 mg (40%) of 4b as a yellow oil. H NMR
(CDCl3) δ 1.65 (s, 9H, C(CH3)3), 1.80 (dt, 1H, J1 = 13.7 Hz, J2
= 3.5 Hz, CH2CH2N), 2.22–2.32 (m, 1H, CH2CH2N), 3.14–3.22
(m, 1H, CH2CH2N), 3.34 (s, 3H, OCH3), 3.43 (td, 1H, J1
=
13.0 Hz, J2 = 3.5 Hz, CH2CH2N), 3.80 (t, 2H, J = 4.5 Hz,
CH2CHvCH2), 3.91 (s, 3H, OCH3), 4.99 (dd, 1H, J1 = 9.7 Hz,
7172 | Org. Biomol. Chem., 2012, 10, 7167–7176
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1H, J = 10.3 Hz, CH2CHvCH2), 5.22 (d, 1H, J = 5.6 Hz,
CH2CHvCH2), 5.71–5.84 (m, 2H, CH2CHvCH2 and Indole–
CHvCH–CH2), 6.72 (d, 1H, J = 9.6 Hz, Indole-CHvCH–
CH2), 7.26–7.33 (m, 2H, Ar), 7.52 (d, 1H, J = 4.4 Hz, Ar), 8.09
(d, 1H, J = 4.8 Hz, Ar). 13C NMR (CDCl3) δ 21.0, 28.3, 30.9,
50.8, 52.7, 52.8, 52.9, 53.3, 53.4, 53.8, 84.0, 84.9, 115.6, 116.1,
117.8, 118.0, 118.6, 122.8, 124.7, 124.9, 128.9, 129.6, 134.8,
135.5, 150.3, 153.9, 160.7, 166.0, 168.1, 168.9, 188.1. IR
(NaCl): 1735, 1694, 1576 cm−1. Anal. Calcd for C33H40N2O11:
C, 61.86; H, 6.29; N, 4.37. Found: C, 61.97; H, 6.41; N, 4.49.
ESI-MS: m/z = 641 [M + H]+.
C), 135.7 (Ts C), 136.3 (Indole C), 144.7 (Ts C), 153.8 (C2),
165.9 (COOMe), 168.1 (COOMe), 173.3 (COOMe). IR (NaCl):
1738, 1696, 1642 cm−1. Anal. Calcd for C32H36N2O8S: C,
63.14; H, 5.96; N, 4.60. Found: C, 63.05; H, 5.91; N, 4.52.
ESI-MS: m/z = 631 [M + Na]+.
General procedure C for the reaction of 11-tosyl-5,6,11,11b-
tetrahydro-3H-indolizino[8,7-b]indole 8 with internal alkynes
To a solution of 11-tosyl-5,6,11,11b-tetrahydro-3H-indolizino-
[8,7-b]indole 7 (1.0 mmol) in anhydrous DCM (16 mL mmol−1
)
was added via a syringe the alkyne (5.0 mmol) at room
temperature. The reaction mixture was stirred for 48 h, and
the solvent was eliminated under reduced pressure. The
resulting mixture was purified by flash chromatography on
silica gel.
Preparation of dimethyl (E)-2-(9-tosyl-1-vinyl-1,3,4,9-tetra-
hydro-2H-β-carbolin-2-yl)but-2-enedioate, 5a. Following general
procedure B the reaction of 2-allyl-9-tosyl-1-vinyl-2,3,4,9-tetra-
hydro-1H-β-carboline, 1a (100.0 mg, 0.26 mmol), DMAD
(753.2 mg, 1.27 mmol) and AuCl3 (3.9 mg, 0.013 mmol) in
DCM (4.2 mL mmol−1) at 0 °C afforded after flash chromato-
graphy (Hex–AcOEt 9 : 1 to 4 : 1) 28.1 mg (20%) of 2a as a
General procedure D for the reaction 11-tosyl-5,6,11,11b-
tetrahydro-3H-indolizino[8,7-b]indole 8 with internal alkynes
1
yellow oil and 70.6 mg (55%) of 5a as a yellow oil. H NMR
(CDCl3) δ 2.17 (s, 3H, CH3), 2.65 (dd, 1H, J1 = 16.2 Hz, J2 =
3.6 Hz, CH2CH2N), 2.87–2.98 (m, 1H, CH2CH2N), 3.42–3.67
(m, 2H, CH2CH2N), 3.68 (s, 3H, OCH3), 4.00 (s, 3H, OCH3),
5.03 (s, 1H, HCvC), 5.05 (dd, 1H, J1 = 17.8 Hz, J2 = 1.1 Hz,
CHvCH2), 5.36 (dd, 1H, J1 = 10.4 Hz, J2 = 0.8 Hz,
CHvCH2), 5.78 (bs, 1H, H4), 6.10–6.21 (m, 1H, CHvCH2),
7.17–7.35 (m, 5H, Ar), 7.62 (d, 2H, J = 8.5 Hz, Ar), 8.06
(d, 1H, J = 8.1 Hz, Ar). 13C NMR (CDCl3) δ 21.9, 30.7, 31.3,
51.4, 53.6, 86.4, 115.5, 119.0, 119.3, 124.3, 125.6, 125.9, 127.1,
127.9, 129.7, 130.0, 130.3, 132.5, 135.1, 137.0, 145.4, 154.4,
166.5, 168.6. IR (NaCl): 1731, 1690, 1572 cm−1. Anal. Calcd
for C26H26N2O6S: C, 63.14; H, 5.30; N, 5.66. Found: C, 63.09;
H, 5.75; N, 6.39. ESI-MS: m/z = 495 [M + H]+.
To a solution of the alkyne (5 mmol) and gold trichloride
(0.05 mmol) in 8 mL of anhydrous DCM at 0 °C was added via
a syringe the 11-tosyl-5,6,11,11b-tetrahydro-3H-indolizino[8,7-b]-
indole in 8 mL of DCM. The reaction was controlled by t.l.c.,
and upon disappearance of the starting materials it was filtered
through Celite and extracted with water (15 mL), brine (15 mL)
and dried over MgSO4. The solvent was eliminated under
reduced pressure. The resulting mixture was purified by flash
chromatography on silica gel.
Preparation of dimethyl (9E,11Z)-8-tosyl-8,14-diazatetracyclo-
[12,2,2,01,9,02,7]octadeca-2,4,6,9,11,15-hexaen-15,16-dicarboxylate,
9a. Following general procedure D the reaction of 11-tosyl-
5,6,11,11b-tetrahydro-3H-indolizino[8,7-b]indole, 8 (100.0 mg,
0.27 mmol), gold trichloride (4.1 mg, 0.013 mmol) and DMAD
(191.8 mg, 1.35 mmol) in DCM (4.3 mL) at room temperature
afforded after flash chromatography (Hex–AcOEt 9 : 1) 61.0 mg
Preparation of dimethyl 2-(allyl(2-(2-((E)-5-methoxy-5-oxopent-
1-enyl)-1-tosyl-1H-indol-3-yl)ethyl)amino)maleate, 7. To a sol-
ution of dimethyl 2-(allyl(2-(2-((E)-6-methoxy-4-(methoxycar-
bonyl)-5,6-dioxohex-1-enyl)-1-tosyl-1H-indol-3-yl)ethyl)amino)-
maleate, 4a (70.0 mg, 0.10 mmol) in DCM (5 mL) at room
temperature, 5 mL of 1 N NaOH were added and the mixture
was extracted after 5 min stirring. The solvent was dried over
MgSO4 and eliminated under reduced pressure to give 48.3 mg
1
(58%) of 9a as a brown oil. H NMR (CDCl3) δ 0.04–0.10 (m,
1H, CH2CH2N), 1.51–1.62 (m, 1H, CH2CH2N), 2.35 (s, 3H,
CH3), 3.03–3.09 (m, 2H, CH2CH2N), 3.24 (s, 3H, OCH3),
3.53–3.70 (m, 2H,vCCH2N), 3.77 (s, 3H, OCH3), 5.45 (dd,
1H, J1 = 14.6 Hz, J2 = 2.9 Hz, H12), 5.98 (t, 1H, J = 12.5 Hz,
H11), 6.76 (d, 1H, J = 7.3 Hz, Ar), 6.88 (d, 1H, J = 9.7 Hz,
H10), 7.07 (t, 1H, J = 7.8 Hz, Ar), 7.16 (d, 2H, J = 7.8 Hz, Ar),
7.27 (t, 1H, J = 8.8 Hz, Ar), 7.51 (d, 2H, J = 8.3 Hz, Ar), 7.88
(d, 1H, J = 7.8 Hz, Ar). 13C NMR (CDCl3) δ 21.6, 35.0, 46.5,
47.4, 51.3, 52.7, 53.0, 116.8, 118.3, 121.2, 121.7, 122.1, 125.3,
127.3, 128.0, 128.4, 129.3, 134.7, 136.5, 139.5, 141.4, 144.8,
147.8, 166.8, 167.2. IR (NaCl) 1730, 1620 cm−1. Anal. Calcd
for C27H26N2O6S: C, 64.02; H, 5.17; N, 5.53. Found: C, 63.92;
H, 5.02; N, 5.74. ESI-MS: m/z = 529 [M + Na]+.
1
of 7 (80%) as a yellow oil. H NMR (CDCl3) δ 2.23 (s, 3H,
CH3), 2.53–2.61 (m, 4H, 2 × CH2), 2.84–2.88 (m, 2H, CH2),
3.16–3.25 (m, 4H, 2 × CH2), 3.57 (s, 3H, OCH3), 3.65, (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 4.59 (s, 1H, H1), 4.84 (d, 1H, J =
17.1 Hz, CH2CHvCH2), 5.03 (d, 1H,
J = 10.2 Hz,
CH2CHvCH2), 5.43–5.65 (m, 1H, CH2CHvCH2), 5.70–5.80
(dt, 1H, J1 = 16.2 Hz, J2 = 6.0 Hz, Indole–CHvCH–CH2), 6.67
(d, 1H, J = 16.2 Hz, Indole-CHvCH–CH2), 7.05 (d, 2H, J =
8.1 Hz, Ar), 7.16–7.33 (m, 3H, Ar), 7.50 (d, 2H, J = 8.1 Hz,
Ar), 8.15 (d, 1H, J = 8.1 Hz, Ar). 13C NMR (CDCl3) δ 21.5
(Ts–CH3), 22.7 (br, Indole-CH2), 28.3 (MeO2C–CH2–CH2),
33.2 (CH2–CH2–CO2Me), 49.7 (br, CH2–CH2–N), 50.8 (OCH3),
51.8 (OCH3), 52.9 (OCH3), 53.6 (br, N–CH2–CHv), 84.7 (HC-
(3)), 115.4 (Indole CH), 118.2 (Indole C), 118.3 (vCH2), 118.8
(Indole CH), 121.0 (Indole-CHvCH), 131.5 (CHvCH2), 123.9
(Indole CH), 125.2 (Indole CH), 126.8 (Ts 2 × CH), 129.5 (Ts 2
× CH), 130.5 (Indole C), 135.4 (Indole-CHvCH), 135.6 (Indole
Preparation of diethyl (9E,11Z)-8-tosyl-8,14-diazatetracyclo-
[12,2,2,01,9,02,7]octadeca-2,4,6,9,11,15-hexaen-15,16-dicarboxylate,
9b. Following general procedure D the reaction of 11-tosyl-
5,6,11,11b-tetrahydro-3H-indolizino[8,7-b]indole, 8 (100.0 mg,
0.27 mmol), gold trichloride (4.1 mg, 0.013 mmol) and diethyl
but-2-ynedioate (233.4 mg, 1.35 mmol) in DCM (4.3 mL) at
room temperature afforded after flash chromatography (Hex–
This journal is © The Royal Society of Chemistry 2012
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1
AcOEt 9 : 1) 70.5 mg (49%) of 9b as a brown oil. H NMR
58.7, 71.6, 75.3, 115.5, 118.7, 123.1, 123.6, 125.5, 126.2,
129.3, 129.6, 132.3, 136.1, 137.9, 144.3, 145.1, 146.6, 161.1,
(CDCl3) δ −0.04–0.01 (m, 1H, CH2CH2N), 0.60 (t, 3H, J =
7.2 Hz, OCH2CH3), 1.15–1.22 (m, 3H, OCH2CH3), 1.45–1.56
(m, 1H, CH2CH2N), 2.27 (s, 3H, CH3), 2.95–3.01 (m, 2H,
CH2CH2N), 3.44–3.54 (m, 1H,vCCH2N), 3.58–3.66 (m, 1H,v
CCH2N), 4.10–4.25 (m, 3H, OCH2CH3), 4.59–4.73 (m, 1H,
OCH2CH3), 5.37 (dd, 1H, J1 = 14.6 Hz, J2 = 3.8 Hz, H12), 5.90
(t, 1H, J = 12.3 Hz, H11), 6.72 (dd, 1H, J1 = 7.5 Hz, J2 = 0.7
Hz, Ar), 6.79 (d, 1H, J = 10.2 Hz, H10), 6.98 (t, 1H, J = 7.5 Hz,
Ar), 7.08 (d, 2H, J = 8.0 Hz, Ar), 7.16–7.22 (m, 1H, Ar), 7.43
(d, 2H, J = 8.2 Hz, Ar), 7.79 (d, 1H, J = 8.2 Hz, Ar). 13C NMR
(CDCl3) δ 13.4, 13.9, 21.6, 35.1, 46.6, 47.5, 52.7, 60.2, 62.0,
116.8, 118.2, 121.6, 121.8, 125.3, 127.4, 127.9, 128.5, 129.3,
129.9, 134.8, 136.9, 139.8, 141.7, 144.8, 148.1, 165.3, 165.5. IR
(NaCl): 1732, 1597 cm−1. Anal. Calcd for C29H30N2O6S: C,
65.15; H, 5.66; N, 5.24. Found: C, 65.31; H, 5.43; N, 5.54.
ESI-MS: m/z = 557 [M + Na]+.
161.6, 171.5, 172.8. IR (NaCl) ν 1740, 1650, 1590 cm−1
.
Anal. Calcd for C33H32N2O10S (648.68): C, 61.10; H, 4.97;
N, 4.32. Found: C, 60.87; H, 5.16; N, 4.08. ESI-MS: m/z = 649
[M + H]+.
Preparation of tetraethyl (2S*,2bS*,9bS*,11aS*,11bR*)-
9-tosyl-1,2,2a,3,4,9,11a,11b-octahydro-2b,9-diazadicyclobuta[a,c]-
indeno[2,3-e]indene-2,2a,10,11-tetracarboxylate, 10b. Following
general procedure C the reaction of 11-tosyl-5,6,11,11b-tetra-
hydro-3H-indolizino[8,7-b]indole, 8 (52 mg, 0.15 mmol) and
diethyl but-2-ynedioate (173.8 mg, 0.77 mmol) in DCM
(2.4 mL) at room temperature afforded after flash chromato-
graphy (Hex–AcOEt 4 : 1 to 2 : 1) 63.4 mg (60%) of 10b as a
brown oil. 1H NMR (CDCl3) δ 1.01 (t, 3H, J = 7.2 Hz,
OCH2CH3), 1.17–1.28 (m, 6H, 2 × OCH2CH3), 1.38 (t, 3H, J =
7.2 Hz, OCH2CH3), 1.90–2.00 (m, 1H, H1), 2.29 (s, 3H, CH3),
2.29–2.43 (m, 1H, H1), 2.77 (dt, 1H, J1 = 15.8 Hz, J2 = 2.5 Hz,
H4), 2.85–2.97 (m, 2H, H4 and H11b), 3.43–3.53 (m, 3H, 2 ×
H3 and H2), 3.68–3.88 (m, 2H, OCH2CH3), 4.00–4.17 (m, 4H,
2 × OCH2CH3), 4.27 (s, 1H, H11a), 4.32 (q, 2H, J = 7.2 Hz,
OCH2CH3), 7.09 (d, 2H, J = 8.2 Hz, Ar), 7.28–7.37 (m, 3H,
Ar), 7.46 (d, 2H, J = 8.5 Hz, Ar), 8.26 (d, 1H, J = 7.7 Hz, Ar).
13C NMR (CDCl3) δ 13.8, 13.9, 14.2, 14.3, 21.5, 23.1, 25.4,
37.8, 39.9, 45.1, 58.7, 60.3, 60.7, 60.8, 61.0, 71.8, 74.7, 115.7,
118.7, 123.2, 123.7, 125.5, 126.3, 129.3, 129.6, 132.8, 136.4,
138.0, 144.3, 145.1, 147.0, 160.8, 161.5, 171.0, 172.6. IR
Preparation of di-tert-butyl (9E,11Z)-8-tosyl-8,14-diazatetra-
cyclo-[12,2,2,01,9,02,7]octadeca-2,4,6,9,11,15-hexaen-15,16-dicarboxy-
late, 9c. Following general procedure D the reaction of 11-tosyl-
5,6,11,11b-tetrahydro-3H-indolizino[8,7-b]indole, 8 (82.5 mg,
0.23 mmol), gold trichloride (3.8 mg, 0.011 mmol) and di-tert-
butyl but-2-ynedioate (256.1 mg, 1.13 mmol) in DCM (3.7 mL)
at 0 °C afforded after flash chromatography (Hex–AcOEt 9 : 1 to
4 : 1) 53.3 mg (39%) of 9c as a yellow solid (mp: 157–160 °C).
1H NMR (CDCl3) δ −0.06–0.00 (m, 1H, CH2CH2N), 0.98 (s,
9H, C(CH3)3), 1.47 (s, 9H, C(CH3)3), 1.47–1.52 (m, 1H,
CH2CH2N), 2.34 (s, 3H, CH3), 2.98–3.03 (m, 2H, CH2CH2N),
3.52 (dd, 1H, J1 = 19.6 Hz, J2 = 1.5 Hz,vCCH2N), 3.72 (dd,
1H, J1 = 19.9 Hz, J2 = 5.2 Hz,vCCH2N), 5.41 (dd, 1H, J1 =
14.6 Hz, J2 = 3.8 Hz, H12), 5.95 (t, 1H, J = 14.5 Hz, H11), 6.84
(d, 1H, J = 11.2 Hz, H10), 6.85 (d, 1H, J = 7.3 Hz, Ar), 7.07
(td, 1H, J1 = 7.4 Hz, J2 = 0.9 Hz, Ar), 7.14 (d, 2H, J = 8.0 Hz,
Ar), 7.27 (td, 1H, J1 = 7.9 Hz, J2 = 1.3 Hz, Ar), 7.50 (d, 2H, J =
8.3 Hz, Ar), 7.87 (d, 1H, J = 8.0 Hz, Ar). 13C NMR (CDCl3) δ
21.6, 27.5, 27.5, 34.8, 46.5, 47.4, 52.6, 80.1, 82.4, 113.8, 116.4,
118.2, 121.5, 122.1, 125.4, 127.4, 127.6, 128.6, 129.3, 134.8,
137.8, 139.9, 142.3, 144.7, 149.3, 164.7, 164.9. IR (KBr): 1732,
1597 cm−1. Anal. Calcd for C33H38N2O6S: C, 67.10; H, 6.48;
N, 4.74. Found: C, 67.21; H, 6.32; N, 4.54. ESI-MS: m/z = 613
[M + Na]+.
(NaCl): 1726, 1645, 1555 cm−1
.
Anal. Calcd for
C37H40N2O10S: C, 63.05; H, 5.72; N, 3.97. Found: C, 63.19; H,
5.84; N, 4.01. ESI-MS: m/z = 703 [M + H]+.
Preparation of tetra-tert-butyl (2S*,2bS*,9bS*,11aS*,11bR*)-
9-tosyl-1,2,2a,3,4,9,11a,11b-octahydro-2b,9-diazadicyclobuta[a,c]-
indeno[2,3-e]indene-2,2a,10,11-tetracarboxylate, 10c. Following
general procedure C the reaction of 11-tosyl-5,6,11,11b-tetra-
hydro-3H-indolizino[8,7-b]indole, 8 (80 mg, 0.22 mmol) and di-
tert-butyl but-2-ynedioate (182.0 mg, 1.08 mmol) in DCM
(3.6 mL) at room temperature afforded after flash chromato-
graphy (Hex–AcOEt 20 : 1 to 9 : 1) 75.5 mg (42%) of 10c as a
1
brown oil. H NMR (CDCl3) δ 1.06 (s, 9H, C(CH3)3), 1.44 (s,
9H, C(CH3)3), 1.46 (s, 9H, C(CH3)3), 1.55 (s, 9H, C(CH3)3),
1.76–1.85 (m, 1H, H1), 2.18–2.27 (m, 1H, H1), 2.27 (s, 3H,
CH3), 2.72 (dd, 1H, J1 = 15.5 Hz, J2 = 5.1 Hz, H4), 2.81–2.92
(m, 2H, H4 and H11b), 3.27–3.49 (m, 3H, 2 × H3 and H2), 4.23
(s, 1H, H11a), 7.12 (d, 2H, J = 8.0 Hz, Ar), 7.22–7.33 (m, 2H,
Ar), 7.38–7.41 (m, 1H, Ar), 7.57 (d, 2H, J = 8.3 Hz, Ar), 8.20
(d, 1H, J = 7.9 Hz, Ar). 13C NMR (CDCl3) δ 21.9, 23.1, 28.1,
28.4, 28.5, 28.6, 30.1, 32.0, 37.7, 46.6, 58.8, 72.4, 75.5, 80.9,
81.2, 81.8, 81.9, 116.2, 118.9, 123.3, 123.9, 125.5, 126.9, 130.1,
130.4, 134.1, 136.7, 138.2, 144.7, 147.3, 149.0, 160.3, 161.0,
171.2, 173.1. IR (NaCl): 1731, 1696 cm−1. Anal. Calcd for
C45H56N2O10S: C, 66.15; H, 6.91; N, 3.43. Found: C, 66.21; H,
6.82; N, 3.54. ESI-MS: m/z = 817 [M + H]+.
Preparation of tetramethyl (2S*,2bS*,9bS*,11aS*,11bR*)-
9-tosyl-1,2,2a,3,4,9,11a,11b-octahydro-2b,9-diazadicyclobuta[a,c]-
indeno[2,3-e]indene-2,2a,10,11-tetracarboxylate, 10a. Following
general procedure C the reaction of 11-tosyl-5,6,11,11b-tetra-
hydro-3H-indolizino[8,7-b]indole, 8 (100 mg, 0.27 mmol) and
DMAD (194.7 mg, 1.37 mmol) in DCM (4.3 mL) at room temp-
erature afforded after flash chromatography (Hex–AcOEt 4 : 1 to
1
2 : 1) 110.4 mg (65%) of 10a as a brown oil. H NMR (CDCl3)
δ (ppm): 1.92–2.01 (m, 1H, H1), 2.32 (s, 3H, CH3), 2.39–2.48
(m, 1H, H1), 2.79 (dd, 1H, J1 = 16.1 Hz, J2 = 4.4 Hz, H4),
2.87–2.99 (m, 2H, H4 and H11b), 3.37–3.42 (m, 3H, 2 × H3
and H2), 3.44 (s, 3H, CH3), 3.63 (s, 3H, CH3), 3.69 (s,
3H, CH3), 3.88 (s, 3H, CH3), 4.25 (s, 1H, H11a), 7.11 (d, 2H,
J = 8.5 Hz, Ar), 7.30–7.38 (m, 2H, Ar), 7.42–7.49 (m, 3H, Ar),
8.26 (d, 1H, J = 7.9 Hz, Ar). 13C NMR (CDCl3) δ (ppm):
21.4, 22.8, 25.3, 37.9, 40.1, 44.8, 51.4, 51.8, 51.9, 52.0,
Preparation of methyl (2Z and 2E)-2-[11-(tosyl)-6,11-dihydro-
5H-indolizino[8,7-b]indol-3-yl]-but-2-enedioate, Z-11 and E-12.
To a solution of 11-tosyl-6,11-dihydro-5H-indolizino[8,7-b]-
indole, 11 (64.1 mg, 0.18 mmol) in anhydrous DCM (3.0 mL)
DMAD (125.7 mg, 0.88 mmol) was added via a syringe at room
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temperature. The reaction mixture was stirred for 3 h. The
solvent was eliminated under reduced pressure and the resulting
mixture was purified by flash chromatography on silica gel
(Hex–AcOEt 9 : 1 to 4 : 1) to yield 43.7 mg (48%) of E-12 as a
red oil and 12 mg (13%) of Z-12 as an orange oil. Data for
Notes and references
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1
E-12: H NMR (CDCl3) δ 2.27 (s, 3H, CH3), 2.82 (t, 2H, J =
6.7 Hz, CH2CH2N), 3.68 (s, 3H, OCH3), 3.72 (t, 2H, J = 6.7 Hz,
CH2CH2N), 3.85 (s, 3H, OCH3), 6.33 (d, 1H, J = 4.1 Hz, H1),
7.05 (s, 1H, HCv), 7.06 (d, 2H, J = 8.2 Hz, Ar), 7.08 (d, 1H,
J = 4.1 Hz, H2), 7.23–7.32 (m, 3H, Ar), 7.45 (d, 2H, J = 8.3 Hz,
Ar), 8.26 (d, 1H, J = 9.4 Hz, Ar). 13C NMR (CDCl3) δ 21.6,
29.7, 42.2, 52.0, 53.1, 110.8, 112.6, 116.9, 117.5, 118.0, 124.5,
124.7, 125.3, 126.3, 126.9, 128.4, 129.3, 129.7, 129.9, 134.2,
134.6, 138.3, 144.4, 165.4, 166.4. IR (NaCl): 1722, 1595 cm−1
.
Anal. Calcd for C27H24N2O6S: C, 64.27; H, 4.79. Found: C,
64.32; H, 4.62; N, 6.61. ESI-MS: m/z = 527 [M + Na]+ Data for
1
Z-12: H NMR (CDCl3) δ 2.28 (s, 3H, CH3), 2.90 (t, 2H, J =
6.9 Hz, CH2CH2N), 3.79 (s, 3H, OCH3), 3.96 (s, 3H, OCH3),
4.13 (t, 2H, J = 6.8 Hz, CH2CH2N), 5.86 (s, 1H, HCv), 6.54
(d, 1H, J = 4.4 Hz, H1), 7.05 (d, 2H, J = 8.0 Hz, Ar), 7.10 (d,
1H, J = 4.2 Hz, H2), 7.26–7.34 (m, 3H, Ar), 7.40 (d, 2H, J =
8.3 Hz, Ar), 7.27 (d, 1H, J = 9.2 Hz, Ar). 13C NMR (CDCl3) δ
21.6, 29.7, 41.7, 52.0, 53.0, 112.1, 113.9, 115.8, 116.9, 118.4,
119.1, 124.7, 125.4, 126.7, 127.8, 128.4, 128.8, 129.3, 129.4,
134.1, 138.6, 139.9, 144.7, 165.5, 167.8. IR (NaCl): 1743,
1791, 1597 cm−1. Anal. Calcd for C27H24N2O6S: C, 64.27; H,
4.79; N, 5.55. Found: C, 64.21; H, 4.83; N, 6.73. ESI-MS: m/z =
527 [M + Na]+.
4-(1,2-Bis-ethoxycarbonyl-vinyl)-11-(toluene-4-sulfonyl)-5,6,11,11b-
tetrahydro-3H-indolizino[8,7-b]indol-4-ium chloride, 13. Fol-
lowing general procedure D the reaction of 11-tosyl-5,6,11,11b-
tetrahydro-3H-indolizino[8,7-b]indole, 7 (50.0 mg, 0.14 mmol),
gold trichloride (12.3 mg, 0.039 mmol) and diethyl but-2-yne-
dioate (117.7 mg, 0.67 mmol) in DCM (2.3 mL) at 0 °C afforded
after flash chromatography (Hex–AcOEt 9 : 1 to 4 : 1) 17.5 mg
(25%) of 9b as a brown oil and 31 mg (42%) of 13 as a yellow
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1
solid (mp: 76 °C, dec). H NMR (CDCl3) δ 1.27–1.29 (m, 3H,
OCH2CH3), 1.44 (t, 3H, J = 4.3 Hz, OCH2CH3), 2.35 (s, 3H,
CH3), 2.68 (dd, 1H, J1 = 16.0 Hz, J2 = 4.1 Hz, H6), 3.03–3.09
(m, 1H, H6), 3.53–3.59 (m, 1H, H5), 3.66 (dd, 1H, J1 = 14.2
Hz, J2 = 5.7 Hz, H5), 4.13–4.18 (m, 2H, OCH2CH3), 4.21–4.36
(m, 2H, 2 × H3), 4.44–4.56 (m, 2H, OCH2CH3), 5.03 (s,
1H,vCHCO2Et), 5.76–5.88 (m, 2H, H1 and H2), 5.90 (d, 1H,
J = 5.3 Hz, H11b), 7.23–7.25 (m, 2H, Ar), 7.26–7.29 (m,
1H, Ar), 7.32–7.39 (m, 2H, Ar), 7.71 (d, 2H, J = 8.5 Hz, Ar),
8.05 (d, 1H, J = 8.2 Hz, Ar). 13C NMR (CDCl3) δ 14.4,
14.9, 22.0, 30.1, 39.9, 60.1, 63.1, 68.6, 88.6, 115.3, 118.8,
119.2, 119.7, 124.4, 125.8, 127.2, 129.6, 130.0, 130.4, 130.6,
134.0, 135.2, 136.8, 145.6, 153.8, 165.9, 167.7. IR (KBr): 2982,
2927, 2871, 1375, 1699, 1575 cm−1
. Anal. Calcd for
C29H31ClN2O6S: C, 60.99; H, 5.47; Cl, 6.21; N, 4.91. Found
C, 61.15; H, 5.60; Cl, 6.31; N, 5.02. ESI-MS: m/z = 593
[M + Na]+.
Funding of this project by Spanish MEC (No. CTQ2009-
07738/BQU) is acknowledged. S.M. thanks FUSP-CEU for a
pre-doctoral fellowship. We thank Dr Ulises Amador for help
with X-ray analysis.
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PtCl2 which resulted in a sluggish crude from which 40% of 8a was iso-
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a catalyst for selective organic
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7176 | Org. Biomol. Chem., 2012, 10, 7167–7176
This journal is © The Royal Society of Chemistry 2012