Novel chemistry of β-carbolines. Expedient synthesis of polycyclic scaffolds

Article abstract of DOI:10.1016/j.tet.2009.02.051

Functionalization of β-carbolines is a challenge as numerous natural alkaloids with different biological activities present this heterocycle. The RCM is used herein with allyl-, vinyl-, ethynyl-, and propargyl-β-carbolines to generate additionally fused h

Full text of DOI:10.1016/j.tet.2009.02.051

Tetrahedron 65 (2009) 3378–3391
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel chemistry of
b-carbolines. Expedient synthesis of polycyclic scaffolds
´
*
´
´
´
´
Alvaro Gonzalez-Gomez, Gema Domınguez, Javier Perez-Castells
Departamento de Qu´ımica, Facultad de Farmacia, Universidad San Pablo-CEU, Urb. Montepr´ıncipe, Boadilla del Monte, 28668 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 January 2009
Received in revised form 20 February 2009
Accepted 20 February 2009
Available online 27 February 2009
Functionalization of b-carbolines is a challenge as numerous natural alkaloids with different biological
activities present this heterocycle. The RCM is used herein with allyl-, vinyl-, ethynyl-, and propargyl-b-
carbolines to generate additionally fused hetero- and carbocycles, and it is combined with other cycli-
zation processes to achieve great molecular complexity in one synthetic step. Thus, an RCM–Diels–Alder
sequence gives pentacyclic compounds related with certain alkaloids. On the other hand, vinyl-
pyrrolo[2,1-a]-b-carbolines and vinyl-b-carbolines give different products upon reaction with activated
dienophiles. Thus, a novel domino processes affords complex polycycles like 35–38. Other alkynes like
3-butyn-2-one give a Stevens rearrangement.
Keywords:
Metathesis
b-Carbolines
Ó 2009 Elsevier Ltd. All rights reserved.
Domino reactions
Rearrangements
Diels–Alder
1. Introduction
drug. In addition to these important natural products, many
groups have designed new
drugs for the treatment of various diseases. Some synthetic
-carbolines present antineoplasic activity,2 others show antima-
larial and antiparasite activities3 while certain
-carbolines
inhibited TNF-a4 or MK2.5 A new class of mGluR1 antagonists was
designed bearing tricyclic
-carboline template.6 Bromo
-carbolines were also described as neu-
b-carboline derivatives as potential
The
b-carboline structure is found abundantly in naturally
occurring compounds as part of numerous alkaloids, which often
exhibit biological activity. The interest in these compounds de-
mands efficient synthetic methodologies, for the construction of
the heterocyclic system and for its functionalization.1 Natural
b
b
a
b
b
-carboline containing compounds can be classified into two
substituted tetrahydro-
b
groups: first those of low molecular weight, like the harman
family, including eudistomines and manzamines, or canthines,
with an additional fused cycle (Fig. 1). Initially known for their
potent psychoactive and hallucinogen abilities, harmane, harmine,
rotoxic agents.7
The metathesis reaction is a powerful method to generate
different sized hetero- and carbocycles.8 This reaction can serve
to construct
examples of ring-closing metathesis (RCM) involving
containing substrates were performed on -carbolines bearing
enamines.9 Recently, this reaction was used for the synthesis of
azabicyclo[m.n.1]alkenes (m¼3–5; n¼2–3) including some
carbolines,10 but RCM has not been used for the total synthesis
b
-carbolines with additional heterocycles. The first
and harmaline
b
-carboline alkaloids like (þ)-harmicine, exert
b
-carboline
a wide range of pharmacological properties including antimicro-
bial and anti-HIV activities. The second group includes those more
complex systems like eburnamine, vincamine, and alkaloids from
Schizozygia species, which have varied pharmacological activities
on the cell multiplication, and cardiovascular system. This group
comprises the heteroyohimban family, which includes corynan-
theidine, ajmalicine, prescribed widely in the treatment of car-
diovascular diseases, pleiocarpamine, vobasine, and spargine
alkaloids like (þ)-vellosimine, which is used for the treatment of
b
b
-
of
b-carboline alkaloids such as those depicted in Figure 1. In
a preliminary communication of this work11 we established the
efficacy of employing RCM reactions for the construction of
fused nitrogen heterocycles, from suitable substituted 1-vinyl-b-
carbolines. When we expanded this methodology combining
RCM with the Diels–Alder cycloaddition12 we reached polycyclic
complex structures bearing natural alkaloid skeletons. In addi-
tion, with certain alkynes a new reactivity was observed leading
to products with high connectivity.13 Herein we present the
neuralgia, migraine, and hypertension. More complex b-carboline
alkaloids are yohimbine, which has been used to treat erectile
dysfunction, and reserpine, an antipsychotic and antihypertensive
complete study on the behavior of
b-carbolines bearing un-
saturated substituents in metathesis reactions and with acti-
vated dienophiles.
* Corresponding author. Tel.: þ34 913724700; fax: þ34 913510496.
´
E-mail address: jpercas@ceu.es (J. Perez-Castells).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.051

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3379
Br
H
H
N
N
O
N
N
N
N
H
N
H
H
S
H2N
O
HO
H
Me
CO2Me
(+)-vincamine
OMe
5-methoxycanthin-6-one
(+)-harmicine
(-)-eudistomin L
H
H
H
O
H
H
N
N
CHO
Me
O
H
N
Me
N
H
H
N
N
H
H
H
O
O
(+)-schizozygine
MeO2C
(-)-ajmalicine
(+)-vellosimine
N
N
MeO
H
O
H
N
H
OMe
N
H
H
H
H
H
O
OMe
OMe
MeO2C
MeO2C
OMe
OH
(+)-yohimbine
(-)-reserpine
Figure 1. Some of the most representative and bioactive
b-carboline alkaloids.
2. Results and discussion
7c reacted after 6 days with [Ru]-III giving a low yield of 16c (16%)
with traces of the expected enyne metathesis product 15c (entry
11). The formation of 16 is the result of an oxidation of 15 in the
reaction media, possibly mediated by the ruthenium catalyst. This
ability to oxidize the reaction product is a known non-metathetic
behavior of ruthenium catalysts and it is particularly observed with
complexes of type [Ru]-III.18
The synthesis of the starting enynes was accomplished from
derivatives 1–5, bearing allyl and propargyl substituents. These
substrates were easily prepared from tryptamine.14 Compounds 1–
5 were cyclized using the Bischler–Napieralski reaction, giving the
corresponding dihydro-
salts, which were reacted with an appropriate Grignard reagent. In
the case of substrates 1 and 2 the resulting -carboline was pro-
tected as tosyl, Boc or acetyl derivatives.15 These procedures
allowed us to have a group of -carboline-enynes, -dienynes, and
b-carbolines or dihydro-b-carbolinium
The RCM reaction of substrate 8, allowed us to perform
a straightforward racemic synthesis of the natural product
b
(ꢀ)-harmicine. This compound has received some synthetic at-
tention although it has never been obtained through a metathesis
reaction.19 Thus, after obtaining 17 in good yield, we hydrogenated
the double bond to give 18, and the final deprotection of the tosyl
gave the (ꢀ)-harmicine, 19.
b
-endiynes, in order to study the metathesis reaction including the
possibility of cascade metathesis (Schemes 1 and 2).
The tuning up of the metathesis reaction conditions, showed
that with [Ru]-I none of the substrates reacted. The difficulties in
performing metathesis reactions with nitrogen containing prod-
ucts are well known. The problem is their ability to coordinate to
metal–alkylidene complexes and to interfere unproductively with
catalytic activity. It is thought that efficient metathesis reactions are
only possible by conversion of the amines to the corresponding
carbamates or ammonium salts.16 However, in the case of our
substrates, [Ru]-II, and the Hoveyda–Grubbs complex Ru-[III],
were able to give the desired products, although there is a critical
dependence of the results with the substitution pattern of the
substrates. Best results were achieved in toluene, at room tem-
perature and with 5–10 mol % of catalyst (see Table 1). With sub-
strates 6a and 6b, the reactions were slow, needing at least 3 days
to complete (entries 1, 2, 4). This problem was circumvented by
performing the reaction under an ethylene atmosphere (entries 3
and 5). Ethylene is known to have a beneficial effect in metathesis
reactions.17 These conditions allowed the synthesis of 14a and 14b
in 95% and 85% yield, respectively, in only 3 h, using 5% of catalysts.
In contrast, compounds 6c and 6d did not react when using com-
plex [Ru]-III or led to extensive decomposition if [Ru]-II was used
(Scheme 1, entries 6 and 7). Metathesis reactions of 7a and 7b using
[Ru]-II catalyst gave the corresponding dienes 15a and 15b in good
yield along with small amounts of the pyrroles 16a and 16b (entries
8 and 9). The reaction of 7a with [Ru]-III was slow and after 3 days
the only product that could be isolated in moderate yield (35%,
entry 10) was 16a. On the other hand the Boc protected compound
Next we addressed the reactions of substrates 9a and 9b. Al-
though these compounds are structurally similar to the previous
ones, only the Boc protected compound 9b gave a 32% yield of the
oxidized product 20, which was unstable and could not be char-
acterized (entries 13 and 14). Compound 10 was precursor of a six-
membered ring and gave a moderated yield of the desired me-
tathesis product 21 (entry 15).
Our final aim in this study on the metathesis reactions of
b-carboline based substrates was to perform some cascade pro-
cesses. Thus, when reacting compound 11a under conditions sim-
ilar to those used above, we isolated in low yield the new
pentacyclic structure 22 (entry 16). The cascade metathesis of
compound 11a starts by the coordination of the ruthenium first
with the allyl group in position 9 of the starting material20 to give
the corresponding cascade metathesis product, which is oxidized
under the reaction medium to 22.21 This product was obtained in
better yields by raising the reaction temperature to 80 ꢁC (entry 17)
and with complex [Ru]-III, a more stable catalyst toward heat,
which was added to the reaction in 2 mol % portions every 24 h
during 3 days (entry 18). Substrate 11b did not react under any of
these reaction conditions.
In contrast to the previous substrates, compounds 12 and 13
were unreactive in the presence of these ruthenium catalysts. We
decided to transform them into less coordinating compounds, to
avoid the interaction with the catalyst (Scheme 3). First we
obtained the ammonium salts 23 and 24, by reaction of 12 and 13

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3380
1) POCl3
2)
N
Pg
N
R
R
1 = Allyl
2 = H
(1)
Pg
R
BrMg
R
RCM
N
N
3) NaH, p-TsCl, or
NaH, (BOC)2O or
Et3N, AcCl
R
14a
6a, R = H, Pg = Ts, 39%
14b
6b, R = Me, Pg = Ts, 43%
6c, R = H, Pg = Boc, 40%
6d, R = H, Pg = Ac, 63%
R1 = H
1) NaH, p-TsCl
R
NCHO
R2
2 = Allyl
2) POCl3
3)
BrMg
R
RCM
N
(2)
N
N
+
or 1) POCl3
N
Pg
N
R1
1-2
N
Pg
N
Pg
BrMg
R
2)
3) NaH, (BOC)2O
R
R
R
15a
15b
-
16a
16b
16c
7a, R = H, Pg = Ts, 54%
7b, R = Me, Pg = Ts, 44%
7c, R = H, Pg = Boc, 20%
R
1 = H
RCM
1) NaH, p-TsCl
R2 = Allyl
N
N
2) POCl3
(2)
N
Ts
N
Ts
3)
BrMg
17
8 (74%)
H2, Pd/C
N
Mes
N
Cl
Cl
N Mes
Mes
N
N Mes
PCy3
Ru
PCy3
EtONa
Cl
Cl
N
Cl
Ru
O
Ru
Ph
Cl
N
N
Ts
Ph
H
PCy3
18, 64%
[Ru]-I
[Ru]-II
[Ru]-III
( )-harmicine, 19, 94%
Scheme 1. Synthesis of b-carboline substrates 6–8 and their behavior in metathesis reactions.
1) NaH, p-TsCl
2) POCl3
3)
BrMg
RCM
RCM
N
N
or
N
Boc
N
Pg
1) POCl3
2)
3) NaH, (BOC)2O
R1 = H
BrMg
R2
=
CH2
9a, Pg = Ts, 51%
9b, Pg = Boc, 46%
20
(3)
1) NaH, p-TsCl
2) POCl3
N
N
NCHO
R2
N
Ts
N
Ts
3)
BrMg
N
R1
3-5
10 (51%)
21
R1 = Allyl
1) POCl3
R
2 = Allyl
RCM
N
2)
(4)
BrMg
R
N
N
N
R1
=
CH2
1) POCl3
2 = CH2
2)
R
R
( )n
BrMg
11a, R = H, 75%
11b, R = Me, 91%
22
(5)
RCM
N
n.r.
N
( )n
12, n = 0, 80%
13, n = 1, 64%
Scheme 2. Synthesis of b-carboline substrates 9–13 and their behavior in metathesis reactions.

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3381
Table 1
Reaction conditions and results for the metathesis reactions of
b
-carbolines 6–11
No.
Substrate
Catalysta
Time
Temp
Product
Yield (%)
1
2
3
4
5
6
7
8
6a
6a
6a
6b
6b
6c
6d
7a
7b
7a
7c
[Ru]-II, 5%
3 days
6 days
3 hb
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
14a
14a
14a
14b
52
55
95
72
85
d
[Ru]-III, 10%
[Ru]-II, 5%
[Ru]-II, 10%
[Ru]-II, 5%
[Ru]-II, 5%
[Ru]-II, 5%
[Ru]-II, 10%
[Ru]-II, 10%
[Ru]-III, 10%
[Ru]-III, 10%
[Ru]-II, 5%
[Ru]-III, 10%
[Ru]-III, 10%
[Ru]-II, 10%
[Ru]-II, 10%
[Ru]-II, 6%e
[Ru]-III, 6%e
[Ru]-II, 6%e
3 days
3 hb
14b
3 hb
n.r./dec
n.r./dec
15a/16a
15b/16b
16a
3 hb
d
3 h
3 h
62/9
51/<5
35
16
76
d
9
10
11
12
13
14
15
16
17
18
19
3 days
6 daysc
3 days
14 days
14 days
3 days
5 days
3 days
3 days
3 days
80 ꢁ
rt
C
C
16c
8
17d
9a
9b
10
11a
11a
11a
11b
rt
80 ꢁ
rt
dec
20
21
22
22
22
n.r.
32
44
15
45
67
d
rt
80 ꢁ
80 ꢁ
80 ꢁ
C
C
C
a
b
c
All the reactions in toluene. No substrates reacted with complex [Ru]-I.
Performed under a 1 atm of ethylene.
No reaction was observed under same conditions with [Ru]-II after 10 days.
d
e
A small amount of the corresponding pyrrolo-b-carboline (4%) was detected and characterized.
2 mol % added every 24 h.
with excess of iodomethane.22 The reaction of 23 with [Ru]-III
complex was carried out in refluxing THF to allow complete solu-
tion of the salt. In these conditions, an allylic rearrangement took
place giving azocine 25 in moderate yield. This reaction was not
observed in the absence of the ruthenium catalyst. In these con-
ditions, 24 did not react. On the other hand both 12 and 13 were
reacted with m-chloroperbenzoic acid (MCPBA) in DCM in an at-
tempt to form the corresponding N-oxides and to submit them to
metathesis. Compound 12 gave only 23% of the desired oxide 26,
the major product being 27 as a result of an allylic rearrangement.
In a similar way, compound 13, gave, upon reaction with MCPBA,
product 28 as a mixture of Z/E isomers.
Our next aim after the construction of vinyl-pyrrolo-[2,1-a]-b-
carbolines and vinyl-indolo-[3,2,1-de]-naphthyridine via enyne
metathesis reactions was to study the [4þ2] cycloadditions of these
compounds with several dienophiles (Scheme 4).
The reaction of 14a with two dienophiles, dimethyl acetylene-
dicarboxylate (DMAD), and dimethyl maleate gave the corre-
sponding cycloadducts, 29 and 30 in moderate yields. These
reactions were totally stereoselective in view of the NMR spectra of
the crude mixtures where no other cycloadducts could be detected.
The relative stereochemistry of the adducts was assigned by NOE
experiments (see Supplementary data). The synthesis of 30 was
also carried out from 6a in a one pot fashion, without isolation of
[Ru]-III
N
Me, I
Me
MeI
THF
N
N
THF
N
n = 0
N
N
( )n
25 (44%)
n = 1
23, n = 0, (76%)
24, n = 1 (53%)
No reaction
N
O
O
MCPBA
N
N
+
DCM
n = 0
N
N
N
( )n
27 (48%)
26 (23%)
N
n = 0, 12
n = 1, 13
O
N
MCPBA
DCM
n = 1
HO
N
N
+ 13
O
N
N
H
28 (55%)
Scheme 3.

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3382
CO2Me
Ts
N
H
H
N
CO2Me
14a
DCM, 7d
MeO2C
29 (40%)
CO2Me
CO2Me
Ts
N
H
H
1) [Ru]-III , 7%
N
Ts
toluene, 3d
CO2Me
N
14a
N
2) DMAD, 3d
DCM, 3d
6a
MeO2C
30 (42% from 14a; 27% from 6a)
CO2Me
CO2Et
N
N
Ts
N
CO2Et
Me
14b
N
DCM, 3d
N
N
CO2Et
EtO2C
31 (35%, unstable material)
CO2Me
N
H
N
H
H
CO2Me
H
CO2Me
CO2Me
15a
CO2Me
DCM, 7d
N
N
Ts
+
Ts
CO2Me
32a (42%)
CO2Et
N
32b (14%)
N
CO2Et
N
N
EtONa/EtOH
15b
CO2Et
CO2Et
Δ, 4h
DCM
24h
N
N
N
H
N
H
Me
Me
33b (63%)
34 (56%)
CO2Me
N
N
H
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
15a
SnCl4, 1.5 eq.
N
N
+
DCM, 7d -
Ts
Ts
78 °C to r.t.
35b (13%)
b-carbolines.
35a/35b: 2:1; 35a (27%)
Scheme 4. Diels–Alder reactions of
Figure 2. ORTEP drawing for 35a.

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3383
CO2Me
N
MeO2C
CO2Me
CO2Me
MeO2C
CO2Me
N
Δ
(a)
N
N
Ts
R
N
Ts
A
N
Ts
R
36a-b
37a
R
CO2Me
CO2Me
CO2Me
(b)
N
CO2Me
CO2Me
N
N
N
Ts
CO2Me
Pg
6a
N
R
R
A
11b
R
38a-b, Pg= Ts
N
Ts
(b)
1
39, Pg= H, R= Me
CO2Me
CO2Me
(c)
1) EtONa
2) DMAD
2'
CO2Me
CO2Me
15a-b
N
N
O
N
H
N
H
R
(c)
O
B
40
H
H
O
H
N
[1,2]
N
N
N
Ts
H
N
Ts
N
Ts
O
41
C
D
Scheme 5. Cascade reactions of b-carbolines 15 with alkynes.
the metathesis product and by just adding the dienophile once the
starting material of the metathesis step had disappeared (TLC). For
the metathesis, a 7 mol % of Ru-[III] catalyst was used. The yield of
the combined procedure was lower (27%) than the stepwise re-
action (40% from 6a). On the other hand, the reaction with diethyl
azodicarboxylate, was rather sluggish and gave compound 31 with
low yield as an single stereoisomer. In addition, the product rapidly
decomposed after its isolation so we could not assign the stereo-
chemistry. When 15a was reacted in the same conditions as 14a,
with dimethyl maleate, a mixture of the four possible Diels–Alder
adducts was formed. The two major isomers, 32a and 32b, were
isolated with 42% and 14% yields, respectively and their stereo-
chemical assignment made by NOE experiments. Contrary to 15a,
compound 15b did not react with any of the dienophiles used. As
the steric hindrance was supposed to be the cause of this behavior
we eliminated the tosyl protecting group in 15b using sodium
ethoxide. Thus, with compound 33b in hand, we performed the
reaction with diethyl azodicarboxylate, which gave 34 as an only
isomer. This reaction gave a moderate yield of the cycloadduct,
which was unstable and decomposed before being completely
characterized. The Diels–Alder reaction of 15a with DMAD required
the presence of a Lewis acid to avoid the nucleophilic attack of the
begins with the formation of species A. Then, an intramolecular
attack of this intermediate either to carbon 6a (path a), to carbon 1
(path b) or to carbon 20 (path c) would give compounds 36, 38, 39,
and 40. Our aim was to find adequate reaction conditions to favor
one of the three possible paths, avoiding the formation of complex
mixtures. With 15a, the best yield in 36a was achieved in DCM at rt,
reaching 56% of this compound with isolation of a 17% of 38a
and 5% of 16a (entry 1). Compound 15b gave, under these condi-
tions a mixture of 36b (52%) and divinyl compound 38b (8%,
entry 2). Product 36b was submitted to X-ray diffraction analysis
(Fig. 3).
When the reaction of 15a was performed in THF, no divinyl
compound 38a was detected, and the isolated yield of 36a was 42%.
Additionally, we obtained an 11% yield of pyrrole 16a, and we
detected Diels–Alder product 35a in the crude mixture, which
could not be completely purified (entry 3). Elevation of the reaction
temperature to refluxing THF gave a new product, 37a, in 46% yield,
jointly with a small amount of 16a and traces of 35a (entry 4).
Compound 37a is the Z isomer of 36a. As the formation of
Table 2
Reaction conditions and results of the cascade cyclization process
b
-carboline nitrogen to the triple bond of DMAD and subsequent
Entry Substrate Alkyne
Temp Solvent Time
Other Result
(in pure product)
rearrangement (vide infra). Thus, we carried out the reactions in
the presence of BF3 or SnCl4. Best results were achieved with the
latter acid, which gave a crude reaction mixture that showed a 2:1
ratio of Diels–Alder adducts 35a and 35b. Adduct 35a was isolated
in 27% yield while a 13% of 35b was obtained unpurified with 35a.
The stereochemical assignment of these two adducts was made
with NOE experiments and further supported by an X-ray analysis
of 35a (Fig. 2).
1
15a
DMAD
rt
DCM
1 days
d
36a, 56%; 38a,
17%; 16a, 5%
2
3
4
5
6
7
15b
15a
15a
33a
33b
7a
DMAD
DMAD
DMAD
DMAD
DMAD
DMAD
rt
rt
D
rt
rt
DCM
THF
THF
DCM
DCM
2 days
3 days
2 days
4 days
2 days
d
d
d
d
d
36b, 52%; 38b, 8%
36a, 42%; 16a, 11%
37a, 46%; 16a, 16%
40, 58%
39, 51%
60 ꢁC Toluene 4 days [Ru]-II 36a, 41%; 15a, 8%
As indicated above, the reaction of compounds 15a and 15b with
triple bonded dienophiles, in the absence of a Lewis acid, gave
þ5 h
5%
d
8
9
15a
8
3-Butyn- rt
2-one
DCM
DCM
24 h
41, 53%
unexpected products due to the Michael type attack of the
b-car-
DMAD
rt
16 h
d
42, 10%; 43, 24%
boline nitrogen to the dienophile (Scheme 5, Table 2). The reaction

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3384
means the attack has occurred at carbon 1 following path b (entry
6). All these novel cascade reactions are related to the rearrange-
ment of - and -carbolines described recently by Voskressenky
b
g
and co-workers. The b-carbolines used by this group give, however,
completely different products.24
The enyne RCM reaction used for the synthesis of 15a could be
combined with the rearrangement process in a one pot fashion.
Thus, reaction of 7a with 5% of Ru-[II] catalyst and addition of
DMAD after completion of the metathesis gave a 41% yield of
compound 36a along with a small amount (<5%) of 16a. In addition,
8% of the metathesis product 15a was recovered (entry 7).
The rearrangement reaction was next effected with another
dienophile. Thus, compound 15a was reacted with 3-butyn-2-one
under the same reaction conditions. The only reaction product was
assigned to structure 41 (53%, entry 8). This product is the result of
the quenching of the intermediate C, due to the presence of acidic
protons in the media and subsequent Stevens rearrangement.25
To gain more information on the process we reacted vinyl-b-
carboline 8 with DMAD under the same conditions (Scheme 6). This
substrate gave a mixture of products 42 and 43 in 1:3 ratio, with 43
being an unstable product (entry 9). These products come from the
attack of the negative carbon in intermediate E either with carbon
6a (path of type-a) to give 43 or with carbon 20 at the vinyl moiety
(path of type c) to give 42. This confirms that the latter process
takes place only when there are less conformational restraints on
the starting compounds.
3. Conclusions
In conclusion, the functionalization of the
and its use as synthetic intermediate for the synthesis of more
complex heterocycles is a challenge as the -carboline system has
b-carboline system,
b
been found in a widespread of natural products, with intriguing
and useful biological activities. The RCM and its combination with
Diels–Alder reactions and other novel cyclization processes have
been shown. These reactions give complex structures, some of
Figure 3. ORTEP drawing for 36b.
compound 37a only occurs under refluxing conditions,23 we as-
sume that it comes from the thermal isomerization of 36a, which is
primarily formed in the reaction. The cascade process through path
c is not observed with these substrates although it involves the
attack to carbon 20, which is sterically unhindered. As can be seen
from these results summarized in Table 2, these reactions are slow,
and only after many hours reach completion. During that time, part
of the starting material is spontaneously oxidized to the pyrrole 16.
Our next step was the deprotection of compounds 15 to study
them related with natural alkaloids. In particular, vinyl-b-carbo-
lines give, upon convenient choice of reaction conditions and re-
actants, a Michael type addition followed by nucleophilic attack to
one unsaturated carbon, which leads to new polycycles with
a substantial increase in skeletal complexity.
4. Experimental
the behavior of the corresponding unprotected
b-carbolines 33a
and 33b against DMAD. To our delight, compound 33a gave the
4.1. General procedures
cyclohepta-b-carboline 40 in moderate yield, which implies the
attack of the negative carbon in intermediate B to carbon 20 and
thus the feasibility of path c (entry 5). In contrast, the parent
compound 33b gave in the same conditions, compound 39, which
1H NMR and 13C NMR spectra were taken on a 300 MHz spectro-
meter. Chemical shifts (Ô) are in parts per million relative to tetra-
methylsilane at 0.00 ppm. TLC analyses were performed on
N
CO2Me
H
(type-a)
CO2Me
N
Ts
MeO2C
CO2Me
CO2Me
MeO2C
N
H
6a
42
+
N
MeO2C
MeO2C
N
1
N
Ts
Ts
N
(type-c)
8
E
N
Ts
43
Scheme 6. Cascade reactions of
b-carboline 8 with alkynes.

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3385
commercial aluminum sheets bearing 0.25-mm layer of Silica gel
60F254. Silica gel 60 of 230–400 mesh ASTM was used for column
chromatography. Medium pressure liquid chromatography (MPLC)
was performed using Si 25þM 2593-2 compact columns. Elemental
analyses were carried out at the Elemental Analysis Center of the
Complutense University of Madrid, using a CHN instrument. The
solvents for the reactions carried under argon atmosphere were
distilled just before their use. THF was refluxed over Na/benzophe-
none, and DCM and toluene over CaH. X-ray diffraction analysis was
carried out in the CAI DRX of the Complutense University of Madrid.
126.5, 129.2, 131.2, 133.3, 136.0, 137.7, 139.1, 142.5, 144.5. IR (KBr)
n
1600,
1370, 1170 cmꢂ1. MS (ESI) m/z 391 (MþH). Anal. Calcd for C23H22N2O2S
(390.50): C, 70.74; H, 5.68; N, 7.17. Found: C, 70.50; H, 5.59; N, 7.25.
4.2.3.2. 11-Tosyl-1-vinyl-6,11-dihydro-5H-indolizino[8,7-b]indole,
16a. 1H NMR (CDCl3, 300 MHz)
d (ppm): 2.24 (s, 3H), 2.76 (t, 2H,
J¼6.3 Hz), 3.98 (br s, 2H), 5.13 (dd, 1H, J1¼11.0 Hz, J2¼1.6 Hz),
5.55 (dd, 1H, J1¼17.6 Hz, J2¼1.6 Hz), 6.52 (d, 1H, J¼2.8 Hz), 6.73
(d, 1H, J¼2.8 Hz), 6.94 (d, 2H, J¼7.7 Hz), 7.16–7.38 (m, 6H), 8.20
(d, 1H, J¼7.7 Hz). 13C NMR (CDCl3, 75 MHz)
d (ppm): 21.5, 22.4,
44.7, 104.9, 109.2, 118.0, 118.6, 121.5, 121.7, 121.8, 122.7, 124.4,
125.3, 127.3, 128.4, 131.2, 131.3., 131.5, 133.2, 139.5, 144.3. IR
4.2. Metathesis reactions
(KBr)
n
1620, 1590, 1370 cmꢂ1. MS (ESI) m/z 389 (MþH). Anal.
4.2.1. Synthesis of 3-tosyl-4-vinyl-2,3,3a,6-tetrahydro-1H-
indolo[3,2,1-de][1,5]naphthyridine, 14a
Calcd for C23H20N2O2S (388.48): C, 71.11; H, 5.19; N, 7.21. Found:
C, 70.92; H, 5.03; N, 7.09.
To a 0.01 M solution of 6a (0.20 g, 0.51 mmol) in anhydrous
toluene, [Ru]-II catalysts (22 mg, 0.026 mmol) was added and the
resulting mixture was stirred at rt under ethylene atmosphere for
3 h. The reaction mixture was filtered off through a Celite pad and
washed with toluene. The solvent was removed under reduced
pressure and purified by column chromatography (hexane/EtOAc
9:1) giving pure 14a (0.19 g, 95%) as yellow oil. 1H NMR (C6D6, 60 ꢁC,
4.2.4. Synthesis of 1-isopropenyl-11-tosyl-5,6,11,11b-tetrahydro-
3H-indolizino[8,7-b]indole, 15b
Following the same procedure than for the synthesis of 14a,
from 7b (0.50 g, 1.24 mmol) and [Ru]-II catalysts (0.10 g,
0.12 mmol) under argon atmosphere, and upon purification by
column chromatography (hexane/EtOAc 4:1), giving 15b (0.26 g,
51%) as a yellow oil. Compound 16b was detected in crude but not
300 MHz)
d (ppm): 1.76 (s, 3H), 2.17–2.21 (m, 2H), 3.90–4.09 (m,
4H), 5.11 (d, 1H, J¼12.1 Hz), 5.48 (d, 1H, J¼17.0 Hz), 5.68 (br s, 1H),
6.30 (s, 1H), 6.59 (d, 2H, J¼8.2 Hz), 6.97 (d, 1H, J¼7.7 Hz), 7.01–7.13
(m, 3H), 7.24 (d, 1H, J¼7.7 Hz), 7.62 (d, 2H, J¼8.2 Hz). 13C NMR (C6D6,
isolated. 1H NMR (CDCl3, 300 MHz)
d (ppm): 1.98 (s, 3H), 2.25 (s,
3H), 2.56–2.65 (m, 1H), 2.78–2.97 (m, 2H), 3.09–3.17 (m, 1H), 3.53
(dt, 1H, J1¼14.8 Hz, J¼2.2 Hz), 3.89 (d, 1H, J¼14.8 Hz), 4.78 (br s, 1H),
5.01 (br s, 1H), 5.66 (br s, 1H), 5.78 (br s, 1H), 7.06 (d, 2H, J¼8.2 Hz),
7.19–7.32 (m, 3H), 7.48 (d, 2H, J¼8.2 Hz), 8.05 (d, 1H, J¼7.7 Hz). 13C
60 ꢁC, 75 MHz)
d (ppm): 20.3, 21.0, 42.9, 46.8, 53.1, 106.1, 109.5,
115.4,118.8,119.9,120.2, 121.6,127.3,128.4,129.5,129.9, 131.5,134.5,
137.7,139.1,143.1. IR (film)
n
1600,1340,1160 cmꢂ1. MS (ESI) m/z 391
NMR (CDCl3, 75 MHz) d (ppm): 19.7, 21.4, 23.6, 46.0, 57.8, 64.8,
(MþH). Anal. Calcd for C23H22N2O2S (390.50): C, 70.74; H, 5.68; N,
114.4, 115.9, 118.3, 121.0, 123.8, 124.4, 124.9, 126.4, 129.3, 130.6,
7.17. Found: C, 70.99, H, 5.89, N, 7.08.
134.0, 135.6, 137.2, 140.0, 144.3, 146.6. IR (film) n 3050, 1630, 1590,
1370 cmꢂ1. MS (ESI) m/z 405 (MþH). Anal. Calcd for C24H24N2O2S
4.2.2. Synthesis of 4-isopropenyl-3-tosyl-2,3,3a,6-tetrahydro-1H-
indolo[3,2,1-de][1,5]naphthyridine, 14b
(404.53): C, 71.26; H, 5.98; N, 6.93. Found: C, 71.00; H, 5.63; N, 7.27.
Following the same procedure than for the synthesis of 14a, from
6b (0.50 g 1.24 mmol) and [Ru]-II catalysts (52 mg, 0.062 mmol)
under ethylene atmosphere, and upon purification by column
chromatography (hexane/EtOAc 4:1 and 2:1), giving 14b (0.42 g,
4.2.5. Synthesis of tert-butyl 1-vinyl-5,6-dihydroindolizino[8,7-
b]indole-11-carboxylate, 16c
Following the same procedure than for the synthesis of 14a,
from 7c (0.05 g, 0.15 mmol) and [Ru]-III catalysts (9 mg,
0.015 mmol) under argon atmosphere was stirred at 80 ꢁC for 6
days, and upon purification by column chromatography (hexane/
EtOAc 4:1 to EtOAc), giving 16c (8 mg, 16%) as yellow wax. 1H NMR
1
85%) as white solid, mp 162–164 ꢁC. H NMR (DMSO-d6, 120 ꢁC,
300 MHz) d (ppm): 2.03 (s, 3H), 2.05 (s, 3H), 2.45–2.50 (m,1H), 2.69–
2.80 (m,1H), 3.91 (t, 2H, J¼6.1 Hz), 4.72 (t, 2H, J¼3.7 Hz), 5.03 (s,1H),
5.21 (s, 1H), 5.70 (br s, 1H), 6.19–6.24 (m, 1H), 6.89 (d, 2H, J¼7.9 Hz),
(CDCl3, 300 MHz)
d
(ppm): 1.64 (s, 9H), 2.97 (t, 2H, J¼6.6 Hz), 4.16 (t,
6.98 (t, 1H, J¼7.3 Hz), 7.09 (t, 1H, J¼7.3 Hz), 7.19 (d, 1H, J¼8.5 Hz),
2H, J¼6.6 Hz), 4.99 (dd, 1H, J1¼11.0 Hz, J2¼1.6 Hz), 5.48 (dd, 1H,
J1¼17.6 Hz, J2¼1.6 Hz), 6.39 (d,1H, J¼2.7 Hz), 6.62–6.71 (m,1H), 6.69
(d, 1H, J¼2.7 Hz), 7.23–7.31 (m, 2H), 7.41–7.47 (m, 1H), 8.03–8.06
13
7.31–7.35 (m, 3H). C NMR (DMSO-d6, 120 ꢁC, 75 MHz)
d (ppm):
19.0, 21.0, 41.6, 45.7, 52.0, 52.2, 103.9, 108.9, 112.6, 117.2, 118.7, 120.0,
125.7, 126.8, 127.8, 128.1, 130.4, 135.4, 137.2, 140.1, 141.8, 148.4. IR
(m, 1H). IR (film)
n .
1620, 1580 cmꢂ1
(KBr)
n
1610, 1590, 1340, 1150 cmꢂ1. Anal. Calcd for C24H24N2O2S
(404.53): C, 71.26; H, 5.98; N, 6.93. Found: C, 71.44; H, 6.09; N, 6.95.
4.2.6. Synthesis of 11-tosyl-5,6,11,11b-tetrahydro-3H-
indolizino[8,7-b]indole, 17
4.2.3. Metathesis reaction of 2-allyl-1-ethynyl-9-tosyl-2,3,4,9-
tetrahydro-1H-b-carboline, 7a: synthesis of 15a and 16a
To a solution of 8 (0.10 g, 0.25 mmol) in toluene (25 mL), [Ru]-II
catalyst was added and the mixture was stirred at rt for 3 days. The
reaction mixture was filtered off through a Celite pad and washed
with toluene. The solvent was removed under reduced pressure
and purified by column chromatography (hexane/EtOAc 1:1 to
EtOAc) giving pure 17 (69 mg, 76%) as yellow oil and recovering
Following the same procedure than for the synthesis of 14a,
from 7a (0.50 g,1.28 mmol) and [Ru]-II catalysts (0.11 g, 0.13 mmol)
under argon atmosphere, and upon purification by column chro-
matography (hexane/EtOAc 4:1 to EtOAc), 0.310 g (62%) of 15a were
obtained as a white solid (mp 65 ꢁC, dec), and 0.045 g (9%) of 16a as
yellow solid (mp 85 ꢁC, dec).
12 mg of starting material. 1H NMR (CDCl3, 300 MHz)
d (ppm): 2.31
(s, 3H), 2.45 (d, 1H, J¼16.5 Hz), 2.86–2.96 (m, 1H), 3.08 (td, 1H,
J1¼11.0 Hz, J2¼3.9 Hz), 3.30 (dd, 1H, J1¼13.2 Hz, J2¼3.3 Hz), 3.69 (dd,
1H, J1¼13.7 Hz, J2¼2.2 Hz), 3.80 (d, 1H, J¼13.2 Hz), 5.45 (br s, 1H),
5.88 (d,1H, J¼4.4 Hz), 6.43 (dd,1H, J1¼6.0 Hz, J2¼1.6 Hz), 7.14 (d, 2H,
J¼8.2 Hz), 7.20–7.31 (m, 2H), 7.35 (dd,1H, J1¼8.2 Hz, J2¼1.6 Hz), 7.59
(d, 2H, J¼8.2 Hz), 8.10 (d, 1H, J¼7.7 Hz). 13C NMR (CDCl3, 75 MHz)
4.2.3.1. 11-Tosyl-1-vinyl-5,6,11,11b-tetrahydro-3H-indolizino[8,7-
b]indole, 15a. 1H NMR (CD3OD, 300 MHz)
d (ppm): 2.25 (s, 3H), 2.45–
2.54 (m, 1H), 2.76–2.82 (m, 2H), 2.87–3.15 (m, 1H), 3.61 (d, 1H,
J¼15.8 Hz), 3.92 (d, 1H, J¼15.2 Hz), 5.13 (d, 1H, J¼11.0 Hz), 5.48 (d, 1H,
J¼17.1 Hz), 5.65 (br s, 1H), 6.01 (br s, 1H), 6.84 (dd, 1H, J1¼17.7 Hz,
J2¼11.0 Hz), 7.05 (d, 2H, J¼7.9 Hz), 7.18–7.31 (m, 3H), 7.47 (d, 2H,
d
(ppm): 17.2, 21.5, 44.2, 56.0, 63.9, 115.2, 118.4, 118.7, 123.7, 124.5,
126.4, 128.5, 129.6, 130.6, 131.8, 135.0, 136.7, 137.1, 144.6. IR (film)
n
J¼8.5 Hz), 8.15 (d, 1H, J¼7.9 Hz). 13C NMR (CD3OD, 75 MHz)
d
(ppm):
1600 cmꢂ1. Anal. Calcd for C21H20N2O2S (364.46): C, 69.20; H, 5.53;
N, 7.69. Found: C, 69.37; H, 5.29; N, 7.83.
18.9, 21.4, 45.9, 57.6, 64.7, 115.5, 116.5, 118.4, 122.4, 123.3, 124.2, 124.6,

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3386
4.2.7. Synthesis of 11-tosyl-2,3,5,6,11,11b-hexahydro-1H-
indolizino[8,7-b]indole, 18
solvent was removed under reduced pressure and the residue pu-
rified by column chromatography (Hexane/EtOAc 49:1) giving 22
To a solution of 17 (0.15 g, 0.38 mmol) in EtOAc (5 mL) under H2
atmosphere was added Pd(C) (10% weight) and the mixture was
stirred at rt for 3 h. The reaction mixture was filtered off through
a Celite pad and washed with EtOAc. The solvent was removed
under reduced pressure and purified by column chromatography
(EtOAc to EtOAc/MeOH 3%) giving pure 18 (89 mg, 64%) as yellow
(0.10 g, 67%) as a yellow oil. 1H NMR (CDCl3, 300 MHz)
d (ppm): 3.16
(t, 2H, J¼6.8 Hz), 4.22 (t, 2H, J¼6.8 Hz), 4.82 (d, 2H, J¼5.5 Hz), 5.61–
5.69 (m, 1H), 6.14 (d, 1H, J¼2.7 Hz), 6.65 (d, 1H, J¼11.0 Hz), 6.70 (d,
1H, J¼2.7 Hz), 7.11 (td, 1H, J1¼7.7 Hz, J2¼1.1 Hz), 7.18 (td, 1H,
J1¼8.2 Hz, J2¼1.1 Hz), 7.34 (d, 1H, J¼8.2 Hz), 7.51 (d, 1H, J¼7.7 Hz).
13C NMR (CDCl3, 75 MHz)
d (ppm): 21.4, 44.0, 45.2, 103.0, 107.4,
oil. 1H NMR (CDCl3, 300 MHz)
d
(ppm): 1.89–1.97 (m, 2H), 2.30 (s,
109.3, 116.1, 116.5, 117.8, 119.6, 121.0, 121.7, 127.5, 127.6, 128.3, 130.0,
3H), 2.55–3.16 (m, 8H), 4.68 (br s, 1H), 7.12 (d, 2H, J¼8.2 Hz), 7.20–
137.2. IR (film)
n
1620, 1600 cmꢂ1. MS (APCI), m/z: 247 [MþH]þ.
7.28 (m, 2H), 7.32 (t,1H, J¼7.6 Hz), 7.58 (d, 2H, J¼8.2 Hz), 8.10 (d, 1H,
Anal. Calcd for C17H14N2 (246.31): C, 82.90; H, 5.73; N, 11.37. Found:
C, 82.72; H, 5.67; N, 11.48.
J¼7.2 Hz). 13C NMR (CDCl3, 75 MHz)
d (ppm): 14.2, 18.7, 21.5, 23.4,
32.0, 44.9, 58.3, 115.3, 117.9, 118.4, 123.8, 124.5, 126.5, 129.6, 130.2,
134.8, 136.9, 144.6. IR (film)
n
1600 cmꢂ1
.
Anal. Calcd for
4.2.12. Synthesis of 2-methyl-2,9-dipropargyl-1-vinyl-2,3,4,9-
C21H22N2O2S (366.48): C, 68.82; H, 6.05; N, 7.64. Found: C, 68.57; H,
6.28; N, 7.91.
tetrahydro-1H-b-carbolin-2-ium iodide, 23
To a solution of 12 (0.15 g, 0.55 mmol) in THF (8 mL) was added
MeI (0.10 mL, 1.64 mmol) and the mixture was stirred at rt for 3
days. The reaction mixture was filtered off and the solid was
washed with cooled THF, giving 23 (0.16 g, 76%) as white solid
4.2.8. Synthesis of (ꢀ)-harmicine, 19
To a solution of EtONa (0.55 g, 8.10 mmol) in absolute EtOH
(3 mL), generated in situ, was added 18 (0.10 g, 0.27 mmol) in ab-
solute EtOH (3 mL) and the mixture was refluxed for 4 h. The
mixture was quenched with water and the mixture was extracted
with EtOAc (ꢃ3). The organic layer was washed with water and
brine, dried (MgSO4), and the solvent was removed under reduced
pressure. The crude residue was purified by flash chromatography
on silica gel (EtOAc/MeOH 2%), giving 19 (54 mg, 94%).18
(mixture of isomers). 1H NMR (DMSO-d6, 300 MHz)
d (ppm): 3.22
(s,1H), 3.31 (s,1H), 3.39 (s, 3H), 3.85 (br s, 2H), 4.17 (d,1H, J¼7.3 Hz),
4.41–4.66 (m, 3H), 4.79–4.91 (m, 1H), 5.02–5.11 (m, 1H), 5.74–5.87
(m, 3H), 6.10–6.32 (m, 1H), 7.16 (t, 1H, J¼7.3 Hz), 7.29 (t, 1H,
J¼7.6 Hz), 7.59 (t, 2H, J¼7.9 Hz). 13C NMR (DMSO-d6, 75 MHz)
d
(ppm): 17.0, 17.1, 32.7, 32.8, 45.9, 48.8, 50.4, 53.1, 54.1, 54.2, 66.6,
67.4, 71.7, 71.8, 75.4, 75.6, 78.3, 78.6, 83.7, 84.1, 105.2, 105.5, 110.3,
110.4,118.9,119.0,120.1,122.9,123.0,125.1,125.2,126.3,126.7,128.2,
4.2.9. Synthesis of tert-butyl 2-vinyl-5,6-dihydroindolizino[8,7-b]-
indole-11-carboxylate, 20
128.3, 128.8, 136.9, 137.0. IR (KBr) n
3200, 2100, 1590 cmꢂ1. Anal.
Calcd for C20H21IN2 (416.30): C, 57.70; H, 5.08; N, 6.73. Found: C,
57.98; H, 5.27; N, 6.46.
To a solution of 9b (0.10 g, 0.30 mmol) in toluene (30 mL), [Ru]-
III catalyst was added and the mixture was stirred at 80 ꢁC for 14
days. The reaction mixture was filtered off through a Celite pad and
washed with toluene. The solvent was removed under reduced
pressure and purified by column chromatography (hexane/EtOAc
4:1) giving a mixture of compounds 20 with traces of 9b (32 mg,
32%), which decomposed after a few hours. 1H NMR (CDCl3,
4.2.13. Synthesis of 1-allyl-2-methyl-2,9-dipropargyl-2,3,4,9-
tetrahydro-1H-b-carbolin-2-ium iodide, 24
To a solution of 13 (0.15 g, 0.52 mmol) in THF (8 mL) was added
MeI (0.10 mL, 1.56 mmol) and the mixture was stirred at rt for 5
days. The reaction mixture was concentrated until precipitation of
the salt. The solid was filtered off and washed with cooled THF,
giving 24 (0.12 g, 53%) as white solid (mixture of isomers). 1H NMR
300 MHz)
d
(ppm): 1.74 (s, 9H), 3.03 (t, 2H, J¼7.1 Hz), 4.16 (t, 2H,
J¼7.1 Hz), 4.98 (dd, 1H, J1¼10.4 Hz, J2¼1.6 Hz), 5.45 (dd, 1H,
J1¼17.6 Hz, J2¼1.6 Hz), 6.57–6.66 (m, 1H), 6.77 (d, 1H, J¼1.6 Hz), 6.91
(d, 1H, J¼1.6 Hz), 7.23–7.29 (m, 2H), 7.42–7.45 (m, 1H), 8.04–8.07
(CDCl3, 300 MHz)
d (ppm): 2.28 (s, 3H), 2.36 (s, 1H), 3.00 (s, 1H),
3.12–3.26 (m, 4H), 3.51 (d, 1H, J¼17.6 Hz), 3.69–3.75 (m, 3H), 3.99
(br s, 1H), 4.33 (d, 1H, J¼16.5 Hz), 5.03 (s, 1H), 5.15–5.28 (m, 2H),
5.76–5.94 (m,1H), 7.21–7.27 (m,1H), 7.37 (t,1H, J¼7.7 Hz), 7.46–7.57
(m, 1H). IR (film)
n .
1620, 1580 cmꢂ1
4.2.10. Synthesis of 12-tosyl-3-vinyl-1,4,6,7,12,12b-hexahydro-
indolo[2,3-a]quinolizine, 21
(m, 2H). IR (KBr) n .
3200, 2100, 1600 cmꢂ1
To a solution of 10 (0.15 g, 0.37 mmol) in toluene (37 mL), [Ru]-II
catalyst (31 mg, 0.037 mmol) was added and the mixture was
stirred at rt for 3 days. The reaction mixture was filtered off through
a Celite pad and washed with toluene. The solvent was removed
under reduced pressure and purified by column chromatography
(hexane/EtOAc 4:1), giving pure 21 (67 mg, 44%) as yellow oil. 1H
4.2.14. Synthesis of (5Z)-3,7-dipropargyl-2,3,4,7-tetrahydro-1H-
azocino[5,4-b]indole, 25
To a solution of 23 (0.10 g, 0.24 mmol) in THF (50 mL), [Ru]-III
catalyst (11 mg, 0.017 mmol) was added and the mixture was
refluxed for 5 days. The reaction mixture was filtered off through
a Celite pad and washed with THF. The solvent was removed under
reduced pressure and purified by column chromatography (hex-
ane/EtOAc 9:1 to 2:1) giving pure 25 (29 mg, 44%) as yellow oil. 1H
NMR (CDCl3, 300 MHz)
d (ppm): 2.28 (s, 3H), 2.64–2.87 (m, 3H),
3.13–3.31 (m, 2H), 3.64 (br s, 2H), 4.15–4.19 (m, 1H), 5.00 (d, 1H,
J¼11.0 Hz), 5.07 (d, 1H, J¼17.6 Hz), 5.90 (d, 1H, J¼4.4 Hz), 6.34–6.45
(m, 1H), 7.09 (d, 2H, J¼8.2 Hz), 7.19–7.37 (m, 4H), 7.51 (d, 2H,
NMR (CDCl3, 300 MHz)
d
(ppm): 2.25 (t, 1H, J¼2.5 Hz), 2.28 (t, 1H,
J¼2.5 Hz), 3.02 (s, 4H), 3.39 (d, 2H, J¼7.7 Hz), 3.47 (d, 2H, J¼2.2 Hz),
4.82 (d, 2H, J¼2.2 Hz), 6.09–6.17 (m, 1H), 6.78 (d,1H, J¼11.0 Hz), 7.15
(td, 1H, J1¼7.7 Hz, J2¼1.1 Hz), 7.27 (td, 1H, J1¼7.1 Hz, J2¼1.1 Hz), 7.38
(d, 1H, J¼7.7 Hz), 7.56 (d, 1H, J¼8.2 Hz). 13C NMR (CDCl3, 75 MHz)
J¼8.2 Hz), 8.11 (d, 1H, J¼8.2 Hz). 13C NMR (CDCl3, 75 MHz)
d (ppm):
21.5, 22.4, 32.0, 48.2, 53.6, 55.9, 110.4, 116.0, 118.4, 124.1, 124.5,
126.2, 126.5, 127.2, 128.6, 129.2, 129.3, 130.8, 133.8, 137.4, 137.9,
144.5. IR (film)
n
1600, 1370, 1170 cmꢂ1. Anal. Calcd for C24H24N2O2S
d (ppm): 23.3, 32.9, 46.0, 50.3, 51.0, 72.3, 72.6, 78.4, 80.1, 109.0,
(404.53): C, 71.26; H, 5.98; N, 6.93. Found: C, 71.45; H, 6.18; N, 6.76.
114.3, 118.6, 119.6, 121.8, 122.4, 128.0, 130.2, 132.5, 136.3. IR (film) n
3280, 2100, 1650 cmꢂ1. Anal. Calcd for C19H18N2 (274.36): C, 83.18;
H, 6.61; N, 10.21. Found: C, 83.45; H, 6.48; N, 9.93.
4.2.11. Synthesis of 1,10-dihydro-11H-5a,11a-
diazabenzo[cd]fluoranthene, 22
To a solution of 11a (0.15 g, 0.54 mmol) in anhydrous toluene
(30 mL), [Ru]-III catalyst (7 mg, 0.011 mmol) was added every 24 h
during 3 days while stirring at 80 ꢁC. The reaction mixture was
filtered off through a Celite pad and washed with dry toluene. The
4.2.15. Synthesis of 26 and 27
To a solution of 12 (0.10 g, 0.36 mmol) in DCM (10 mL) at 0 ꢁC
was added MCPBA (63 mg, 0.36 mmol) and the mixture was stirred
at this temperature for 5 h and one more hour at rt. The reaction

´
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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3387
mixture was quenched with water and the mixture was extracted
with DCM (ꢃ3). The organic layer was washed with HCl (1 N),
NaOH (10%), water and brine, dried (MgSO4), and the solvent was
removed under reduced pressure. The crude residue was purified
by flash chromatography on silica gel (Hexane/EtOAc 9:1), giving 27
(50 mg, 48%) as colorless oil and 26 (24 mg, 23%) as pale wax
(mixture of isomers).
/H3.40, 14.0%). 13C NMR (CDCl3, 75 MHz)
d
(ppm): 20.1, 21.5, 25.0,
37.2, 41.3, 42.2, 42.7, 44.1, 51.5, 52.0, 54.4, 104.7, 109.1, 118.2, 119.1,
119.8, 121.0, 126.5, 126.8, 129.1, 129.9, 131.8, 135.8, 138.0, 143.5,
170.9, 173.4. IR (KBr) n
1720, 1590 cmꢂ1. Anal. Calcd for C29H30N2O6S
(534.62): C, 65.15; H, 5.66; N, 5.24. Found: C, 64.88; H, 5.79; N, 5.42.
4.3.2. Synthesis of dimethyl 1-tosyl-1,2,3,8a,11,12b-hexahydro-8H-
1,7b-diazabenzo[e]acephenanthrylene-9,10-dicarboxylate, 30
4.2.15.1. 2,9-Dipropargyl-1-vinyl-2,3,4,9-tetrahydro-1H-
b-carboline
2-oxide, 26. 1H NMR (CDCl3, 300 MHz)
d
(ppm): 2.27 (t, 1H,
4.3.2.1. Procedure A. Treatment of 14a (0.15 g, 0.38 mmol) in DCM
(10 mL), and DMAD (0.09 mL, 0.76 mmol) at rt, gave after 3 days,
and upon removal of the solvent and after flash chromatography
(hexane/EtOAc, 4:1), pure 30 (86 mg, 42%) as brown solid (mp
118 ꢁC, des.).
J¼1.9 Hz), 2.31 (t,1H, J¼2.1 Hz), 3.08–3.19 (m, 2H), 3.23–3.32(m, 2H),
3.73 (d, 2H, J¼2.2 Hz), 4.66–4.81 (m, 3H), 5.40 (d,1H, J¼10.5 Hz), 5.74
(d, 1H, J¼6.1 Hz), 6.23–6.31 (m, 1H), 7.17 (t, 1H, J¼7.4 Hz), 7.25 (t, 1H,
J¼7.4 Hz), 7.38 (d, 1H, J¼8.2 Hz), 7.57 (d, 1H, J¼7.1 Hz). IR (film)
n
2100, 1650, 1590 cmꢂ1
.
4.3.2.2. Procedure B. To a solution of 6a (0.12 g, 0.32 mmol) in tol-
uene (32 mL) was added [Ru]-III catalysts (14 mg, 0.022 mmol) and
the mixture was stirred at rt for 3 days. DMAD (0.08 mL,
4.2.15.2. (6Z)-3,8-Dipropargyl-2,3,5,8-tetrahydro-1H-[1,2]oxazonino-
[6,5-b]indole, 27. 1H NMR (CDCl3, 300 MHz)
(ppm): 2.25 (t, 1H,
d
J¼2.7 Hz), 2.26 (t, 1H, J¼2.2 Hz), 3.07 (br s, 2H), 3.14–3.18 (m, 2H),
3.54 (br s, 2H), 4.46 (br s, 2H), 4.78 (d, 2H, J¼2.7 Hz), 6.24–6.32 (m,
1H), 6.71 (d, 1H, J¼11.5 Hz), 7.15 (td, 1H, J1¼7.7 Hz, J2¼1.1 Hz), 7.26
(td, 1H, J1¼7.7 Hz, J2¼1.1 Hz), 7.40 (d, 1H, J¼8.2 Hz), 7.56 (d, 1H,
0.64 mmol) was added stirring was continued for 3 days. The re-
action mixture was filtered off through a Celite pad and washed
with dry toluene. The solvent was removed under reduced pressure
and the residue purified by column chromatography (Hexane/
EtOAc 4:1) giving 30 (45 mg, 27%) as brown solid (mp 118 ꢁC, des.).
J¼7.7 Hz). 13C NMR (CDCl3, 75 MHz)
d (ppm): 23.9, 33.1, 48.2, 57.7,
72.2, 72.6, 72.9, 78.4, 79.0, 109.3, 114.6, 118.8, 119.4, 122.0, 123.6,
1H NMR (CDCl3, 300 MHz)
d (ppm): 2.11–2.23 (m, 1H), 2.49 (s, 3H),
127.9, 133.5, 134.9, 136.2. IR (film)
n
2100, 1650, 1590 cmꢂ1. Anal.
2.49–2.54 (m, 1H), 3.07–3.18 (m, 3H), 3.39 (t, 1H, J¼11.0 Hz), 3.83 (s,
3H), 3.91 (s, 3H), 4.03–4.11 (m, 1H), 4.25 (dd, 1H, J1¼14.0 Hz,
J2¼3.0 Hz), 4.64 (dd, 1H, J1¼10.4 Hz, J2¼6.0 Hz), 5.37 (br s, 1H), 6.04
(br s, 1H), 7.10 (t, 1H, J¼7.4 Hz), 7.18 (t, 1H, J¼7.4 Hz), 7.25–7.32 (m,
Calcd for C19H18N2O (290.36): C, 78.59; H, 6.25; N, 9.65. Found: C,
78.73; H, 6.21; N, 9.40.
4.2.16. Synthesis of N-(2-{2-[(1E)-buta-1,3-dien-1-yl]-1-propargyl-
1H-indol-3-yl}ethyl)-N-hydroxyprop-2-yn-1-amine, 28
3H), 7.37 (d, 1H, J¼7.4 Hz), 7.80 (d, 2H, J¼8.2 Hz). NOE (H3.39/H5.37
,
0%). 13C NMR (CDCl3, 75 MHz)
d (ppm): 20.8, 21.5, 28.4, 35.6, 43.7,
To a solution of 13 (0.25 g, 0.87 mmol) in DCM (15 mL) at 0 ꢁC
was added MCPBA (0.15 g, 0.87 mmol) and the mixture was stirred
at this temperature for 5 h and two more hour at rt. The reaction
mixture was quenched with water and the mixture was extracted
with DCM (ꢃ3). The organic layer was washed with brine, dried
(MgSO4), and the solvent was removed under reduced pressure.
The crude residue was purified by flash chromatography on silica
gel (Hexane/EtOAc 9:1 to 4:1), giving 28 (145 mg, 55%) as red oil
49.1, 52.5, 52.6, 55.1, 108.1, 110.1, 114.9, 118.2, 120.3, 121.9, 127.1,
127.7, 130.0, 131.2, 131.2, 133.0,136.0, 137.5, 138.3, 143.8, 167.2, 168.0.
IR (KBr)
n
1730, 1650, 1600 cmꢂ1. Anal. Calcd for C29H28N2O6S
(532.61): C, 65.40; H, 5.30; N, 5.26. Found: C, 65.72; H, 5.13; N, 5.41.
4.3.3. Synthesis of dimethyl 12-methyl-1-tosyl-2,3,8,8a,11,12b-
hexahydro-1H-1,7b,9,10-tetraazabenzo[e]acephenanthrylene-
9,10-dicarboxylate, 31
Treatment of 14b (0.20 g, 0.49 mmol) and diethyl azodicarboxy-
late (0.18 mL, 0.99 mmol) at rt, gave after 3 days, upon removal of
the solvent and after flash chromatography (petroleum ether/
diethyl ether, 1:1) pure 31 (105 mg, 35%) as yellow oil. This product
begins to decomposed into other products in minutes. 1H NMR
(mixture of isomers). 1H NMR (CDCl3, 300 MHz)
d
(ppm): 2.25 (s,
1H), 2.34 (s, 1H), 3.05–3.19 (m, 4H), 3.68 (dd, 2H, J1¼13.7 Hz,
J2¼2.2 Hz), 4.75 (d, 1H, J¼2.2 Hz), 4.87 (d, 1H, J¼2.2 Hz), 5.27 (d, 1H,
J¼9.9 Hz), 5.43 (d, 1H, J¼17.6 Hz), 6.37–6.84 (m, 3H), 7.13–7.18 (m,
1H), 7.24–7.29 (m, 1H), 7.36–7.44 (m, 1H), 7.60–7.66 (m, 1H). 13C
NMR (CDCl3, 75 MHz)
d
(ppm): 22.5, 22.6, 33.3, 33.6, 49.3, 49.4,
(CDCl3, 300 MHz) d (ppm): 1.17–1.40 (m, 6H), 2.02–2.07 (m, 2H),
58.2, 58.5, 72.3, 72.6, 73.8, 74.0, 77.4, 77.5, 78.3, 78.6, 109.2, 109.6,
112.0, 112.7, 118.7, 118.8, 118.9, 119.0, 119.8, 120.0, 120.5, 121.0, 122.2,
122.8,128.0, 128.1,132.9,133.5,133.6, 133.7,136.4, 136.6, 137.1, 137.3.
2.24 (s, 3H), 2.26 (s, 3H), 2.28–2.36 (m, 1H), 2.45 (s, 1H), 2.51–2.65
(m, 1H), 3.48–3.67 (m, 2H), 4.12–4.37 (m, 4H), 4.49 (dd, 1H,
J1¼14.9 Hz, J2¼5.2 Hz), 4.57–4.70 (m, 1H), 5.17 (dd, 1H, J1¼9.8 Hz,
J2¼6.1 Hz), 6.77 (d, 1H, J¼7.9 Hz), 7.01 (d, 1H, J¼7.3 Hz), 7.06 (d, 2H,
J¼7.9 Hz), 7.19 (d, 2H, J¼7.9 Hz), 7.33–7.40 (m, 1H), 7.78 (d, 1H,
IR (film)
n
3290, 2110, 1600 cmꢂ1. Anal. Calcd for C20H20N2O
(304.39): C, 78.92; H, 6.62; N, 9.20. Found: C, 79.13; H, 6.39; N, 9.33.
J¼8.5 Hz). IR (film)
n .
1690, 1600 cmꢂ1
4.3. Diels–Alder reactions
4.3.4. Reaction of 11-tosyl-1-vinyl-5,6,11,11b-tetrahydro-3H-
indolizino[8,7-b]indole, 15a with dimethyl maleate: synthesis
of 32a and 32b
4.3.1. Synthesis of dimethyl (8aR
*
,9R
*
,10S
*
,12bR )-1-tosyl-
*
1,2,3,8a,9,10,11,12b-octahydro-8H-1,7b-diazabenzo[e]-
acephenanthrylene-9,10-dicarboxylate, 29
Treatment of 15a (0.20 g, 0.51 mmol) and dimethyl maleate
(0.13 mL, 1.03 mmol) at rt, gave after 7 days, and upon removal of
the solvent a mixture of 4 isomers. After flash chromatography
(hexane/EtOAc, 1:2 to EtOAc), pure 32a (0.11 g, 42%) as yellow oil
and 32b (38 mg, 14%) as yellow oil were isolated.
Treatment of 14a (0.25 g, 0.64 mmol) in DCM (10 mL), with di-
methyl maleate (0.12 mL, 0.96 mmol) at rt, gave after 7 days, upon
removal of the solvent and after flash chromatography (hexane/
EtOAc, 4:1), pure 29 (140 mg, 40%) as brown solid (mp 214–216 ꢁC).
1H NMR (CDCl3, 300 MHz)
d (ppm): 2.16–2.31 (m, 1H), 2.39 (s, 3H),
2.45–2.50 (m, 3H), 2.76 (s, 3H), 2.98–3.05 (m, 1H), 3.08–3.14 (m,
1H), 3.40 (s, 2H), 3.67 (s, 3H), 4.18 (dd, 1H, J1¼13.7 Hz, J2¼3.4 Hz),
4.35–4.49 (m, 2H), 5.61 (br s, 1H), 6.03 (br s, 1H), 7.03 (td, 1H,
J1¼7.3 Hz, J2¼1.0 Hz), 7.15 (td, 1H, J1¼7.3 Hz, J2¼1.0 Hz), 7.26 (d, 2H,
J¼8.3 Hz), 7.29 (d, 1H, J¼8.3 Hz), 7.34 (d, 1H, J¼7.8 Hz), 7.77 (d, 2H,
J¼8.3 Hz). NOE (H5.61/H4.35–4.49, 0.0%; H2.98–3.05/H4.35–4.49, 0.0%;
4.3.4.1. Dimethyl (7aS
octahydro-6H-6a,12-diazaindeno[1,2-a]fluorene-8,9-dicarboxylate,
32a. 1H NMR (CDCl3, 300 MHz)
(ppm): 2.25 (s, 3H), 2.38–2.53 (m,
*
,8R
*
,9S
*
,11bR
*
)-12-tosyl-5,7,7a,8,9,10,11b,12-
d
2H), 2.59–2.66 (m, 1H), 2.72–2.88 (m, 3H), 2.95–3.18 (m, 4H), 3.31
(dd, 1H, J1¼6.1 Hz, J2¼3.7 Hz), 3.68 (s, 6H), 5.28 (br s, 1H), 6.41 (br s,
1H), 7.06 (d, 2H, J¼7.9 Hz), 7.18–7.31 (m, 3H), 7.48 (d, 2H, J¼7.9 Hz),

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3388
8.06 (d, 1H, J¼7.9 Hz). NOE (H3.31/H2.59–2.66, 6.8%; /H2.87, 7.5%).
13C NMR (CDCl3, 75 MHz)
(ppm): 18.5, 21.4, 25.5, 38.6, 41.1, 41.3,
300 MHz) d (ppm): 1.25–1.30 (m, 6H), 2.15 (s, 3H), 3.09–3.18 (m,
3H), 4.10–4.31 (m, 7H), 5.21 (s, 1H), 5.33 (s, 1H), 6.15 (br s, 1H), 7.00
d
45.6, 51.4, 51.9, 53.0, 61.2, 116.1, 118.3, 121.2, 122.0, 124.0, 124.6,
126.2, 129.2, 130.7, 134.1, 135.7, 136.9, 137.7, 144.3, 171.6, 173.9. IR
(film) 1730, 1590 cmꢂ1. Anal. Calcd for C29H30N2O6S (534.62): C,
65.15; H, 5.66; N, 5.24. Found: C, 65.28; H, 5.50; N, 5.09.
(br s, 1H), 7.09–7.18 (m, 2H), 7.33 (dd, 1H, J1¼6.6 Hz, J2¼1.6 Hz), 7.50
(dd, 1H, J1¼7.7 Hz, J2¼1.6 Hz), 8.70 (br s, 1H). IR (KBr)
n 1690,
1590 cmꢂ1
.
4.3.8. Reaction of 11-tosyl-1-vinyl-5,6,11,11b-tetrahydro-3H-
4.3.4.2. Dimethyl (7aS
octahydro-6H-6a,12-diazaindeno[1,2-a]fluorene-8,9-dicarboxylate,
32b. 1H NMR (CDCl3, 300 MHz)
(ppm): 2.29 (s, 3H), 2.44 (dd, 1H,
*
,8S
*
,9R*,11bR
*
)-12-tosyl-5,7,7a,8,9,10,11b,12-
indolizino[8,7-b]indole, 15a with DMAD
d
4.3.8.1. Procedure A. To a solution of 15a (0.10 g, 0.26 mmol), SnCl4
(0.05 mL, 0.38 mmol) in DCM at ꢂ78 ꢁC, DMAD (0.08 mL, 0.51 mmol)
was added. The mixture was allowed to reach rt and was stirred for 7
days. To the reactionwas added 40 mL of ice/H2O and the mixture was
extracted with EtOAc (ꢃ3). The organic layers were dried over MgSO4,
and the solvent was removed under vacuum giving a 2:1 mixture of
35a and 35b. Purification by silica gel flash chromatography (hexane/
EtOAc, 1:2 to EtOAc), afforded 35a (37 mg, 27%) and a 13% of 35b
unpurified with 35a.
J1¼9.7 Hz, J2¼3.4 Hz), 2.47–2.57 (m, 2H), 2.72–2.83 (m, 1H), 2.85–
3.09 (m, 4H), 3.13–3.22 (m, 1H), 3.39 (dd, 1H, J1¼5.9 Hz, J2¼3.9 Hz),
3.46–3.58 (m, 1H), 3.54 (s, 3H), 3.71 (s, 3H), 5.36 (br s, 1H), 6.38 (br
s, 1H), 7.10 (d, 2H, J¼8.3 Hz), 7.17–7.32 (m, 3H), 7.52 (d, 2H,
J¼8.3 Hz), 7.93 (dd, 1H, J1¼7.8 Hz, J2¼1.0 Hz). NOE (H3.39/H2.44
,
14.8%). 13C NMR (CDCl3, 75 MHz)
d (ppm): 18.0, 21.5, 27.6, 34.6,
40.0, 45.7, 46.2, 51.9, 52.0, 56.8, 61.4, 115.9, 118.5, 121.2, 121.9,
124.0, 124.7, 126.7, 129.4, 130.8, 134.0, 135.5, 137.7, 138.8, 144.4,
173.4, 173.6. IR (film) 1730, 1590 cmꢂ1. Anal. Calcd for C29H30N2O6S
(534.62): C, 65.15; H, 5.66; N, 5.24. Found: C, 64.90; H, 5.44; N,
4.99.
4.3.8.2. Procedure B. A solution of 15a (0.20 g, 0.51 mmol) and
BF3$OEt2 (0.10 mL, 0.77 mmol) in toluene at ꢂ20 ꢁC was stirred for
1 h. DMAD (0.19 mL, 1.54 mmol) was then added and the mixture
was allowed to reach rt and was stirred for 16 h. The solvent was
removed under vacuum giving a crude mixture containing 15a, 37a,
35a, and 35b, in the following ratios as calculated from integration
of well resolved 1H NMR signals (2:3:2:1). Separation by silica gel
flash chromatography (hexane/EtOAc, 4:1 to EtOAc) afforded 15a
(20 mg, 10%), 37a (73 mg, 27%) as yellow oil, and 35a (36 mg, 13%)
as yellow solid (mp 177–179 ꢁC).
4.3.5. Synthesis of 1-vinyl-5,6,11,11b-tetrahydro-3H-indolizino[8,7-
b]indole, 33a
To a solution of EtONa (1.57 g, 23.10 mmol) in absolute EtOH
(8 mL), generated in situ, was added 15a (0.30 g, 0.77 mmol) in
absolute EtOH (8 mL) and the mixture was refluxed for 4 h. The
mixture was quenched with water and the mixture was extracted
with EtOAc (ꢃ3). The organic layer was washed with water and
brine, dried (MgSO4), and the solvent removed under reduced
pressure. The crude residue was purified by flash chromatography
on silica gel (EtOAc to EtOAc/MeOH, 5%), giving 33a (0.15 mg, 81%)
4.3.8.3. Dimethyl (7aR
6H-6a,12-diazaindeno [1,2-a]fluorene-8,9-dicarboxylate, 35a. 1H NMR
(CDCl3, 300 MHz) (ppm): 2.29 (s, 3H), 2.48–2.58 (m, 1H), 2.63–2.69
*
,11bS )-12-tosyl-5,7,7a,10,11b,12-hexahydro-
*
as brown wax. 1H NMR (CDCl3, 300 MHz)
d
(ppm): 2.66 (dd, 1H,
d
J1¼15.4 Hz, J2¼4.6 Hz), 3.04–3.16 (m, 1H), 3.31–3.50 (m, 2H), 3.73
(dd, 1H, J1¼14.8 Hz, J2¼2.7 Hz), 3.83 (d, 1H, J¼16.5 Hz), 5.39 (s, 1H),
5.45 (d, 1H, J¼10.7 Hz), 5.57 (d, 1H, J¼17.6 Hz), 5.91 (s, 1H), 6.76 (dd,
1H, J1¼17.6 Hz, J2¼10.7 Hz), 7.14–7.25 (m, 2H), 7.36 (d, 1H, J¼7.2 Hz),
7.58 (d, 1H, J¼6.9 Hz), 7.90 (br s, 1H). 13C NMR (CDCl3, 75 MHz)
(m, 1H), 2.77 (t, 1H, J¼9.1 Hz), 2.79–2.87 (m, 1H), 2.99–3.11 (m, 3H),
3.44 (t, 1H, J¼9.1 Hz), 3.61–3.72 (m, 1H), 3.75 (s, 3H), 3.82 (s, 3H), 5.38
(s,1H), 6.03 (br s,1H), 7.11 (d, 2H, J¼8.5 Hz), 7.22–7.34 (m, 3H), 7.54 (d,
2H, J¼8.0 Hz), 8.16 (d, 1H, J¼8.5 Hz). NOE (H5.38/H3.61–3.72, 4.3%). 13
C
NMR (CDCl3, 75 MHz)
d (ppm): 18.8, 21.5, 28.9, 39.1, 46.1, 52.2, 52.3,
d
(ppm): 15.8, 44.0, 53.8, 59.9, 107.5, 110.8, 114.9, 118.0, 119.3, 121.6,
54.2, 59.2, 115.8, 118.1, 118.5, 120.3, 124.1, 124.7, 126.5, 127.7, 129.5,
130.6, 132.5, 133.9, 135.8, 137.1, 138.2, 144.7, 167.7, 168.1. IR (KBr) 1720,
1630 cmꢂ1. Anal. Calcd for C29H28N2O6S (532.61): C, 65.40; H, 5.30; N,
5.26. Found: C, 65.73; H, 5.15; N, 5.48.
127.0, 129.5, 133.5, 134.0, 135.6, 141.4. IR (film)
n .
3450, 1620 cmꢂ1
Anal. Calcd for C16H16N2 (236.31): C, 81.32; H, 6.82; N, 11.85. Found:
C, 81.47; H, 6.70; N, 11.99.
4.3.6. Synthesis of 1-isopropenyl-5,6,11,11b-tetrahydro-3H-
indolizino[8,7-b]indole, 33b
Following the same procedure than for the synthesis of 33a,
from 15b (0.27 g, 0.67 mmol) and EtONa (1.37 g, 20.10 mmol), and
upon purification by chromatography on silica gel (EtOAc), giving
33b (106 mg, 63%) as a brown wax. 1H NMR (CDCl3, 300 MHz)
4.3.8.4. Dimethyl (7aR
6H-6a,12-diazaindeno[1,2-a]fluorene-8,9-dicarboxylate, 35b. 1H NMR
(CDCl3, 300 MHz) (ppm): 2.29 (s, 3H), 2.48–2.58 (m, 1H), 2.63–2.69
*
,11bR )-12-tosyl-5,7,7a,10,11b,12-hexahydro-
*
d
(m,1H), 2.79–2.87 (m,1H), 2.99–3.11 (m, 3H), 3.15–3.28 (m, 2H), 3.61–
3.72 (m, 1H), 3.75 (s, 3H), 3.78 (s, 3H), 5.38 (s,1H), 6.40 (br s,1H), 7.10
(d, 2H, J¼8.2 Hz), 7.22–7.34 (m, 3H), 7.48 (d, 2H, J¼8.2 Hz), 8.05 (d,1H,
J¼7.7 Hz).
d
(ppm): 2.06 (s, 3H), 2.67 (dd, 1H, J1¼16.0 Hz, J2¼4.4 Hz), 3.06–3.18
(m, 1H), 3.33–3.51 (m, 2H), 3.77 (dd,1H, J1¼14.3 Hz, J2¼2.8 Hz), 3.87
(d, 1H, J¼16.5 Hz), 5.33–5.43 (m, 3H), 5.93 (s, 1H), 7.14–7.24 (m, 2H),
7.36 (dd, 1H, J1¼7.1 Hz, J2¼1.1 Hz), 7.58 (dd, 1H, J1¼7.2 Hz, J2¼1.1 Hz),
4.4. Rearrangement reaction using an activated alkyne
7.99 (br s, 1H). 13C NMR (CDCl3, 75 MHz)
d (ppm): 15.8, 20.6, 44.0,
54.2, 60.8, 107.3, 110.8, 113.2, 117.9, 119.2, 121.5, 126.6, 127.0, 134.2,
4.4.1. Reaction of 11-tosyl-1-vinyl-5,6,11,11b-tetrahydro-3H-
indolizino[8,7-b]indole, 15a
135.4, 140.6, 143.0. IR (film)
n
3450, 1620, 1600 cmꢂ1. Anal. Calcd for
C17H18N2 (250.34): C, 81.56; H, 7.25; N, 11.19. Found: C, 81.44; H,
7.00; N, 11.32.
4.4.1.1. Procedure A. Treatment of 15a (0.10 g, 0.26 mmol) with
DMAD (0.06 mL, 0.51 mmol) in 10 mL of DCM (24 h) gave, upon
elimination of the solvent, a crude mixture containing 16a, 36a,
38a, and 35b in the following ratio as calculated from integration of
well resolved 1H NMR signals (2:11:5:1). Separation of this mixture
by flash chromatography (hexane/EtOAc, 4:1), afforded pure 16a
(5 mg, 5%) as yellow solid (mp 85 ꢁC, dec), 36a (77 mg, 56%) as
brown wax, and 38a (23 mg, 17%) as yellow oil, which decomposed
after few hours.
4.3.7. Synthesis of diethyl 11-methyl-5,7,7a,10,11b,12-hexahydro-
6H-6a,8,9,12-tetraaza-indeno[1,2-a]fluorene-8,9-dicarboxylate, 34
Treatment of 33 (61 mg, 0.25 mmol) and diethyl azodicarboxy-
late (0.05 mL, 0.29 mmol) at rt, gave after 24 h, upon removal of the
solvent and after flash chromatography (hexane/EtOAc, 9:1 to 4:1),
pure 34 (58 mg, 56%) as a yellow oil, which begun its trans-
formation into other products in minutes. 1H NMR (CDCl3,

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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3389
4.4.1.2. Procedure B. To a solution of 15a (0.10 g, 0.26 mmol) in THF
(6 mL) was added DMAD (0.06 mL, 0.51 mmol) and the mixture was
stirred for 3 days at rt. The solvent was removed under vacuum
giving a crude mixture containing 16a, 36a, and 35b, in the fol-
lowing ratios as calculated from integration of well resolved 1H
NMR signals (1:3:1). Separation by silica gel flash chromatography
(hexane/EtOAc, 4:1 to 1:1), afforded pure 16a (11 mg, 11%) and 36a
(58 mg, 42%).
J1¼11.0 Hz, J2¼1.6 Hz), 5.47 (s, 1H), 5.57 (dd, 1H, J1¼11.5 Hz,
J2¼1.6 Hz), 5.59 (dd, 1H, J1¼17.6 Hz, J2¼1.6 Hz), 6.67 (dd, 1H,
J1¼17.6 Hz, J2¼11.0 Hz), 6.95–7.03 (m, 3H), 7.11–7.28 (m, 3H), 7.50
(d, 2H, J¼8.2 Hz), 7.93 (d, 1H, J¼7.7 Hz). DEPT 135-NMR (CDCl3,
75 MHz) d (ppm): 21.5 (CH3), 29.7 (CH2), 49.0 (CH2), 51.0 (CH3), 52.0
(CH), 53.2 (CH3), 119.2 (CH), 120.7 (CH2), 121.3 (CH2), 124.6 (CH),
125.8 (CH), 127.2 (CH), 127.4 (CH), 128.9 (CH),132.0 (CH), 132.7 (CH).
IR (film) 1730, 1615 cmꢂ1
.
4.4.1.3. Procedure C. To a solution of 15a (0.10 g, 0.26 mmol) in THF
(6 mL) was added DMAD (0.06 mL, 0.51 mmol) and the mixture was
stirred for 2 days at refluxing temperature. The solvent was re-
moved under vacuum giving a crude mixture containing 16a, 37a,
and 35b, in the following ratios as calculated from integration of
well resolved 1H NMR signals (3:5:1). Separation by silica gel flash
chromatography (hexane/EtOAc, 4:1 to 1:1), afforded pure 16a
(16 mg, 16%) and 37a (63 mg, 46%).
4.4.2. Reaction of 1-isopropenyl-11-tosyl-5,6,11,11b-tetrahydro-3H-
indolizino[8,7-b]indole, 15b
Treatment of 15b (0.13 g, 0.33 mmol) with DMAD (0.08 mL,
0.66 mmol) in 10 mL of DCM at rt (2 days) gave, upon elimination of
the solvent, a crude mixture containing 16b, 36b, and 38b, in the
following ratios as calculated from integration of well resolved 1H
NMR signals (1:16:3). Separation by flash chromatography (hex-
ane/EtOAc, 4:1 to 2:1) gave pure 36b (94 mg, 52%) as yellow solid
(mp 160–162 ꢁC) and 38b (14 mg, 8%) as yellow oil, which
decomposed in a few hour.
4.4.1.4. Procedure D. To a solution of 7a (0.39 g, 1.0 mmol) in tolu-
ene (100 mL) was added [Ru]-II (0.04 g, 0.05 mmol) and the mix-
ture was stirred for 4 days. Then, DMAD (0.24 mL, 2.0 mmol) was
added and the mixture was heated at 60 ꢁC for 5 h. The crude was
filtered off through a Celite pad and washed with EtOAc (30 mL).
The solvent was removed under reduced pressure giving a crude
mixture containing 15a, 16a, and 36a, in the following ratios as
calculated from integration of well resolved 1H NMR signals
(4:1:12). Separation by silica gel flash chromatography (hexane/
EtOAc, 4:1 to EtOAc) afforded pure 15a (32 mg, 8%) as yellow solid
(mp 85 ꢁC, dec) and 36a (0.21 g, 41%).
4.4.2.1. Dimethyl
cyclo[12,2,2,01,9,02,7]octadeca-2,4,6,9,11,15-hexaene-15,16-dicarboxy-
late, 36b. 1H NMR (CDCl3, 300 MHz)
(ppm): 0.83–0.92 (m, 1H),
(9E,11Z)-8-tosyl-11-isopropenyl-8,14-diazatetra-
d
1.36–1.46 (m, 1H), 1.83 (s, 3H), 2.38 (s, 3H), 2.93–3.12 (m, 2H), 3.35
(s, 3H), 3.57–3.64 (m, 1H), 3.70–3.86 (m, 1H), 3.74 (s, 3H), 4.90 (s,
1H), 4.94 (s, 1H), 5.57 (t, 1H, J¼6.6 Hz), 6.69 (s, 1H), 6.85 (d, 1H,
J¼7.7 Hz), 7.06 (t, 1H, J¼7.7 Hz), 7.20–7.28 (m, 3H), 7.66 (d, 2H,
J¼8.2 Hz), 7.84 (d, 1H, J¼8.2 Hz). NOE (H6.69/H4.94, 7.0%; H5.57
/
H1.83, 9.3%). 13C NMR (CDCl3, 75 MHz)
d (ppm): 21.5 (2C), 38.7, 48.5,
49.2, 51.4, 51.7, 52.6, 114.8, 117.1, 119.0, 121.7, 122.2, 124.2, 125.1,
127.2, 128.0, 129.4, 135.3, 135.9, 139.4, 140.2, 141.0, 144.7, 146.3,
146.8, 164.5, 166.4. IR (KBr) 1720, 1610 cmꢂ1. Anal. Calcd for
C30H30N2O6S (546.64): C, 65.92; H, 5.53; N, 5.12. Found: C, 65.82; H,
5.69; N, 5.01.
4.4.1.5. Dimethyl (9E,11Z)-8-tosyl-11-vinyl-8,14-diazatetracyclo[12,-
2,2,01,9,02,7]octadeca-2,4,6,9,11,15-hexaene-15,16-dicarboxylate,
36a. 1H NMR (CDCl3, 300 MHz)
d (ppm): 0.60–0.67 (m, 1H), 1.42–
1.52 (m, 1H), 2.38 (s, 3H), 2.94–3.15 (m, 2H), 3.35 (s, 3H), 3.61–3.70
(m, 1H), 3.76 (s, 3H), 3.80–3.86 (m, 1H), 5.05 (d, 1H, J¼10.4 Hz), 5.20
(d, 1H, J¼17.0 Hz), 5.55 (t, 1H, J¼5.8 Hz), 6.29 (dd, 1H, J1¼17.0 Hz,
J2¼10.4 Hz), 6.83 (d, 1H, J¼7.1 Hz), 6.86 (s, 1H), 7.07 (t, 1H, J¼7.4 Hz),
7.21 (d, 2H, J¼8.2 Hz), 7.28 (t, 1H, 7.1 Hz), 7.65 (d, 2H, J¼8.2 Hz), 7.88
(d, 1H, J¼7.7 Hz). NOE (H6.86/H5.20, 6.4%). 13C NMR (CDCl3,
4.4.2.2. Dimethyl 1-isopropenyl-11-tosyl-1-vinyl-5,6,11,11b-tetrahydro-
1H-indolizino[8,7-b]indole-2,3-dicarboxylate, 38b. 1H NMR (CDCl3,
300 MHz)
d
(ppm): 1.99 (s, 3H), 2.22 (s, 3H), 2.72 (dd, 1H, J1¼17.0 Hz,
J2¼4.9 Hz), 3.13–3.17 (m, 1H), 3.53–3.66 (m, 1H), 3.64 (s, 3H), 3.73–
3.94 (m, 1H), 4.04 (s, 3H), 5.40 (dd, 1H, J1¼11.0 Hz, J2¼1.6 Hz), 5.43 (d,
1H, J¼1.6 Hz), 5.44 (d, 1H, J¼1.6 Hz), 5.50 (dd, 1H, J1¼17.0 Hz,
J2¼1.6 Hz), 5.57 (s, 1H), 6.67 (dd, 1H, J1¼17.0 Hz, J2¼11.0 Hz), 6.96 (d,
2H, J¼8.2 Hz), 7.13–7.27 (m, 3H), 7.48 (d, 2H, J¼8.2 Hz), 7.84 (d, 1H,
75 MHz)
d (ppm): 21.6, 37.9, 48.4, 48.5, 51.4, 52.4, 52.7, 115.1, 116.7,
117.2, 121.2, 121.6, 125.0, 127.2, 127.5, 128.1, 129.5, 135.3, 135.4, 135.7,
139.4, 141.3, 142.1, 144.7, 146.9, 164.8, 166.2. IR (film): 1730, 1610,
1590 cmꢂ1. Anal. Calcd for C29H28N2O6S (532.61): C, 65.40; H, 5.30;
N, 5.26. Found: C, 65.81; H, 5.05; N, 5.55.
J¼7.7 Hz). IR (film) 1720, 1610 cmꢂ1
.
4.4.1.6. Dimethyl (9Z,11Z)-8-tosyl-11-vinyl-8,14-diazatetracyclo[12,2,-
4.4.3. Synthesis of dimethyl 1-isopropenyl-1-vinyl-5,6,11,11b-
tetrahydro-1H-indolizino[8,7-b]indole-2,3-dicarboxylate, 39
Treatment of 33b (90 mg, 0.36 mmol) with DMAD (0.07 mL,
0.54 mmol) in 10 mL of DCM at rt (2 days) gave, upon elimination of
the solvent and after flash chromatography (hexane/EtOAc, 4:1)
compound 39 (65 mg, 51%) as yellow oil, which decomposed in
2,01,9,02,7]octadeca-2,4,6,9,11,15-hexaene-15,16-dicarboxylate, 37a. 1H
NMR (CDCl3, 300 MHz)
d
(ppm): 0.90 (dd, 1H, J1¼14.3 Hz,
J2¼3.8 Hz), 2.19–2.32 (m, 1H), 2.39 (s, 3H), 2.79 (s, 3H), 3.03 (dd, 1H,
J1¼13.7 Hz, J2¼7.1 Hz), 3.50 (dd, 1H, J1¼13.7 Hz, J2¼8.2 Hz), 3.80–
4.06 (m, 2H), 3.86 (s, 3H), 5.15 (d, 1H, J¼10.4 Hz), 5.31 (d, 1H,
J¼17.6 Hz), 5.88 (t, 1H, J¼7.7 Hz), 6.39 (dd, 1H, J1¼17.6 Hz,
J2¼10.4 Hz), 6.76 (d, 1H, J¼7.1 Hz), 6.98 (td, 1H, J1¼7.7 Hz, J2¼1.1 Hz),
7.05 (s, 1H), 7.24–7.30 (m, 3H), 7.73 (d, 2H, J¼8.2 Hz), 7.99 (d, 1H,
a few hours. 1H NMR (CDCl3, 300 MHz)
d (ppm): 2.05 (br s, 3H), 2.80
(dd, 1H, J1¼16.5 Hz, J2¼3.3 Hz), 3.15–3.28 (m, 1H), 3.54 (dd, 1H,
J1¼13.7 Hz, J2¼3.3 Hz), 3.60 (s, 3H), 3.80–3.87 (m, 1H), 4.00 (s, 3H),
5.30–5.41 (m, 4H), 5.66 (s, 1H), 6.67 (dd, 1H, J1¼17.6 Hz, J2¼10.4 Hz),
7.10 (td, 1H, J1¼7.1 Hz, J2¼1.1 Hz), 7.22 (td, 1H, J1¼7.1 Hz, J2¼1.1 Hz),
7.32 (d, 1H, J¼8.2 Hz), 7.47 (d, 1H, J¼7.7 Hz), 8.88 (br s, 1H). DEPT
J¼7.7 Hz). NOE (H6.39/H5.88, 14.8%; /H5.15, 6.8%), (H7.05/H5.31
,
8.3%). 13C NMR (CDCl3, 75 MHz)
d (ppm): 21.6, 28.0, 34.8, 45.9, 51.5,
53.0, 71.0, 107.5, 107.6, 114.6, 115.4, 123.5, 124.8, 127.2, 127.6, 128.8,
129.5, 133.2, 134.5, 137.3, 140.4, 140.9, 144.9, 151.3, 158.8, 164.8,
170.5. IR (film): 1730, 1610, 1590 cmꢂ1. Anal. Calcd for C29H28N2O6S
(532.61): C, 65.40; H, 5.30; N, 5.26. Found: C, 65.55; H, 5.43; N, 5.14.
135-NMR (CDCl3, 75 MHz)
d (ppm): 22.7 (CH3), 29.7 (CH2), 46.7
(CH2), 50.7 (CH), 51.0 (CH3), 53.0 (CH3), 111.1 (CH), 118.9 (CH2), 120.1
(CH), 123.8 (CH2), 126.2 (CH), 136.3 (CH), 141.9 (CH). IR (film) 1720,
1610 cmꢂ1
n
.
4.4.1.7. Dimethyl
dolizino[8,7-b]indole-2,3-dicarboxylate, 38a. 1H NMR (CDCl3,
300 MHz)
11-tosyl-1,1-divinyl-5,6,11,11b-tetrahydro-1H-in-
4.4.4. Synthesis of dimethyl 1-vinyl-6,7,12,12b-tetrahydro-3H-
5a,12-diazabenzo[b]cyclohepta[g]indene-4,5-dicarboxylate, 40
d
(ppm): 2.22 (s, 3H), 2.73 (dd, 1H, J1¼17.0 Hz, J2¼4.9 Hz),
3.08–3.19 (m, 1H), 3.56–3.76 (m, 1H), 3.64 (s, 3H), 3.81–3.94 (m,
Treatment of 33a (0.10 g, 0.45 mmol) with DMAD (0.11 mL,
1H), 4.04 (s, 3H), 5.34 (dd, 1H, J1¼17.6 Hz, J2¼1.6 Hz), 5.44 (dd, 1H,
0.92 mmol) in 10 mL of DCM at rt (4 days) gave, upon elimination of

´
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A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3390
the solvent and after flash chromatography (hexane/EtOAc, 4:1)
7.18 (d, 2H, J¼7.9 Hz), 7.26 (td, 1H, J1¼7.6 Hz, J2¼1.2 Hz), 7.59 (d, 2H,
pure 40 (127 mg, 58%) as red solid (mp 198–200 ꢁC). 1H NMR
J¼8.5 Hz), 7.90 (d, 1H, J¼7.9 Hz). IR (film) 1720, 1640 cmꢂ1
.
(CDCl3, 300 MHz)
d (ppm): 3.07–3.11 (m, 2H), 3.37–3.41 (m, 2H),
3.64 (s, 3H), 3.66–3.72 (m, 2H), 3.79 (s, 3H), 4.64 (br s, 1H), 5.22 (d,
1H, J¼11.0 Hz), 5.51 (s, 1H), 5.52 (d, 1H, J¼17.6 Hz), 6.46 (dd, 1H,
J1¼17.6 Hz, J2¼11.0 Hz), 7.08–7.18 (m, 2H), 7.28 (dd, 1H, J1¼7.4 Hz,
J2¼1.6 Hz), 7.46 (d, 1H, J¼7.1 Hz), 7.68 (br s, 1H). 13C NMR (CDCl3,
Acknowledgements
Funding of this project by Spanish MEC (No. CTQ2006-00601/
BQU) is acknowledged. A.G.G. thanks Spanish MEC and FUSP-CEU
for a pre-doctoral fellowship. We thank Dr. Ulises Amador for X-ray
analysis.
75 MHz) d (ppm): 22.5, 29.7, 50.9, 51.4, 52.9, 54.1, 110.5, 112.6, 117.6,
119.3, 121.6, 127.0, 127.1, 127.7, 129.0, 132.4, 135.7, 139.1, 140.7, 153.6,
166.1, 168.0. IR (KBr)
n
3380, 1740, 1570 cmꢂ1. Anal. Calcd for
C22H22N2O4 (378.42): C, 69.83; H, 5.86; N, 7.40. Found: C, 70.02; H,
5.63; N, 7.66.
Supplementary data
Experimental procedures and spectroscopic data for com-
pounds 1–13 and spectra for new compounds. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2009.02.051.
4.4.5. Reaction of 11-tosyl-1-vinyl-5,6,11,11b-tetrahydro-3H-
indolizino[8,7-b]indole, 15a with 3-butyn-2-one
Treatment of 15a (0.20 g, 0.51 mmol) and 3-butyn-2-one
(0.08 mL, 1.03 mmol) in 10 mL of DCM at rt (24 h) gave, upon
elimination of the solvent and after flash chromatography (hexane/
EtOAc, 4:1), pure 41 (126 mg, 53%) as yellow oil.
References and notes
1. (a) Hesse, M. Alkaloids: Nature’s Curse or Blessing; Verlag Helvetica Chimica Acta,
Wiley-VCH: Zurich, 2002; (b) The Chemistry of Heterocyclic Compounds; Saxton,
J. E., Ed.; Wiley: Chichester, UK, 1994; Part 4, supplement of, Vol. 25; (c) Lou-
nasmaa, M.; Hanhinen, P.; Westersund, M. The Alkaloids. In The Sarpagine Group
of Indole Alkaloids; Cordell, G. A., Ed.; Academic: San Diego, CA, 1999; Vol. 52;
(d) Bi, Y.; Hamaker, L. K.; Cook, J. M. Studies in Natural Products Chemistry,
Bioactive Natural Products, Part A. In The Synthesis of Macroline Related Alka-
loids; Basha, F Z., Rahman, A., Eds.; Elsevier Science: Amsterdam, 1993; Vol. 13,
p 383; (e) The Chemistry and Biology of Isoquinoline Alkaloids; Philipson, J. D.,
Roberts, M. F., Zenk, M. H., Eds.; Springer: New York, NY, 1985; (f) Indole and
Biogenetically Related Alkaloids; Philipson, J. D., Zenk, M. H., Eds.; Academic:
London, 1980; (g) Introduction to Alkaloids: A Biosynthetic Approach; Cordell,
G. A., Ed.; Wiley: New York, NY, 1981; (h) Saxton, J. E. In The Alkaloids: Chemistry
and Biology; Cordell, G. A., Ed.; Academic: San Diego, CA, 1998; Vol. 51, pp 1–
197; (i) Lounasmaa, M.; Tolvanen, A. The Alkaloids. In Eburnamine–Vincamine
Alkaloids; Cordell, G A., Ed.; Academic: San Diego, CA, 1992; Vol. 42.
2. Hassani, M.; Cai, W.; Koelsch, K. H.; Holley, D. C.; Rose, A. S.; Olang, F.; Line-
swala, J. P.; Holloway, W. G.; Gerdes, J. M.; Behforouz, M.; Beall, H. D. J. Med.
Chem. 2008, 51, 3104–3115 and references cited therein.
4.4.5.1. 4-[11-Tosyl-1-vinyl-6,11-dihydro-3H,5H-indolizino[8,7-b]in-
dol-11b-yl]-but-3-en-2-one, 41. 1H NMR (CDCl3, 300 MHz)
d (ppm):
2.26 (s, 3H), 2.38 (s, 3H), 2.46 (dd, 1H, J1¼17.1 Hz, J2¼4.9 Hz), 3.07–
3.42 (m, 3H), 3.48 (d, 1H, J¼13.4 Hz), 3.61 (d, 1H, J¼13.4 Hz), 5.20
(dd, 1H, J1¼11.0 Hz, J2¼1.2 Hz), 5.44 (dd, 1H, J1¼17.1 Hz, J2¼1.2 Hz),
6.02 (br s, 1H), 6.37 (d, 1H, J¼15.8 Hz), 6.95 (dd, 1H, J1¼17.1 Hz,
J2¼11.0 Hz), 7.06 (d, 2H, J¼7.9 Hz), 7.17–7.32 (m, 3H), 7.36 (d, 2H,
J¼8.5 Hz), 7.65 (d, 1H, J¼15.9 Hz), 7.98 (d, 1H, J¼7.9 Hz). 13C NMR
(CDCl3, 75 MHz)
d (ppm): 18.2, 21.4, 27.2, 39.7, 52.9, 71.8, 115.8,
116.8,118.7,124.1,124.5,125.3,125.9,126.7,129.2,130.4,130.6,131.8,
134.4, 137.2, 138.7, 144.3, 144.4, 148.1, 199.4. IR (film) 1670, 1620,
1590 cmꢂ1. Anal. Calcd for C27H26N2O3S (458.57): C, 70.72; H, 5.71;
N, 6.11. Found: C, 70.59; H, 5.53; N, 6.36.
3. Gupta, L.; Srivastava, K.; Singh, S.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med.
Chem. Lett. 2008, 18, 3306–3309 and references cited therein.
4. Trujillo, J. I.; Meyers, M. J.; Anderson, D. R.; Hegde, S.; Mahoney, M. W.; Vernier,
W. F.; Buchler, I. P.; Wu, K. K.; Yang, S.; Hartmann, S. J.; Reitz, D. B. Bioorg. Med.
Chem. Lett. 2007, 17, 4657–4663.
5. Gautschi, E.; Goldberg, D. R.; Kashem, M. A.; Lukas, S.; Mao, W.; Martin, L.;
Morwick, T.; Moss, N.; Pargellis, C.; Patel, U. R.; Patnaude, L.; Peet, G. W.; Skow,
D.; Snow, R. J.; Ward, Y.; Werneburg, B.; White, A. Bioorg. Med. Chem. Lett. 2007,
17, 4664–4669.
6. Di Fabio, R.; Micheli, F.; Alvaro, G.; Cavanni, P.; Donati, D.; Gagliardi, T.; Fontana,
G.; Giovannini, R.; Maffeis, M.; Mingardi, A.; Tranquillini, M. E.; Vitulli, G. Bioorg.
Med. Chem. Lett. 2007, 17, 2254–2259.
4.4.6. Reaction of 2-allyl-9-tosyl-1-vinyl-2,3,4,9-tetrahydro-1H-b-
carboline, 8 with DMAD
Treatment of
8 (0.25 g, 0.64 mmol) and DMAD (0.16 mL,
1.28 mmol) in 10 mL of DCM at rt (16 h) gave, upon elimination of
the solvent a crude mixture containing 42 and 43, in the following
ratios as calculated from integration of well resolved 1H NMR sig-
nals (1:3). Separation by flash chromatography (hexane/EtOAc, 2:1)
afforded pure 42 (33 mg, 10%) as yellow oil and 43 (83 mg, 24%) as
yellow oil, which decomposed after few hours.
7. Bringmann, G.; Feineis, D.; Bru¨ckner, B.; Blank, M.; Peters, K.; Peters, E. M.;
Reichmann, H.; Janetzky, B.; Grote, C.; Clement, H.-W.; Wesemann, W. Bioorg.
Med. Chem. 2000, 8, 1467–1478.
8. For reviews on olefin metathesis, see: (a) Bieniek, M.; Michrowska, A.; Usanov,
D. L.; Grela, K. Chem.dEur. J. 2008, 14, 806–818; (b) Katz, T. J. Angew. Chem., Int.
Ed. 2005, 44, 3010–3019; (c) Schrock, R. R. J. Mol. Catal. A: Chem. 2004, 213, 21–
30; (d) Hoveyda, A.H.; Schrock, R.R. In Comprehensive Asymmetric Catalysis,
2004; Suppl 1, pp 207–233; (e) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140;
(f) Grubbs, R. H.; Trnka, T. M. In Ruthenium in Organic Synthesis; Murahashi, S.-I.,
Ed.; Wiley-VCH: Weinheim, 2004; Chapter 6.
9. Evans, P.; Grigg, R.; York, M. Tetrahedron Lett. 2000, 41, 3967–3970.
10. Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867–8878.
11. Gonza´lez-Go´ mez, A.; Domı´nguez, G.; Pe´rez-Castells, J. Tetrahedron Lett. 2005,
46, 7267–7270.
12. (a) Boyer, F.-D.; Hanna, I. Org. Lett. 2007, 9, 715–718; (b) Yang, Y. K.; Choi, J. H.;
Tae, J. J. Org. Chem. 2005, 70, 6995–6998; (c) Rosillo, M.; Domı´nguez, G.;
4.4.6.1. Dimethyl (4E,7E)-3-allyl-9-tosyl-2,3,6,9-tetrahydro-1H-aze-
cino[5,4-b]indole-4,5-dicarboxylate, 42. 1H NMR (CDCl3, 300 MHz)
d
(ppm): 2.32 (s, 3H), 2.64–2.79 (m, 2H), 2.80–3.06 (m, 2H), 3.21–
3.37 (m, 1H), 3.38–3.55 (m, 2H), 3.75 (s, 3H), 3.83 (s, 3H), 3.92–4.09
(m, 1H), 5.08 (d, 1H, J¼10.4 Hz), 5.16 (d, 1H, J¼17.1 Hz), 5.27–5.37
(m, 1H), 5.69–5.82 (m, 1H), 6.79 (d, 1H, J¼16.5 Hz), 7.16 (d, 2H,
J¼8.5 Hz), 7.21–7.35 (m, 3H), 7.69 (d, 2H, J¼8.5 Hz), 8.20 (d, 1H,
J¼7.9 Hz). NOE (H6.79/H5.27–5.37, 0.0%). 13C NMR (CDCl3, 75 MHz)
d
(ppm): 21.5, 24.3, 32.6, 51.2, 52.1, 52.5, 60.4, 114.8, 115.5, 117.5,
118.4, 123.1, 123.4, 123.6, 125.0, 126.7, 127.9, 129.6, 131.1, 134.4, 135.1,
135.3, 135.6, 144.7, 150.5, 166.8, 168.9. IR (film) 1730, 1620 cmꢂ1
.
Anal. Calcd for C29H30N2O6S (534.62): C, 65.15; H, 5.66; N, 5.24.
Found: C, 65.34; H, 5.47; N, 5.32.
´
Casarrubios, L.; Amador, U.; Perez-Castells. J. Org. Chem. 2004, 69, 2084–2093.
13. Gonza´lez-Go´mez, A.; Domı´nguez, G.; Amador, U.; Pe´rez-Castells, J. Tetrahedron
Lett. 2008, 49, 5467–5470.
14. The reaction of tryptamine with ethylformate gives a formamide, which when
treated with NaH and allyl bromide gives a mixture of 1, 2, and 3. With a careful
selection of the reaction conditions mono- or diallyl products can become
major products selectively. Compound 5 was obtained by reaction with excess
propargyl bromide. See Supplementary data for details.
4.4.6.2. Dimethyl 1-tosyl-10-allyl-2-(prop-2-en-1-ylidene)-1,2,50,60-
tetrahydro-10H-spiro[indole-3,40-pyridine]-20,30-dicarboxylate,
43. 1H NMR (CDCl3, 300 MHz)
d
(ppm): 0.60 (dt, 1H, J1¼14.0 Hz,
J2¼3.6 Hz),1.50 (dd,1H, J1¼13.4 Hz, J2¼4.3 Hz), 2.35 (s, 3H), 2.86 (dt,
1H, J1¼12.8 Hz, J2¼4.3 Hz), 3.12 (td, 1H, J1¼12.8 Hz, J2¼3.6 Hz), 3.23
(s, 3H), 3.63–3.87 (m, 2H), 3.89 (s, 3H), 5.09 (dd, 1H, J1¼9.8 Hz,
J2¼1.8 Hz), 5.20–5.29 (m, 3H), 5.76–5.87 (m, 1H), 6.58–6.71 (m, 1H),
6.82 (d, 1H, J¼11.6 Hz), 6.91 (d, 1H, J¼6.7 Hz), 7.06 (t, 1H, J¼7.3 Hz),
15. Alternatively to the synthesis of 6a and 6b from 1, as this starting material is
obtained in low yield, dihydro-
rivative, and reacted with an alkynylmagnesium bromide. The resulting 1-
ethynyl or 1-(1-propynyl)-9-tosyltetrahydro- -carboline was allylated giving
b-carboline was protected as the tosyl de-
b
6a and 6b in a global yield of 42 and 49%, respectively.
16. Compain, P. Adv. Synth. Catal. 2007, 349, 1829–1846.

´
´
´
A. Gonzalez-Gomez et al. / Tetrahedron 65 (2009) 3378–3391
3391
17. See: (a) Mori, M.; Kuzuba, Y.; Kitamura, T.; Sato, Y. Org. Lett. 2002, 4, 3855–3858;
(b) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803–805; (c) Nun˜ez, A.; Cuadro,
A. M.; Alvarez-Builla, J.; Vaquero, J. J. Chem. Commun. 2006, 2690–2692.
18. Alcaide, B.; Almendros, P. Chem.dEur. J. 2003, 9, 1258–1262.
19. Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.;Wojtasiewicz, K.; Leniewski, A.; Maurin,
J. K.; Czarnocki, Z.; Drabowicz, J. Tetrahedron: Asymmetry 2007, 18, 406–413.
20. Although it was generally accepted that enyne metathesis reactions follow an
yne-ene pathway involving initial coordination of the alkyne to the metal,
there is actually evidence for an ene-yne pathway, see: Sohn, J. H.; Kim, K. H.;
Lee, H. Y.; No, Z. S.; Ihee, H. J. Am. Chem. Soc. 2008, 130, 16506–16507 and
references cited therein.
Unfortunately we observed no reaction after 3 days, recovering the starting
material unchanged.
23. Compound 37a appeared as a minor product in the reaction of 15a with DMAD
in the presence of BF3$OEt2. This reaction gave a mixture of 15a, 37a, 35a, and
35b, in the following ratios (2:3:2:1). From this mixture, 15a (10%), 37a (27%),
and 35a (13%) were isolated.
24. (a) Voskressensky, L. G.; Voroviev, I. V.; Borisova, T. N.; Varlamov. J. Org. Chem.
2008, 73, 4596–4601; (b) Voskressensky, L. G.; Borisova, T. N.; Kulikova, L. N.;
Varlamov, A. V.; Catto, M.; Altomare, C.; Carotti, A. Eur. J. Org. Chem. 2004, 3128–
3135; (c) Voskressensky, L. G.; Borisova, T. N.; Kostenev, I. S.; Kulikova, L. N.;
Varlamov, A. V. Tetrahedron Lett. 2006, 47, 999–1001; (d) Voskressensky, L. G.;
Borisova, T. N.; Kostenev, I. S.; Vorobiev, I. V.; Varlamov, A. V. Tetrahedron Lett.
2005, 46, 1975–1979.
21. These kinds of oxidations have been used for the synthesis of aromatic compounds.
See:Donohoe, T. J.; Fishlock, L. P.;Procopiou, P. A. Chem.dEur. J. 2008,14, 5716–5726.
22. We also tried the reaction of 12 in the presence of Ti(OiPr)4, following a pro-
cedure described in: Yang, Q.; Xiao, W. J.; Yu, Z. Org. Lett. 2005, 7, 871–874.
25. For a recent review on Stevens rearrangement, see: Vanecko, J. A.; Wan, H.;
West, F. G. Tetrahedron 2006, 62, 1043–1062.