Novel domino reactions in β-carbolines with triple bonded dienophiles

Article abstract of DOI:10.1016/j.tetlet.2008.07.025

Vinylpyrrolo-[2,1-a]-β-carbolines 1 give different products upon reaction with dienophiles. With dimethyl acetylenedicarboxylate (DMAD), a novel domino process takes place, involving Michael attack and rearrangement, affording complex polycycles like 3, 4, and 5. Diels-Alder cycloadditions are favored in the presence of Lewis acids and are the only reactions with dimethyl maleate. When 3-butyn-2-one is used as dienophile, a Stevens rearrangement is observed giving product 9.

Full text of DOI:10.1016/j.tetlet.2008.07.025

Tetrahedron Letters 49 (2008) 5467–5470
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Novel domino reactions in b-carbolines with triple bonded dienophiles
*
Álvaro González-Gómez, Gema Domínguez, Ulises Amador, Javier Pérez-Castells
Departamento de Química, Facultad de Farmacia, Universidad San Pablo-CEU, Urb. Montepríncipe, 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:
Vinylpyrrolo-[2,1-a]-b-carbolines
1 give different products upon reaction with dienophiles. With
Received 17 June 2008
Revised 2 July 2008
Accepted 2 July 2008
Available online 6 July 2008
dimethyl acetylenedicarboxylate (DMAD), a novel domino process takes place, involving Michael attack
and rearrangement, affording complex polycycles like 3, 4, and 5. Diels–Alder cycloadditions are favored
in the presence of Lewis acids and are the only reactions with dimethyl maleate. When 3-butyn-2-one is
used as dienophile, a Stevens rearrangement is observed giving product 9.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Carbolines
Rearrangement
Domino reactions
Indoles
The tetrahydro-b-carboline system is present in numerous nat-
urally occurring alkaloids, many of which display useful and inter-
esting biological activities like mutagenic properties, significant
anti-tumor and anti-HIV activities, and inhibition of topoisomerase
I.1 Among the most widely used methods to build these kinds of
compounds are the classical Pictet–Spengler cyclization,2 the Bis-
chler–Napieralski reaction,3 and certain coupling reactions cata-
lyzed by palladium complexes.4 In particular, vinyl-substituted
tetrahydro-1H-b-carbolines are of prime importance for the con-
struction of b-carboline-containing compounds.5 1-Vinyl moieties
can be introduced through the Pictet–Spengler condensation, the
Bischler–Napieralski condensation/reduction sequence, or catalytic
cyclization of N,O-acetals.5,6
Thus, we reacted compound 1a with dimethyl acetylene dicar-
boxylate (DMAD) in toluene, observing total conversion of the
starting material into two new products after 3 days of stirring
at rt (conditions A, Table 1). None of the products were the
expected [4+2] cycloadducts. After convenient NMR studies, we
assigned them to structures 4a and 5a, the latter being an unstable
compound which decomposed in hours at rt (Scheme 1). This re-
sult showed that a rearrangement process had taken place involv-
ing the formation of intermediate charged species. Thus, we
changed the solvent to a more polar one. With THF no divinyl com-
pound 5a was detected and the isolated yield of 4a increased to
42%. In this reaction, we obtained an 11% yield of pyrrole 2a, which
comes from the oxidation of starting material, and we detected a
Diels–Alder product in the crude mixture, which could not be
completely purified (conditions B). The best yield in 4a was
achieved in DCM reaching 56% with isolation of 17% of 5a and
5% of 2a (conditions C). On the other hand, the reaction of 1a with
DMAD in refluxing THF gave a new product, 3a, jointly with a
small amount of 2a and traces of 7. Compound 3a, isolated in
46% yield, was an isomer of 4a that was assigned to its E isomer
(conditions D).
Next, we combined the enyne RCM reaction used for the syn-
thesis of 1a with the rearrangement process observed above in a
one-pot fashion (conditions E). Thus, reaction of 8 with 5% of Ru[II]
Grubbs’ catalyst and addition of DMAD after completion of the
metathesis gave compound 4a in 41% along with a small amount
of 2a. In addition, 8% of the metathesis product 1a was recovered.
The presence of the ruthenium species in this case hardly affects
the result of the reaction, slightly favoring the oxidation of 1a into
2a.
Previous work in our laboratories7 established the efficacy of
employing ring-closing metathesis (RCM)8 reactions for the con-
struction of fused nitrogen heterocycles such as 1a–b from suitable
substituted 1-vinyl-b-carbolines. The combination of RCM with
other cyclization processes such as Diels–Alder is a powerful syn-
thetic tool that we and others have used in synthesis of complex
molecules.9 Once we had achieved the construction of vinylpyr-
rolo-[2,1-a]-b-carbolines via enyne metathesis reactions, we
addressed the [4+2] cycloadditions of these compounds with
several dienophiles. Our aim was the synthesis of the structures
of alkaloids like those of the geissospermum group.10
* Corresponding author.
E-mail address: jpercas@ceu.es (J. Pérez-Castells).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.025

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The formation of 3a, 4a, and 5a is explained in Scheme 2.
Recently, Voskressenky described a rearrangement of b- and
c-
carbolines in the presence of DMAD that gave azocines upon
reaction with carbon 11b.11 The reaction begins with the nucleo-
philic attack to the DMAD that behaves as a Michael acceptor,
and subsequent reaction of the species A with carbon
a to the
nitrogen at the carboline system. This transformation required
the presence of methanol to stabilize the intermediate. In our
case, the process would start in the same way and, after the
formation of A, an intramolecular attack of this intermediate
either to carbon 6a (path a) or to carbon 1 (path b) would
give, respectively, compounds 4 and 5. The formation of com-
pound 3 only occurs under refluxing conditions or in the pres-
ence of a Lewis acid (vide infra). Thus, we assume that it
comes from the isomerization of 4, which is primarily formed
in the reaction.
With these results in hand, we carried out the same reactions in
the presence of a Lewis acid to avoid the nucleophilic attack of the
b-carboline nitrogen, thus favoring the Diels–Alder process. With
BF3, the crude reaction mixture showed a 2:1 ratio of Diels–Alder
adducts and product 3a (conditions F). With SnCl4, the formation
of 3a was avoided and both [4+2] adducts 6 and 7 were formed
in 2:1 ratio (conditions G). Adduct 6 was isolated in 27% yield,
while 7 was obtained unpurified with 6. The stereochemical
assignment of these two adducts was made with NOE experiments
and was further supported by an X-ray analysis of 6 (see Supple-
mentary data).
Finally, compound 1b gave, under conditions C, a mixture of
divinyl compounds 5b and 4b. The latter product could be crystal-
lized and submitted to X-ray diffraction analysis. This was used to
confirm the structure of 3a and 4a. An ORTEP drawing is shown in
Figure 1.
The rearrangement reaction was next effected with other dieno-
philes. Thus, compound 1a was reacted with 3-butyn-2-one in con-
ditions C (Table 1). The only reaction product was assigned to
structure 9 (53%). This product is the result of the quenching of
the intermediate B, due to the presence of acidic protons in the
media and subsequent Stevens rearrangement.12 This is a [1,2]
rearrangement of ammonium salts via ammonium ylides that nor-
mally needs the presence of a strong base. In our case, the stabiliza-
tion of the negative charge in ylide C makes it possible for the
process to take place in our reaction conditions. On the other hand,
the reaction of 1a in the same conditions with dimethyl maleate
gave a mixture of the four possible Diels–Alder adducts. The two
major isomers, 10 and 11, were isolated in 42% and 14% yields,
respectively, and their stereochemical assignment was made by
NOE experiments (Scheme 3).
Finally, we studied the reaction of 2-allyl-1-vinyl-b-carboline
12 with DMAD under conditions C. This substrate gave
a
mixture of products 13 and 14 in 1:3 ratio, 13 being an unstable
product. These products come, respectively, from the same rear-
rangement reaction. The intermediate D reacts either with carbon
6a (path a, Scheme 4) or with the vinyl moiety at carbon 1
(path b). The latter process was not observed with previous sub-
strates possibly because of conformational restraints of those
compounds.
In conclusion, a novel rearrangement process of vinyl b-
carbolines is shown. Upon convenient choice of reaction condi-
tions and reactants, these compounds give a Michael type addi-
tion followed by nucleophilic attack to one unsaturated carbon
which leads to new polycycles with high increase in skeletal
complexity. Alternatively, Stevens rearrangement or Diels–Alder
cycloadditions can be carried out. The complete study on
the scope and limitations of these reactions and further applica-
tions in natural alkaloid syntheses is underway in our
laboratory.

Á. González-Gómez et al. / Tetrahedron Letters 49 (2008) 5467–5470
5469
N
N
Mes N N Mes
Ph
Cl
Ru
N
Ts
N
1)
Cl
PCy3
Ts
DMAD
[Ru]-II
R
1a, R = H
8
2) DMAD
1b, R = Me
CO2Me
N
CO2Me
CO2Me
MeO2C
N
N
CO2Me
CO2Me
N
N
N
Ts
CO
2M
e
CO
2M
e
N
N
N
R
Ts
N
Ts
Ts
Ts
R
R
R
4
2
3
5
6, 7
Scheme 1. Reaction of compounds 1 with DMAD under different conditions and RCM-rearrangement domino reaction of 8.
E
E
6a
E
N
E
N
N
11b
N
Ts
A
1
Ts
R
R
1
E
E
E
(a)
E
E
E
N
N
N
Ts
N
Ts
4
R
A
Δ
R
(b)
E
E
N
E
N
N
Ts
N
Ts
E
R
R
5
3
Scheme 2. Mechanistic proposal for the rearrangement of 1 into 3, 4, and 5.
Figure 1. ORTEP diagram for compound 4b.
O
H
O
H
O
[1,2]
N
N
N
N
H
H
N
Ts
N
Ts
N
Ts
B
1a
C
9
O
(53%)
H
H
N
+
CO2Me
CO2Me
N
Ts
N
Ts
H
CO2Me
CO2Me
10
(24%)
11
(14%)
CO2Me
CO2Me
Scheme 3. Reactions of 1a with 3-butyn-2-one and dimethyl maleate.

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6a
References and notes
N
N
Ts
1
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12
E
E
E
E
E
N
E
N
N
N
Ts
Ts
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D
D
(a)
(b)
E
N
E
N
E
H
N
Ts
E
N
Ts
H
14
13
Scheme 4. Reaction of 12.
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Funding of this project by spanish MEC (No. CTQ2006-00601/
BQU) is acknowledged. A.G.G. thanks spanish MEC for a pre-doc-
toral fellowship.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic data and spectra for new compounds as well as CIF files
for structures 4b and 6) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.07.025.
12. For a recent review on Stevens rearrangement, see: Vanecko, J. A.; Wan, H.;
West, F. G. Tetrahedron 2006, 62, 1043–1062.