New MCR-Heck-isomerization cascade toward indoles

Article abstract of DOI:10.1021/ol801217a

(Chemical Equation Presented) The use of ortho-iodonitrophenol in Ugi-Smiles reaction coupled with Heck cyclization gives new access to indole scaffolds. The sequence can be performed in a one-pot reaction if the residual isocyanide is neutralized prior to the addition of the palladium catalyst.

Full text of DOI:10.1021/ol801217a

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3417-3419
New MCR-Heck-Isomerization
Cascade toward Indoles
Laurent El Kaim,* Marion Gizzi, and Laurence Grimaud*
Laboratoire Chimie et Proce´de´s, Ecole Nationale Supe´rieure de Techniques AVance´es,
32 Bd Victor, 75739 Paris Cedex 15, France
laurent.elkaim@ensta.fr; laurence.grimaud@ensta.fr
Received May 29, 2008
ABSTRACT
The use of ortho-iodonitrophenol in Ugi-Smiles reaction coupled with Heck cyclization gives new access to indole scaffolds. The sequence
can be performed in a one-pot reaction if the residual isocyanide is neutralized prior to the addition of the palladium catalyst.
Research on indoles has been and still represents one of the
most active fields in heterocyclic chemistry.1 The constant
search for new synthetic routes to this bicyclic core stems
from the impressive diversity of the biological activities2
displayed by indole alkaloids. Among all the synthetic
approaches reported in the last decades, palladium catalysis
has emerged as a powerful tool for the construction of these
scaffolds.3 More recently, diverse strategies have been
adapted to new multicomponent formation of indoles which
can be used for high-throughput screenings.4
We recently disclosed a new four-component conversion
of phenols into highly functionalized aniline derivatives.
Inspired by this straightforward formation of N-allylanilines,
we envisaged a modular route to the indole core based on a
Ugi-Smiles-Heck coupling cascade sequence (Scheme 1).
Scheme 1. General Strategy for the Synthesis of Indoles
(1) Gribble, G. W. J. Chem. Soc., Perkin Trans 1 2000, 1045. Sundberg,
R. J. Indoles; Academic Press: San Diego, 1996. Humphrey, G. R.; Kuethe,
J. T. Chem. ReV. 2006, 106, 2875–2911.
(2) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761. Somei,
M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278.
(3) For recent reviews, see: Patil, S.; Buolamwini, J. K. Curr. Org. Synth.
2006, 3, 477–498. Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873–
2920. For selected recent examples, see: Jia, Y.; Zhu, J. J. Org. Chem. 2006,
71, 7826–7834. Zhao, J.; Larock, R. J. Org. Chem. 2006, 71, 5340–5348.
(4) For a recent review, see: Campo, J.; Garcia-Valverde, M.; Marcaccini,
S.; Rojo, M. J.; Torroba, T. Org. Biomol. Chem. 2006, 4, 757–765. For
recent examples, see: Kalinski, C.; Umkehrer, M.; Schmidt, J.; Ross, G.;
Kolb, J.; Burdack, C.; Hiller, W.; Hoffmann, S. D. Tetrahedron Lett. 2006,
47, 4683–4686. Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett.
2007, 9, 4223–4226. Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem.,
Int. Ed. 2007, 46, 2295–2298. Barluenga, J.; Jimenez-Aquino, A.; Valdes,
C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 1529–1532. Leogane, O.;
Lebel, H. Angew. Chem., Int. Ed. 2008 47, 350-352, and references cited
therein.
Furthermore, the easy functionalization of the starting
phenols (halogenation, Mannich, Claisen,...) could lead to
indoles with high molecular diversity.
Since we had already reported the successful coupling of
the commercially available 2-chloro-4-nitrophenol in the Ugi-
Smiles reaction, this strategy was initially tested on chlori-
nated compounds.5 Various catalyst systems were investi-
(5) For an example of Heck coupling using chlorinated compounds, see:
Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10–11.
10.1021/ol801217a CCC: $40.75
Published on Web 07/11/2008
2008 American Chemical Society

Table 1. Ugi-Smiles Coupling with 2-Iodophenols
Table 3. Tandem Heck Coupling-Isomerizationa
product
(yield %)
entry
R1
R2
Bn
Bn
Cy
p-ClBn
p-ClBn
R3
X
1
2
3
4
5
i-Bu
Et
i-Bu
i-Bu
i-Bu
H
H
H
H
H
H
H
Cl
H
1a (95)
1b (65)
1c (32)
1d (73)
1e (49)
Me
Table 2. Ugi-Smiles Coupling with Iodinated Heterocyclic
Phenols
a Yields given from Ugi-Smiles adducts.
gated: different sources of Pd, namely Pd2(dba)3 and
Pd(OAc)2, and several phosphines (tri-tert-butylphosphine,
dppf, tricyclohexylphosphine, and 2-dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl) were used with Cs2CO3 in THF
or in 1,4-dioxane; however, none of these conditions gave
the desired cyclized product (Scheme 2).
These results prompted us to reinvestigate this strategy
with iodinated phenols. The multicomponent coupling turned
out to be quite inefficient under classical conditions (MeOH
or toluene at 60 °C). Use of a 10:1 mixture of toluene/water
as solvent (containing 1 equiv of NH4Cl) improved the yields
of the four-component coupling (4-CC) reactions signifi-
cantly.6 Under these optimized conditions, the scope of the
Ugi-Smiles couplings of iodinated phenols was found to be
fairly wide, as shown in Table 1. Various isocyanides and
(6) Oble, J.; El Ka¨ım, L.; Gizzi, M.; Grimaud, L. Heterocycles 2007,
73, 503–517.
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Org. Lett., Vol. 10, No. 16, 2008

one-pot processes. The reaction gave the expected indoles
after one day in satisfying yields (Table 3).
Table 4. One-Pot Procedure
Under the previous conditions, the pyrimidine derivatives
cyclized sluggishly, and methanol was finally selected for
this transformation (Table 4). In this case, mixtures (from
1:1 to 3:1) of the desired indolopyrimidines and the corre-
sponding exo-methylene products were obtained. The latter
were stirred overnight in methanol at 60 °C with one
equivalent of trifluoroacetic acid to complete the isomeriza-
tion process, and the indolopyrimidines were obtained as the
sole products (Scheme 3).
Scheme 3. Heck Cyclization with Iodopyrimidines
These results called for the extension of this strategy to a
one-pot Ugi-Smiles-Heck coupling-isomerization proce-
dure. First trials of such a cascade were disappointing since
a significant amount (0.6-0.8 equiv) of Pd(0) was required
to drive the reaction to completion. We surmised that an
interaction of the residual isocyanide with palladium could
alter the catalytic cycle. After completion of the Ugi-Smiles
coupling, addition of 0.2-0.3 equiv of trifluoroacetic acid
at room temperature allows the hydrolysis of the remaining
isocyanide. The following Heck coupling was carried out
on the crude mixture using the same amount of palladium
as in the two-pot procedure. The desired indoles were
obtained in good yields using this new one-pot, three-step
procedure (Table 4).
In summary, we have developed a new strategy for the
construction of the indole framework. This Ugi-Smiles/Heck
coupling/isomerization cascade can be done in a one-pot
procedure by destroying the residual isocyanide before the
Pd coupling. We are now exploring the formation of
polycyclic alkaloids to exploit the diversity offered by such
a process.
Scheme 2. Attempted Indole Synthesis from Chlorophenols
carbonyl derivatives were coupled with allylamine and
iodophenols in moderate to excellent yields.
To extend the scope of this reaction, we prepared various
4-CC adducts from iodinated heterocyclic phenol derivatives
such as hydroxy pyridines and pyrimidines. The latter were
subjected to the Ugi-Smiles coupling under standard condi-
tions (toluene at 80 °C or methanol at 60 °C) to afford the
desired products in good yields after a few hours for the
pyridines and after 3 days for the pyrimidines (Table 2).
The indole formation was first tested on purified allyl
arylamine 1d under two sets of conditions: with 5 mol % of
Pd(OAc)2 and triethylamine in DMF or with 15 mol % of
Pd(OAc)2 and triethylamine and triphenylphosphine in
toluene. Under both conditions, the tandem Heck coupling-
isomerization of the resulting double bond led to the desired
indole 2d in 74% yield (Table 3).
Acknowledgment. M.G. thanks the De´le´gation Ge´ne´rale
pour l’Armement for a fellowship. Financial support was
provided by the ENSTA.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
This Heck cyclization-isomerization cascade was then
explored using toluene as solvent for further extension to
OL801217A
Org. Lett., Vol. 10, No. 16, 2008
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