Palladium-catalyzed tandem C,N-arylation of immobilized enamine for solid phase indole synthesis

Article abstract of DOI:10.1039/b206378f

Intramolecular palladium-catalyzed N-arylation of immobilized dehydrohalophenylalaninate was found to proceed smoothly to form indolecarboxylates. The method was successfully combined with the Heck reaction to perform one pot indole synthesis via palladium-catalyzed tandem C,N-arylation reactions.

Full text of DOI:10.1039/b206378f

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Palladium-catalyzed tandem C,N-arylation of immobilized
enamine for solid phase indole synthesis†
Kazuo Yamazaki,‡ Yosuke Nakamura and Yoshinori Kondo*
1
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku,
Sendai 980–8578, Japan. E-mail: ykondo@mail.pharm.tohoku.ac.jp; Fax: 022–217–6804;
Tel: 022–217–6804
Received (in Cambridge, UK) 2nd July 2002, Accepted 22nd August 2002
First published as an Advance Article on the web 30th August 2002
Intramolecular palladium-catalyzed N-arylation of
immobilized dehydrohalophenylalaninate was found to
proceed smoothly to form indolecarboxylates. The method
was successfully combined with the Heck reaction to
perform one pot indole synthesis via palladium-catalyzed
tandem C,N-arylation reactions.
Scheme 1
The palladium-catalyzed amination reaction is one of the most
important methods for the preparation of arylamines, amides
and carbamates.1,2 An intramolecular version of the amination
has allowed us to synthesize a wide variety of nitrogen-
containing heterocyclic compounds.3
A combination of
amination and Heck reactions provides an attractive indole
synthesis, for example, the palladium-catalyzed tandem
amination–Heck reaction between 1,2-dibromobenzene and
enaminone,4 however further examples are not yet known. Tan-
dem reactions have recently been of interest in the field of
organic synthesis,5 the sequential formation of carbon–carbon
and carbon–heteroatom bonds can be accomplished in one syn-
thetic step using a single catalyst. Therefore we have focussed
our interest on solid phase indole synthesis6 using palladium
catalyzed tandem C,N-arylation reactions on a polymer sup-
port, as shown in Fig. 1. To date, the application of intra-
Scheme 2
Fig. 1
Method A: the Heck reaction of immobilized N-acetyl-
dehydroalanine 39 with 1-bromo-2-iodobenzene was performed
under Heck coupling conditions of the regeneratable Michael
(REM) resin.10
Method B: a rhodium catalyzed insertion reaction of im-
mobilized α-diazophosphonoacetate6c with benzyl carbamate
gave immobilized N-Cbz-α-phosphonylglycine 4 followed by
Horner–Emmons reactions with 2-bromobenzaldehyde or
2-formylphenyl trifluoromethanesulfonate were performed. The
loading values of 5a–c were estimated by elemental analysis of
nitrogen on the polymer beads or from yields after cleavage
using Et3N–MeOH at 50 ЊC. The values indicated smooth and
reasonable progression of the transformation.
Palladium-catalyzed intramolecular amination of immobil-
ized substrates was performed using similar reaction conditions
as the solution phase procedure. Thus, immobilized intermedi-
ates 5a–c were heated at 80–100 ЊC in the presence of Pd2(dba)3,
ligand and Cy2NMe in toluene or DME.11 This was followed by
the transesterification of polymer-bound indolecarboxylate
using MeONa in MeOH–THF, and methyl indole-2-carboxyl-
ate 612 was obtained in good to moderate yields (Scheme 3).
Next, we investigated the tandem C,N-arylation reactions for
one-pot indole synthesis using the immobilized intermediate 3
(Scheme 4). In our approach, the initial step involves Heck
molecular amination in the solid phase chemistry is unprece-
dented in the literature. Here we report that tandem C,N-
arylation reactions can be successfully applied in solid phase
indole synthesis
In solution phase chemistry, Brown has already demon-
strated that the intramolecular palladium-catalyzed annulation
of dehydroiodophenylalanine can yield N-substituted indole-2-
carboxylate derivatives.3d However, using the reported condi-
tions, our cyclization reactions were not successful and we
decided to optimize the catalytic system for the cyclization. We
screened phosphine ligands for the intramolecular amination of
8
1a,b, and t-Bu3P7 and t-Bu3PHBF4 were found to be the best
ligands, as shown in Scheme 1.
On the basis of the above solution-phase results, we investi-
gated the solid phase intramolecular palladium-catalyzed
amination reaction. The substrates for the amination reaction,
5a–c were synthesized by the following two methods, as shown
in Scheme 2.
† Electronic supplementary information (ESI) available: experimental
procedures. See http://www.rsc.org/suppdata/p1/b2/b206378f/
‡ On leave from the Central Research Laboratories, SSP Co. Ltd.,
Narita, Japan.
DOI: 10.1039/b206378f
J. Chem. Soc., Perkin Trans. 1, 2002, 2137–2138
This journal is © The Royal Society of Chemistry 2002
2137

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Notes and references
§ The IUPAC name for triflate is trifluoromethanesulfonate.
1 (a) J. P. Wolfe, S. Wagaw, J.-F. Marcoux and S. L. Buchwald,
Acc. Chem. Res., 1998, 31, 805–818; (b) B. H. Yang and S. L.
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(c) S. Cacchi, G. Fabrizi, A. Goggiamani and G. Zappia, Org. Lett.,
2001, 3, 2539–2541.
Scheme 3
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52, 7525–7546; (b) B. H. Yang and S. L. Buchwald, Org. Lett., 1999,
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Int. Ed. Engl., 1993, 32, 131–163.
6 Recent solid phase indole synthesis: (a) C. Macleod, R. C. Hartley
and D. W. Hamprecht, Org. Lett., 2002, 4, 75–78; (b) T. Y. H. Wu,
S. Ding, N. S. Gray and P. G. Schultz, Org. Lett., 2001, 3, 3827–3830;
(c) K. Yamazaki and Y. Kondo, Chem. Commun., 2002, 210–211;
(d ) K. Yamazaki and Y. Kondo, J. Comb. Chem., 2002, 4, 191–192
and references therein.
Scheme 4
coupling followed by the amination reaction to yield a polymer-
bound indole. It was found that 1,2-dibromobenzene works
better than 1-bromo-2-iodobenzene for the tandem reaction,
and the reaction at 100 ЊC led to indolecarboxylate in good
yields after transesterification. Aryl triflates§ were also used as
substrates, however further modification of reaction conditions
seems to be necessary.
As an extension of the Heck reaction of the immobilized
dehydroalanate, we examined isoquinoline synthesis. The Heck
reactionsofimmobilizedN-acetyldehydroalaninewith2-bromo-
benzaldehyde or methyl 2-bromobenzoate followed by trans-
esterification gave isoquinoline-3-carboxylates 713 or 814 in
moderate yield (Scheme 5).15
7 (a) M. Nishiyama, T. Yamamoto and Y. Koie, Tetrahedron Lett.,
1998, 39, 617–620; (b) T. Yamamoto, M. Nishiyama and Y. Koie,
Tetrahedron Lett., 1998, 39, 2367–2370; (c) M. Watanabe,
T. Yamamoto and M. Nishiyama, Angew. Chem. Int. Ed., 2000, 39,
2501–2504.
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9 (a) M. Barbaste, V. Rolland-Fulcrand, M.-L. Roumestant,
P. Viallefont and J. Martinez, Tetrahedron Lett., 1998, 39, 6287–
6290; (b) A.-M. Yim, Y. Vidal, P. Viallefont and J. Martinez,
Tetrahedron Lett., 1999, 40, 4535–4538.
10 Y. Kondo, K. Inamoto and T. Sakamoto, J. Comb. Chem., 2000, 2,
232–233.
11 See also supplementary infomation†.
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Lett., 1993, 34, 2059–2062.
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15 Typical experimental procedure: To a mixture of resin 3 (300 mg,
0.285 mmol, 0.95 mmol gϪ1), 1,2-dibromobenzene (0.051 ml, 0.428
mmol) tris(dibenzylideneacetone)dipalladium()ؒCHCl3 (39 mg,
0.043 mmol) and N,N-dicyclohexyl-N-methylamine (Cy2NMe)
(0.18 ml, 0.855 mmol) in toluene (3 ml) was added 0.5 M toluene
solution of tri-tert-butylphosphine (0.34 ml, 0.17 mmol) and the
mixture was heated at 100 ЊC for 24 h. The resin was collected by
filtration and washed with DMF (×3), DMF–H2O = 1 : 1 (×3),
DMF (×3), THF (×3), MeOH (×3) and the resin was dried under
reduced pressure at 40 ЊC. The above resin and NaOMe (15 mg,
0.285 mmol) in THF (3 ml) and MeOH (1.5 ml) were agitated at
room temperature for 16 h. The resin was separated by filtration and
washed with ethyl acetate, the filtrate was washed with saturated
aqueous NH4Cl, water and brine, dried over Na2SO4 and evaporated
to afford the crude product. The crude product was purified by
chromatography on silica gel using hexane–ethyl acetate (4 : 1) to
afford 39 mg (78%) of 6 as a colorless solid.
Scheme 5
In summary, the first solid phase intramolecular amination
reaction for the synthesis of indolecarboxylate was achieved in
high yield in the presence of palladium catalyst. The palladium
catalyzed tandem C,N-arylation also provides a new one-pot
method for solid phase indole synthesis. Further investigation
on the scope and limitations towards synthesis of diverse
heterocyclic libraries is currently under way.
Acknowledgements
This work was partly supported by the Grant-in Aid for
Scientific Research (No.12557198) from the Ministry of
Education, Science, Sports and Culture, Japan.
2138
J. Chem. Soc., Perkin Trans. 1, 2002, 2137–2138