Palladium-catalysed synthesis of 1-isoindolecarboxylic acid esters and sequential Diels-Alder reactions: Access to bridged- and fused-ring heterocycles

Article abstract of DOI:10.1039/b909701e

The Pd-catalysed intramolecular α-arylation of α-amino acid esters provides a useful methodology for the synthesis of substituted isoindole derivatives, which have been used in Diels-Alder reactions to access diverse skeletal frameworks.

Full text of DOI:10.1039/b909701e

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Palladium-catalysed synthesis of 1-isoindolecarboxylic acid esters
and sequential Diels–Alder reactions: access to bridged- and
fused-ring heterocycles†
Daniel Sole´* and Olga Serrano
Received 18th May 2009, Accepted 2nd July 2009
First published as an Advance Article on the web 9th July 2009
DOI: 10.1039/b909701e
The Pd-catalysed intramolecular a-arylation of a-amino acid
esters provides a useful methodology for the synthesis of
substituted isoindole derivatives, which have been used in
Diels–Alder reactions to access diverse skeletal frameworks.
Isoindoles have long attracted the attention of organic chemists
due to their high level of reactivity in cycloaddition reactions1,2
and fluorescent and electroluminescent properties.3 However, the
difficulties in the preparation of isoindoles together with their
instability have frequently restricted their synthetic use, creating
a demand for new and straightforward methods to access these
substrates. In this context, recent progress in synthetic organic
chemistry has led to the development of new methods for the
preparation of diversely substituted isoindoles.4
Scheme 1 Sequential Pd(0)-catalysed a-arylation and Diels–Alder reac-
tion of amino esters 1a,b.
As part of our ongoing program on the synthesis of nitrogen
heterocycles, we have recently reported an efficient methodology
for the synthesis of indoles based on the Pd(0)-catalysed in-
tramolecular a-arylation of b-(2-iodoanilino) esters.5 Continuing
our research on this palladium chemistry,6 we considered that the
intramolecular coupling of aryl halides and ester enolates might
also be a suitable route towards substituted isoindoles. The ester
group was an attractive substituent not only because it could be
elaborated into other frameworks, but also because, as part of
a conjugated donor–acceptor system with the nitrogen, it would
provide the isoindole nucleus with some electronic stabilisation.
In this communication we present our preliminary studies on
the application of the Pd(0)-catalysed arylation reaction to the
synthesis of 1-isoindolecarboxylic acid esters7 to be used in
Diels–Alder reactions (Scheme 1).
Our standard conditions developed for the synthesis of
3-indolecarboxylic acid esters employ the catalyst Pd(PPh3)4 and
the base K3PO4 in the presence of a catalytic quantity of phenol
in DMF.5 When the same conditions were applied to the reaction
of a-amino ester 1a, a clean reaction mixture was obtained, from
which 1-isoindolecarboxylic acid ester 2a, resulting from the Pd
catalysed dehydrogenation8 of the initially formed a-arylation
compound,9 was isolated in 76% yield (Scheme 1). However, isoin-
dole 2a was difficult to characterise because of its high tendency to
undergo aerial oxidation on standing in solution. Nevertheless, to
our delight, treatment of 2a with dimethyl acetylenedicarboxylate
in dichloromethane at reflux afforded cycloadduct 3a in 61% yield.
The a-arylation/dehydrogenation/Diels–Alder reaction se-
quence was also successfully applied with a-aminoesters 1b and
4, although due to their instability, the isoindole intermediates
were not purified and the crude arylation reaction mixtures were
directly treated with DMAD in order to characterise the Diels–
Alder cycloadducts (Schemes 1 and 2). It should be noted that
cycloadducts 3a-b and 5 are robust compounds, which allowed the
NMR spectra to be recorded in CDCl3 at 50 ◦C, thus overcoming
conformational mobility problems. In contrast with this stability,
a closely related cycloadduct resulting from the Diels–Alder
reaction of a 1-isoindolecarboxamide with DMAD displays a high
tendency to undergo the retro-process.4a
Scheme 2 Sequential Pd(0)-catalysed a-arylation and Diels–Alder reac-
tion of amino ester 4.
TheDiels–Alder reactions ofisoindole 2a withother dienophiles
were also examined. Thus, for example, treatment of crude 2a
with NMM afforded a 1:2 mixture of the starting material and
the ENDO cycloadduct 6;10 however, further separation and
characterisation of 6 failed because of partial decomposition by
retro-reaction during NMR experiments (Scheme 3).
Laboratori de Qu´ımica Orga`nica, Facultat de Farma`cia, and Institut de
Biomedicina (IBUB), Universitat de Barcelona, Av., Joan XXIII s/n, 08028,
Barcelona, Spain. E-mail: dsole@ub.edu; Fax: +34 93 402 45 39; Tel: +34
93 402 45 40
† Electronic supplementary information (ESI) available: Experimental
procedure and characterisation data for new compounds. See DOI:
10.1039/b909701e
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Table 1 Sequential Pd(0)-catalysed intramolecular arylation of N-aryl esters/Diels–Alder reaction with DMADa
Entry
1
Ar
R
H
Solvent
CH2Cl2
T
Products (yield)b
7a
reflux
8a (62%)
2
3
7a
7b
DMF
CH2Cl2
90 ◦C
reflux
8a (20%)
8b (46%)
9a (23%)
9b (35%)
9d (23%)
H
4
5
7b
7c
DMF
CH2Cl2
90 ◦
C
8b (10%)
8c (46%)
H
reflux
reflux
reflux
6
7
7d
7e
H
CH2Cl2
CH2Cl2
8d (37%)
8e (50%)
8e (42%)
Me
8
9
7e
7f
DMF
CH2Cl2
90 ◦
reflux
C
H
10 (55%)
a-Arylation reactions were performed using 7 (0.2 mmol), Pd(PPh3)4 (10 mol%), K3PO4 (3 equiv) and phenol (30 mol%) in DMF (3 mL) at 90 ◦C for
a
24 h. Diels–Alder reactions were performed using the crude isoindoles and DMAD (1.5 equiv) in CH2Cl2 (10 mL) at reflux or in DMF (5 mL) at 90 ◦
for 12 h. b Isolated yield.
C
temperature, 8d slowly evolved into 9d, the conversion being
completed after a lengthy heating at reflux. Interestingly, when
starting from 7a and 7b and using DMF as the solvent in the
Diels–Alder step, aziridines 9a and 9b were obtained, respectively,
as the main products (Table 1, entries 2 and 4). However, under
these reactions conditions 7c afforded a complex mixture in which
the only identifiable products were those resulting from the aerobic
oxidation of the isoindole. When starting from amino ester 7e,
cycloadduct 8e was obtained regardless of whether the solvent in
the cycloaddition reaction was CH2Cl2 or DMF (Table 1, entries
7 and 8).
Finally, the a-arylation/Diels–Alder sequence was attempted
with amino ester 7f. However, in this case, neither the Diels–Alder
cycloadduct nor aziridine were detected in the reaction mixture,
which contained trimethyl naphthalenetricarboxylate (10, 55%
yield)12 as the major and only identifiable product (Table 1,
entry 9).
It is known that the Diels–Alder cycloadducts of isoindoles
undergo transformation into other systems,4b but, to the best
of our knowledge, their evolution into aziridines has not been
previously described. Similarly, the formation of aromatic systems
(i.e. naphthalenes) by nitrene extrusion from the azanorbornenes
produced in the Diels–Alder reaction of pyrroles and isoindoles is a
common reaction when the nitrogen contains an amino group,4b,13
Scheme 3 Diels–Alder reaction of isoindole 2a with NMM.
On the other hand, no cycloadduct could be obtained in
the reactions of 2a with methyl propiolate, maleic anhydride or
p-benzoquinone, the isoindole being recovered unchanged.
The studies on the a-arylation/Diels–Alder sequence were
extended to amino esters 7a-f, which bear aryl substituents at
the nitrogen. Interestingly, somewhat different behaviour was
observed with these substrates. Thus, while 7a, 7b, and 7c afforded
the cycloadducts 8a, 8b, and 8c, respectively, as the only isolated
products (Table 1, entries 1, 3, and 5),11 7d gave cycloadduct 8d
(37%) and aziridine 9d (23%) under the same reaction conditions
(Table 1, entry 6). The analysis of the crude reaction mixture
showed a 4:1 ratio of 8d and 9d, suggesting a partial transformation
of the cycloadduct into the aziridine during the purification
process. In fact, on standing in chloroform solution at room
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but there is no reported precedent in N-aryl systems. Both novel
processes are somewhat surprising, particularly because similar
reactions were not observed from cycloadducts 3a-b and 5,
which bear a benzyl group at the nitrogen (vide supra). This
stability, together with the markedly faster evolution of the
cycloadduct intermediates bearing electron-donating groups at
the aryl substituent, suggested that both unexpected transfor-
mations could be explained by the participation of a nitrenium
intermediate. Thus, the heterolysis of the cycloadduct would give a
zwitterionic intermediate, stabilised by resonance,14 which in turn
would undergo intramolecular nucleophilic attack to afford the
corresponding aziridine (Scheme 4). The formation of aziridines
as the main products in the Diels–Alder reactions in DMF may
reflect not only an increase in temperature but also solvent polarity.
On the other hand, naphthalene 10 would be formed by nitrene
extrusion from the corresponding zwitterionic intermediate.
Acknowledgements
We thank the “Ministerio de Educacio´n y Ciencia”, Spain, for
financial support (project CTQ2006-00500/BQU).
Notes and references
1 (a) R. J. Sundberg, Comprehensive Heterocyclic Chemistry II, Vol. 2,
A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Eds., Pergamon, Oxford,
1996, Chap. 3, 119; (b) T. J. Donohoe, Product class 14: 1H- and
2H-isoindoles, Sci. Synth., 2001, 10, 653.
2 For recent examples, see: (a) Y.-L. Chen, M.-H. Lee, W.-Y. Wong and
A. W. M. Lee, Synlett, 2006, 2510; (b) Z. Chen, P. Mu¨ller and T. M.
Swager, Org. Lett., 2006, 8, 273; (c) R. Rinco´n and J. Plumet, Synlett,
2008, 911.
3 See for example: B.-X. Mi, P.-F. Wang, M.-W. Liu, H.-L. Kwong, N.-B.
Wong, C.-S. Lee and S.-T. Lee, Chem. Mater., 2003, 15, 3148.
4 (a) D. Kadzimirsz, D. Hildebrandt, K. Merz and G. Dyker, Chem.
Commun., 2006, 661; (b) S. Duan, D. K. Sinha-Mahapatra and J. W.
Herndorn, Org. Lett., 2008, 10, 1541; (c) B. W.-Q. Hui and S. Chiba,
Org. Lett., 2009, 11, 729.
5 D. Sole´ and O. Serrano, J. Org. Chem., 2008, 73, 2476.
6 (a) D. Sole´, L. Vallverdu´ and J. Bonjoch, Adv. Synth. Catal., 2001,
343, 439; (b) D. Sole´, L. Vallverdu´, E. Peidro´ and J. Bonjoch, Chem.
Commun., 2001, 1888; (c) D. Sole´, L. Vallverdu´, X. Solans, M. Font-
Bardia and J. Bonjoch, J. Am. Chem. Soc., 2003, 125, 1587; (d) D. Sole´,
X. Urbaneja and J. Bonjoch, Tetrahedron Lett., 2004, 45, 3131; (e) D.
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7 (a) G. Cignarella, F. Savelli and P. Sanna, Synthesis, 1975, 252; (b) G.
Cignarella, R. Cerri, G. Grella and P. Sanna, Gazz. Chim. Ital., 1976,
106, 65.
8 For a related process, see: R. Grigg, A. Somasunderam, V. Sridharan
and A. Kepp, Synlett, 2008, 97.
9 O. Gaertzen and S. L. Buchwald, J. Org. Chem., 2002, 67,
465.
10 R. P. Kreher, G. Sewarte-Ross and G. Vogt, Chem. Ber., 1992, 125,
183.
11 A. R. Katritzky, M. H. Paluchowska and J. K. Gallos, J. Heterocycl.
Chem., 1989, 26, 421.
Scheme 4 Proposed mechanisms for the formation of 9a-d and 10.
12 The structure of 10 was unambiguously established from its 1H and
13C NMR data, with the aid of 2D-NMR experiments (HSQC and
HMBC). These data are consistent with those described for other 1,2,3-
trisubstituted naphthalenes,4b but clearly differ from those previously
reported for 10; see: M. A. Bennett and E. Wenger, Organometallics,
1996, 15, 5536.
In summary, in this report we show that the Pd(0)-catalysed
intramolecular arylation of a-amino acid esters and a sequential
Diels–Alder reaction offer a new opportunity to create complex
and diverse scaffolds from readily accessible starting materials.
Further investigations on the scope and synthetic applications of
this sequence are currently in progress and will be reported in due
course.
13 H. Hart, C.-Y. Lai, G. Chukuemeka-Nwokogu and S. Shamouilian,
Tetrahedron, 1987, 43, 5203.
14 L. Greci, R. Castagna, P. Carloni, P. Stipa, C. Rizzoli, L. Righi and P.
Sgarabotto, Org. Biomol. Chem., 2003, 1, 3768.
3384 | Org. Biomol. Chem., 2009, 7, 3382–3384
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The Royal Society of Chemistry 2009
©