Selective synthesis of either isoindole- or isoindoline-1-carboxylic acid esters by Pd(0)-catalyzed enolate arylation

Article abstract of DOI:10.1021/jo101054j

Figure presented. Two efficient palladium-catalyzed intramolecular α-arylation reactions of α-amino acid esters have been developed that allow either 1-isoindolecarboxylic acid esters or the corresponding isoindolines to be selectively synthesized simply by a slight change of reaction conditions.

Full text of DOI:10.1021/jo101054j

pubs.acs.org/joc
which make them attractive candidates for organic light-emitting
devices (OLEDs).6
Selective Synthesis of Either Isoindole- or
Isoindoline-1-carboxylic Acid Esters by
Pd(0)-Catalyzed Enolate Arylation
However, the instability of the isoindole nucleus together with
the lack of a general method for the synthesis of substituted deri-
vatives have frequently restricted their use, creating a demand
for new and straightforward methodologies to access these
substrates. Apart from the aromatization of existing rings, the
classical and most generally applicable methods for the synthesis
of isoindoles include cyclizative condensations of o-disubstitu-
ted benzenes, elimination reactions (inter alia from isoindolinium
salts, isoindoline N-oxides, or 2-substituted isoindolines), retro-
cycloaddition processes, and nucleophilic addition reactions to
phthalamidines.7 Recent progress in synthetic organic chemistry
has led to the development of new methods for the preparation
of diversely substituted isoindoles.8
ꢀ
Daniel Sole* and Olga Serrano
´
ꢁ
ꢁ
Laboratori de Quımica Organica, Facultat de Farmacia,
and Institut de Biomedicina (IBUB), Universitat de Barcelona,
08028 Barcelona, Spain
dsole@ub.edu
Received May 31, 2010
Regarding the isoindoline family, the synthesis of 1- and
1,3-substituted derivatives is also clearly underdeveloped,9
and very few reports about metal- or organocatalyzed
syntheses of isoindolines can be found in the literature.10
As part of our ongoing program on the synthesis of nitro-
gen heterocycles,11 we have recently reported an efficient
methodology for the synthesis of indole-3-carboxylic acid
derivatives based on the palladium-catalyzed intramolecular
R-arylation of β-(2-iodoanilino) esters12a and amides.12b
Interestingly, in the ester series, depending on the reaction
conditions, the R-arylation reaction gave access to either
indoles or indolines (Scheme 1).12a
Two efficient palladium-catalyzed intramolecular R-aryla-
tion reactions of R-amino acid esters have been developed
that allow either 1-isoindolecarboxylic acid esters or the
corresponding isoindolines to be selectively synthesized
simply by a slight change of reaction conditions.
These studies in the indole series and our previous dis-
covery that isoindoles could be directly obtained by seq-
uential palladium-catalyzed arylation/dehydrogenation of
R-amino ketones11c (Scheme 2) encouraged us to examine
the cyclization of R-amino esters to establish a general method
for the synthesis of 1-isoindolecarboxylic acid esters.13
The isoindole moiety and its reduced counterpart isoindo-
line (2,3-dihydro-1H-isoindole) have become attractive tar-
gets in organic and medicinal chemistry. These heterocyclic
frameworks are an integral part of the structure of some bio-
logically active compounds1 and a few naturally occurring
products.2 Moreover, the isoindoles have been widely used for
their high level of reactivity in cycloaddition reactions3 and, more
recently, for their fluorescent and electroluminescent properties,4,5
(6) (a) Naef, R. Dyes Pigments 1985, 6, 233–249. (b) Gauvin, S.; Santerre,
F.; Dodelet, J. P.; Ding, Y.; Hlil, A. R.; Hay, A. S.; Anderson, J.; Armstrong,
N. R.; Gorjanc, T. C.; D’Iorio, M. Thin Solid Films 1999, 353, 218–222.
(c) Ding, Y.; Hay, A. S. J. Polym. Sci., Part A: Polym. Chem. 1999, 37, 3293–
3299. (d) Mi, B.-X.; Wang, P.-F.; Liu, M.-W.; Kwong, H.-L.; Wong, N.-B.;
Lee, C.-S.; Lee, S.-T. Chem. Mater. 2003, 15, 3148–3151.
(7) (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II,
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 2, Chapter 3, pp 119-206. (b) Donohoe, T. J. Product class 14:
1H- and 2H-isoindoles. Sci. Synth. 2001, 10, 653–692.
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J.; Patel, J. B. Bioorg. Med. Chem. Lett. 1993, 3, 55–60. (b) Portevin, B.;
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343–349. (e) Diana, P.; Martorana, A.; Barraja, P.; Montalbano, A.; Dattolo,
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J. W. Org. Lett. 2008, 10, 1541–1544. (c) Hui, B. W.-Q.; Chiba, S. Org. Lett.
2009, 11, 729–732. (d) Heugebaert, T. S. A.; Stevens, C. V. Org. Lett. 2009,
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1226-1230 and references cited therein.
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Feng, B. J. Antibiot. 2002, 55, 693–695. (c) Horiuchi, M.; Ohnishi, K.; Iwase, N.;
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(11) (a) Sole, D.; Vallverdu, L.; Bonjoch, J. Adv. Synth. Catal. 2001, 343,
439–442. (b) Sole, D.; Vallverdu, L.; Peidro, E.; Bonjoch, J. Chem. Commun.
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2001, 1888–1889. (c) Sole, D.; Vallverdu, L.; Solans, X.; Font-Bardia, M.;
(3) For recent examples, see: (a) Chen, Y.-L.; Lee, M.-H.; Wong, W.-Y.;
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911–913.
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(12) (a) Sole, D.; Serrano, O. J. Org. Chem. 2008, 73, 2476–2479. (b) Sole,
(4) Simons, S. S., Jr.; Johnson, D. F. J. Org. Chem. 1978, 43, 2886–2891.
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DOI: 10.1021/jo101054j
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Published on Web 08/25/2010
J. Org. Chem. 2010, 75, 6267–6270 6267
2010 American Chemical Society

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Sole and Serrano
JOCNote
SCHEME 1
SCHEME 3a
aLigand: 2-(diphenylphosphino)-20-(N,N-dimethylamino)biphenyl.
SCHEME 4
SCHEME 2
palladium-catalyzed dehydrogenation process, as evidenced
when isoindole 3 was obtained in 78% yield after treat-
ing isoindoline 2 with Pd(PPh3)4 (0.05 equiv) and K3PO4
(2 equiv) in DMF at 90 °C.
Interestingly, under Buchwald’s conditions, which involve
the use of a biaryl-based phosphine as the ligand and
t-BuOLi as the base,10a isoindole 3 was obtained in 44% yield.
The different behavior of 1a and the R-amino esters studied
by Buchwald under these reaction conditions could be due to
the substitution pattern of the substrates. Thus, the combi-
nation of the N-aryl substituent and the tert-butyl ester could
have prevented the aromatization process.
The ester group appeared to be 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 stabilization.
It should be noted that Buchwald has reported the
synthesis of dihydroisoindoles by palladium-catalyzed
intramolecular R-arylation14 of tert-butyl R-amino esters
(Scheme 3).10a
Aryl bromide 1b, triflate 1c, and carbamate 1d were less
efficient than 1a in the R-arylation reactions. None of them
led to the corresponding isoindole under the reaction condi-
tions optimized with 1a, 1b being completely unreactive and
1c and 1d decomposing.
Herein, we report the development of palladium-catalyzed
intramolecular R-arylation reactions of R-(2-iodobenzyl-
amino) esters for the selective syntheses of either 1-isoindole-
carboxylic acid esters or the corresponding isoindolines
(Scheme 4).
The scope of the developed selective R-arylation processes
was then examined using a range of diversely substituted
R-(2-iodobenzylamino) esters (Tables 1 and 2).
As shown in Table 1, the synthesis of both isoindolines and
isoindoles19 was generally carried out with good yields. It
should be noted that although we were able to isolate and
characterize the majority of the isoindoles, they are rather
unstable compounds with a high tendency to undergo aerial
oxidation on standing in solution,20 which necessitates
avoiding any contact with chloroform.
The R-arylation reactions were not restricted to methyl
esters. When ethyl and tert-butyl esters were used as sub-
strates, both cyclization products were obtained in similar
yields (entries 1-4). As previously observed during the
optimization studies carried out with 1a, isoindolines can
be prepared using Cs2CO3 instead of K3PO4 although with
lower yields (entries 6 and 11).21 Under the reaction condi-
tions of method A, the R-arylation of the amino esters
bearing aryl substituents at the nitrogen proceeded more
slowly than in the case of the N-benzyl-substituted sub-
strates. Furthermore, it was not possible to characterize
isoindoline 9d, which was obtained from p-phenylendiamine
Our initial investigation was carried out with iodides 1a
and 1d, bromide 1b, and triflate 1c, screening a variety of
bases, ligands, and solvents (see more details in the Support-
ing Information). These optimization studies gave us two
different procedures for the cyclization reactions of 1a. Thus,
while the use of Pd(PPh3)4 (0.1 equiv) in combination with
K3PO4 (3 equiv) as the base in THF at 110 °C (method A)
gave isoindoline 2, the use of Pd(PPh3)4 and K3PO4 together
with a catalytic amount of phenol (0.3 equiv) in DMF at
90 °C (method B) afforded isoindole 3, which results from the
palladium-catalyzed dehydrogenation of the initially formed
isoindoline.15,16
Although the additive phenol seems to play a positive role
in the R-arylation reaction,12a,17,18 it is not necessary for the
(14) For recent reviews on the palladium-catalyzed R-arylation of carbo-
nyl compounds, see: (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003,
36, 234–245. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082–1146.
(c) Johansson, C. C. C; Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676–707.
(15) For a related dehydrogenation process, see: Grigg, R.; Somasunderam,
A.; Sridharan, V.; Keep, A. Synlett 2009, 97–99.
(16) Tsai, H.-H. G.; Chung, M.-W.; Chou, Y.-K.; Hou, D.-R. J. Phys.
Chem. A 2008, 112, 5278–5285.
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(17) Sole, D.; Urbaneja, X.; Bonjoch, J. Adv. Synth. Catal. 2004, 346,
1646–1650.
(18) Rutherford, J. L.; Rainka, M. P.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 15168–15169.
(19) For a preliminary account of the use of the crude 1-isoindole-
(20) Ahmed, I.; Cheeseman, G. W. H.; Jaques, B. Tetrahedron 1979, 35,
1145–1149.
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carboxylic acid esters in Diels-Alder reactions, see: Sole, D.; Serrano, O.
Org. Biomol. Chem. 2009, 7, 3382–3384.
(21) The cyclization reaction of 8b using Cs2CO3 as the base afforded a 4:1
mixture of isoindoline 9b and the hydrodehalogenation product.
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Sole and Serrano
JOCNote
TABLE 1. Synthesis of Dihydroisoindole- and Isoindole-1-carboxylic Acid Esters
aMethod A: 10 mol % of Pd(PPh3)4 and K3PO4 (3 equiv) in THF at 110 °C in a sealed tube. Method B: 10 mol % of Pd(PPh3)4, K3PO4 (3 equiv), and
phenol (0.3 equiv) in DMF at 90 °C. bUnless otherwise indicated, yields refer to pure products isolated by flash chromatography. c5 mol % of Pd(PPh3)4
and Cs2CO3 (3 equiv) were used. d1H NMR analysis of the crude reaction mixture gave a 1:1 mixture of 8d and isoindoline 9d. e1H NMR analysis of
the crude reaction mixture gave isoindole 10e as the only reaction product. The reaction of crude 10e with DMAD afforded the corresponding
f
Diels-Alder adduct in 46% overall yield for the R-arylation/Diels-Alder sequence. See ref 19. 1.2:1 mixture of isomers. g4:1 mixture of isomers.
h3.5:1 mixture of isomers.
8d as a 1:1 mixture with the starting material, after 4 days
under the reaction conditions of method A. Unfortunately,
9d oxidized during the purification process to give isoindo-
line 10d (entry 13).
Both cyclization methods were successfully applied to the
preparation of 1,3-disubstituted substrates (entries 17-24).
However, the palladium-catalyzed dehydrogenation of the
initially formed isoindolines proceeded somewhat slowly in
the substrates with the bulky propyl and phenyl groups at the
benzylic position (entries 20 and 22). For these substrates,
short reaction times resulted in the isolation of significant
amounts of the corresponding isoindolines together with the
isoindoles. R-Amino esters 17a and 17b, which have an allyl
substituent at the benzylic position, failed to undergo the
R-arylation reactions and only afforded the Heck cyclization
products. Interestingly, the best results were obtained when
J. Org. Chem. Vol. 75, No. 18, 2010 6269

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Sole and Serrano
JOCNote
TABLE 2. Synthesis of Benzoisoindolecarboxylic Acid Esters
aMethod A: 10 mol % of Pd(PPh3)4 and K3PO4 (3 equiv) in THF at 110 °C in a sealed tube. Method B: 10 mol % of Pd(PPh3)4, K3PO4 (3 equiv), and
phenol (0.3 equiv) in DMF at 90 °C. bUnless otherwise indicated, yields refer to pure products isolated by flash chromatography.
SCHEME 5
enolate arylation and the dehydrogenation of the initially
formed isoindoline. Besides the potential synthetic applica-
tion of the above methodologies, the reactions described in
this paper are of interest because they illustrate how small
changes in the reaction conditions can be used to increase the
diversity of palladium-catalyzed processes.
Experimental Section
Representative Procedure for the Synthesis of Isoindolines.
A mixture of ester 1a (100 mg, 0.25 mmol), K3PO4 (159 mg,
0.75 mmol), and Pd(PPh3)4 (29 mg, 0.025 mmol) in THF (8 mL)
was stirred at 110 °C in a sealed tube for 24 h. The reaction
mixture was poured into water and extracted with Et2O. The
organic extracts were washed with brine, dried, and concen-
trated. The residue was purified by flash chromatography (SiO2,
from CH2Cl2 to CH2Cl2-MeOH 1%) to give methyl 2-benzyl-
isoindoline-1-carboxylate (2, 56 mg, 84%).
Representative Procedure for the Synthesis of Isoindoles.
A mixture of ester 1a (100 mg, 0.25 mmol), K3PO4 (159 mg,
0.75 mmol), phenol (7 mg, 0.075 mmol), and Pd(PPh3)4 (29 mg,
0.025 mmol) in DMF (3 mL) was stirred at 90 °C for 24 h. The
reaction mixture was poured into water and extracted with
Et2O. The organic extracts were washed with brine and 1 N
NaOH solution, dried, and concentrated. The residue was
purified by chromatography (SiO2, CH2Cl2) to give methyl
2-benzylisoindole-1-carboxylate (3, 50 mg, 76%).
t-BuOK/phenol were used as additives in these palladium-
catalyzed reactions (Scheme 5).22 The use of other bases
resulted in the formation of significant amounts of double-
bond isomerization products.
The palladium-catalyzed cyclizations were also extended
to the preparation of benzo-fused derivatives (Table 2).23,24
While the isoindolines were generally obtained in good
yields, the formation of isoindoles seems to be highly sub-
strate dependent. Thus, in the benzo[f]-fused series, only 24a
could be obtained, the N-aryl derivatives being too unstable
to be isolated and characterized.25
In summary, we have developed two palladium-catalyzed
intramolecular R-arylation reactions that allow the selective
synthesis of either 1-isoindolecarboxylic acid esters or the
corresponding isoindolines. The synthesis of isoindoles takes
place through a palladium-catalyzed cascade involving an
Acknowledgment. This research was supported by MEC
(Spain)-FEDER (Project No. CTQ2006-00500/BQU and
CTQ2009-07175).
(22) The positive role of phenol as a catalytic additive in the Heck reaction
ꢀ
has been previously observed; see: Bennasar, M.-L.; Zulaica, E.; Sole, D.;
Alonso, S. Synlett 2008, 667–670.
(23) Naphtho-fused heterocycles have been recently identified as good
candidates for light-harvesting dyes in solar cells; see: Paci, I.; Johnson, J. C.;
Chen., X.; Rana, G.; Popovic, D.; David, D. E.; Nozik, A. J.; Ratner, M. A.;
Michl, J. J. Am. Chem. Soc. 2006, 128, 16546–16553.
(24) Hsu, D.-T.; Lin, C.-H. J. Org. Chem. 2009, 74, 9180–9187.
(25) Under the reaction conditions of method B, 22b afforded 2-phenyl-
2,3-dihydrobenzo[ f ]isoindol-1-one in 35% yield.
Supporting Information Available: Optimization studies,
characterization data for all new compounds, and experimental
1
procedures for preparation of starting materials. H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
6270 J. Org. Chem. Vol. 75, No. 18, 2010