Synthesis of 3-substituted isoindolin-1-ones via a palladium-catalysed 3-component carbonylation/amination/Michael addition process

Article abstract of DOI:10.1016/j.tetlet.2003.08.036

A novel palladium-catalysed three component cascade process is described involving carbonylation of an aryl iodide to generate an acyl palladium species which is intercepted by a primary aliphatic/aromatic amine, amide or sulfonamide followed by intramolecular Michael addition to afford 3-substituted isoindolin-1-ones in good yield.

Full text of DOI:10.1016/j.tetlet.2003.08.036

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7441–7443
Synthesis of 3-substituted isoindolin-1-ones via a
palladium-catalysed 3-component
carbonylation/amination/Michael addition process
Xinjie Gai,a Ronald Grigg,a,* Tossapol Khamnaen,b Shuleewan Rajviroongit,b
Visuvanathar Sridharan,a Lixin Zhang,a Simon Collardc and Ann Keepc
aMolecular Innovation Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, Leeds University, Leeds LS2
9JT, UK
bDepartment of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Rajthevee, Bangkok 10400, Thailand
cJohnson Matthey, Orchard Road, Royston, Herts SG8, UK
Received 9 July 2003; revised 28 July 2003; accepted 8 August 2003
Abstract—A novel palladium-catalysed three component cascade process is described involving carbonylation of an aryl iodide to
generate an acyl palladium species which is intercepted by a primary aliphatic/aromatic amine, amide or sulfonamide followed by
intramolecular Michael addition to afford 3-substituted isoindolin-1-ones in good yield.
© 2003 Elsevier Ltd. All rights reserved.
Substituted isoindolinones of general structure 1 pos-
sess anxiolytic activity and are of interest as sedatives,
hypnotics and muscle relaxants.1 Typical examples are
the anxiolytics pazinaclone 2, pagoclone 3 (Aventis/
Pfizer–phase III clinical trials),2 and the anxiolytic/anti-
convulsant zopiclone 4.3 The isoindolone moiety also
features in anti-cancer drug candidates including
protein kinase inhibitors.
catalysed cyclisation–anion capture cascades.4 As part
of our ongoing interest in designing palladium-
catalysed carbonylation processes in a tactical combina-
tion with core reactions, we explored combinations with
Michael addition processes as the key step to synthesise
isoindolinone derivatives (Scheme 1).
Compounds of type 5 react with carbon monoxide (1
atm) and a primary amine in the presence of palla-
dium(0) to afford 3-substituted isoindolin-1-ones via
path a or path b. In path a carbon monoxide insertion
is followed by amination to give the amide 6, which
We have demonstrated that carbon monoxide and
allene are powerful relay switches in the palladium-
Scheme 1.
* Corresponding author. E-mail: r.grigg@chem.leeds.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.036

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X. Gai et al. / Tetrahedron Letters 44 (2003) 7441–7443
Table 1. Three component carbonylation–amination-
Table 2. Three component carbonylation cascade with
a,b-unsaturated amide Michael acceptorsa,b
Michael addition cascadesa
undergoes intramolecular Michael addition to afford
substituted isoindolin-1-ones 7. In path b an inter-
molecular Michael addition occurs first. We selected
8a–j as the prototypical dual aryl iodide/Michael accep-
tors to evaluate this novel 3-component cascade.
Recently we have reported a similar process but using
allene as a relay switch, in place of CO, to synthesise
carbo- and hetero-cycles.5 Thus 8a–d (1 mmol) react

X. Gai et al. / Tetrahedron Letters 44 (2003) 7441–7443
7443
with carbon monoxide (1 atm), Pd(OAc)2 (10 mol%),
PPh3 (20 mol%), Cs2CO3 (2 mol equiv.) and an aro-
matic/hetero-aromatic or aliphatic amine (1.2 mol
equiv.) in toluene at 90°C for 24 h to afford heterocy-
cles 9–15 in good yield (Table 1, entries 1–7). Next, we
briefly studied the diastereoselectivity of the Michael
addition reaction in the presence of a chiral amine
(Table 1, entries 8 and 9). (R)-(+)-a-Methylbenxylamine
afforded 16a and 16b as 1:1 and 2:3 diastereomeric
mixtures whilst S-alanine methyl ester afforded 17 as a
1:1 diastereomeric mixture.
Pd(PPh3)2Cl2 10 mol%, TFP 12 mol% and Cs2CO3 (2
mol equiv.) in toluene at 110°C was used (Table 2,
entries 4–6). Pazinaclone 2 was successfully synthesised
in 64% yield (unoptimised) (Table 2, entry 4). Amides
and sulfonamides were also successfully used as nucle-
ophiles in the above cascades (Table 2, entries 7 and 8).
When trifluoroacetamide was employed as a nucle-
ophile, hydrolysis occurred furnishing NH amides 25e
and 25f in good yield (entry 9). This opens up further
synthetic opportunities.
We have briefly probed the mechanism of the reaction
and conclude that it is more likely to proceed via path
a than path b. A control experiment in which carbon
monoxide was omitted as the reagent and benzylamine
used as a nucleophile was carried out but no Michael
adduct, resulting from the reaction of 8a with ben-
zylmine, was detected under the standard reaction
conditions.
In conclusion, we have demonstrated a novel three
component palladium-catalysed carbonylation/amina-
tion/Michael addition cascade for the synthesis of 3-
substituted isolindolin-1-ones. Further work is in hand
on this and related cascades.
Acknowledgements
We thank Johnson Matthey, Leeds University, the
Thailand Research Fund (TRF) of the Royal Golden
Jubilee project and the Thailand Postgraduate Educa-
tion and Research in Chemistry (PERCH) Fund for
support.
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