A new simple and convenient synthesis of 3-substituted phthalimidines

Article abstract of DOI:10.1016/S0040-4039(00)00155-6

An efficient and versatile synthesis of 3-substituted phthalimidines based upon an organometallic reagent addition reduction sequence performed on an appropriate N-protected phthalimide is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00155-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2347–2350
A new simple and convenient synthesis of 3-substituted
phthalimidines
Eric Deniau † and Dieter Enders ∗
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen,
Germany
Received 20 December 1999; accepted 18 January 2000
Abstract
An efficient and versatile synthesis of 3-substituted phthalimidines based upon an organometallic reagent
addition reduction sequence performed on an appropriate N-protected phthalimide is described. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Grignard reagents; hydrazides; iminium salts; lactams; phthalimidines.
3-Substituted 2,3-dihydro-1H-isoindol-1-ones 1 have attracted much attention from the scientific
community, because they represent the core unit of a wide range of naturally occurring substances1
or bio-active compounds.1a,c,2 Accordingly, the synthesis of this heterobicyclic system has developed
remarkably in recent years, which is also obviously linked to the potential of compounds comprising
the 3-substituted phthalimidine unit as synthetic building blocks.1a,c,3 They are accessible by different
chemical processes, which include the rearrangement of six-membered rings,4 elimination reactions from
3,3-disubstituted compounds,5 the Parham protocol,6 or, more recently, a carbocationic pathway.7
The most commonly employed synthetic method,8 however, involves the construction of the lactam
unit from an elaborated benzenic precursor in the final step. However, these methods are rather restricted
in scope and do not allow the incorporation of a great variety of substituents at the 3-position of the
heterocyclic nucleus.
In this paper, we describe a new, concise and efficient synthetic approach to 3-substituted phthali-
midines 1 as depicted in the retrosynthetic Scheme 1. The new procedure is based on the sequential
addition of an organometallic reagent to an appropriate N-protected phthalimide 4, followed by reduction
of the corresponding adduct 3 and subsequent N-deprotection of 2 to afford the title compounds. Crucial
for the success of our strategy was, therefore, the ability to identify a protecting group (PG), which
would be sufficiently robust to survive the projected addition reaction and would also be labile enough
∗
†
Corresponding author. Fax: +49 (0)241/8888-127; e-mail: enders@rwth-aachen.de (D. Enders)
On leave from UST Lille 1 F59655, Villeneuve d’Ascq Cedex, France.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00155-6
tetl 16435

2348
to be removed in the final step. This dual requirement prompted us to incorporate the dimethylamino
group (PG=NMe2) in our model. Besides the fact that additions of organometallic reagents on N-amino
phthalimides have formed the subject of rather scarce studies,9 the choice of this group was dictated
by the properties of the hydrazine N–N bond, which is well-known to be cleaved under numerous
conditions.10 Furthermore, we anticipated that an electron-withdrawing group connected to the lactamic
nitrogen should facilitate the addition step and then should allow the use of indifferently Grignard
reagents and more interestingly of lithiated species, which have been rarely employed in this context
owing to their higher reactivity. At last, the use of a protecting group should allow a decrease in the
amount of the organometallic reagent generally required for nucleophilic additions involving unprotected
imides and, consequently, should minimize the formation of by-products.
Scheme 1.
This synthetic route, depicted in Scheme 2, necessitated the preliminary elaboration of the N-
dimethylamino phthalimide 4, which was easily obtained11 by condensation between phthalic anhydride
and dimethylhydrazine. As anticipated, we found that the imide 4 reacted readily with a stoichiometric
amount of Grignard or organolithium reagents (M=MgX, Li) at low temperature to afford, exclusively,
the carbinolamines 5a–e in high yields (Table 1). In order to remove the hydroxy function of these
preliminarily formed compounds, N,O-hemiacetals 5a–e were subsequently treated with an excess of
trifluoroacetic acid to give the transient iminium salts 6a–e, which were then smoothly reduced in situ
with triethylsilane12,13 to furnish the N-protected bicyclic compounds 7a–e. Finally, removal of the N-
dimethylamino group in lactams 7a–e was achieved cleanly under reductive acidic conditions by heating
with an excess of zinc in refluxing acetic acid14 to deliver the targeted 3-substituted phthalimidines 1a–e
in good yields.
Scheme 2.
By means of a new synthetic approach, involving the addition of an organometallic reagent over a pro-
tected phthalimide as the key step, and followed by the reduction of the intermediate carbinolamines and
a deprotection step, we have disclosed a concise and efficient synthesis of 3-substituted 1-isoindolinones.
Owing to the efficiency and simplicity of this methodology, this process deserves attention and further

2349
Table 1
Generation of compounds 5, 7 and 1
work aimed at performing these reactions with asymmetric induction by means of chiral hydrazines is
currently under investigation in our laboratory.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (Leibniz-Preis) and the Fonds der
Chemischen Industrie. We thank Degussa-Hüls AG, BASF AG, the former Hoechst AG, Bayer AG and
Wacker Chemie for the donation of chemicals.
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NMe2), 4.94 (br. s, 1H, OH), 7.43–7.66 (m, 4H, Harom); 13C NMR (CDCl3, TMS) δ ppm: C 166.0 (CO), 144.6, 130.4, 90.6,
CH 131.8, 128.7, 122.5, 121.7, CH2 35.6, 31.1, 28.8, 23.7, 22.1, CH3 44.7, 13.6. MS, m/z (%): 276 (M+, 11), 59 (100). IR
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(m, 7H), 2.97 (s, 6H, NMe2), 4.43 (dd, J=6.0, 4.0 Hz, 1H, NCHAr), 7.31–7.44 (m, 2H, Harom), 7.49 (dt, J=7.4, 1.4 Hz, 1H,
Harom), 7.75 (d, J=7.4 Hz, 1H, Harom); 13C NMR (CDCl3, TMS) δ ppm: C 167.5 (CO), 144.1, 132.4, CH 131.4, 127.8, 123.1,
122.3, 61.0, CH2 31.6, 30.8, 29.4, 23.5, 22.5, CH3 44.1, 14.0. MS, m/z (%): 260 (M+, 31), 218 (98), 146 (100), 132 (54). IR
(KBr) 1699 (CO).
1
18. Selected data for compound 1d: mp 84–85°C; H NMR (CDCl3, TMS) δ ppm: 0.83 (t, J=6.9 Hz, 3H, Me), 1.18–1.51
(m, 7H), 1.57–1.68 (m, 1H), 1.87–1.99 (m, 1H), 4.60 (dd, J=7.4, 4.7 Hz, 1H, NCHAr), 7.38–7.46 (m, 2H, Harom), 7.52 (dt,
J=7.4, 1.1 Hz, 1H, Harom), 7.82 (d, J=7.4 Hz, 1H, Harom), 8.22 (br. s, 1H, NH); 13C NMR (CDCl3, TMS) δ ppm: C 171.3
(CO), 147.8, 132.0, CH 131.5, 127.8, 123.6, 122.3, 57.2, CH2 34.6, 31.6, 29.2, 25.5, 22.6, CH3 14.1. MS, m/z (%): 217 (M+,
16), 132 (100). IR (KBr) 1686 (CO), 3192 (NH).
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