A concise and efficient synthesis of isoindolin-1-ones. New synthetic approach to the polycyclic framework of vitedoamine A

Article abstract of DOI:10.1016/j.tet.2007.01.021

A concise and efficient synthesis of 2,3-dihydro-1H-isoindol-1-ones based upon the Parham-type cyclization of iodinated benzyldicarbamates is reported. The synthetic potential of this approach was further emphasized by the assembly of the polycyclic frame

Full text of DOI:10.1016/j.tet.2007.01.021

Tetrahedron 63 (2007) 2664–2669
A concise and efficient synthesis of isoindolin-1-ones.
New synthetic approach to the polycyclic framework
of vitedoamine A
*
Marc Lamblin, Axel Couture, Eric Deniau and Pierre Grandclaudon
´
UMR 8009 ‘Chimie Organique et Macromoleculaire’, Laboratoire de Chimie Organique Physique, Ba^timent C3(2),
´
Universite des Sciences et Technologie de Lille, F-59655 Villeneuve d’Ascq Cedex, France
´
Received 5 December 2006; revised 10 January 2007; accepted 14 January 2007
Available online 17 January 2007
Abstract—A concise and efficient synthesis of 2,3-dihydro-1H-isoindol-1-ones based upon the Parham-type cyclization of iodinated benzyl-
dicarbamates is reported. The synthetic potential of this approach was further emphasized by the assembly of the polycyclic framework of
vitedoamine A.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
O
N
R1
There is an increasing interest in the development of new
synthetic methodologies for the preparation of isoindolinone
derivatives of generic structure 1 (Fig. 1) because of their
importance as key intermediates in organic synthesis1 and
their profound physiological and chemotherapeutic activi-
ties.2 Many compounds containing the isoindolinone skele-
ton have indeed shown biological properties as exemplified
by the anti-inflammatory activities of indoprofen 23 and the
inhibitory activities on tumor necrosis factor production
and on histone deacetylase (HDAC) of deoxythalidomide4
and hydroxamic acid derivatives,5 3 and 4, respectively
(Fig. 1). The isoindolinone moiety is also an integral part
of a variety of naturally occurring bioactive compounds.6
1
O
O
N
O
N
N
H
COOH
O
2
3
O
O
N
Ph
HOHN
Ph
X
O
4
OR2
N
R1
5 X = Br, I
During the past few decades a number of synthetic strategies
have been developed for the elaboration of isoindolin-1-ones
1 and among the possible synthetic routes the simplest one
is undoubtedly the transformation of lactones to lactams.7
They are also accessible (i) by reduction of the corre-
sponding phthalimides,8 (ii) by amination and cyclization
of 2-bromomethylbenzoyl esters,9 (iii) by Pd(OAc)2-
catalyzed carbonylation of secondary amines,10 (iv) by a
base-induced cyclization–dephosphorylation sequence
applied to 2-halogeno-N-(phosphorylmethyl)benzamide
derivatives,11 and (v) by a base-induced cyclization of
2-hydroxymethylbenzamide derivatives.12
Figure 1.
Isoindolinones can also be synthesized (i) by Ph3P and
n-Bu3N catalyzed carbonylation of ortho-bromoanilines,13
(ii) by palladium nanoparticle-catalyzed carbonylation–
amination reaction of 2-iodobenzylbromides,14 (iii) by pal-
ladium catalyzed reaction of 2-iodobenzamides,15 and (iv)
by a reductive amination process applied to 2-acylbenzoic
acids.16 All these synthetic approaches are of procedural
simplicity and generally proceed in good yields but they
are generally fraught with difficulties associated with the
elaboration of models equipped with specific substituents
in particular positions on the basic benzene nucleus and
particularly when the synthetic routes inevitably lead to mix-
ture of regioisomers. Furthermore all models elaborated by
these methods are invariably N-substituted on the lactam
Keywords: Mitsunobu reaction; Iminodicarboxylates; Parham procedure;
Isoindolinones.
* Corresponding author. Tel.: +33 (0)3 20 43 44 32; fax: +33 (0)3 20 33 63
09; e-mail: axel.couture@univ-lille1.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.021

M. Lamblin et al. / Tetrahedron 63 (2007) 2664–2669
2665
O
HN
O
unit and consequently the construction of unsubstituted
models 1 (R1¼H), which may serve as a handle for further
synthetic planning, e.g., N- and C-benzyl functionaliza-
tions17 require a supplementary deprotection step. In this
respect structural modification of the most commonly used
benzyl N-lactam protecting group was necessary to address
the problem associated with the selective removal of the
benzylic side chain.18
OMe
OMe
R4
R4
R5
R6
I
R5
R6
I
O
N
OMe
OMe
OH
i
R7
R7
O
6a-e
5a-e
R4
R4
R7
O
R5
R6
Li
R5
R6
2. Results and discussion
O
O
OMe
OMe
N
ii
OMe
N
We therefore considered that for the convenient synthesis of
a variety of differentially substituted 2,3-dihydroisoindol-
1-ones 1 (R1¼H) a more versatile procedure would be nec-
essary and we wish to delineate in this paper a concise and
efficient synthesis of the title compounds that relies upon
our long standing experience in the field of the Parham cycli-
zation reactions.19 This annulation technique, which hinges
upon aromatic lithiation and subsequent trapping with an
internal electrophile has been used for the assembling of a
wide array of carbo- and heterocyclic systems20 but applica-
tions of this concept for the elaboration of five-membered
lactams are scarce.21 In recent years our group has developed
a new synthetic approach to 2-alkylisoindol-1-ones 1 based
on the Parham-type cyclization of the suitably substituted
2-bromo- or iodobenzylcarbamates 5 (Fig. 1). This operation
released an alkoxide species as the internal nucleofuge and
we then reasoned that incorporation in the annulated com-
pounds 1 of a temporary protecting group R1 that is highly
sensitive to nucleophilic attacks would conceivably deliver
the NH free models 1 (R1¼H) in a straightforward manner.
The choice of the alkoxycarbonyl group (R1¼COOR3) origi-
nated from the following premises: (i) the carbamate group
is endowed with a remarkable propensity to react with basic
and nucleophilic reagents, particularly with alkoxy moieties,
inter- and intramolecularly22 and (ii) the presence of a sym-
metrical N-diacyl functionality in the parent model 5 should
not alter the annulation process leading to the fused benzo-
lactams 1.
R7
O
+ MeOLi
8
7
R4
R7
R4
R7
O
O
R5
R6
O
R5
R6
OMe
OMe
N
NH
+ O=C(OMe)2
iii
9
1a-e
Scheme 1. Reagents and conditions: (i) PPh3, DEAD, THF, 0 ꢁC then rt
overnight; (ii) n-BuLi, THF, ꢀ90 ꢁC then rt, then reflux for 30 min; and
(iii) H3O+.
A representative series of compounds, which have been
prepared by this method are presented in Table 1 where it
may be seen that this simple procedure affords satisfactory
yields of the targeted 2,3-dihydro-1H-isoindol-1-ones. From
a mechanistic point of view one can reasonably assume that
as anticipated, the methoxylate released upon the annulation
step giving rise to 8 can attack the latent methoxycarbonyl
group of the N-acylated carbamate moiety to afford the
highly reactive alkoxyketal-type intermediate 9. Ultimate
rearrangement according to the mechanistic pathway por-
trayed in Scheme 1 triggered off the formation of the NH
free annulated models 1a–e, with the release of dimethylcar-
bonate upon aqueous work up under acidic conditions.
The first facet of the synthesis was the elaboration of a range
of iodinated benzyldicarbamates 5a–e, which are liable to
favor halogen–metal interconversion20b,e upon treatment
with organolithiated reagents while sparing the diacylamine
functionality. We envisaged building up these parent com-
pounds on reliance with the Mitsunobu coupling reaction
and for this purpose the appropriate 2-iodobenzyl alcohols
6a–e were allowed to react with dimethyl iminodicarboxy-
late (Scheme 1). The bulkiness of the reagents had no steric
impact on the coupling reaction since compounds 5a–e,
candidates for the planned Parham cyclization reaction
were obtained with very satisfactory yields (Table 1).
To evaluate the synthetic potential of this new conceptual
approach we then set out to prepare the 4-phenylbenzo-
isoindolinone framework of alkaloid vitedoamine A. Vitedo-
amine A is a new phenylnaphthalene-type lignan alkaloid
recently isolated from the seeds of Vitex negundo that are
used as a folk medicine for analgesia and sedation, and is
endowed with strong anti-oxidative activity.23
The synthesis started with the elaboration of the requisite
iodinated benzyl alcohol 10. This compound was readily as-
sembled from the easily accessible 1-bromo-2-naphthalene-
methanol 12 by the two step sequence depicted in Scheme 2.
To ensure the formation of the mandatory lithiated inter-
mediate 7, a THF solution of dicarbamates 5a–e was sub-
sequently exposed to n-butyllithium at ꢀ90 ꢁC for few
minutes. The intramolecular ring closure was instantaneous
as demonstrated by the essentially complete consumption of
the parent compounds 5a–e and we were pleased to observe
that subsequent warming to rt followed by refluxing the
reaction mixture for a short period delivered the desired
NH annulated products1a–e upon acidicworkup(Scheme 1).
Table 1. Dicarbamates 5a–e and isoindolin-1-ones 1a–e produced via
Scheme 1
Compd Yield (%) Compd Yield (%) R4
R5
R6
R7
5a
5b
5c
5d
5e
71
69
81
79
76
1a
1b
1c
1d
1e
55
51
52
64
65
OMe
H
OCH2O
OBn OMe
H
H
H
OMe
H
H
H
H
H
H
H
H
C4H4

2666
M. Lamblin et al. / Tetrahedron 63 (2007) 2664–2669
Initially Suzuki cross-coupling reaction between 12 and phe-
nylboronic acid afforded 1-phenyl-2-naphthalenemethanol
11. Even though the hydroxymethyl group ranks modestly
in the hierarchy of ortho-directing metalation groups,24 aro-
matic lithiation and then electrophilic iodination of 11 oc-
curred regioselectively at the ortho-site to deliver the
required 3-iodo-1-phenyl-2-naphthalenemethanol 10 albeit
in modest yield. The subsequent installation of the N-diacyl
functionality was ensured by Mitsunobu reaction with di-
methyl imidodicarboxylate to afford the rather congested
compound 13 possessing the appropriate functionalities lia-
ble to secure the creation of the lactam unit. Gratifyingly the
cyclization reaction following the previously described an-
nulation protocol proceeded uneventfully to afford the benzo-
indolinone derivative 14; the arylated tricyclic nucleus of
alkaloid vitedoamine A with a fairly good yield (Scheme 2).
4. Experimental
4.1. General
Tetrahydrofuran (THF) was pre-dried with anhydrous
Na2SO4 and distilled over sodium benzophenone ketyl under
Ar before use. DMF, CH2Cl2, NEt3, and toluene were
distilled from CaH2. Dry glassware was obtained by oven-
drying and assembly under dry Ar. The glassware was equip-
ped with rubber septa and reagent transfer was performed by
syringe techniques. For flash chromatography, Merck silica
gel 60 (40–63 mm; 230–400 mesh ASTM) was used. The
melting points were obtained on a Reichert–Thermopan ap-
paratus and are not corrected. NMR spectra: Bruker AM 300
(300 MHz and 75 MHz, for 1H and 13C), CDCl3 or DMSO-
d6 (for 1a–e) as solvent, TMS as an internal standard. Micro-
analyses were performed by the CNRS microanalysis center.
PhB(OH)2
Pd(PPh3)4
4.1.1. Syntheses of the 2-iodobenzyl alcohol derivatives
6a–e and 10. The 2-iodobenzyl alcohol derivatives 6a,25
6b,26 and 6e,25 were synthesized according to literature
methods.
OH
OH
K2CO3
toluene, MeOH
Br
12
95%
11
4.1.1.1. 2-Iodo-3,4-methylenedioxybenzyl alcohol (6c).
From piperonol (3,4-methylenedioxybenzyl alcohol), follow-
ing the procedure described for 6a.25 Yield 53%; white solid;
mp 106–107 ꢁC (from hexane–toluene); 1H NMR (dH): 2.13
(br s, 1H, OH), 4.62 (s, 2H, CH2O), 6.05 (s, 2H, OCH2O),
6.75 (d, J¼7.8 Hz, 1H, aromatic H), 6.92 (d, J¼7.8 Hz, 1H,
aromatic H) ppm; 13C NMR (dC): 68.2 (CH2O), 76.6 (C–I),
100.7 (OCH2O), 108.0 (CH), 122.2 (CH), 135.6 (C),
145.7 (C), 149.7 (C) ppm. Anal. calcd for C8H7IO3 (277.9):
C, 34.56; H, 2.54%. Found: C, 34.42; H, 2.81%.
O
HN
O
OMe
OMe
I
1. n-BuLi, THF, - 78 °C
2. r.t., 4h
OH
3. I2
54%
PPh3, DEAD, THF
0 °C then r.t., 20 h
65%
O
10
I
1. n-BuLi, THF
- 78 °C, 15 min
O
OMe
NH
4.1.1.2. 3-Benzyloxy-2-iodo-4-methoxybenzyl alcohol
(6d). By reduction of 3-benzyloxy-2-iodo-4-methoxy-
benzaldehyde27 with NaBH4 in MeOH. Yield 92%; white
N
2. - 78 °C to r.t.
OMe
3. Δ, 30 min
4. H3O+
O
1
solid; mp 78–79 ꢁC (from hexane–toluene); H NMR (dH):
13
63%
14
2.15 (br s, 1H, OH), 3.90 (s, 3H, OCH3), 4.67 (s, 2H,
CH2O), 5.03 (s, 2H, CH2O), 6.94 (d, J¼8.3 Hz, 1H, aromatic
H), 7.20 (d, J¼8.3 Hz, 1H, aromatic H) ppm; 13C NMR (dC):
56.1 (CH3), 69.2 (CH2), 74.3 (CH2), 97.2 (C–I), 112.3 (CH),
122.6 (C), 124.5 (CH), 128.1 (CH), 128.4 (2ꢂCH), 128.6
(2ꢂCH), 135.8 (C), 137.1 (C), 152.2 (C) ppm. Anal. calcd
for C15H15IO3 (370.0): C, 48.67; H, 4.08%. Found: C,
48.51; H, 4.05%.
O
MeO
HO
NH
OMe
OH
Vitedoamine A
4.1.1.3. 1-Phenyl-2-naphthalenemethanol (11). A solu-
tion of 1-bromo-2-naphthalenemethanol28 (1 g, 4.22 mmol)
and Pd(PPh3)4 (46 mg, 0.04 mmol) in toluene (14 mL)
was added to a solution of phenylboronic acid (616 mg,
5.06 mmol) in EtOH (12 mL), followed by addition of
K2CO3 (1.11 g, 9.3 mmol). The mixture was refluxed for
20 h under N2 and allowed to cool to rt. To the reaction
mixture was added 0.5 M NaOH solution (30 mL) and the
mixture was extracted with CH2Cl2 (2ꢂ50 mL). The organic
layers were combined, dried (MgSO4), and filtered. The
solvent was removed under reduced pressure and the yellow
oily residue was purified by column chromatography using
AcOEt–hexane (30:70) as an eluent to give a colorless
Scheme 2.
3. Conclusion
In conclusion we have developed a new, general concise and
efficient approach for the synthesis of poly and diversely
substituted isoindol-1-ones based on readily available pre-
cursors. The synthetic potential of this method has been
further demonstrated by the synthesis of the vitedoamine
A framework. Our synthetic approach involving an N-diacyl
moiety enriches the repertoire of the annulation reactions
relying on the Parham cyclization process then emphasizing
the prominent place of this technique in the arsenal of the
synthetic tactics for the assembling of heterocyclic systems,
namely alkaloids.
1
oil. Yield 95% (938 mg); H NMR (dH): 2.18 (br s, 1H,
OH), 4.56 (s, 2H, CH2O), 7.27–7.33 (m, 2H, aromatic H),
7.38–7.43 (m, 6H, aromatic H), 7.71 (d, J¼8.5 Hz, 1H,

M. Lamblin et al. / Tetrahedron 63 (2007) 2664–2669
2667
aromatic H), 7.88–7.73 (m, 2H, aromatic H) ppm; 13C NMR
(dC): 63.3 (CH2), 125.7 (CH), 125.8 (CH), 126.1 (CH), 126.7
(CH), 127.5 (CH), 127.9 (CH), 128.0 (CH), 128.5 (2ꢂCH),
130.2 (2ꢂCH), 132.7 (C), 132.9 (C), 135.7 (C), 137.9 (C),
138.2 (C) ppm. Anal. calcd for C17H14O (349.1): C, 87.15;
H, 6.02%. Found: C, 87.05; H, 6.07%.
(C), 149.6 (C), 154.0 (2ꢂCO) ppm. Anal. calcd for
C12H12INO6 (393.0): C, 36.66; H, 3.08; N, 3.56%. Found:
C, 36.55; H, 3.03; N, 3.25%.
4.1.2.4. 3-Benzyloxy-2-iodo-4-methoxy-N,N-di(meth-
oxycarbonyl)benzylamine (5d). Yield 79%; yellow solid;
1
mp 105–107 ꢁC; H NMR (dH): 3.84 (s, 6H, 2ꢂOCH3),
4.1.1.4. 2-Iodo-1-phenyl-2-naphthalenemethanol (10).
From 11 following the procedure described for 6e.25 The
crude oily reaction product was purified by column chroma-
tography using AcOEt–hexane (30:70) as an eluent to afford
a pale yellow oil. Yield 54%; 1H NMR (dH): 2.13 (br s, 1H,
OH), 4.65 (s, 2H, CH2O), 7.28–7.42 (m, 4H, aromatic H),
7.46–7.56 (m, 4H, aromatic H), 7.76 (d, J¼8.1 Hz, 1H, aro-
matic H), 8.49 (s, 1H, aromatic H) ppm; 13C NMR (dC): 66.8
(CH2), 98.1 (C–I), 126.7 (CH), 126.8 (CH), 126.9 (CH),
127.4 (CH), 127.8 (CH), 128.4 (2ꢂCH), 130.1 (2ꢂCH),
132.6 (C), 134.4 (C), 136.2 (C), 138.3 (C), 139.0 (CH),
141.1 (C) ppm. Anal. calcd for C17H13IO3 (360.0): C,
56.69; H, 3.64%. Found: C, 56.75; H, 3.61%.
3.87 (s, 3H, OCH3), 4.89 (s, 2H, CH2), 5.03 (s, 2H, CH2),
6.82 (d, J¼8.5 Hz, 1H, aromatic H), 6.90 (d, J¼8.5 Hz,
1H, aromatic H), 7.33–7.44 (m, 3H, aromatic H), 7.62 (d,
J¼7.2 Hz, 2H, aromatic H) ppm; 13C NMR (dC): 54.2
(2ꢂCH3), 54.7 (CH2), 56.1 (CH3), 74.3 (CH2), 96.6 (C–I),
112.5 (CH), 121.3 (CH), 128.1 (CH), 128.4 (2ꢂCH),
128.5 (2ꢂCH), 132.0 (C), 137.1 (C), 147.6 (C), 151.7 (C),
154.1 (2ꢂCO) ppm. Anal. calcd for C19H20INO6 (485.0):
C, 47.03; H, 4.15; N, 2.89%. Found: C, 46.79; H, 4.37; N,
3.05%.
4.1.2.5. N,N-Di(methoxycarbonyl)-(2-iodonaphtha-
len-1-yl)methylamine (5e). Yield 76%; yellow solid; mp
1
84–85 ꢁC; H NMR (dH): 3.73 (s, 6H, 2ꢂOCH3), 5.55 (s,
4.1.2. Syntheses of the dicarbamates 5a–e and 11. Gen-
eral procedure. A solution of DEAD (2.5 mL, 40% in tolu-
ene, 5.5 mmol) was added dropwise at 0 ꢁC under N2 to
a stirred solution of the appropriate 2-iodobenzyl alcohol de-
rivative (5 mmol), triphenylphosphine (1.44 g, 5.5 mmol),
and dimethyl iminodicarboxylate (1.33 g, 10 mmol) in dry
THF (50 mL). The mixture was then stirred at rt for an addi-
tional 24 h, quenched with water (2 mL), and concentrated
under vacuum. The oily residue was purified by column
chromatography (CH2Cl2–Et2O–hexane, 50:30:20). The
solid iminodicarboxylates were recrystallized from hexane–
toluene.
2H, CH2), 7.45 (d, J¼8.7 Hz, 1H, aromatic H), 7.48–7.56
(m, 2H, aromatic H), 7.77–7.83 (m, 1H, aromatic H), 7.90
(d, J¼8.7 Hz, 1H, aromatic H), 8.04–8.11 (m, 1H, aromatic
H) ppm; 13C NMR (dC): 53.3 (CH2), 54.0 (2ꢂCH3), 101.7
(C–I), 123.3 (C), 123.9 (CH), 126.3 (CH), 127.3 (CH), 128.7
(CH), 129.8 (CH), 133.4 (C), 134.5 (C), 136.6 (C), 154.2
(2ꢂCO) ppm. Anal. calcd for C15H14INO4 (399.0): C,
45.13; H, 3.54; N, 3.51%. Found: C, 45.31; H, 3.54; N, 3.39%.
4.1.2.6. N,N-Di(methoxycarbonyl)-(3-iodo-1-phenyl-
naphthalen-2-yl)amine (13). Yield 65%; yellow oil; H
1
NMR (dH): 3.57 (s, 6H, 2ꢂOCH3), 5.16 (s, 2H, CH2), 7.19
(d, J¼8.6 Hz, 1H, aromatic H), 7.23 (d, J¼7.9 Hz, 2H, aro-
matic H), 7.32 (t, J¼8.4 Hz, 1H, aromatic H), 7.42–7.52 (m,
4H, aromatic H), 7.72 (d, J¼8.2 Hz, 1H, aromatic H), 8.52
(s, 1H, aromatic H) ppm; 13C NMR (dC): 53.4 (CH2), 53.6
(2ꢂCH3), 99.1 (C–I), 126.6 (CH), 126.65 (CH), 126.7
(CH), 126.75 (CH), 127.5 (CH), 128.4 (2ꢂCH), 130.1
(2ꢂCH), 132.8 (C), 133.1 (C), 133.8 (C), 137.8 (C), 139.2
(CH), 140.5 (C), 153.2 (2ꢂCO) ppm. Anal. calcd for
C21H18INO4 (475.0): C, 53.07; H, 3.82; N, 2.95%. Found:
C, 52.99; H, 3.75; N, 3.10%.
4.1.2.1. 2-Iodo-3-methoxy-N,N-di(methoxycarbonyl)-
benzylamine (5a). Yield 71%; yellow solid; mp 96–98 ꢁC;
1H NMR (dH): 3.81 (s, 6H, 2ꢂOCH3), 3.89 (s, 3H, OCH3),
4.92 (s, 2H, CH2), 6.67 (d, J¼7.5 Hz, 1H, aromatic H),
6.74 (d, J¼7.9 Hz, 1H, aromatic H), 7.24–7.29 (m, 1H, aro-
matic H) ppm; 13C NMR (dC): 54.2 (2ꢂCH3), 55.5 (CH2),
56.6 (CH3), 89.2 (C–I), 109.5 (CH), 117.9 (CH), 129.3
(CH), 141.0 (C), 153.9 (C), 158.0 (2ꢂCO) ppm. Anal. calcd
for C12H14INO5 (379.0): C, 38.01; H, 3.72; N, 3.69%.
Found: C, 37.85; H, 3.89; N, 3.71%.
4.1.3. Syntheses of the isoindolinones 1a–e and 14. Gen-
eral procedure. A solution of n-BuLi (1.4 mL, 1.6 M in
hexanes, 2.2 mmol) was added dropwise at ꢀ90 ꢁC under
N2 to a solution of the dicarbamate (2 mmol) in dry THF
(30 mL). The reaction mixture was stirred at ꢀ90 ꢁC for
an additional 15 min, slowly allowed to warm to rt over
1 h and then refluxed for 30 min. The reaction mixture was
cooled to rt, quenched with saturated aq NH4Cl solution
(10 mL), and extracted with Et2O (3ꢂ10 mL). The com-
bined organic extracts were washed with brine and dried
(Na2SO4). After evaporation of the solvent the crude oily
residue was purified by column chromatography using
AcOEt as an eluent to afford the annulated compounds
(recrystallization from CH3CN–Et2O).
4.1.2.2. 2-Iodo-5-methoxy-N,N-di(methoxycarbonyl)-
benzylamine (5b). Yield 69%; yellow solid; mp 77–79 ꢁC;
1H NMR (dH): 3.74 (s, 3H, OCH3), 3.81 (s, 6H, 2ꢂOCH3),
4.83 (s, 2H, CH2), 6.54 (d, J¼8.6 Hz, 1H, aromatic H),
6.23 (s, 1H, aromatic H), 6.68 (d, J¼8.6 Hz, 1H, aromatic
H) ppm; 13C NMR (dC): 54.2 (2ꢂCH3), 54.8 (CH2), 55.4
(CH3), 85.4 (C–I), 112.8 (C), 114.0 (C), 139.9 (C), 140.1
(C), 153.9 (C), 160.3 (2ꢂCO) ppm. Anal. calcd for
C12H14INO5 (379.0): C, 38.01; H, 3.72; N, 3.69%. Found:
C, 37.77; H, 3.62; N, 3.78%.
4.1.2.3. 2-Iodo-3,4-methylenedioxy-N,N-di(methoxy-
carbonyl)benzylamine (5c). Yield 81%; yellow solid; mp
1
141–142 ꢁC; H NMR (dH): 3.82 (s, 6H, 2ꢂOCH3), 4.83
(s, 2H, CH2), 6.03 (s, 2H, OCH2O), 6.58 (d, J¼8.0 Hz,
1H, aromatic H), 6.71 (d, J¼8.0 Hz, 1H, aromatic H) ppm;
13C NMR (dC): 53.4 (CH2), 54.2 (2ꢂCH3), 74.3 (C–I),
100.7 (OCH2O), 108.2 (CH), 119.1 (CH), 131.9 (C), 145.2
4.1.3.1.
2,3-Dihydro-7-methoxy-1H-isoindol-1-one
1
(1a). Yield 55%; white solid; mp 144–145 ꢁC; H NMR
(dH): 3.82 (s, 3H, OCH3), 4.27 (s, 2H, CH2), 6.98 (d,
J¼7.1 Hz, 1H, aromatic H), 7.07 (d, J¼7.1 Hz, 1H, aromatic

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M. Lamblin et al. / Tetrahedron 63 (2007) 2664–2669
H), 7.50 (t, J¼7.1 Hz, 1H, aromatic H), 8.22 (br s, 1H,
NH) ppm; 13C NMR (dC): 44.7 (CH2), 55.8 (CH3), 110.7
(CH), 116.0 (CH), 119.9 (C), 133.5 (CH), 147.4 (C), 157.5
(C), 169.3 (CO) ppm. Anal. calcd for C9H9NO2 (163.0): C,
66.25; H, 5.56; N, 8.58%. Found: C, 66.38; H, 5.54; N, 8.62%.
References and notes
ꢀ
ꢀ
1. (a) Stajer, G.; Csende, F. Curr. Org. Chem. 2005, 9, 1277–1286;
ꢀ
ꢀ
ꢀ
(b) Sanchez-Sanchez, C.; Perez-Inestrosa, E.; Garcıa-Segura,
R.; Suau, R. Tetrahedron 2002, 58, 7267–7274; (c)
Abramovitch, R. A.; Shinkai, I.; Mavunkel, B. J.; More,
K. M.; O’Connor, S.; Ooi, G. H.; Pennington, W. T.;
Srinivasan, P. C.; Stowers, J. R. Tetrahedron 1996, 52, 3339–
3354; (d) Heaney, H.; Shuhaibar, K. F. Synlett 1995, 47–48.
2. (a) Pendrak, I.; Barney, S.; Wittrock, R.; Lambert, D. M.;
Kingsbury, W. D. J. Org. Chem. 1994, 59, 2623–2625; (b) De
Clercq, E. J. Med. Chem. 1995, 38, 2491–2517.
4.1.3.2.
2,3-Dihydro-5-methoxy-1H-isoindol-1-one
(1b). Yield 51%; white solid; mp 160–161 ꢁC (lit.:29 161–
1
162 ꢁC); H NMR (dH): 3.81 (s, 3H, OCH3), 4.30 (s, 2H,
CH2), 7.00 (d, J¼8.3 Hz, 1H, aromatic H), 7.10 (s, 1H, aro-
matic H), 7.57 (d, J¼8.3 Hz, 1H, aromatic H), 8.35 (br s, 1H,
NH) ppm; 13C NMR (dC): 45.2 (CH2), 56.0 (CH3), 108.4
(CH), 115.2 (CH), 124.5 (CH), 125.5 (C), 147.0 (C), 162.6
(C), 170.4 (CO) ppm.
3. (a) Nannini, G.; Giraldi, P. N.; Molgora, G.; Biasoli, G.;
Spinelli, F.; Logemann, W.; Dradi, E.; Zanni, G.; Buttinoni,
A.; Tommasini, R. Arzneim. Forsch. 1973, 23, 1090–1100;
(b) Hisamitsu (Pharmaceutical Co., Inc.). Jpn. Kokai Tokkyo
Koho JP 149257, 1980; Chem. Abstr. 1981, 94, 174879.
4. Schmahl, H. J.; Dencker, L.; Plum, C.; Chahoud, I.; Nau, H.
Arch. Toxicol. 1996, 11, 749–756.
5. Shinji, C.; Maeda, S.; Imai, K.; Yoshida, M.; Hashimoto, Y.;
Miyachi, H. Bioorg. Med. Chem. 2006, 14, 7625–7651.
6. (a) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M.
Tetrahedron Lett. 1982, 23, 39–42; (b) Rodriguez, G.; Cid,
M. M.; Saa, C.; Castedo, L.; Dominguez, D. J. Org. Chem.
4.1.3.3.
6,7-Dihydro-1,3-8H-dioxolo[4,5-e]isoindol-
1
8-one (1c). Yield 52%; white solid; mp 258–259 ꢁC; H
NMR (dH): 4.28 (s, 2H, CH2), 6.14 (s, 2H, OCH2O), 6.95
(d, J¼7.6 Hz, 1H, aromatic H), 7.11 (d, J¼7.6 Hz, 1H, aro-
matic H), 8.45 (br s, 1H, NH) ppm; 13C NMR (dC): 45.3
(CH2), 102.6 (OCH2O), 111.6 (CH), 113.4 (C), 116.3
(CH), 137.9 (C), 143.3 (C), 147.9 (C), 167.9 (CO) ppm.
Anal. calcd for C9H7NO3 (177.0): C, 61.02; H, 3.98; N,
7.91%. Found: C, 60.78; H, 4.09; N, 7.93%.
€
1996, 61, 2780–2782; (c) Daıch, A.; Marchalin, S.; Pigeon,
P.; Decroix, B. Tetrahedron Lett. 1998, 39, 9187–9190.
4.1.3.4. 2,3-Dihydro-7-benzyloxy-6-methoxy-1H-iso-
indol-1-one (1d). Yield 64%; white solid; mp 95–96 ꢁC;
1H NMR (dH): 3.85 (s, 3H, OCH3), 4.36 (s, 2H, CH2), 5.35
(s, 2H, CH2), 7.08–7.11 (m, 2H, aromatic H), 7.27–7.38
(m, 3H, aromatic H), 7.59–7.63 (m, 2H, aromatic H), 7.84
(br s, 1H, NH) ppm; 13C NMR (dC): 44.7 (CH2), 56.8
(CH3), 76.5 (CH2), 117.1 (CH), 118.3 (CH), 124.9 (C),
127.9 (CH), 128.2 (2ꢂCH), 128.7 (2ꢂCH), 137.2 (C),
137.6 (C), 146.1 (C), 152.4 (C), 170.1 (CO) ppm. Anal.
calcd for C16H15NO3 (269.1): C, 71.36; H, 5.61; N, 5.20%.
Found: C, 71.33; H, 5.41; N, 5.16%.
€
7. (a) Spath, E.; Lintner, J. Chem. Ber. 1936, 69B, 2727–2731;
(b) Barrios, I.; Camps, P.; Comes-Franchini, M.; Mun˜oz-
Torrero, D.; Ricci, A.; Sanchez, L. Tetrahedron 2003, 59,
1971–1979.
8. Horii, Z.-I.; Iwata, C.; Tamura, Y. J. Org. Chem. 1961, 26,
2273–2276.
9. (a) Pendergast, W.; Dickerson, S. H.; Dev, I. K.; Ferone, R.;
Duch, D. S.; Smith, G. K. J. Med. Chem. 1994, 37, 838–844;
(b) Taylor, E. C.; Jennings, L. D.; Mao, Z.; Hu, B.; Jun, J.-G.;
Zhou, P. J. Org. Chem. 1997, 62, 5392–5403; (c) Wang, H.;
Ganesan, A. Tetrahedron Lett. 1998, 39, 9097–9098.
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H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.;
Tokuda, M. J. Org. Chem. 2006, 71, 5951–5958.
11. Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2000, 655–660.
4.1.3.5. 2,3-Dihydro-1H-benzo[e]isoindol-1-one (1e).
1
Yield 65%; white solid; mp 189–190 ꢁC; H NMR (dH):
4.75 (s, 2H, CH2), 7.64–7.72 (m, 3H, aromatic H), 7.98–
8.05 (m, 3H, aromatic H), 8.67 (br s, 1H, NH) ppm; 13C
NMR (dC): 44.7 (CH2), 119.9 (CH), 124.2 (CH), 127.6
(CH), 128.2 (CH), 128.4 (C), 128.9 (CH), 129.2 (CH),
130.3 (C), 134.8 (C), 143.8 (C), 171.1 (CO) ppm. Anal.
calcd for C12H9NO (183.1): C, 78.67; H, 4.95; N, 7.65%.
Found: C, 78.84; H, 4.81; N, 7.66%.
12. Tsuritani, T.; Kii, S.; Akao, A.; Sato, K.; Nonoyama, N.; Mase,
T.; Yasuda, N. Synlett 2006, 801–803.
13. (a) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978, 43, 1684–
1687; (b) Campbell, J. B.; Dedinas, R. F.; Trumbower-Walsh,
S. A. J. Org. Chem. 1996, 61, 6205–6211; (c) Luzzio, F. A.;
Zacherl, D. P. Tetrahedron Lett. 1998, 39, 2285–2288.
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2003, 44, 6979–6982.
15. Wahab Khan, Md.; Masud Reza, A. F. G. Tetrahedron 2005, 61,
11204–11210.
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J. Org. Chem. 1978, 43, 3719–3723.
4.1.3.6.
4-Phenyl-2,3-dihydro-1H-benzo[f]isoindol-
1-one (14). Yield 63%; mp 277–279 ꢁC (lit.:30 268–
269.5 ꢁC); 1H NMR (dH): 4.27 (s, 2H, CH2), 7.44–7.58 (m,
7H, aromatic H), 7.65 (d, J¼7.8 Hz, 1H, aromatic H), 8.20
(d, J¼7.6 Hz, 1H, aromatic H), 8.37 (s, 1H, aromatic H),
8.75 (br s, 1H, NH) ppm; 13C NMR (dC): 44.8 (CH2),
123.1 (CH), 125.6 (CH), 126.4 (CH), 128.2 (CH), 128.5
(CH), 129.3 (2ꢂCH), 130.1 (2ꢂCH), 130.2 (CH), 130.9
(C), 133.35 (C), 133.4 (C), 134.6 (C), 136.6 (C), 137.8
(C), 170.0 (CO) ppm.
17. (a) Guo, Z.; Schultz, A. G. J. Org. Chem. 2001, 66, 2154–2157;
(b) Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P.
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8266.
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This research was supported by the Centre National de la
Recherche Scientifique and MENESR (grant to M.L.).

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