Kinetic versus thermodynamic access to imidazoisoindolones, benzimidazoisoindolones, and [1,4]diazepinoisoindolones: Intramolecular nitrogen and π-aromatic trapping of N-acyliminium cation

Article abstract of DOI:10.1016/j.tet.2004.07.107

Efficient assembly of substituted imidazo[2,1-a]isoindolones I is reported from suitable α,β-diamine IV (or corresponding β-nitroamine) and phthalic anhydride (1) in a three- or four-step sequence in good yields. The key step of this methodology is based on an intramolecular α-aza- amidoalkylation of the N-acyliminium species. Furthermore, when R₂ is an aromatic moiety a competing α-amidoalkylation took place and imidazo[2,1-a]isoindolones (or benzimidazo[2,1-a]isoindolones) I and/or isoindolo[1,4]benzodiazepines III were obtained under kinetic or thermodynamic control. The chemoselectivity of these transformations is also discussed.

Full text of DOI:10.1016/j.tet.2004.07.107

Tetrahedron 60 (2004) 11029–11039
Kinetic versus thermodynamic access to imidazoisoindolones,
benzimidazoisoindolones, and [1,4]diazepinoisoindolones:
intramolecular nitrogen and p-aromatic trapping of
N-acyliminium cation
a
Armelle Cul, Adam Daıch, Bernard Decroix, Gerard Sanz and Luc Van Hijfte
a,
a
b
b
*
´
¨
a
´
Laboratoire de chimie, URCOM, EA 3221, UFR des Sciences and Techniques de l’Universite du Havre, B.P: 540, 25 rue Philippe Lebon,
F-76058 Le Havre Cedex, France
bJohnson & Johnson, Pharmaceutical Research & Development, Division of Janssen-Cilag, Campus de Maigremont, B.P: 615,
F-27106 Val-de-Reuil Cedex, France
Received 24 May 2004; revised 28 June 2004; accepted 5 July 2004
Available online 5 October 2004
Abstract—Efficient assembly of substituted imidazo[2,1-a]isoindolones I is reported from suitable a,b-diamine IV (or corresponding
b-nitroamine) and phthalic anhydride (1) in a three- or four-step sequence in good yields. The key step of this methodology is based on an
intramolecular a-aza-amidoalkylation of the N-acyliminium species. Furthermore, when R2 is an aromatic moiety a competing
a-amidoalkylation took place and imidazo[2,1-a]isoindolones (or benzimidazo[2,1-a]isoindolones) I and/or isoindolo[1,4]benzodiazepines
III were obtained under kinetic or thermodynamic control. The chemoselectivity of these transformations is also discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
ability to induce unscheduled DNA synthesis in rat
hepatocytes.9
The importance of the imidazo[2,1-a]isoindolone skeleton is
well recognized due to its significance as a subunit of a wide
panel of synthetic pharmaceutical compounds. Some of these
structures are patented and have been reported to possess a
wide variety of biological activities as: psychostimulant,
analgesic, anti-inflammatory, antifungal, antipyretic and
hypertensive,1 blood pressure lowering, spasmolytic, anti-
tussive and tranquilizer properties,2 and use in the treatment
of rheumatism.3 Furthermore, they are useful intermediates
in organic synthetic chemistry, especially in the elaboration
of imidazo[2,1-a]isoindolol-based anorectics,1,4a,b central
nervous system (CNS) stimulants1,4c,d and antidepressants,5
respectively. Finally, this class of compounds has also
demonstrated to be highly effective plant growth regulating
agents6 with effects on the plant budding process.7 More
recently related benzimidazo[2,1-a]isoindolones have been
reported and their biological activities evaluation show
Batracylin comparable anti-tumor activities8 as well as their
The traditional synthesis of imidazo[2,1-a]isoindolones
involves the reaction between a 1,2-diamine and an aromatic
or non aromatic keto acid, or equivalent, under azeotropic
removal of water with10 or without11 a catalytic amount of
acid (i.e., p-toluenesulfonic acid). More recent methods
include a reaction of a 1,2-diamine with phthalic anhydride
(or dicarboxylic acid equivalent) followed by thermal
cyclodehydration,9,12 a palladium catalyzed reaction via
carbonylative cyclization between an a,b-diamine and
2-bromobenzaldehyde under controlled carbon monoxide
pressure,13 an iminocyclization of N-azidoalkyl(or aryl)
phthalimides14a or the N-(O-aminoaryl)phthalimides14b via
intramolecular Aza–Wittig reaction, and finally a cationic
cyclization involving N-acyliminium species.15,16
2. Results and discussion
In our laboratory we are interested in the development of
synthetic methodologies towards original aza-heterocyclic
systems containing imidazole, benzimidazole and benzo-
diazepine moieties with promising pharmaceutical activities.
In association with our recent reports dealing with
Keywords: Isoindole; Imidazole; Benzimidazole; [1,4]Diazepine; N-
Acyliminium ion; a-Aza-amidoalkylation; Kinetic versus thermodynamic
control.
* Corresponding author. Tel.: C33 2 32 74 44 03; fax: C33 2 32 74 43 91;
e-mail: adam.daich@univ-lehavre.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.107

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A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
Scheme 1. Retrosynthetic scheme leading to imidazo(or benzimidazo)[2,1-a]isoindolones I and related isoindolo[1,4]benzodiazepines III.
intramolecular a-thio-amidoalkylation17 and a-oxo-
amidoalkylation,18 we reasoned that a suitably substituted
N-acyliminium precursor of type II (Scheme 1) could allow a
facile approach to the tricyclic derivative (I) or tetracyclic
(I and III) cores of the title targets. The cationic cyclization
using a nitrogen atom as an internal nucleophile has been
mentioned first during the synthesis of 9a-phenyl-5,6,6a,11-
tetrahydroisoindolo[2,1a]quinazoline-5,11-dione without
isolation of the opened amide-hydroxylactam intermediate.16a
Some 10 years later it was used by Speckamp et al.16b in
the total synthesis of (G)-physostigmine ((G)-eserine), the
principal alkaloid of Calabar bean. The essence of the few
reports of this process concern its use in chiral version to
access imidazo[2,1-a]isoindole-2,5-diones,15 imidazoiso-
quinolinones,16c functionalized peptidomimetics,16d and aza-
bicyclo[4.4.0]alkane amino acids.19 To the best of our
knowledge utilization of the present application in an
intramolecular N-acyliminium mediated cyclization reaction,
as depicted in Scheme 1, to form a central five- or seven-
membered ring as a cyclic N,N-acetal or [1,4]diazepine
structure, represents a novel illustration of this chemistry. In
the intermediate II, cyclisation to the N-acyliminium cation
may indeed be originated from intramolecular attack of either
the nitrogen nucleophile or from the p-aromatic system, in
case the latter is sufficiently activated.
As a starting point of our study, the a-hydroxylactam
derivative 5a, as N-acyliminium precursor, constituted a
valuable target molecule. We expected to obtain it in a two-
step sequence from phthalic anhydride (1) and o-nitro-
aniline (3a) by thermal amino-anhydride condensation in
refluxing acetic acid for 24 h,20 followed by selective sodium
borohydride reduction of one of the carbonyl functions of the
imide function under mild conditions (Scheme 2). In the case
of borohydride reduction of 4a, the process led to a mixture of
compounds containing none of the desired amino-alcohol
product 5a. Instead, the isoindolobenzimidazole 8a was
identified as a minor product (13%), while the major
compound proved to be 10b-methoxyisoindolobenzimida-
zole 80a (39% yield) which resulted from the methanol
Table 1. Yields of the intermediates 4a–c, 5a–c, 6a–c and the cyclized isoindolo[2,1-a]benzimidazole 8a,b,d and 80a produced via Scheme 1
Products 4
Yield (%)
Products 5
Yield (%)
Products 6
Yield (%)
Products 8
Yield (%)a
b
b
4a
4b
4c
4d
89
91
91
91
5a
5b
5c
5d
—
6a
6b
6c
6d
—
8a
8b
80a
8d
45–61 (82)c
63 (54)a
39
b
—
65
—
—
85
89
91
a After recrystallization or chromatographic purification.
b Product not isolated.
c Isolated yields after reaction of diamines 7a,b and 2-formylbenzoic acid (2).
Scheme 2. Reagents and conditions: (i) Phthalic anhydride (1), AcOH, reflux, 24 h; (ii) 1.5–3 equiv of NaBH4, MeOH, K5 to 0 8C, 45 min to 1 h; (iii) Fe, 50%
aq. AcOH, 60 8C, 4 h or H2/Pd-C, AcOH–H2O (v/v), 50 psi, 6 h; (iv) see Ref. 25a for product 3c and Ref. 25b for product 3d; (v) 1, toluene, reflux, NEt3,
Dean–Stark, 12 h; (vi) (a) acid hydrolysis during the work-up of the reduction of 5a,b with 10% HCl or 6 M H2SO4; (b) For 6c,d: TFA, CH2Cl2, rt, 4 h.

A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
11031
addition onto the imine function of 8a under the protic acid
activation conditions used during the reduction. Further-
more, in the presence of 2 equiv of additional nickel (II)
chloride hexahydrate, the borohydride reduction reaction
showed the same profile with however product 8a obtained in
larger quantity. Interestingly, treatment of 4a with conjointly
iron powder as a reductant and a 50% aqueous acetic acid
as a proton source at 60 8C over 4 h,9 provided only
6-oxoisoindolo[2,1-a]benzimidazole (8a) in 44% yield
after chromatography. The product 8a was also obtained in
61% yield, without formation of the methoxy adduct 80a,
from 4a via catalytic hydrogenation at 50 psi over Pd–C 10%
for 6 h in ethanol in the presence of acetic acid as a proton
source. Interestingly, in this case no ethoxy adduct analogous
to 80a could be observed (Table 1).
benzimidaz-ole (8b) in comparable yields (63%) after
chromatography and recrystallisation from dry ethanol.
The synthetic pathway leading to 8b occurred through a
cascade process by subsequent reduction of the nitro group
of 5b into the non isolated amino-alcohol 6b, followed by
loss of water, to form the N-acyliminium cation A,
nucleophilic attack by the nitrogen atom (Scheme 2) and
finally by spontaneous oxidation22-elimination of the
resulting unstable 10b,11-dihydro-6-oxoisoindolo[2,1-a]-
benzimidazole (B). In the case of 8a, there was no direct
evidence for the nucleophilic attack of the nitrogen atom
onto the N-acyliminium cation since the nitro-hydroxylac-
tam 5a was not isolated under the set of reduction
conditions.
The structure of 8a,b was equally confirmed chemically, as
outlined in Scheme 3, by treatment of an equimolar amount
of o-phenylenediamine (7a), or 2-amino-4-methyl-aniline
(7b) and 2-formylbenzoic acid (2) under azeotropic removal
of water according to the classical reported procedure.23
The ease of intramolecular a-aza-amidoalkylation by the
amino-ketone cyclodehydration9,14 or the N-cyclization of
the supposed amino–alcohol intermediate 6a, depending of
the reduction sequence, caused us to investigate additional
stabilization of these species. To this end, we considered the
para-methyl substituted series based on the idea that an
electron-donating methyl group would provide some
increased stability of the nitro functions in 4b with respect
to reducing agents. Interestingly, treatment of 4b using
3 equiv of NaBH4 in methanol at 0 8C during 2 h (conditions
ii outlined in Scheme 2), gave successfully the nitro-
hydroxylactam 5b as a crystalline and stable product in 65%
yield. This observation was in line with the fact that the
reduction of the nitro-imide functionality into the nitro-
alcohol was already achieved by us on related products
using sodium borohydride at lower temperature.21 Further-
more, reaction of 5b under conditions iii as outlined above
(Scheme 2), gave directly 2-methyl-6-oxoisoindolo[2,1-a]
It is interesting to note that this process in the case of the
4-methyl derivative 7b proceeded in a highly regioselective
manner. Scheme 4 demonstrates a plausible mechanism of
the formation of the sole 2-methyl-6-oxoisoindolo[2,1-a]
benzimidazole (8b). So, because the amine function at C1 of
7b is more nucleophilic than the one at C2, the amino-
aldehyde condensation yielded the imine C which then
cyclized to afford the imidazoline D. This latter, after an
intramolecular cyclodehydration into B followed in an
ultimate step by a spontaneous oxidation/elimination
reaction afforded the corresponding imidazole derivative
8b.24 In contrast, the opposite profile was obtained with the
o-phenylenediamine substrate 7e. In fact, the condensation
of 2 with 7e took another course with a more reactive amine
function at C2, giving the imine E. This latter intermediate,
after a sequential set of reactions as outlined for 8b, led to
the product 8e with the ester function at the C8 position.25
We decided next to explore another approach starting from
o-phenylenediamine (7a) which was protected at one
nitrogen atom with di-t-butyldicarbonate (Boc2O) and
acetic anhydride (Ac2O) into carbamate 3c26a and acetamide
3d,26b respectively (Scheme 2). The choice of these groups
was based on two considerations: first, the NHBoc and
NHAc groups were rarely engaged in the intramolecular
cationic cyclization, and we expected that both groups,
Scheme 3. Univocally‘one-pot’procedureaccessto11-oxoisoindolo[2,1-a]-
benzimidazole derivatives 8a and 8b.
Scheme 4. Plausible sequential mechanism leading to 2-methyl(or 3-methoxycarbonyl)-6-oxoisoindolo[2,1-a]benzimidazole 8a or 8b.

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A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
especially the t-Boc, could be removed easily during16d or
after cyclization to form the benzimidazole derivative 8a,b,
respectively. Second, both the t-butyloxy carbamate and
acetyl groups are electron-withdrawing groups which could
render the amino group less nucleophilic leading to the
amino-alcohols 6c,d as isolable intermediates. Thus, treat-
ment of 3c,d with 1 equiv of phthalic anhydride (1) in
toluene at reflux in the presence of a catalytic amount of
triethylamine over 12 h gave the imides 4c and 4d in 85 and
91% yields, respectively. These imides were then converted
regioselectively to the N-acyliminium ions precursors 6c,d
by borohydride reduction as described above for 5b in 85
and 89% yield.
group, we decided to use a weaker acid, such as AcOH, for
the cyclization process, hoping to be able to maintain the
t.Boc protective group. Thus, a-hydroxy-lactam 6c upon
treatment with neat AcOH for 8 h or in CH2Cl2 for 24 h at
reflux gave again 8a in comparable yields of about 67%. In
order to avoid the deprotection process, the aza-acylated
a-hydroxylactam 6d (R2ZAc) was used as N-acyliminium
ion precursor. In fact, the acetyl derivative 6d, after
treatment with neat TFA at rt over 4 h gave 11-acyl-6-
oxoisoindolo[2,1-a]benzimidazo-le (8d) in 80% yield after
recrystallization from ethanol.
Having established that the intramolecular a-aza-amido-
alkylation route is effective for the preparation of the
isoindolo[2,1-a]benzimidazole derivatives 8a–d, we
decided to elaborate another class of a-hydroxylactam
precursors in which a nitrogen atom bear another nucleo-
phile such as an aromatic or heteroaromatic system. Thus, as
depicted in Scheme 5, the requisite a-hydroxy-lactams
11a–c were obtained in a two-step sequence using classical
procedures. Imides 10a–c were readily prepared by amine-
anhydride condensation from commercial diamines 9a–c
and phthalic anhydride (1) as indicated for 4c,d in 76, 85
and 86%, respectively. The reaction was accelerated by
adding dry triethylamine in catalytic quantity. Regioselec-
tive reduction of imides 10a–c was accomplished with a
large excess of sodium borohydride in methanol at K5 to
0 8C. In all cases, a regular addition of an ethanolic
hydrogen chloride solution was necessary as already
mentioned elsewhere for related structures,17,18,21 and
after 1 h of the reaction, a-hydroxylactams 11a–c were
isolated in, respectively, 80, 88 and 82% yield.
According to our previous reports showing that trifluoro-
acetic acid (TFA) and acetic acid (AcOH) are good catalysts
for the intramolecular a-amidoalkylation and a-hetero-
amidoalkylation, treatment of hydroxy-lactam 6c with TFA
in CH2Cl2 for 24 h or neat TFA for 4 h at room temperature
afforded in both cases 8a in about 73% yield. This product,
which was identical to the one obtained from the nitro-imide
4a (Scheme 2), resulted from an intramolecular cyclization
of the N-acyliminium intermediate of type A with a nitrogen
atom as nucleophile in parallel with Boc deprotection. We
do have some evidence that the t-Boc deprotection occurs
subsequently to the cyclization due to different deprotection
kinetics, but this was not confirmed. Taking into account
that TFA is a standard deprotecting agent for the t-Boc
In the first set of cationic cyclizations in this series, substrate
11a was chosen as a model for the N-acyl-iminium ion
precursor. So, the subjection of a-hydroxy-lactam 11a to
weak AcOH (method A), weak TFA (method B) or catalytic
p-toluenesulfonic acid (PTSA) (method C) in CH2Cl2 at
room temperature for 12 h (Table 2, entry 1, 2 or 3) afforded
only 11-phenyl-6-oxoisoindolo[2,1-a]benzimidazole (12a)
in 65, 80 or 79% yield, respectively. This product resulted
invariably from an intramolecular aza-cationic cyclization
of the endocyclic N-acyliminium ion intermediate of type H
(Scheme 6).
Scheme 5. Sequential set leading to a-hydroxylactam precursors 11a–c.
Reagents and conditions: (i) Toluene, cat. NEt3, reflux, Dean–Stark, 12 h;
(ii) 3 equiv of NaBH4, MeOH, K5 to 0 8C, aq. HCl in ethanol, 1 h.
On the basis on our precedent work in this field and to avoid
the intramolecular a-aza-amidoalkylation process to the
Table 2. Isoindolo[2,1-a]benzimidazole and corresponding isoindolo[1,4]dibenzodiazepine derivatives 12a,b and 13a,b produced via Scheme 6
Reactant
Quantitya mmol
Conditions
Method
Product
Yield (%)b
1
2
3
4
5
6
7
8
11a
11a
11a
11a
11a
12a
12a
12a
11b
11b
12b
2.0
2.5
3.0
4.0
4.0
3.0
6.0
5.0
5.0
5.0
4.5
4 equiv of AcOH, CH2Cl2, rt, 12 h
4 equiv of TFA, CH2Cl2, rt, 12 h
Catalytic PTSA, CH2Cl2, rt, 12 h
Neat AcOH, rt, 12 h
Neat TFA, rt, 12 h
Neat AcOH, reflux, 24 h
Neat TFA, reflux, 24 h
Catalytic PTSA, toluene, reflux, 24 h
Catalytic PTSA, CH2Cl2, rt, 12 h
Neat TFA, rt, 12 h
A
B
C
D
E
F
G
H
C
E
G
12a
12a
12a
13a
13a
13a
13a
13a
12b
13bc
13b
65
80
79
69
74
83
81
90
82
93
89
9
10
11
Neat TFA, reflux, 24 h
a The reaction was conducted on 2–6 mmol of reactant under stirring. For entries 6–8, the isoindolo[2,1-a]benzimidazole 12a was used as starting material.
b Isolated yield after purification by recrystallization or chromatography on silica gel column.
1
c A trace of the kinetic product 12b were detected by H NMR analysis and its quantity not exceed 5% of the products mixture.

A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
11033
Scheme 6. Reagents and conditions: (i) 2, toluene, cat. NEt3, reflux, Dean–Stark, 12 h; (ii) See text and Table for others procedures.
detriment of others, different reaction conditions were
considered. So, the intramolecular arylation leading to
isoindolo[1,4]dibenzodiazepine product 13a as a single
product occurred when neat AcOH (method D, Table 2,
entry 4, 69%) or neat TFA (method E, Table 2, entry 5, 74%)
was used as a proton source. Furthermore, to check the
reversibility of the aza-cyclization reaction, taking into
account that cyclic N,N-aminal 12a could generate the
N-acyliminium ion under acidic influence according to
previously observations,18c,27 we envisaged the treatment of
acetal 12a with neat AcOH (method F, Table 2, entry 6), neat
TFA (method G, Table 2, entry 7) or catalytic amount of
PTSA in toluene (method H, Table 2, entry 8) at reflux. Under
these conditions all reactant 12a disappeared (monitored by
TLC) and the expected isoindolodibenzodiazepine product
13a was obtained in good yield (81–90%).
the acidic activation. Under stronger conditions, cleavage of
the CH–N bond in 12a led back to the N-acyliminium ion
congener H which in turn led to the diazepine compound
13a as the thermodynamically more stable product.
To establish the generality and versatility of this process we
studied the effect of varying the nucleophilicity of the
nitrogen atom which is interacts with the N-acyliminium ion
during the cyclization process. For this purpose, two kinds
of N-acyliminium ion precursors were considered; 11b and
11c in which the nitrogen atom nucleophilicity is altered
with respect to the one in the reactant 11a, and which bear a
benzene or pyridine ring as a competing p-nucleophile or
aza-nucleophile, respectively.
So, treatment of hydroxylactam 11b according to method
C (Table 2, entry 9), gave exclusively 1-phenyl-5-oxoiso-
indolo[2,1-a]imidazole (12b) under the kinetic control in
82% yield (Schemes 6 and 7). Similarly, reaction under
conditions of method E, 11b led to the cyclized thermo-
dynamic [1,4]benzodiazepine product 13b in excellent
yield (Table 2, entry 10, 93%). During this reaction, the
1-phenyl-5-oxoisoindolo[2,1-a]imidazole structure 12b
was detected as a minor product but its yield did not
exceed 5% in all cases.28 As for the diazepine derivative
13a, the product 13b was also isolated in 89% yield
starting from the kinetic product 12b under conditions
outlined in Table 2 (method G, entry 11) in a one pot
procedure involving N-acyliminium ion intermediate H
(Schemes 6 and 7).
The formation of these cycles 12a and 13a in acidic medium
seems to proceed by invoking the kinetic vs thermodynamic
control using the formal N-acyliminium ion H as inter-
mediate (Schemes 6, 7). In fact, under mild conditions
(methods A, B and C), the cationic intermediate H lead to
isoindolo[2,1-a]benzimidazole derivative 12a as the sole
reaction product under kinetic process (fast reaction). In
contrary, under stronger acidic conditions (neat acid at room
temperature; methods D and E) and/or higher temperatures,
the same intermediate provided in an alternate pathway
isoindolo[1,4]dibenzodiazepine 13a under thermodynamic
control (slow reaction). The difference in reactivity between
the two pathways can easily be contributed to the fact that
the formation of 13a requires higher activation energy due
to the loss of aromaticity in the transition state. In addition,
the compound 13a proves to be about 20 kcal/mol more
stable than its corresponding imidazoline 12a according to
AM1 calculations (86.29 kcal/mol vs 106.66 kcal/mol in the
case of R-R1ZPh), what clearly explains the complete
conversion from 12a to 13a under more drastic conditions.
These results confirm that the formation of the CH–N
linkage of the kinetic product 12a is reversible depending on
In contrast, the hydroxylactam 11c, with a reduced
nucleophilicity with respect to both the N and p-aromatic
nucleophilic centers due to the nitro group, afforded in
all attempts with differing acidic and/or temperature
conditions, the imidazoline derivative 12c in comparable
yields (85%). These results suggest that the formation of the
azepine type structures 13 and 14 requires sufficiently
activated aromatic systems (Scheme 8).29
Scheme 7. Kinetic vs thermodynamic scheme leading to imidazole and diazepine derivatives 12a,b and 13a,b. Reagents and conditions: (i) H2, 10% Pd–C,
AcOH–HCl, 50 8C, 6.5 h (see Ref. 30 for more details); (ii) 2, toluene, cat. NEt3, reflux, Dean–Stark, 12 h.

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A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
disappears in the corresponding DEPT program spectra as
the consequence of the aza-amidoalkylation cyclization
process. Interestingly, if the quaternary angular carbon
of the CZN bond appears at dZ156.4 ppm (8a),
dZ152.4 ppm (8b), and dZ155.0 ppm (8e) in comparable
chemical shift values reported in the literature for related
products,14b the one of 80a appeared downfield with more
significant deshielding at dZ166.7 ppm. This fact is due to
the proximity of three heteroatoms which belong to amide,
amine and etheroxide functionalities, respectively.
Especially diagnostic was the differentiation between the
formed five-membered ring products 8b and 12a–c and the
cyclized seven-membered ring ones 13a,b.
In fact, for the isoindolobenzimidazole 8b the appearance
of the CZN signal at dZ152.4 ppm constitutes the
consequence of the intramolecular cyclization of 4b. This
value is similar to those obtained for related structures.14
Interestingly, it can be seen that the aza-cyclization process
of 11a,b into 12a,b induces a weak variation in the
carbon angular absorbance which is DdZC1.2 ppm and
DdZC7.3 while the p-cyclization into 13a,b of 11a,b
shifted dramatically the absorbance of the angular carbon to
higher fields. In these case, an important deshielding of
DdZC21.2 ppm and DdZC20.5 ppm was observed.
Scheme 8. Possible structures which could be resulted form a pyridine
attack on the N-acyliminium ion intermediate H.
As a direct method for structural confirmation of imidazole
and benzimidazole derivatives, the condensation of
o-formylbenzoic acid (2) with diamines 7a,b and 12a–c
under azeotropic removal of water was used successfully,
thus providing isoindoloimidazoles 12b (82%) and 12c
(96%), and isoindolobenzimidazoles 8a (69%), 8b (54%),
and 12a (89%) identical to the compounds obtained by the
N-acyliminium sequence. Furthermore, the structure eluci-
dation of these products as well as all compounds
intermediates was based on their spectroscopic data
3. Conclusion
1
(IR, H NMR and 13C NMR including NOE Difference
In summary, we have shown that N-acyliminium ion
precursors 6a–d could be generated in two pathways from
nitro-hydroxylactams 5a,b or corresponding amino-imides
4c,d by regioselective reduction processes using iron/acetic
acid or sodium borohydride/methanol, respectively. The
N-acyliminium ion in turn furnished via an intramolecular
a-aza-amidoalkylation with a nitrogen atom as nucleophile
various and new 6-oxoisoindolo[2,1-a]benzimidazole
products 8a–d in good yields. In some cases, the amino-
hydroxylactam intermediates 6 were not isolated but
cyclized directly into product 8.
and DEPT experiments) as well as their microanalyses.
The NMR data of the imidazole product 8a has been
previously reported in some details.9,14b For related
compounds 80a, 8b, and 8e, the 1H NMR data have a
same profile globally as for 8a with however a side chain
signal corresponding to a methoxy (dZ3.79 ppm), methyl
(dZ2.47 ppm), and methoxycarbonyl (dZ3.95 ppm)
groups, respectively, with an additional NH signal at
dZ10.48 ppm for 80a. No signals for the proton in position
C4b of the isoindole system, appearing classically at about
dZ6.0 ppm, was observed in theses cases.
Similar a-hydroxylactams 11a,b, under the same process,
produced efficiently under thermodynamic control the
expected isoindolo[1,4]benzodiazepines 13a,b in good
yields and excellent regiocontrol. These latter were also
obtained starting from isoindoloimidazoles 12a,b, which
turned out to be the kinetically formed products from
cyclization of the nitrogen onto the iminium ion species
produced by acid treatment of the a-hydroxylactams 11a,b.
The hydroxylactam 11c only gave rise to the imidazoline
derivative 12c, clearly demonstrating the influence of
electronic factors in the p-aromatic attack. Finally, the
structures of the isoindoloimidazole derivatives 8a,b and
12a,b as well as 12c was confirmed chemically by an
alternative synthesis from o-formylbenzoic acid (2) and
corresponding diamines 7a,b or 9a–c in an one pot
procedure. For full exploitation of this route which provides
a novel synthesis of imidazole, benzimidazole and diaze-
pine derivatives and which is short, facile, general and more
competitive, further work is currently underway to enlarge
the scope of this application by accessing a wider variety of
these structures.
In the imidazoisoindolones structures 12a, 12b and 12c, the
angular protons appear as singlets at dZ7.24, 6.12, and
6.61 ppm, respectively. These latter absorb downfield
compared to the same protons of their hydroxylactams
congeners 11a (dZ6.22 ppm), 11b (dZ5.78 ppm), and 11c
(dZ5.83 ppm), respectively. The same fact, was also
observed for the diazepinoisoindolones in comparaison to
their precursors, with however a little difference on the
chemical shift values which are DdZC0.09 ppm and
DdZC0.05 ppm in favour to 13a and 13b to the detriment
of 12a and 12b, respectively. These observations are in
agreement with the fact that C–N and C–C bonds, formed
during the cyclization process, have not the same effect on the
CH angular absorbance. These results are also in agreement
with previous reports on analogous compounds.15–18
Furthermore, the key feature in the 13C NMR spectra of 80a
and 8a–d or 8e, was the appearance of fourteen or fifteen
signals, respectively, in the aromatic region. One of these

A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
11035
4. Experimental
cooled, then concentrated under reduced pressure. The
residue was dissolved into dichloromethane, washed with
5% hydrochloric acid solution then with a 5% sodium
hydrogenocarbonate solution. The organic layer was dried
over magnesium sulfate, concentrated under vacuo, and
recrystallization of the residue gave the expected imides
4c,d or 10a–c in good yields.
4.1. General
All melting points were measured on a Boetius micro hot-
stage and are uncorrected. The infrared spectra of solids
(potassium bromide) and liquids (neat) were recorded on a
Perkin Elmer FT-IR paragon 1000 spectrometer. The 1H and
13C NMR spectra were recorded on a Bruker AC-200
(200 MHz) instrument in deuteriochloroform unless other
indicated solvent and chemical shifts (d) are expressed in
ppm relative to TMS as internal standard. Ascending thin
layer chromatography was performed on precoated plates of
silica gel 60 F 254 (Merck) and the spots visualised using an
ultraviolet lamp or iodine vapour. Mass spectral measure-
ments were recorded on a AEI MS 902 S spectrophoto-
meter. The elemental analyses were carried out by the
microanalysis laboratory of INSA, F-76130 Mt. St. Aignan,
France.
4.3.1. N-(o-Tert-butoxycarbonylamidophenyl)phthali-
mide (4c). This product was isolated as white crystals in
91% yield; mpZ269 8C (decomposition); IR (KBr) v 3417,
1
3034, 2990, 1731, 1714 cmK1; H NMR (CDCl3) d 1.58
(s, 9H, 3CH3), 7.12–7.53 (m, 4H, 4Hbenzene), 7.61–7.82 (m,
2H, 2Hphthalimide), 7.90–7.98 (m, 2H, 2Hphthalimide), 8.15
(s broad, 1H, NH); 13C NMR (CDCl3) d 28.9 (3CH3), 80.1
(Cq), 123.4 (Cq), 124.8 (2CH), 125.6 (CH), 127.3 (CH),
129.6 (Cq), 131.1 (CH), 142.3 (CH), 134.4 (2CH), 140.6
(2Cq), 164.8 (CO), 167.2 (2CO); Anal. Calcd for
C19H18N2O4 (338.36): C, 67.44; H, 5.36; N, 8.28. Found:
C, 67.18; H, 5.22; N, 8.31.
4.2. General procedure for synthesis of imides (4a,b)
4.3.2. N-(o-Acetamidophenyl)phthalimide (4d). This
product was isolated as white crystals in 91% yield; mpZ
200 8C; IR (KBr) v 3244, 3038, 1720, 1657 cmK1; 1H NMR
(CDCl3) d 2.01 (s, 3H, COCH3), 7.24–7.31 (m, 2H,
1Hbenzene and NH, exchangeable with D2O), 7.36–7.58
(m, 2H, 2Hbenzene), 7.77–7.86 (m, 3H, 1Hbenzene and
2Hphthalimide), 7.89–7.96 (m, 2H, 2Hphthalimide); 13C NMR
(CDCl3) d 24.3 (CH3), 124.0 (Cq), 124.2 (2CH), 125.9
(CH), 126.0 (CH), 128.6 (CH), 129.7 (CH), 131.8 (Cq),
133.9 (2Cq), 134.8 (2CH), 167.4 (2CO), 168.6 (CO); Anal.
Calcd for C16H12N2O3 (280.28): C, 68.56; H, 4.32; N, 9.99.
Found: C, 68.39; H, 4.25; N, 10.05.
A mixture of powdered phthalic anhydride (1, 1.48 g,
10 mmol) and o-nitroaniline (3a, 1.38 g, 10 mmol) or
4-methyl-2-nitroaniline (3b, 1.52 g, 10 mmol) in 100 mL
of glacial acetic acid was heated at reflux for 24 h. After
cooling, the precipitate formed was collected by filtration,
washed with cyclohexane, diethyl ether and air dried. The
resulting products were purified by recrystallization from
ethanol to give imides 4a and 4b as yellow needles.
4.2.1. N-(o-Nitrophenyl)phthalimide (4a). This product
was isolated as yellow solid in 89% yield; mpZ190–195 8C
(lit.,31 mpZ202–203 8C); IR (KBr) v 3093, 1715,
1
1525 cmK1; H NMR (CDCl3) d 7.52 (d, 1H, 1Hbenzene
,
4.3.3. N-(o-Phenylaminophenyl)phthalimide (10a). This
product was isolated as a yellow solid in 76% yield; mpZ
JZ7.8 Hz), 7.61 (t, 1H, 1Hbenzene, JZ7.8, 7.0 Hz), 7.74–
7.83 (m, 3H, 1Hbenzene and 2Hphthalimide), 7.93–7.98 (m, 2H,
2Hphthalimide), 8.18 (d, 1H, 1Hbenzene, JZ7.8 Hz); 13C NMR
(CDCl3) d 124 (2CH), 125.6 (Cq), 125.9 (CH), 129.8 (CH),
131.0 (CH), 131.9 (Cq), 134.3 (CH), 134.9 (2CH), 145.8
(2Cq), 166.5 (2CO); Anal. Calcd for C14H8N2O4 (268.22):
C, 62.69; H, 3.01; N, 10.44. Found: C, 62.48; H, 2.95; N,
10.22.
1
200 8C (ethanol); IR (KBr) n 3320, 3006, 1710 cmK1; H
NMR (CDCl3) d 6.04 (s, 1H, NH, exchangeable with D2O),
7.08–7.27 (m, 4H, 4Hbenzene), 7.37–7.80 (m, 5H, 5Hbenzene),
8.01–8.12 (m, 2H, 2Hphthalimide), 8.17–8.26 (m, 2H,
2Hphthalimide); 13C NMR (CDCl3) d 118.5 (2CH), 121.4
(CH), 121.7 (CH), 123.3 (Cq), 123.9 (CH), 124.2 (2CH),
129.6 (2CH), 129.7 (CH), 130.2 (CH), 132.3 (2Cq), 134.8
(2CH), 140.8 (Cq), 143.4 (Cq), 167.7 (2CO); Anal. Calcd
for C20H14N2O2 (314.34): C, 76.42; H, 4.49; N, 8.91.
Found: C, 76.09; H, 4.25; N, 8.71.
4.2.2. N-(40-Methyl-o-nitrophenyl)phthalimide (4b). This
product was isolated as yellow needles in 91% yield; mpZ
181 8C (lit.,32 mpZ187 8C); IR (KBr) v 3082, 1716, 1534,
1383 cmK1; 1H NMR (DMSO d6) d 2.50 (s, 3H, CH3), 7.67
(d, 1H, 1Hbenzene, JZ7.6 Hz), 7.77 (d, 1H, 1Hbenzene, JZ
4.3.4. N-(o-Phenylaminoethyl)phthalimide (10b). This
product was isolated as a white solid in 85% yield; mpZ
100 8C (ethanol); IR (KBr) n 3345, 3010, 2989, 1712; H
1
7.6 Hz), 7.94–8.08 (m, 2H, 1Hbenzene and 4Hphthalimide); 13
C
NMR (DMSO d6) d 19.8 (CH3), 121.4 (Cq), 123.4 (2CH),
125.0 (CH), 130.3 (CH), 130.6 (Cq), 134.6 (CH), 134.8
(2CH), 140.6 (Cq), 144.6 (2Cq), 165.8 (2CO); Anal. Calcd
for C15H10N2O4 (282.25): C, 63.83; H, 3.57; N, 9.93.
Found: C, 63.66; H, 3.28; N, 9.87.
NMR (CDCl3) d 3.42 (t, 2H, CH2, JZ6.3 Hz), 3.96 (t, 2H,
CH2, JZ6.3 Hz), 6.57–6.72 (m, 3H, 3Hbenzene), 7.08–7.19
(m, 2H, 2Hbenzene), 7.66–7.75 (m, 2H, 2Hphthalimide), 7.77–
7.87 (m, 2H, 2Hphthalimide); 13C NMR (CDCl3) d 37.7 (CH2),
43.3 (CH2), 112.9 (2CH), 117.9 (CH), 123.7 (2CH), 129.6
(2CH), 132.3 (2Cq), 134.4 (2CH), 147.9 (Cq), 169 (2CO);
Anal. Calcd for C16H14N2O2 (266.29): C, 72.16; H, 5.30; N,
10.52. Found: C, 72.02; H, 5.15; N, 10.41.
4.3. General procedure for synthesis of imides (4c,d) and
(10a–c)
A mixture of a,b-diamine 4c, 4d, 9a, 9b, or 9c (10 mmol),
phthalic anhydride (1) (1.48 g, 10 mmol) and triethylamine
(0.5 mL, 3.6 mmol) in toluene (50 mL) was refluxed with a
Dean–stark apparatus for 12 h. The reaction mixture was
4.3.5. N-(2-(50-Nitropyridin-20-ylamino)ethyl)phthali-
mide (10c). This product was isolated as a white solid in
86% yield; mpZ191 8C (ethanol); IR (KBr) n 3242, 3005,
1
2950, 1710, 1503, 1396; H NMR (DMSO d6) d 3.37–3.76

11036
A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
1
(m, 4H, 2CH2), 6.42 (d, 1H, Hpyridine, JZ8.6 Hz), 7.79–7.85
(m, 2H, 2Hphthalimide), 8.04 (d, 1H, Hpyridine, JZ8.6 Hz),
8.12–8.24 (m, 2H, 2Hphthalimide), 8.71 (s, 1H, Hpyridine), 8.90
(t, 1H, NH, JZ2.4 Hz, exchangeable with D2O); 13C NMR
(DMSO d6) d 36.9 (CH2), 38.5 (CH2), 108.5 (CH), 122.6
(2CH), 131.4 (CH), 131.6 (Cq), 133.9 (2CH), 134.4 (2Cq),
146.1 (CH), 161.4 (Cq), 167.8 (2CO); Anal. Calcd for
C15H12N4O4 (312.09): C, 57.69; H, 3.87; N, 17.94. Found:
C, 57.51; H, 3.66; N, 17.63.
3082, 1690, 1532, 1383 cmK1; H NMR (CDCl3) d 2.43
(s, 3H, CH3), 3.59 (d, 1H, OH, JZ11.7 Hz, exchangeable
with D2O), 6.17 (d, 1H, CH, JZ11.7 Hz), 7.35–7.55 (m, 3H,
1Hbenzene and 2Hisoindole), 7.56–7.75 (m, 3H, 1Hbenzene and
2Hisoindole), 7.84 (d, 1H, 1Hbenzene, JZ10.6 Hz); 13C NMR
(CDCl3) d 20.9 (CH3), 83.9 (CH), 123.8 (CH), 124.6 (CH),
125.9 (CH), 127.5 (Cq), 130.2 (CH), 130.6 (CH), 130.8
(Cq), 134.0 (CH), 135.4 (CH), 139.7 (Cq), 145.4 (Cq), 146.7
(Cq), 166.9 (CO); Anal. Calcd for C15H12N2O4 (284.27): C,
63.38; H, 4.25; N, 9.85. Found: C, 63.21; H, 4.08; N, 9.71.
4.4. General procedure for reduction of imides (4a–d)
and (10a–c)
4.4.5. 3-Hydroxy-2,3-dihydro-2-(o-tert-butoxycarbon-
ylamidophenyl)isoindol-1-one (6c). This product was
isolated as a white solid in 85% yield; mpZ188 8C; IR
To a mixture of 5 mmol of imide 4a (4b, 4c, 4d, 10a, 10b or
10c) in dry methanol (40 mL) at K5 to 0 8C was added
sodium borohydride (283–565 mg, 7.5–15 mmol) by por-
tions during 5 min. To this mixture was added 5 drops of
ethanolic hydrochloric acid solution (prepared by addition
of nine drops of concentrated hydrochloric acid into 9 mL of
dry ethanol) at regular intervals of 10 min. The reaction was
monitored by TLC using CH2Cl2 as eluent (CH2Cl2/MeOH
(9/1) in the case of 10c). After the end of the reaction
(45 min to 1 h), the excess of sodium borohydride was
decomposed by careful addition of cold water (15 mL) and
10% hydrochloric acid until pH 4. Sodium hydrogen
carbonate was added and the solvent was evaporated. The
resulting residue was triturated with water and dichloro-
methane and the organic layer was separated, washed with
water, brine, dried and concentrated in vacuo. The resulting
product was purified by chromatography on silica gel
column or by recrystallization to give in appreciable yield
5b, 6c, 6d, 8a, 80a, 11a, 11b or 11c, respectively.
1
(KBr) v 3446, 3280, 3010, 2970, 1736, 1663 cmK1; H
NMR (DMSO d6) d 1.39 (s, 9H, 3CH3), 6.23 (d, 1H, OH,
JZ7.1 Hz, exchangeable with D2O), 6.77 (d, 1H, CH, JZ
7.1 Hz), 7.14 (t, 1H, 1Hbenzene, JZ7.8, 7.0 Hz), 7.34 (t, 2H,
1Hbenzene and 1Hisoindole, JZ7.8, 7.8 Hz), 7.58–7.88 (m, 5H,
2Hbenzene and 3Hisoindole), 8.35 (s, 1H, NH, exchangeable
with D2O); 13C NMR (DMSO d6) d 28.1 (3CH3), 79.5 (Cq),
83.6 (CH), 122.2 (CH), 122.9 (CH), 123.5 (CH), 123.7
(CH), 127.5 (Cq), 128.0 (CH), 129.2 (CH), 129.6 (CH),
131.4 (Cq), 132.6 (Cq), 136.6 (Cq), 145.8 (Cq), 152.9 (CO),
165.8 (CO); Anal. Calcd for C19H20N2O4 (340.37): C,
67.05; H, 5.92; N, 8.23. Found: C, 67.12; H, 5.81; N, 8.09.
4.4.6. 3-Hydroxy-2,3-dihydro-2-(o-acetamidophenyl)-
isoindol-1-one (6d). This product was isolated as a white
solid in 89% yield; mpZ185 8C (ethanol); IR (KBr) v 3439,
3247, 3006, 2923, 1689, 1673 cmK1; 1H NMR (DMSO d6) d
1.98 (s, 9H, CH3), 6.17 (s, 1H, CH), 6.65 (s broad, 1H, OH,
exchangeable with D2O), 7.11–7.34 (m, 3H, 3Hbenzene),
7.46–7.56 (m, 1H, 1Hbenzene), 7.60–7.62 (m, 2H, 2Hisoindole),
4.4.1. 3-Hydroxy-2,3-dihydro-2-(o-nitrophenyl)isoind-
ol-1-one (5a). This product was not isolated but react
immediately in situ to give the cyclised product 80a and/or
8a.
7.79 (d, 1H, 1Hisoindole, JZ7.8 Hz), 8.03 (d, 1H, 1Hisoindole
,
JZ7.8 Hz),isoindole), 8.48 (s, 1H, NH, exchangeable with
D2O); 13C NMR (DMSO d6) d 24.3 (CH3), 84.6 (CH), 123.5
(2CH), 124.1 (CH), 125.0 (CH), 127.7 (CH), 128.4 (CH),
129.7 (CH), 131.0 (Cq), 132.7 (CH), 135.8 (Cq), 141.3 (Cq),
144.9 (Cq), 170.1 (CO), 174.9 (CO); Anal. Calcd for
C16H14N2O3 (282.29): C, 68,07; H, 5,00; N, 9,92. Found: C,
67,98; H, 4,81; N, 9,84.
4.4.2. 6-Oxoisoindolo[2,1-a]benzimidazole (8a). This
product was obtained in a range of 45–61% yield
and have same characteristics to that reported in literature
(lit.,9 mpO290 8C, 39% yield).
4.4.3. 10b-Methoxy-10b,11-dihydrobenzo[4,5]imida-
zo[2,1-a]isoindol-6-one (80a). This product was isolated
as orange crystals in 39% yield after chromatography on
silica gel column using a mixture of dichloromethane/
cyclohexane (7:3) as eluent; mpZ128 8C; IR (KBr) v 3246,
4.4.7. 3-Hydroxy-2,3-dihydro-2-(o-phenylaminophe-
nyl)-1H-isoindol-1-one (11a). This product was isolated
as a yellow solid in 80% after recrystallization from ethanol;
1
mpZ73 8C; IR (KBr) n 3381, 3333, 3038, 1703 cmK1; H
NMR (CDCl3) d 6.22 (s, 1H, CH), 7.17–7.36 (m, 9H,
9Hbenzene), 6.65–7.64 (m, 12H, 9Hbenzene and 3Hisoindole),
7.80–7.89 (m, 1H, 1Hisoindole); 13C NMR (CDCl3) d 84.5
(CH), 118.5 (2CH), 120.5 (CH), 121.2 (CH), 122.5 (CH),
123.8 (CH), 124.2 (CH), 127.0 (Cq), 128.3 (CH), 129.1
(CH), 129.6 (2CH), 130.5 (CH), 131.3 (Cq), 133.1 (CH),
141.5 (Cq), 143.6 (Cq), 144.3 (Cq), 167.2 (CO); Anal. Calcd
for C20H16N2O2 (316.35): C, 75.93; H, 5.10; N, 8.86.
Found: C, 75.80; H, 5.02; N, 8.65.
1
3023, 2958, 1718 cmK1; H NMR (CDCl3) d 3.80 (s, 3H,
OCH3), 7.16 (t, 1H, 1Hisoindole, JZ7.8, 7.0 Hz), 7.46–7.57
(m, 3H, 3Hbenzene), 7.65 (t, 1H, 1Hisoindole, JZ7.8, 7.0 Hz),
7.91 (d, 1H, 1Hbenzene, JZ7.0 Hz), 8.17 (d, 1H, 1Hisoindole
,
JZ7.8 Hz), 8.84 (d, 1H, 1Hisoindole, JZ7.8 Hz), 10.45 (s,
3H, NH, exchangeable with D2O); 13C NMR (CDCl3) d 52.8
(OCH3), 122.6 (CH), 123.8 (CH), 125.9 (CH), 127.3 (CH),
129.2 (Cq), 130.6 (CH), 130.7 (CH), 132.6 (CH), 134.7
(Cq), 136.3 (CH), 136.8 (Cq), 137.9 (Cq), 166.8 (CO), 167.9
(Cq); Anal. Calcd for C15H12N2O2 (252.27): C, 71.42; H,
4.79; N, 11.10. Found: C, 71.25; H, 4.64; N, 11.01.
4.4.8. 3-Hydroxy-2,3-dihydro-2-(o-phenylaminoethyl)-
1H-isoindol-1-one (11b). This product was isolated as a
white solid in 88% after recrystallization from ethanol;
1
4.4.4. 3-Hydroxy-2,3-dihydro-2-(40-methyl-o-nitro-
phen-yl)isoindol-1-one (5b). This product was isolated as
a yellow solid in 65% yield; mpZ158 8C; IR (KBr) v 3351,
mpZ76 8C; IR (KBr) n 3363, 3009, 2988, 1709 cmK1; H
NMR (CDCl3) d 3.35 (t, 2H, CH2, JZ5.5 Hz), 3.51–3.67
(m, 1H, CH2), 3.72–3.88 (m, 1H, CH2), 4.09 (s large, 1H,

A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
11037
NH, exchangeable with D2O), 5.78 (s, 1H, CH), 6,58 (d, 2H,
JZ7.8 Hz), 6,69 (t, 1H, JZ7.1 Hz), 7.12 (t, 2H, JZ7.8 Hz),
7.39–7.57 (m, 3H, 3Hisoindole), 7.66 (d, 1H, 1Hisoindole, JZ
7.1 Hz); 13C NMR (CDCl3) d 40.3 (CH2), 43.4 (CH2), 83
(CH), 113.5 (2CH), 118.3 (CH), 123.5 (2CH), 129.6 (2CH),
130.1 (CH), 131.5 (Cq), 132.7 (CH), 144.1 (Cq), 147.9 (Cq),
168.6 (CO); Anal. Calcd for C16H16N2O2 (268.31): C,
75.93; H, 5.10; N, 8.86. Found: C, 75.80; H, 5.02; N, 8.65.
appropriate acid or catalytic amount (in the case of PTSA)
was left to react at room temperature or reflux in the
presence or not of the solvent (For details see Table 2). After
the required time, the solvent was evaporated in vacuo, and
the residue was diluted with dichloromethane (10 mL) and
treated with a saturated solution of hydrogenocarbonate.
After separation, the organic layer was washed with water,
brine, dried and concentrated in vacuo. The resulting residue
was purified either by recrystallisation from ethanol or
through a silica gel column.
4.4.9. 3-Hydroxy-2,3-dihydro-2-[2-(50-nitropyridin-20-
ylamino)ethyl]-1H-isoindol-1-one (11c). This product
was isolated as a yellow solid in 82% after recrystallization
from dry ethanol; mpZ120 8C (decomposition); IR (KBr) n
3467, 3307, 3093, 2935, 1704, 1504, 1337 cmK1; 1H NMR
(CDCl3, this product is no stable in the solution) d 3.08 (s
broad, 1H, NH, exchangeable with D2O), 3.28–3.71 (m, 3H,
CH2–CH2), 4.13–4.18 (m, 1H, CH2–CH2), 3.08 (s broad,
1H, OH, exchangeable with D2O), 5.83 (s, 1H, CH), 6.37
(d, 1H, 1Hpyridine, JZ9.4 Hz), 7.29–7.43 (m, 1H, 1Hbenzene),
7.47–7.57 (m, 3H, 3Hbenzene), 7.99 (d, 1H, 1Hpyridine, JZ
9.4 Hz), 8.58 (s, 1H, 1Hpyridine); Anal. Calcd for
C15H14N4O4 (314.30): C, 57.32; H, 4.49; N, 17.83. Found:
C, 57.18; H, 4.27; N, 17.65.
4.6.1. 6-Oxoisoindolo[2,1-a]benzimidazole (8c). This pro-
duct is identical to 8a described above.
4.6.2. 11-Acetyl-10b,11-dihydrobenzo[4,5]imidazo[2,1-
a]isoindol-6-one (8d). This product was isolated as a
white-yellow crystals after chromatography on silica gel
column using a mixture of chloroform/cyclohaxane (2:3) as
eluent in 91% yield; mpZ168 8C; IR (KBr) v 3021, 2943,
1
1732, 1667 cmK1; H NMR (CDCl3) d 2.52 (s, 3H, CH3),
6.93 (s, 1H, CH), 7.05–7.19 (m, 3H, 3Hbenzene), 7.49–7.64
(m, 2H, 1Hbenzene and 1Hisoindole), 7.66–7.75 (m, 1H,
1Hisoindole), 7.85 (d, 1H, 1Hisoindole, JZ7.0 Hz), 8.25
(d, 1H, 1Hisoindole, JZ7.0 Hz); 13C NMR (CDCl3) d 25.3
(CH3), 79.4 (CH), 113.1 (CH), 117.2 (CH), 124.1 (CH),
124.5 (CH), 124.9 (CH), 128.3 (CH), 130.3 (CH), 132.1
(Cq), 132.8 (Cq), 133.7 (CH), 136.0 (Cq), 145.0 (Cq), 169.3
(CO), 171.6 (CO); Anal. Calcd for C16H12N2O2 (264.28): C,
72.72; H, 4.58; N, 10.60. Found: C, 72.59; H, 4.32; N, 10.28.
4.5. Procedure for the reductive cyclization of nitro-
hydroxylactam 5b
To a solution of 6 mmol of nitro-hydroxylactam 5b in dry
methanol (40 mL) at K5 to 0 8C was added sodium
borohydride (679 mg, 18 mmol) by portions during
10 min. To this mixture was added 5 drops of ethanolic
hydrochloric acid solution (as prepared above) at regular
intervals of 5 min. The reaction was monitored by TLC
using CH2Cl2 as eluent. After the end of the reaction (2 h),
the excess of sodium borohydride was decomposed by
careful addition of cold water (15 mL) and 10% hydro-
chloric or H2SO4 acid until pH 4. After sodium hydrogen
carbonate was added and the solvent was evaporated. The
resulting residue was triturated with water and dichlor-
omethane and the organic layer was separated, washed with
water, brine, dried and concentrated in vacuo.
4.6.3. 11-Phenyl-6(10bH)-oxoisoindolo[2,1-a]benzim-
idazole (12a). This product was obtained as white crystals
in 79% after recrystallization from ethanol; mpZ208–
1
210 8C (decomposition); IR (KBr) n 3015, 1709 cmK1; H
NMR (CDCl3) d 7.03–7.12 (m, 1H, H benzene), 7.24 (s, 1H,
CH), 7.26–7.42 (m, 2H, 2Hbenzene), 7.64–8.03 (m, 9H,
9Hbenzene), 8.28–8.37 (m, 1H, 1Hbenzene); 13C NMR (CDCl3)
d 83.3 (CH), 108.6 (CH), 116.9 (CH), 120.4 (CH), 124.2
(CH), 124.8 (2CH), 125.3 (CH), 125.6 (CH), 126.4 (CH),
130.2 (2CH), 130.4 (CH), 131.5 (Cq), 133.1 (CH), 133.9
(Cq), 141.9 (Cq), 144.1 (Cq), 146.3 (Cq), 170.7 (CO); Anal.
Calcd for C20H14N2O (298.34): C, 80.52; H, 4.73; N, 9.39.
Found: C, 80.42; H, 4.59; N, 9.19.
4.5.1. 2-Methyl-6-oxoisoindolo[2,1-a]benzimidazole (8b).
This product was obtained as a white powder in 63% after
recrystallization from absolute ethanol; mpZ238 8C; IR
(KBr) n 3025, 2952, 1719, 1640 cmK1; 1H NMR (CDCl3) d
2.47 (s, 3H, CH3), 7.1 (d, 1H, 1Hbenzene, JZ8.1 Hz), 7.41 (s,
1H, 1Hbenzene), 7.49 (d, 1H, 1Hbenzene, JZ8.1 Hz), 7.57–
7.94 (m, 4H, 4Hisoindole); 13C NMR (CDCl3) d 22.8 (CH3),
115.8 (CH), 116.6 (CH), 125.4 (CH), 131.2 (Cq), 131.4
(2CH), 131.7 (CH), 132.7 (Cq), 133.3 (CH), 134.6 (Cq),
138.4 (Cq), 139.6 (Cq), 152.4 (Cq), 170.4 (CO); Anal. Calcd
for C15H10N2O (234.26): C, 76.91; H, 4.30; N, 11.96.
Found: C, 76.81; H, 4.09; N, 12.05.
4.6.4. 5-Phenyl-4b,5,6,7-tetrahydroimidazo[2,1-a]iso-
indol-9-one (12b). This product was obtained as a white
powder in 82% after recrystallization from absolute ethanol;
mpZ143 8C; IR (KBr) n 3005, 2992, 1711 cmK1; 1H NMR
(CDCl3) d 3.39–3.68 (m, 2H, CH2), 3.77–3.92 (m, 1H,
CH2), 4.26–4.39 (m, 1H, CH2), 6.12 (s, 1H, CH), 6.87–7.28
(m, 3H, 3Hbenzene), 7.29–7.41 (m, 2H, 2Hbenzene), 7.44–7.54
(m, 2H, 2Hisoindole), 7.71–7.86 (m, 2H, 2Hisoindole); 13C
NMR (CDCl3) d 42.4 (CH2), 53.3 (CH2), 75.7 (CH), 114.7
(2CH), 119.3 (CH), 124.6 (2CH), 129.7 (2CH), 130.0 (CH),
132.9 (CH), 133.3 (Cq), 145.7 (Cq), 146.8 (Cq), 173.1 (CO);
Anal. Calcd for C16H14N2O (250.30): C, 76.78; H, 5.64; N,
11.19. Found: C, 76.84; H, 5.48; N, 11.27.
4.6. General procedure for acid cyclization of hydroxy-
lactams (6c,b) and (11a–c)
The procedure is general and concerns the use of neat or
weak TFA, AcOH or catalytic PTSA at rt or reflux without
or with a solvent as CH2Cl2 or toluene. For more details see
Table 2. A stirred solution of 6 mmol of amino-hydroxy-
lactams 6c,d (or hydroxy-lactams 11a–c) in 10 mL of
4.6.5. 2-(1-Benzyl-1H-benzimidazol-2-yl)-3-hydroxy-2,3-
dihydroisoindol-1-one (12c). This product was obtained as
a yellow orange powder in 85% after recrystallization from
absolute ethanol; mpZ234 8C; IR (KBr) n 3079, 2963,
1699, 1513, 1327 cmK1; 1H NMR (DMSO d6) d 3.50–3.82

11038
A. Cul et al. / Tetrahedron 60 (2004) 11029–11039
(m, 2H, CH2), 3.87–3.99 (m, 1H, CH2), 4.33 (dd, 1H, CH2,
JZ6.4, 10.7 Hz), 6.61 (s, 1H, CH), 6.78 (d, 1H, 1Hpyridine
JZ9.1 Hz), 7.56–7.82 (m, 3H, 3Hisoindole), 8.30–8.44
(m, 2H, 2Hisoindole and 1Hpyridine), 9.26 (d, 1H, 1Hpyridine
recrystallization from ethanol to yield the expected
isoindolobenzimidazoles 8a (82%), 8b (54%), 8e (51%) or
12a (91%), or isoindoloimidazoles 12b (82%) or 12c (96%),
respectively, as crystals.
,
,
JZ2.7 Hz); 13C NMR (DMSO d6) d 42.8 (CH2), 50.4 (CH2),
76.2 (CH), 108.6 (CH), 124.3 (CH), 128.2 (CH), 131.2
(CH), 133.2 (Cq), 134.0 (2CH), 136.6 (Cq), 145.3 (Cq),
146.8 (CH), 159.5 (Cq), 173.1 (Cq); Anal. Calcd for
C15H12N4O3 (296.28): C, 60.81; H, 4.08; N, 18.91. Found:
C, 60.70; H, 4.10; N, 18.69.
4.8.1. Products 8a,b and 12a–c. All chemicals and
physicals characteristics of these products 8a,b and 12a–c
are identical to that reported above.
4.8.2. 3-Methoxycarbonyl-6-oxoisoindolo[2,1-a]benzi-
midazole (8e). This product was isolated as white crystals
in 51% yield; mpZ269 8C; IR (KBr) n 3009, 1709, 1698,
1635 cmK1; 1H NMR (DMSO d6) d 3.95 (s, 3H, CH3), 7.64–
7.98 (m, 6H, 3Hbenzene and 3Hisoindole), 8.12 (s, 1H,
Hisoindole); 13C NMR (DMSO d6) d 53.0 (CH3), 115.7
(CH), 118.0 (CH), 124.1 (CH and Cq), 130.5 (CH), 131.1
(CH and Cq), 131.4 (CH), 132.1 (CH), 134.0 (Cq), 140.1
(Cq), 143.3 (Cq), 155.1 (Cq), 167.7 (CO), 169.4 (CO); Anal.
Calcd for C16H10N2O3 (278.27): C, 69.06; H, 3.62; N,
10.07. Found: C, 68.98; H, 3.51; N, 10.01.
4.6.6. 5,15b-Dihydro-11H-isoindolo[2,1-d]dibenzo[b,f]-
[1,4]diazepin-11-one (13a). This product was obtained as
a yellow powder in 81–91% after recrystallization from
absolute ethanol; mpZ248 8C; IR (KBr) n 3346, 3013,
1
1709 cmK1; H NMR (CDCl3) d 6.13 (s, 1H, CH), 6.61–
6.83 (m, 3H, 3Hbenzene), 6.88–7.16 (m, 4H, 4Hbenzene), 7.32
(s, 1H, NH, exchangeable with D2O), 7.42–7.68 (m, 1H,
1Hisoindole), 8.2 (m, 1H, 1Hisoindole); 13C NMR (CDCl3) d
63.3 (CH), 118.9 (CH), 119.3 (CH), 119.5 (CH), 120.1
(CH), 122.7 (CH), 124.2 (CH), 124.4 (CH), 125.3 (CH),
126.1 (Cq), 126.2 (CH), 127.2 (Cq), 128.6 (CH), 129.1
(CH), 131.1 (Cq), 133.1 (Cq), 135.2 (Cq), 142.0 (Cq), 144.1
(Cq), 166.9 (CO); Anal. Calcd for C20H14N2O (298.34): C,
80.52; H, 4.73; N, 9.39. Found: C, 80.41; H, 4.59; N, 9.21.
Acknowledgements
We acknowledge the Johnson and Johnson Pharmaceutical
Research and Development, Division of Janssen–Cilag, for
scientific and financial support of this program. We thank
also the Region of ‘Haute Normandie’ for a ‘Regional-
Industrial Graduate Fellowship’ (BRI), 1998–2001,
attributed to A. Cul. We also thank C. Meyer, from
J&J PRD, a division of Janssen-Cilag, for the AM1
calculations.
4.6.7. 5,6,7,13b-Tetrahydroisoindolo[2,1-d][1,4]benzo-
diazepin-9-one (13b). This product was obtained as a
white solid in 89–93% after chromatography over silica gel
column using a mixture of CH2Cl2/hexane (9.5/0.5) as
eluent and recrystallization from absolute ethanol; mpZ
139 8C (lit.,29 mpZ135–137 8C); IR (KBr) n 3336, 3013,
1
2986, 1709 cmK1; H NMR (CDCl3) d 3.03–3.19 (m, 1H,
CH2), 3.49–3.68 (m, 2H, CH2), 4.0 (s br, 1H, NH,
exchangeable with D2O), 4.25–4.39 (m, 1H, CH2), 5.73
(s, 1H, CH), 6.77–6.92 (m, 2H, 2Hbenzene), 7.03 (d, 1H,
1Hbenzene, JZ7.1 Hz), 7.16–7.25 (t, 1H, 1Hbenzene, JZ
7.1 Hz), 7.47–7.68 (m, 3H, 3Hisoindole), 7.94 (d, 1H,
1Hisoindole, JZ7.2, Hz); 13C NMR (CDCl3) d 44.3 (CH2),
47.5 (CH2), 62.5 (CH), 120.7 (CH), 121.8 (CH), 124.6 (CH),
125.4 (CH), 127.3 (Cq), 127.7 (CH), 128.9 (CH), 129.3
(CH), 131.2 (CH), 133.5 (Cq), 143.1 (Cq), 150.0 (Cq), 168.6
(CO); Anal. Calcd for C16H14N2O (250.30): C, 76.78; H,
5.64; N, 11.19. Found: C, 76.59; H, 5.61; N, 11.08.
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