Oxidized isoquinolinoisoindolinone and benzazepinoisoindolinone alkaloids cores by convergent cyclisation processes: π-aromatic attack of thionium and oxonium species

Article abstract of DOI:10.1016/j.tet.2005.10.017

An efficient methodology for synthesis of isoindoloisoquinoline 5a and isoindolobenzazepine 5b in oxidized forms as tetracyclic alkaloids cores are reported from N-bromoethylphthalimide (6) or phthalic anhydride and 2-phenylthioethylamine (8) in a five- o

Full text of DOI:10.1016/j.tet.2005.10.017

Tetrahedron 62 (2006) 706–715
Oxidized isoquinolinoisoindolinone and benzazepinoisoindolinone
alkaloids cores by convergent cyclisation processes: p-aromatic
attack of thionium and oxonium species
*
¨
Till Bousquet, Jean-Franc¸ois Fleury, Adam Daıch and Pierre Netchitaılo
¨
´
Laboratoire de chimie, URCOM, EA 3221, UFR des Sciences & Techniques de l’Universite du Havre, B.P: 540,
25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
Received 2 September 2005; revised 30 September 2005; accepted 3 October 2005
Available online 2 November 2005
Abstract—An efficient methodology for synthesis of isoindoloisoquinoline 5a and isoindolobenzazepine 5b in oxidized forms as tetracyclic
alkaloids cores are reported from N-bromoethylphthalimide (6) or phthalic anhydride and 2-phenylthioethylamine (8) in a five- or six-step
sequence, respectively, in overall very good yields. The key step of this methodology is based on an intramolecular p-cationic cyclization of
the thionium ion species. Alternatively, another four-step route was explored and based in an ultimate step on the cyclodehydration of an
aldehyde functionality, which used as intermediate in the latest strategy, via the oxonium ion cation.
q 2005 Published by Elsevier Ltd.
1. Introduction
which were thought for long time to be artifacts.7 While
structures 3 and 4 as the sole erythrina alkaloids products
with double bond at C4–C5 linkage, have not showed at this
time any biological properties, they are useful intermediates
The pyrrolo[2,1-a]isoquinoline skeleton is a structural motif
common to a large and diverse family of natural products,
which shown a remarkable array of biological activity.1 The
latter includes for example the so popular marine
lamellarins,2 erythrina3 and aporhoedane4 (including proto-
berberines) families, which produced a plethora of
structures with profound important properties. In contrary,
pyrrolo[2,1-a]isoquinoline motif with an olefinic moiety at
a and b positions of the nitrogen atom of the isoquinoline
nucleus (Scheme 1), as respectively, in iminium salts (1),5
crispine B (2),6 (C)-erythrabine (3)7 and (C)-crystamidine
(4)8 are few explored. Some of unnatural compounds of
type 1 are patented and have been reported to possess
antidepressant activity.5 Crispine B (2) is one of alkaloid
products isolated from extracts of Carduus crispus L. which
have been used in Chinese folk medicine for the treatment
of cold, stomachache and rheumatism. The further screen-
ing of this compound for its inhibitory effect on the growth
of some human-cancer lines in vitro by the SRB method
showed that this product have significant cytotoxic activity.6
Elsewhere, other study have reveled the existence of (C)-
erythrabine (3) and (C)-crystamidine (4) together in nature,
2
2
3
3
, Cl
R
1
1
4
4
N
N
5
5
6
6
Y
MeO
X
MeO
(2) Crispine B
(1) R=H, Me
1
2
1
O
2
O
3
N 3
N
MeO
O
MeO
MeO
4
4
5
5
O
MeO
(3) (+)-Erythrabine
(4) (+)-Crystamidine
O
O
N
N
Keywords: Isoindole; Isoquinoline; Benzazepine; Thionium ion; Oxonium
ion; N-Acyliminium ion; Cyclization; a-Amidoalkylation; Pummerer;
Alkaloid.
5a
Our targets
5b
*
Corresponding author. Tel.: C33 2 32 74 44 03; fax: C33 2 32 74 43 91;
e-mail: adam.daich@univ-lehavre.fr
Scheme 1. Selected examples of clinical important natural and non natural
pyrrolo[2,1-a]isoquinolines (1–4) and our targets 5a,b.
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.10.017

T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
707
in organic synthetic chemistry, especially in the elaboration
of other erythrina alkaloids products exemplified by
erysotrine,9 8-oxoerythrinine,10 and both of enantiomers
of 3-demethoxyerythratidinone.11 Furthermore, the azepinic
homologues of the oxidized pyrrolo[2,1-a]isoquinoline
have been reported to constitute a valuable platform to
access easily homoerythrinan alkaloids as 2,7-dihydro-
homoerysotrine and 3-epischelhammericine.12
utility of N-phenylthioalkylimides as remarkable synthons
for the synthesis of various aza-fused [1,3]thiazines,16,17
[1,3]thiazepines,17 [1,3]thiazocinones in racemic,17,18 or
chiral18 forms as well as isoindolo[2,1-b]isoquinolines
alkaloids cores and their corresponding thio-bridged
systems.19 These compounds are obtained by the tandem
thiocyclization/p-cationic cyclization of N-acyliminium ion
in acidic conditions,16,17 a-amidoalkylation/Friedel-Crafts
type-cyclization18 and finally Pummerer reaction/N-acyl-
iminium ion cyclization.19 In all these methodology, the
phenylthio group was incorporated in the final structure
except during the formation of the isoindolo[2,1-b]-
isoquinoline alkaloid core in which the phenylthio group
was eliminated in an ultimate stage by reduction.19
Most of the hitherto reported syntheses of these type of
compounds rely on a small number of strategies; the sulfur
chemistry constitute an important one of them and in this
case the ring closure was executed by radical or ionic
process as shown in Scheme 2. In fact, if we consider the
formation of the azepine ring system as in aporhoedanes
(protoberberines), erythrinan, and homoerythrinan alkaloids
for examples, the radical approaches have relied on
the generation of the C12b–C13 bond from appropriate
imide-thioacetal B (path 1)13 or imide-thioether C (path 2)14
by photocyclization followed by deketalisation or oxidative
formation with Pb(OAc)4, respectively. In the ionic process,
the sulfur-directed 5-exo selective aryl radical cyclization
onto an enamide functionality using the tandem Bu3SnH/
AIBN followed by the Pummerer type-cyclization was also
operated. During these processes, the ring closure involves
the formation of the C13–C13a bond via the p-cyclization of
the thionium ion generated from the sulfoxide D in acid
conditions (path 3).15
In our search for new synthetic applications for N-phenyl-
thioalkylimides, we wish to report herein our finding in this
area by using the N-acyliminium ion chemistry in
combination with the Pummerer cyclization. So with the
above considerations in hand, we speculated that the
oxidized tetracyclic alkaloids frameworks 5a,b might
conceivably be constructed by formation of the C4a–C5
bond through electrophilic cyclization of the sulfoxide
derivatives E (path 4 in Scheme 2). Interestingly, the
Pummerer reaction seemed to be particularly well adapted
for driving this plan since the cyclized Pummerer product
which bear a phenylthio group at exocyclic position on the
C5 (Scheme 2) could produce efficaciously in concise
manner saturated tetracyclic alkaloids cores or oxidized
tetracyclic systems 5a,b as in Scheme 1 by C-S linkage
reduction or oxidative thiophenol elimination, respectively.
O
O
As a starting point of our study, the N-phenylthioethyl-
a-phenyl(or benzyl)lactam derivatives 11a,b, as sulfoxides
precursors, constitutes a valuable target molecules
(Scheme 3). We expected to obtain these products in a
three-step sequence from the commercially available
N-bromoethylphthalimide (6). So the halide (6) was
S-alkylated with slight excess (1.2 equiv) of thiophenol in
alkaline medium in 88% yield.17,20 This product was also
obtained in high yield of 98% in an alternative pathway
from phthalic anhydride and the known 2-phenylthioethyl-
amine21 by the thermal amino-anhydride condensation in
refluxing toluene in the presence of a catalytic amount of
dry triethylamine under azeotropic removal of water.22
Regioselective carbophilic addition onto the resulted
phthalimide derivative 7 was performed with a large excess
of Grignard reagents (RMgX with RXZPhBr and BnCl) in
analogy to our precedent reports (i.e., RMgX, Et2O, THF,
room temperature, 2–5 h)16 and afforded a-phenyl-
a-hydroxylactam 10a in 88% yield. In the case of the use
of benzylmagnesium chloride, however, the changes
operated in the experimental part notably in the work-up
procedure (acidic or neutral conditions), no traces of
a-benzyl-a-hydroxylactam were detected in the reaction
mixture but only the enamidone 10b as the consequence of
the dehydration reaction of the latter a-hydroxylactam was
isolated in good yield (96%). Because of the apparition of a
N
N
O
O
S
OMe
OMe
OMe
OMe
S
t.Bu-S
m=1,2
B
C
Radical process
path 1
path 2
O
6
8
5
4a
N
4
3
n=1
12b
13a
13
11 12
1
2
A
path 4
path 3
Ionic process
MeO
OMe
O
Y
=
Y
O
N
=O
or
N
n
O
-S
O
O
S O
Ph
D
E
Scheme 2. Retrosynthetic scheme leading to isoindoloisoquinoline (5a,
nZ0) and related isoindolobenzazepine (5b, nZ1).
2. Results and discussion
1
In our laboratory we are interested in the development
of synthetic methodologies towards original aza-hetero-
cyclic systems containing isoindole, isoquinoline and/or
benzazepine moieties with promising pharmaceutical
activities. In this sense, we have recently explored the
stereogenic centre adjacent to the nitrogen atom, the H
NMR spectra of a-phenyl-a-hydroxylactam 10a showed
the magnetically non-equivalence of the methylene
protons (–N–CH2–) of the phenylthioethyl group, which
appears as a classical AB system. Finally, the expected

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T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
Scheme 3. Sequential pathways leading to 2,3-dihydro-2-(2-phenylsulfanylethyl)-3-phenylisoindol-1-one (15a) and 3-benzyl-2-(2-phenylsulfanylethyl)-2,3-
dihydroisoindol-1-one (15b) as thionium ions precursors.
N-phenylthioethyl-a-phenyllactam derivative 11a was
obtained in an ultimate stage from a-phenyl-a-hydroxy-
lactam 10a by removing the hydroxyl function with 2 equiv
of triethylsilane and a large excess of TFA as hydride and
proton sources, respectively. After 4 h of the reaction at
room temperature, the excepted a-phenyllactam derivative
11a was isolated in good yield (89%). Finally, the
Pummerer thionium ion precursor 15a was reached easily
in quantitative yield by m-CPBA oxidation of 11a in dry
dichloromethane at K60 8C. The latter was isolated as
uncoloured oil as a mixture of inseparable two diasteromers
in 54/46 ratio. In addition, to avoid the formation of the non
expected sulfone derivative, 1 equiv of m-CPBA and
few minutes of reaction were necessary (in general only
5–10 min).
the bromine atom with oxygen anion as shown in the
intermediate F (Scheme 3). These oxazoloisoindolones 12a
and 12b were then converted easily to the N-hydroxy-
alcohol derivatives 13a,b by triethylsilane reduction as
described above for 11a in 66 and 64% yields, respectively.
In these cases, the reaction occurred at K60 8C in dry
dichloromethane and in the presence of TiCl4 as catalyst
instead of TFA used above during the transformation of 10a
into 11a. Herein, TiCl4 coordinates efficaciously the oxygen
atom of the oxazole ring in 12a,b inducing the formation of
the N-acyliminium intermediate G (Scheme 3), which easily
reduced by the hydride anion. Interestingly, the reaction
proceeded cleanly and in the case of the reductive-cleavage
of 12b (nZ1), no traces of the byproduct as N-hydroxy-
ethyl-3-benzylidene were isolated. The above alcohol
derivatives 13a,b were treated with 1.5 equiv of thionyl
chloride under reflux of dichloromethane for 2 h and the
resulting halide 14a,b, obtained in quantitative yields, were
S-alkylated in accordance with the procedure described
above for the synthesis of N-(2-phenylthioethyl)phthalimide
(7) to give after chromatography purification (using SiO2
column with a mixture of cyclohexane–AcOEt (4/1) as
eluent) N-(2-phenylthioethyl)isoindolone derivatives 11a,b
in 88% yield in both cases. The reaction was slower then the
one used for the production of the imide 7. Consequently,
the heat at 100 8C for 12 h was necessary for complete
transformation of halides 14a,b into corresponding sulfides
11a,b. The requisite sulfoxides 15a,b were then obtained by
using same procedure reported above for oxidation of 11a
into 15a. The latter 15a and its benzyl isomer 15b were
isolated after short reaction times, which in general do not
exceed 10 min, in quantitative yield for each case.
Furthermore, these sulfoxides were isolated as a mixture
of two diastereomers in comparable ratio of about 55/45.
Because of this strategy was not general (all tentative to
accede a-benzyllactam derivative 11b have failed), our
attention was turned to explore another approach starting
again from N-bromoethylphthalimide (6). The choice of this
sequence was based on two considerations: first, the oxazole
ring in the oxazoloisoindolone tricyclic system might give
the isoindolone ring equipped with alcohol function and aryl
or aralkyl group at suitable positions, respectively. Second,
the oxazoloisoindolone tricyclic system might limitated the
proportion of the enamidone function, which could be
formed after the ring cleavage according to the Meyers
reports.23 Thus, treatment of halide 6 with 1.2 equiv of
Grignard reagents (RMgX with RXZPhBr and BnCl) in
analogy to the procedure described above in dry THF over
48 h gave the tricyclic oxazoloisoindolones 12a24 and 12b
in quantitative yields. The formation of these products
resulted from the regioselective carbophilic addition of
RMgX onto one carbonyl group of the imide function
followed by an intramolecular nucleophilic substitution of

T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
709
Scheme 4. The p-cationic cyclization of sulfoxides 15a,b and corresponding formyl derivatives 17a,b into isoindolinones 5a,b under acidic conditions.
Taking into account that sulfoxides similar to 15a,b (see
also intermediate D in Scheme 2) have been reported in the
literature to constitute excellent precursors for the
Pummerer type-cyclization,19,26 the sulfoxide 15a obtained
above as a model substrate was subjected to TFAA at room
temperature under Pummerer conditions (Scheme 4). The
expected cyclization was readily induced by the inter-
mediary of the thionium species H; and after 30 min of
reaction, 5,12b-dihydro-5-phenylthioisoindolo[1,2-a]iso-
quinolin-8(6H)-one (16a) was formed as a mixture of two
diastereomers in 56/44 ratio (cis and trans isomers). The
purification of the product by short column chromatography
gives pure 16a as uncoloured oil in quantitative yield.
Similarly, cyclization of sulfoxide 15b was also
occurred under identical conditions (quantitative yield)
and, interestingly, furnished directly the benzazepine
product 12b,13-tetrahydrobenzo[4,5]azepino[2,1-a]iso-
indol-8-one (5b) via the intermediacy of the expected and
‘non-isolated’ 5-phenylthio-5,6,12b,13-tetrahydrobenzo-
[4,5]azepino[2,1-a]isoindol-8-one (16b) followed by
spontaneous lost of thiophenol. In order to isolate the
cyclized sulfure 16b, other cyclization protocols, notably
under lower temperature, diluted solution, other solvent,
etc., have failed in all cases. Furthermore, this product 5b
and its isoquinoline derivative 5a were also obtained
in one-step procedure by heating 15a,b and TFAA on
refluxing dichloromethane for 2 h in 100 and 96% yields,
respectively. In addition, exposition of neat sulfure 16a
at laboratory atmosphere or in dichloromethane for 3 h at
room temperature produces quantitatively the oxidized
product 5a.
appendage 17b (nZ1), no traces of N-phthalimidin-
2-ylethanol and/or N-phthalimidin-2-ylacetaldehyde as by
products were observed even when the temperature was
raised (up to room temperature) and the reaction time
prolonged (up to 2 h).
¨
Taking into account that Bronsted acid (HCO2H, AcOH,
H2SO4 and PTSA)27,28 or Lewis acid (ZnCl2 and BF3$
Et2O)28a are reported to induce cyclization of appropriate
amidoacetals to tetrahydroisoquinolines27 and isoindolo-
benzazepines,28 we then proceeded to apply this method to
the synthesis of dihydroisoquinoline 5a and oxidized
benzazepine 5b directly from acetaldehydes 17a and 17b.
Among all attempts used for cyclization of acetaldehydes
17a,b into our targets 5a,b, the tandem AcOH/H2SO4 in 1/2
ratio constitutes the best cyclodehydration combination for
achieving this reaction with, however, low yields (30 and
40%, respectively). In this process, the oxidized alkaloids
cores 5a,b were formed via the intermediacy of the oxonium
cation I followed by the dehydration of the tricyclic
secondary alcohol obtained by the Friedel-Crafts reaction.
The structure elucidation of the cyclized products 5a,b as
well as all compounds intermediates was based on their
1
spectroscopic data (IR, H NMR and 13C NMR including
NOE difference and DEPT experiments) as well as their
microanalyses.
1
The H NMR analyses indicated that in the isoindolones
structures 5a and 5b, the angular protons appear as singlet at
dZ5.86 ppm for 5a and a doublet of doublet at dZ5.08 ppm
for 5b with coupling constant of JZ7.0, 3.1 Hz
characteristics of an AMX system. These latter absorb
downfield compared to the same protons of their
acetaldehydes congeners 17a (dZ5.65 ppm) and 17b
(dZ4.96 ppm), respectively. The same profile was also
observed for these protons in comparison to the ones of their
sulfoxides precursors, with however, a big difference on the
chemical shift values which are DdZC0.44 ppm and
DdZC0.39 ppm in favour of the cyclized products 5a
and 5b, to the detriment of the sulfoxides 15a and 15b.
Interestingly, when the comparison was done with minor
form of 15a and 15b, respectively, only a little difference
(dZ5.73 ppm for 15a and dZ5.01 ppm for 15b in their
In an alternative pathway, compounds 5a and 5b could be
obtained in two-steps starting from the more accessible
N-hydroxyethylisoindolinones 13a and 13b (Scheme 4).
This strategy commences with the oxidation of alcohols
13a,b into corresponding acetaldehydes 17a,b. The Swern
reaction conducted at K60 to 0 8C for 1 h in dichloro-
methane seemed to be more practical since this protocol
delivered straightforwardly, cleanly and with appreciable
yields (72 and 63%, respectively) the expected N-isoindol-
2-ylacetaldehydes 17a (nZ0) and 17b (nZ1), candidates
for the final cyclization step (Scheme 4). In the case of
N-isoindol-2-ylacetaldehyde possessing an benzyl

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T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
minor forms) was observed. Especially diagnostic was also
the appearance of one olefinic proton with coupling constant
of JZ7.8 Hz for 5a and JZ14.1 Hz for 5b at dZ6.20 and
6.10 ppm, respectively. These latter appear as a doublet
in each case characteristic of an AB system and
constitutes ultimately the consequence of the intramolecular
cyclization of 15a,b into 5a,b.
4. Experimental
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 300
(300 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 visualized using an
ultraviolet lamp or iodine vapour. Mass spectral
measurements were recorded on a AEI MS 902 S
spectrophotometer. The elemental analyses were carried
out by the microanalysis laboratory of INSA, F-76130
Mont-Saint-Aignan, France.
Furthermore, the key feature in the 13C NMR spectra of 5a
and 5b, was the appearance of fifteen signals in the aromatic
regions. One of these disappears in the corresponding DEPT
program spectra in comparison to spectra of their precursors
15a,b or 17a,b as the consequence of the p-cationic
cyclization process.
Finally, these observations are in agreement with the fact
that C4a–C5 and C5–C6 bonds, formed during the tandem
p-cyclization/elimination process, have the same effect on
the absorbance of the C12bH angular and the olefinic C5H
and C6H protons absorbance as well as the C5, C6 and C12b
carbon signals. These results are also in agreement with
previous reports dealing on analogous compounds.28
4.1.1. N-(2-Phenylthioethyl)phthalimide (7). Method A.
To a stirred solution, under an atmosphere of dry argon, of
thiophenol (1.32 g, 12 mmol) in 15 mL of dry DMF was
added (65 mg, 12 mmol) of sodium methoxide. After
stirring for 40 min at room temperature, N-bromoethyl-
phthalimide (6, 2.52 g, 10 mmol) was added slowly
dropwise over a period of 5 min. The mixture was then
allowed to react at the ambient temperature for 48 h
(monitored by TLC using CH2Cl2/cyclohexane as eluent)
and hydrolysed by crushed ice. The solution was filtered off
and the solid was recrystallized from dry ethanol to give the
expected imide 7. In the case of the solid is not formed,
the solution was extracted three times with diethyl ether, the
organic layer was dried over MgSO4 and concentrated in
vacuo. The oily residue was passed through short Celite
column and recrystallized in the second time from dry
ethanol to give the above imide 7 in 88% yield. Method B. A
mixture of 2-phenylthioethylamine (8, 1.53 g, 10 mmol),
phthalic anhydride (1.48 g, 10 mmol) and two drops of dry
triethylamine in toluene (50 mL) was refluxed with a
Dean–Stark apparatus for 12 h. After cooling, the reaction
mixture was concentrated under reduced pressure. The
residue was dissolved into CH2Cl2 (50 mL), washed with
5% HCl solution then with a 10% NaHCO3 solution and
then with water. The organic layer was dried over MgSO4,
concentrated under reduced pressure, and recrystallization
of the residue from dry ethanol gave the desired imide 7 in
98% yield; mpZ69 8C (lit.17, isolated as oil in 69% yield);
IR (KBr) y~maxZ1712 cmK1 (C]O); 1H NMR (CDCl3,
300 MHz) d 3.19 (t, 2H, JZ7.0 Hz, C–CH2–S), 3.90 (t, 2H,
JZ7.0 Hz, N–CH2–C), 7.19–7.23 (m, 2H, aromatic),
7.36–7.41 (m, 3H, aromatic), 7.64–7.71 (m, 2H,
phthalimide), 7.74–7.82 (m, 2H, phthalimide); 13C NMR
(CDCl3, 75 MHz) d 31.6, 37.5, 123.3, 126.4, 129.1, 129.6,
132.0, 134.1, 134.9, 168.2; MS (EI): m/zZ283 [MC]. Anal.
Calcd for C16H13NO2S (283.35): C, 67.82; H, 4.62; N, 4.94.
Found. C, 67.78, H, 4.42, N, 4.78.
3. Conclusion
In summary, we have shown that imide 7 could generate in
two-steps a-phenyllactam 11a by successive Grignard
carbophilic addition and a-hydroxylactam triethylsilane
reduction mediated by an N-acyliminium cation. Because of
the benzyl equivalent of a-phenyllactam 11a could not
obtained by this procedure, another approach using the
bicyclic lactams chemistry in a four-step sequence was used
successfully. In these conditions, a-substituted isoindolones
11a and 11b were isolated in an overall good yield from the
readily available N-(2-bromoethyl)phthalimide (6) by the
tandem Grignard addition/SN2 O-cyclisation/oxazoline
cleavage/alcohol chlorination and finally the nucleophilic
chloride displacement with phenylthio anion. In the last
step, the m-CPBA oxidation of 11a and 11b lead to the
expected thionium ion precursors 15a and 15b cleanly, in
very short times, and in quantitative yields.
Treatment of the latter sulfoxides 15a,b under Pummerer
conditions produced efficiently in high yields the cyclized
isoindoloisoquinoline derivative 16a while corresponding
benzazepine component 16b was instable and cyclized
directly into the requisite tricyclic product 5b. Taking
advantage from this behavior, the alkaloids cores 5a and 5b,
were then obtained in comparable high yields in a one-pot
procedure from corresponding sulfoxides 15a,b when the
Pummerer-type cyclization was operated under refluxing
dichloromethane. Alternatively, these targets 15a,b were
also obtained, with however, lower yields, from the formyl
intermediates 17a,b under acid influence. During this
transformation the reaction involves an initial arylation of
oxonium ion, followed by spontaneous water elimination.
This, is resulted from the likely and unstable secondary
alcohol adduct as the resulting product of the ring closure
into isoindolones fused to isoquinoline ring 5a and
benzazepine ring 5b.
4.2. General procedure for Grignard addition onto
N-(2-phenylthioethyl)phthalimide (7)
To a well stirred and cold solution of imide (7, 2.83 g,
10 mmol) under dry nitrogen atmosphere in a mixture of

T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
711
anhydrous diethyl ether and anhydrous THF (40 mL) was
added slowly in dropwise, over a period of 30 min, a 0.5 M
solution of Grignard reagent (phenylmagnesium bromide or
benzylmagnesium chloride (15 mmol)) in dry THF. After 2–
5 h of reaction at room temperature, the reaction was
hydrolysed under stirring with water (40 mL) then with
0.5 M NH4Cl solution (40 mL), and the solution was passed
through Celite. After separation, the organic layer was
washed with water, brine, dried over MgSO4 and
concentrated under reduced pressure. Recrystallization of
the reaction residue from a dry ethanol give a-hydroxy-
lactam 10a or enamidone 10b in yields of 88 and 96%,
respectively.
(m, 1H, CH2–CH2), 3.10–3.31 (m, 2H, CH2–CH2),
3.93–4.07 (m, 1H, CH2–CH2), 5.52 (s, 1H, CH),
7.04–7.33 (m, 11H, aromatic), 7.42–7.46 (m, 2H, aromatic),
7.82–7.95 (m, 1H, aromatic); 13C NMR (CDCl3, 75 MHz) d
31.5, 40.2, 65.6, 123.2, 123.6, 126.1, 127.8, 128.5, 128.9,
129.1, 129.2, 131.4, 132.0, 135.3, 136.9, 146.4, 168.9; MS
(EI): m/zZ345 [MC]. Anal. Calcd for C22H19NOS
(345.46): C, 76.49; H, 5.54; N, 4.05. Found. C, 76.21; H,
5.38; N, 3.79.
4.3. General procedure for Grignard addition onto
N-(2-bromoethyl)phthalimide (6)
To a well stirred and cold solution (0 8C) of halide (6, 6 g,
22.5 mmol) under dry argon atmosphere in anhydrous THF
(150 mL) was added slowly in dropwise, over a period of
30 min, a 0.5 M solution of Grignard reagent (phenyl-
magnesium bromide or benzylmagnesium chloride
(1.2 equiv, 27 mmol)) in dry THF. After 48 h of reaction
at room temperature, the reaction mixture was hydrolysed
under stirring with cold water (100 mL) then passed through
a short column of Celite. After separation, the organic layer
was washed with water, brine, dried over MgSO4 and
concentrated under reduced pressure. Recrystallization of
the reaction residue from a dry ethanol or cyclohexane/
diethyl ether gave oxazoline derivatives 12a or 12b in
quantitative yield.
4.2.1. 3-Hydroxy-3-phenyl-2-(2-phenylthioethyl)-2,3-
dihydroisoindol-1(2H)-one (10a). This product was iso-
lated as white prisms in 88% yield and melted at 150 8C; IR
(KBr) y~maxZ3313 (OH), 1684 (C]O) cmK1 1H NMR
;
(CDCl3, 300 MHz) d 2.61–2.79 (m, 1H, CH2–CH2),
2.94–3.12 (m, 2H, CH2–CH2), 3.44–3.64 (m, 1H,
CH2–CH2), 4.48 (s broad, 1H, OH), 7.02–8.39 (m, 13H,
aromatic), 7.59–8.68 (m, 1H, aromatic); 13C NMR (CDCl3,
75 MHz) d 30.7, 39.1, 122.9, 123.4, 126.0, 126.1, 126.3,
128.5, 128.7, 128.8, 129.1, 129.7, 130.1, 133.1, 135.2,
138.4, 149.9, 168.2; MS (EI): m/zZ361 [MC]. Anal. Calcd
for C22H19NO2S (361.11): C, 73.10; H, 5.30; N, 3.88.
Found. C, 73.00; H, 5.12; N, 3.63.
4.3.1. 2,3-Dihydro-9b-phenyloxazolo[2,3-a]isoindol-5-
(9bH)-one (12a). This product was isolated as yellow-
white solid in quantitative yield and melted at 146 8C (lit.24,
148–150 8C); IR (KBr) y~maxZ3012 and 2995 (CH), 1689
(C]O) cmK1; 1H NMR (CDCl3, 300 MHz) d 3.19–3.35 (m,
1H, CH2–CH2), 4.06–4.20 (m, 2H, CH2–CH2), 4.32–4.44
(m, 1H, CH2–CH2), 7.21–7.65 (m, 8H, aromatic), 7.75–7.88
(m, 1H, aromatic); 13C NMR (CDCl3, 75 MHz) d 41.6, 70.3,
100.5, 123.6, 123.7, 124.4, 125.8, 125.9, 128.9, 129.0,
130.2, 131.2, 133.6, 138.0; MS (EI): m/zZ251 [MC]. Anal.
Calcd for C16H13NO2 (251.09): C, 76.48; H, 5.21; N, 5.57.
Found. C, 76.22; H, 5.06; N, 5.39.
4.2.2. (E)-3-Benzylidene-1,2-dihydro-2-(phenylthio-
ethyl)-1H-isoindol-1-one (10b). This product was isolated
as a yellow oil in 88% yield after chromatograph on silica
gel column using a mixture of diethyl acetate–hexane (3/7)
as eluent; IR (neat) y~maxZ3019 and 2976 (CH), 1700
(C]O) cmK1; 1H NMR (CDCl3, 300 MHz) d 3.28 (dd, 2H,
JZ7.5, 7.1 Hz, CH2–CH2), 4.13 (dd, 2H, JZ7.5, 7.1 Hz,
CH2–CH2), 6.41 (s, 1H, CH]C), 7.16–7.23 (m, 1H,
aromatic), 7.27–7.35 (m, 4H, aromatic), 7.38–7.46 (m,
6H, aromatic), 7.48–7.53 (m, 2H, aromatic), 7.78 (d, 1H,
JZ8.4 Hz, aromatic); 13C NMR (CDCl3, 75 MHz) d 31.6,
39.4, 110.3, 123.3, 123.4, 126.7, 128.0, 128.8, 129.3, 129.5,
129.7, 129.9, 129.7, 130.3, 131.8, 135.1, 135.2, 135.3,
136.1, 166.7; MS (EI): m/zZ357 [MC]. Anal. Calcd for
C23H19NOS (357.12): C, 77.28; H, 5.36; N, 3.92. Found. C,
77.04; H, 5.12; N, 3.87.
4.3.2. 9b-Benzyl-2,3-dihydrooxazolo[2,3-a]isoindol-5-
(9bH)-one (12b). This product was isolated as yellow
solid in quantitative yield and melted at 53 8C (decom-
position); IR (KBr) y~maxZ3021 and 2987 (CH), 1710
(C]O) cmK1; 1H NMR (CDCl3, 300 MHz) d 2.72–2.92 (m,
1H, CH2–CH2), 3.16 (d, 1H, JZ14.0 Hz, CH2–C), 3.38 (d,
1H, JZ14.0 Hz, CH2–C), 3.85–4.05 (m, 3H, CH2–CH2),
7.20–7.36 (m, 5H, aromatic), 7.44–7.62 (m, 3H, aromatic),
7.69–7.72 (m, 1H, aromatic); 13C NMR (CDCl3, 75 MHz) d
43.0, 43.2, 69.9, 100.6, 122.7, 124.2, 127.0, 128.1, 130.1,
130.7, 133.1, 135.2, 138.1, 147.1, 173.9; MS (EI): m/zZ265
[MC]. Anal. Calcd for C17H15NO2 (265.31): C, 76.96; H,
5.70; N, 5.28. Found. C, 76.79; H, 5.54; N, 5.11.
4.2.3. 2,3-Dihydro-3-phenyl-2-(2-phenylthioethyl)-
isoindol-1-one (11a). To a solution of 3-hydroxy-3-
phenyl-2-(2-phenylthioethyl)-2,3-isoindol-1-one (10a,
1.80 g, 5 mmol) in 30 mL of dry dichloromethane, was
added on stirring and cooling at 0 8C dropwise 5 mL of
TFA. After 5 min of reaction, triethylsilane (1.53 mL,
10 mmol) dissolved in 10 mL of anhydrous dichloro-
methane was added slowly over a period of 5 min. After
4 h of the reaction at room temperature, the solvent was
evaporated under reduced pressure. The oily residue was
diluted with 30 mL of dichloromethane and 30 mL of
saturated sodium hydrogenocarbonate solution. The organic
layer was separated, washed twice with water, brine, dried
over MgSO4 and concentrated under reduced pressure.
Recrystallization of the reaction residue from a dry ethanol
give a-phenyllactam 11a in 89% yield as white crystals;
mpZ120 8C; IR (KBr) y~maxZ3009 and 2985 (CH), 1684
4.4. General procedure for cleavage-reduction of
oxazoloisoindolones (12a,b)
To a cold (K60 8C) and stirred solution of oxazoloiso-
indolone (12a) or (12b) (10 mmol) in 40 mL of dry
dichloromethane, was added dropwise (15 mL, 15 mmol)
of 1.0 M TiCl4 solution in dry THF. After 10 min of reaction
under stirring, triethylsilane (4.58 mL, 30 mmol) dissolved
1
(C]O) cmK1; H NMR (CDCl3, 300 MHz) d 2.97–3.05

712
T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
in 10 mL of anhydrous dichloromethane was added slowly
by syringe over a period of 2 min. The reaction mixture was
allowed to reach gradually room temperature during 30 min
and allowed to react again for an additional 30 min. After
addition of 30 mL saturated NH4Cl solution and 30 mL of
dichloromethane, the organic layer was separated, washed
twice with water, brine, dried over MgSO4 and concentrated
under reduced pressure. Purification of the reaction residue
by flash chromatography on silica gel column using a
mixture of cyclohexane–AcOEt (1/1) as eluent give the
expected alcohol derivative (13a) or (13b) in 66 and 64%
yields, respectively.
C16H14ClNO (271.74): C, 70.72; H, 5.19; N, 5.15. Found. C,
70.39; H, 5.01; N, 4.92.
4.5.2. 3-Benzyl-2-(2-chloroethyl)-2,3-dihydroisoindol-1-
one (14b). This product was isolated as an uncolourless
oil in quantitative yield; IR (neat) y~maxZ3021 and 2979
1
(CH), 1685 (C]O) cmK1; H NMR (CDCl3, 300 MHz) d
2.97 (dd, 1H, JZ14.1, 7.8 Hz, CH2–CH), 3.38–3.60 (m, 2H,
CH2–CH2 and CH2–CH), 3.68–3.89 (m, 2H, CH2–CH2),
4.31–4.44 (dt, 1H, JZ5.5, 4.7 Hz, CH2–CH2), 5.06 (dd, 1H,
JZ7.8, 4.7 Hz, CH–CH2), 6.91–6.99 (m, 1H, aromatic),
7.02–7.14 (m, 2H, aromatic), 7.19–7.34 (m, 3H, aromatic),
7.36–7.50 (m, 2H, aromatic), 7.75–7.84 (m, 1H, aromatic);
13C NMR (CDCl3, 75 MHz) d 38.5, 42.5, 42.6, 61.6, 123.1,
123.7, 127.2, 128.4, 128.7, 129.5, 131.4, 131.6, 135.7,
145.2, 168.8; MS (EI): m/zZ285 [MC]. Anal. Calcd for
C17H16ClNO (285.77): C, 71.45; H, 5.64; N, 4.90. Found. C,
71.20; H, 5.36; N, 4.61.
4.4.1. 2-(2-Hydroxyethyl)-2,3-dihydro-3-phenylisoindol-
1-one (13a). This product was isolated as a white solid in
66% yield and melted at 99 8C (methanol/water) (lit.25,
110–112 8C); IR (KBr) y~maxZ3401 (OH), 3009 and 2986
1
(CH), 1702 (C]O) cmK1; H NMR (CDCl3, 300 MHz)
d 2.98–3.11 (m, 1H, CH2–CH2), 3.63–3.85 (m, 2H,
CH2–CH2), 3.87–3.97 (m, 1H, CH2–CH2), 4.41 (s broad,
1H, OH), 5.67 (s, 1H, CH), 7.09–7.79 (m, 9H, aromatic);
13C NMR (CDCl3, 75 MHz) d 44.3, 61.7, 66.2, 123.2, 123.6,
127.8, 128.5, 128.9, 129.3, 131.2, 132.1, 136.8, 146.6,
170.2; MS (EI): m/zZ235 [MCKH2O]. Anal. Calcd for
C16H15NO2 (253.11): C, 75.87; H, 5.97; N, 5.53. Found. C,
75.63; H, 5.81; N, 5.34.
4.6. General procedure for S-alkylation of N-chloro-
ethylisoindolones (14a,b)
The procedure is identical to that used for synthesis of N-(2-
phenylthioethyl)phthalimide (7). After 12 h of reaction at
100 8C, the reaction mixture was cold and diluted with water
(30 mL) and diethyl ether (30 mL). The organic layer was
separated, washed twice with water, brine, dried
over MgSO4 and concentrated under reduced pressure.
Purification of the reaction residue by flash chromatography
on silica gel column using a mixture of cyclohexane–AcOEt
(4/1) as eluent gave the expected sulfure (11a) or (11b) in
88% yield in both cases.
4.4.2. 3-Benzyl-2-(2-hydroxyethyl)-2,3-dihydroisoindol-
1-one (13b). This product was isolated as an uncolourless
oil in 64% yield; IR (neat) y~maxZ3397 (OH), 3015 and 2990
1
(CH), 1673 (C]O) cmK1; H NMR (CDCl3, 300 MHz) d
2.86 (dd, 1H, JZ14.1, 7.8 Hz, CH2–CH), 3.37–3.57 (m, 2H,
CH2–CH2), 3.86 (t, 2H, JZ5.5 Hz, CH2–CH2), 3.95–4.07
(m, 1H, CH2–CH2), 4.91 (dd, 1H, JZ7.8, 4.7 Hz, CH–CH2),
6.85–6.94 (m, 1H, aromatic), 7.02–7.12 (m, 2H, aromatic),
7.23–7.27 (m, 3H, aromatic), 7.35–7.47 (m, 2H, aromatic),
7.71–7.79 (m, 1H, aromatic); 13C NMR (CDCl3, 75 MHz) d
38.5, 44.6, 62.0, 62.3, 123.0, 123.6, 127.2, 128.3, 128.6,
129.6, 131.3, 131.8, 135.9, 145.3, 169.9; MS (EI): m/zZ249
[MCKH2O]. Anal. Calcd for C17H17NO2 (267.32): C,
76.38; H, 6.41; N, 5.24. Found. C, 76.06; H, 6.21; N, 5.06.
4.6.1. 2,3-Dihydro-3-phenyl-2-(2-phenylthioethyl)iso-
indol-1-one (11a). The characteristics of this component,
obtained in 88% yield, are identical to that reported above in
Section 4.2.3
4.6.2.
3-Benzyl-2,3-dihydro-2-(2-phenylthioethyl)-
isoindol-1-one (11b). This product was not isolated in
pure form (impurities do not exceed 5%). The product
obtained as an orange oil in 88% yield (determined by
GC–MS coupling) was used in the next without other
purification; IR (neat) y~maxZ3017 and 2988 (CH), 1694
(C]O) cmK1; 1H NMR (CDCl3, 300 MHz) d 2.75 (dd, 1H,
JZ13.3, 7.8 Hz, CH2–CH), 3.15–3.50 (m, 4H, CH2–CH2
and CH2–CH), 4.15–4.28 (m, 1H, CH2–CH2), 4.87 (dd, 1H,
JZ7.8, 4.7 Hz, CH2–CH), 6.85–6.91 (m, 3H, aromatic),
7.08–7.29 (m, 6H, aromatic), 7.31–7.47 (m, 4H, aromatic),
7.71–7.80 (m, 1H, aromatic); 13C NMR (CDCl3, 75 MHz) d
26.9, 31.8, 38.4, 61.2, 122.9, 123.5, 126.3, 127.1, 128.2,
128.5, 128.7, 129.1, 129.4, 131.1, 131.9, 135.2, 135.7,
145.0, 168.5; MS (EI): m/zZ359 [MC]. Anal. Calcd for
C23H21NOS (359.49): C, 76. 85; H, 5.89; N, 3.90. Found. C,
76.55; H, 5.63; N, 3.68.
4.5. General procedure for chlorination of alcohols
(13a,b)
To a stirred solution of 5 mmol of alcohol 13a or 13b in
40 mL of dry dichloromethane under argon atmosphere was
added slowly 1.5 equiv of freshly distilled thionyl chloride
(0.56 mL, 0.89 g, 7.5 mmol) and the mixture was allowed to
react at reflux for 2 h. After cooling and concentration under
vacuo, the oily residue was diluted with dry dichloro-
methane and treated with charcoal. The concentration of the
solution under reduced pressure give suitable aliphatic
halide 14a or 14b in quantitative yield.
4.5.1. 2-(2-Chloroethyl)-2,3-dihydro-3-phenylisoindol-1-
one (14a). This product was isolated as an orange oil in
quantitative yield; IR (neat) y~maxZ3012 and 2988 (CH),
4.7. General procedure for oxidation of N-phenyl-
thioethylisoindolone derivatives (11a,b)
1689 (C]O) cmK1 1H NMR (CDCl3, 300 MHz) d
;
3.16–3.30 (m, 1H, CH2–CH2), 3.51–3.62 (m, 1H,
CH2–CH2), 3.71–3.83 (m, 1H, CH2–CH2), 4.14–4.27 (m,
1H, CH2–CH2), 5.72 (s, 1H, CH), 7.10–7.96 (m, 9H,
aromatic); MS (EI): m/zZ271 [MC]. Anal. Calcd for
To a solution of sulfides 11a,b (1 mmol) in 10 mL of dry
dichloromethane was added in one portion under vigorous
stirring at K60 8C a solution of m-CPBA (0.18 g, 1 mmol)
in dry dichloromethane (10 mL). After 2–5 min of reaction

T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
713
at this temperature and an additional 5 min at room
temperature, the mixture was alkalinised with a saturated
solution of NaHCO3 (15 mL). The organic layer after
separation, was dried over MgSO4, concentrated under
reduced pressure, and the residue was passed through short
silica gel column using a mixture of cyclohexane–AcOEt
(1/2) as eluent to give the expected cyclic sulfoxides 15a or
15b as inseparable two diastereosomers in quantitative
yield.
4.8.1. (1,3-Dihydro-1-oxo-3-phenylisoindol-2-yl)acetal-
dehyde (17a). This product was isolated as an uncolourless
oil in 72% yield; IR (neat) y~maxZ3010 and 2987 (CH), 1684
(C]O) cmK1; 1H NMR (CDCl3, 300 MHz) d 3.75 (d, 1H,
JZ18.7 Hz, CH2), 4.71 (d, 1H, JZ18.7 Hz, CH2), 5.65 (s,
1H, CH), 7.07–7.19 (m, 3H, aromatic), 7.25–7.51 (m, 5H,
aromatic), 7.87–7.91 (m, 1H, aromatic), 9.52 (s, 1H,
CH]O); 13C NMR (CDCl3, 75 MHz) d 50.4, 65.2, 123.3,
123.8, 127.7, 128.5, 129.1, 129.3, 130.6, 132.3, 136.1,
146.5, 169.0, 196.9; MS (EI): m/zZ251 [MC]. Anal. Calcd
for C16H13NO2 (251.09): C, 76.48; H, 5.21; N, 5.57. Found.
C, 76.29; H, 5.11; N, 5.39.
4.7.1. 2,3-Dihydro-2-(2-phenylsulfanylethyl)-3-phenyl-
isoindol-1-one (15a). This product was isolated as a mixture
of two diastereomers (54/46) as a white solid in quantitative
yield; IR (KBr) y~maxZ3009 and 2986 (CH), 1698 (C]O)
cmK1; 1H NMR (CDCl3, 300 MHz) d 2.83–2.94 (m, 2!1H,
CH2–CH2, mixture), 3.07–3.51 (m, 2!2H, CH2–CH2,
mixture), 3.91–4.18 (m, 2!1H, CH2–CH2, mixture), 5.42
(s, 1H, CH of minor isomer), 5.73 (s, 1H, CH of major
isomer), 7.08–7.18 (m, 2!2H, aromatic, mixture),
7.21–7.62 (m, 2!11H, aromatic, mixture), 7.76–7.92 (m,
2!1H, aromatic, mixture); MS (EI): m/zZ361 [MC]. Anal.
Calcd for C22H19NO2S (361.11): C, 73.10; H, 5.30; N, 3.88.
Found. C, 73.04; H, 5.11; N, 3.65.
4.8.2. (3-Benzyl-1,3-dihydro-1-oxoisoindol-2-yl)acetalde-
hyde (17b). This product was isolated as an uncolourless oil
in 63% yield; IR (neat) y~maxZ3014 and 2992 (CH), 1698
(C]O) cmK1; 1H NMR (CDCl3, 300 MHz) d 2.97 (dd, 1H,
JZ14.1, 7.0 Hz, CH2–CH), 3.14 (dd, 1H, JZ14.1, 6.3 Hz,
CH2–CH), 3.99 (d, 1H, JZ19.6 Hz, CH2), 4.62 (d, 1H, JZ
19.6 Hz, CH2), 4.96 (dd, 1H, JZ7.0, 6.3 Hz, CH–CH2),
7.03–7.10 (m, 3H, aromatic), 7.12–7.55 (m, 5H, aromatic),
7.78–7.83 (m, 1H, aromatic), 9.52 (s, 1H, CH]O); 13C
NMR (CDCl3, 75 MHz) d 39.1, 51.3, 61.4, 122.9, 123.8,
127.3, 128.4, 128.7, 129.3, 131.1, 131.7, 135.9, 145.4,
169.0, 196.9; MS (EI): m/zZ265 [MC]. Anal. Calcd for
C17H15NO2 (265.11): C, 76.96; H, 5.70; N, 5.28. Found. C,
76.78; H, 5.43; N, 5.12.
4.7.2. 3-Benzyl-2-(2-phenylsulfanylethyl)-2,3-dihydro-
isoindol-1-one (15b). This product was isolated as a
mixture of two diastereomers (55/45) as a white solid in
quantitative yield; IR (KBr) y~maxZ3012 and 2990 (CH),
4.9. General procedure for cyclodeshydratation of
aldehydes 17a,b or Pummerer type-cyclization of
sulfoxides 15a,b into cyclic isoindolone 5a,b
1693 (C]O) cmK1 1H NMR (CDCl3, 300 MHz) d
;
2.79–2.92 (m, 1H, CH2–CH of major isomer), 2.96–3.08
(m, 1H, CH2–CH of minor isomer), 3.22–3.53 (m, 2!3H,
CH2–CH2 and CH2–CH, mixture), 3.68–3.89 (m, 2!1H,
CH2–CH, mixture), 4.11–4.31 (m, 2!1H, CH2–CH2,
mixture), 4.69 (dd, 1H, JZ8.6, 4.7 Hz, CH of minor
isomer), 5.01 (dd, 1H, JZ7.8, 4.6 Hz, CH of major isomer),
6.80–7.12 (m, 2!2H, aromatic, mixture), 7.16–7.89 (m,
2!12H, aromatic, mixture); MS (EI): m/zZ375 [MC].
Anal. Calcd for C23H21NO2S (375.13): C, 73.57; H, 5.64; N,
3.73. Found. C, 73.36; H, 5.49; N, 3.61.
Method A: Cyclocondensation. To a stirred and cold
solution of aldehydes (17a,b, 2 mmol) in 15 mL of glacial
acetic acid was added dropwise concentrated sulphuric acid
(96–98%, 30 mL). The mixture was stirred at room
temperature for 4 h and neutralised carefully on cooling
with addition dropwise of 30% ammonia solution. After
extraction with dichloromethane and separation, the organic
layer was washed with water, brine, dried over MgSO4, and
concentrated to dryness in vacuo. Purification of the
reaction residue by flash chromatography on silica gel
column using a mixture of cyclohexane–AcOEt (4/1) as
eluent gave the expected cyclic product (5a) or (5b) in 30%
and 40% yields. Method B: Pummerer cyclization. To a
stirred solution of sulfoxides (15a,b, 2.77 mmol) in 45 mL
of dry dichloromethane was added dropwise TFAA (6 mL,
42.6 mmol). After 2 h of reaction at reflux, the reaction
mixture was washed successively with saturated sodium
hydrogenocarbonate solution and brine. The organic layer
was dried over MgSO4, concentrated under reduced
pressure, and the residue was passed through short silica
gel column using a mixture of cyclohexane–AcOEt (4/1) as
eluent to give the expected cyclic product (5a) or (5b) in 100
and 96% yields, respectively.
4.8. General procedure for Swern oxidation of
N-hydroxyethylisoindolone derivatives (13a,b)
To a mixture of oxalyl chloride (1.01 mL, 11.83 mmol,
3.15 equiv) in 15 mL of anhydrous dichloromethane and
cooled at K60 8C was added dropwise dry DMSO (1.33 m,
18.78 mmol, 5 equiv) and the mixture stirred at K60 8C for
15 min. A solution of N-hydroxyethylisoindolone deriva-
tives (13a,b, 3.75 mmol, 1 equiv) in 30 mL of anhydrous
dichloromethane was then added slowly and the resulting
solution stirred at same temperature for 1 h, at which time
triethylamine (2.80 mL, 19.9 mmol, 5.3 equiv) was added
and the reaction mixture was allowed to warm to 0 8C. After
hydrolysis with saturated sodium hydrogenocarbonate
solution, the solution was then concentrated under reduced
pressure. The residue was redissolved in dichloromethane,
washed twice with water, brine, dried over Na2SO4, and
concentrated to dryness in vacuo. Purification of the
reaction residue by flash chromatography on silica gel
column using a mixture of cyclohexane–AcOEt (2/3) as
eluent give the expected formyl derivative (17a) or (17b) in
acceptable yield.
4.9.1. Isoindolo[1,2-a]isoquinolin-8(12bH)-one (5a). This
product was isolated as an orange solid in yields indicated
above; mpZ122 8C (ethanol/diethyl ether); IR (KBr) y~maxZ
3009 (CH), 1703 (C]O) cmK1; 1H NMR (CDCl3, 300 MHz)
d 5.86 (s, 1H, CH), 6.20 (d, 1H, JZ7.8 Hz, CH]CH),
7.16–7.31 (m, 4H, aromatic), 7.52–7.71 (m, 3H, aromatic),
7.90 (dd, 2H, JZ6.3, 7.8 Hz CH]CHCaromatic); 13C NMR

714
T. Bousquet et al. / Tetrahedron 62 (2006) 706–715
Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42,
1901. (d) Chawla, A. S.; Kapoor, V. K. In Pelletier, S. W., Ed.;
Alkaloids: Chemical and Biological Prospectives; 1995, 86.
3. (a) Schultes, R. E.; Raffauf, D. The Healing Forest. Medicinal
and Toxic Plants of the Northwest Amazonia; R. F.
Dioscorides, 1990; See also the references cited therein. (b)
Amer, M. E.; Shamma, M.; Freyer, A. J. J. Nat. Prod. 1991,
54, 329 and references cited therein. (c) Dyke, S. F.; Quessy,
S. N. In Rodrigo, R. G. A., Ed.; The Alkaloids; Academic:
New York, 1981; Vol. 18.
(CDCl3, 75 MHz) d 57.8, 123.4, 123.9, 124.2, 124.6, 125.6,
126.9, 128.5, 128.6, 128.7, 129.2, 129.3, 132.1, 132.5, 134.5,
172.1; MS (EI): m/zZ233 [MC]. Anal. Calcd for C16H11NO
(233.08): C, 82.38; H, 4.75; N, 6.00. Found. C, 82.21; H,
4.66; N, 5.86.
4.9.2. 12b,13-Dihydrobenzo[4,5]azepino[2,1-a]isoind-ol-
8-one (5b). This product was isolated as a white-yellow
solid in yields indicated above; mpZ110 8C (ethanol); IR
(KBr) y~maxZ3012 (CH), 1701 (C]O) cmK1 1H NMR
;
(CDCl3, 300 MHz) d 3.05 (dd, 1H, JZ14.1, 7.0 Hz,
CH2–CH), 3.51 (dd, 1H, JZ14.1, 3.1 Hz, CH2–CH), 5.08
(dd, 1H, JZ7.0, 3.1 Hz, CH–CH2), 6.10 (d, 1H, JZ14.1 Hz,
CH]CH), 6.88–6.93 (m, 2H, aromatic), 7.05–7.52 (m, 6H,
CH]CHCaromatic), 7.74 (d, 1H, JZ7.0 Hz, aromatic);
13C NMR (CDCl3, 75 MHz) d 42.0, 60.6, 109.9, 121.4,
122.4, 124.3, 127.0, 127.4, 129.0, 129.9, 130.8, 131.2,
133.0, 135.4, 135.9, 144.4, 165.8; MS (EI): m/zZ247 [MC].
Anal. Calcd for C17H13NO (247.10): C, 82.38; H, 4.75; N,
6.00. Found. C, 82.21; H, 4.66; N, 5.86.
4. (a) Shamma, M. In The Protoberberines and Retro-Protober-
berines; Blomquist, A. T., Wasserman, H., Eds.; The
Isoquinoline Alkaloids: Chemistry and Pharmacology;
Academic: New York, 1972; Vol. 25, p 268. (b) Shamma,
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4.9.3. (cis and trans)-5,12b-Dihydro-5-phenylthioiso-
indolo[1,2-a]isoquinolin-8(6H)-one (16a). Following a
procedure similar to that described above for the preparation
of cyclic isoindolines 5a,b, the sulfide 16a as the Pummerer
type-cyclization intermediate was isolated when the
reaction was performed at room temperature for 30 min.
After a similar work-up as above, this product, 16a, was
obtained as a mixture of two diastereomers in 56/44 ratio as
uncolourless oil in quantitative yield; IR (neat) y~maxZ3016
¨
58, 6795. (b) Knolker, H.-J.; Agarwal, S. Tetrahedron Lett.
2005, 46, 1173.
7. (a) Juma, B. F.; Majinda, R. R. T. Phytochemistry 2004, 65,
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1
and 2983 (CH), 1704 (C]O) cmK1; H NMR (CDCl3,
300 MHz) d 3.18 (dd, 1H, JZ14.1, 9.4 Hz, CH2–CHS,
major isomer), 3.32 (dd, 1H, JZ14.1, 5.5 Hz, CH2–CHS,
minor isomer), 4.31 (dd, 1H, JZ14.1, 3.9 Hz, CH2–CHS,
major isomer), 4.44 (dd, 1H, JZ14.1, 5.5 Hz, CH2–CHS,
minor isomer), 4.48 (s, 1H, CH, major isomer), 5.67 (s, 1H,
CH, minor isomer), 6.33 (dd, 1H, JZ9.4, 3.9 Hz,
SCH–CH2, major isomer), 6.47 (d, 1H, JZ5.5 Hz,
SCH–CH2, minor isomer), 6.97–7.41 (m, 2!13H,
aromatic, mixture), 7.83–7.96 (m, 2!1H, aromatic,
mixture); MS (EI): m/zZ233 [MCKPhSH].
9. Tsuda, Y.; Hosoi, S.; Nakai, A.; Ohshima, T.; Sakai, Y.;
Kiuchi, F. J. Chem. Soc., Chem. Commun. 1984, 1216.
¨
10. Jousse, C.; Desmaele, D. Eur. J. Org. Chem. 1999, 909.
11. (a) Allin, S. M.; James, S. L.; Elsegood, M. R. J.; Martin, W. P.
J. Org. Chem. 2002, 67, 9464. (b) Allin, S. M.; Streetley, G. B.;
Slater, M.; James, S. L.; Martin, W. P. Tetrahedron Lett. 2004,
45, 5493.
12. Toda, J.; Niimura, Y.; Sano, T.; Tsuda, Y. Heterocycles 1998,
48, 1599 and the references cited therein.
13. Kessar, S. V.; Singh, T.; Vohra, R. Tetrahedron Lett. 1987, 28,
5323.
14. Mazzocchi, P. H.; King, C. R.; Ammon, H. L. Tetrahedron
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Acknowledgements
15. (a) Ishibashi, H.; Kawanami, H.; Iriyama, H.; Ikeda, M.
Tetrahedron Lett. 1995, 36, 6733. (b) Ishibashi, H.;
Kawanami, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1
1997, 6817.
The authors are grateful for many helpful comments and
fruitful discussions throughout the course of this work with
Professor Bernard Decroix. The authors also thank the
Scientific Council of University of Le Havre, France, for
their support of this research program.
¨
16. Hucher, N.; Decroix, B.; Daıch, A. J. Org. Chem. 2001, 66,
4695.
¨ ¨
17. Hucher, N.; Pesquet, A.; Netchitaılo, P.; Daıch, A. Eur. J. Org.
Chem. 2005, 2758.
¨
18. Cul, A.; Daıch, A.; Decroix, B.; Sanz, G.; Van Hijfte, L.
Heterocycles 2004, 64, 33.
¨
19. Hucher, N.; Daıch, A.; Decroix, B. Org. Lett. 2000, 2, 1201.
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