Application of organolithium and related reagents in synthesis. Part 23: Synthetic strategies based on ortho-aromatic metallation. Synthesis of 4b- arylisoindolo[2,1-a]quinoline derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00403-8

The synthesis of the 2-aryl-3-hydroxyisoindol-1-ones 3 and their successive conversion via the reaction with 1-methoxy-1- trimethylsilyloxyethene in the presence of titanium(IV) chloride into 3- carboxymethylphthalimides 7 and subsequent cyclization via sequential treatment with oxalyl chloride and aluminium chloride as a way of regiospecific transformation of the benzenecarbocylic acids into the corresponding isoindolo[2,1-a]quinoline-5, 11-diones 5 is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00403-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4837±4844
Application of Organolithium and Related Reagents in Synthesis.
Part 23: Synthetic Strategies Based on ortho-Aromatic Metallation.
Synthesis of 4b-Arylisoindolo[2,1-a]quinoline derivatives
*
ÂÂ
Jan Epsztajn, Andrzej Jozwiak, Paweø Koøuda, Izabela Sadokierska and Ilona D. Wilkowska
*
   Â
Department of Organic Chemistry, University of èodz, Narutowicza 68, PL-90-136 èodz, Poland
Received 14 March 2000; revised 25 April 2000; accepted 11 May 2000
AbstractÐThe synthesis of the 2-aryl-3-hydroxyisoindol-1-ones 3 and their successive conversion via the reaction with 1-methoxy-1-
trimethylsilyloxyethene in the presence of titanium(IV) chloride into 3-carboxymethylphthalimides 7 and subsequent cyclization via
sequential treatment with oxalyl chloride and aluminium chloride as a way of regiospeci®c transformation of the benzenecarbocylic
acids into the corresponding isoindolo[2,1-a]quinoline-5,11-diones 5 is described. q 2000 Elsevier Science Ltd. All rights reserved.
In the past few years we have witnessed a tremendous
activity directed towards the synthesis of the dihydroisoin-
dolin-1-ones A.1 The dihydroisoindolin-1-ones A are central
building blocks in a very large number of biologically
active products, for example, non-nucleoside HIV-reverse
transcriptase inhibitors,2 and vasodilators.3 Moreover, they
possess potential utility as versatile key intermediates in the
synthesis of alkaloid classes such as pyrolizidionones.4 In
particular, our attention has been focussed on the
preparation of isoindolo[2,1-a]quinoline derivatives C
(Scheme 1).
Available methods for preparation of the isoindolo[2,1-
a]quinoline
C skeleton generally require multistep
reactions5 and are often unsatisfactory both in yield and
generality. The most attractive route so far reported for
construction of the skeleton of isoindolo[2,1-a]quino-
lines C is the transformation of readily available
Scheme 1.
Keywords: lithiation; anilides; isoindole; N-acyliminium cation.
* Corresponding authors. Fax: 148-42-678-65-83; e-mail: epsztajn@krysia.uni.lodz.pl; e-mail: ajozwiak@krysia.uni.lodz.pl
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00403-8

4838
J. Epsztajn et al. / Tetrahedron 56 (2000) 4837±4844
Table 1. AÐan intractable mixture
Compounds
R1
R2
R3
R4
R5
Electrophile
Yield (%)
3
415
7
a
b
c
d
e
f
g
h
i
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
H
H
OMe
OMe
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
OMe
H
H
Ph
4-(Cl)C6H4
H
4-(Cl)C6H4;
H
Ph
4-(Cl)C6H4
Ph
4-(NO2)C6H4
4-Py
PhCOOMe
4-(Cl)C6H4COOMe
DMF
4-(Cl)C6H4COOMe
DMF
PhCOMe
4-(Cl)C6H4COOMe
PhCOOMe
4-(NO2)C6H4COOMe
4-PyCON(Me)2
82
55
72
78
70
71
52
74
53
80
59121
±
A
±
A
52128
49126
56126
0
85
66
60
60
80
85
60
80
±
j
H
H
0
±
Scheme 2.
3-hydroxyisoindol-1-ones A6e,h into 3-oxoisoindole-1-
acetic acids B and then their Friedel-Crafts cyclization.
Therefore, a general strategy for preparation of desired
systems C boils down to obtaining an effective synthe-
sis of phthalimides B.
non-1-ones A (R4ˆOH) as masked ortho carbonylamides.
However, it has been found that this reaction is limited to
the cases of compounds A in which R3ˆH.7 Alternative
routes for preparation of phthalimides B require a conver-
sion of 3-hydroxyisoindolinon-1-ones A (R4ˆOH) into the
corresponding N-acyliminium cation upon treatment with
protic or Lewis acids and then a reaction with appropriate
nucleophiles.7,8 Nevertheless, it is still mostly related only
The most frequently utilised route to systems B involves
condensation of Wittig reagents6 with 3-hydroxyisoindoli-

J. Epsztajn et al. / Tetrahedron 56 (2000) 4837±4844
4839
to speci®c instances. Till now there have been no reports
concerning the synthesis and reaction of dihydroisoindol-1-
one A in which R1 and R2 are not H. Therefore, the question
remains to what extent formation of dihydroisoindol-1-ones
and their conversion into N-acyliminium cations, as well as
their reaction with nucleophiles as a route to formation of
3-carboxymethylphthalimides B are determined by the
nature and position of the substituents.
position 3 of 2-aryl-3-hydroxyisoindolin-1-ones 3 suggests
that the formation of 3-carboxymethylphthalimides 7 via a
reaction of 1-methoxy-1-trimethylsiloxyethene with 2-aryl-
3-hydroxyisoindolin-1-ones in the presence of titanium(IV)
chloride is general.
In the ®nal steps in the construction of isoindolo[2,1-
a]quinolines
5
isoindolo-1-onyl-3-malonates
4
upon
hydrolytic-decarboxylation and methyl 3-carboxymethyl-
phthalimides 7 after base hydrolysis were quantitatively
converted into corresponding 3-carboxymethylphthalimides
6. Acids 6 after treatment with oxalyl chloride gave the acyl
chlorides, which in the presence of aluminium chloride
cyclized into desired isoindolo[2,1-a]quinolines 5. In the
case of methoxy derivatives of acids 6 the cyclization reac-
tion was accompanied by partially demethylated products,
but treatment of the reaction mixture with methyl iodide in
the presence of potassium carbonate gave fully methylated
isoindolo[2,1-a]quinoline-5,11-diones 5.
Our aim was to extend the scope of this procedure to the
synthesis of new polyheterocyclic systems such as
isoindolo[2,1-a]quinoline-6,12-diones
C
with speci®c
patterns of substituents, and we report here the results
obtained starting with a series 3-hydroxyisoindloin-1-ones
3. This provides access to an ef®cient and regiospeci®c
synthetic sequence as a general strategy for the transforma-
tion of benzoic carboxylic acids into isoindolo[2,1-a]quin-
oline B in a four-step protocol starting from benzanilides 1.
We have reported6h,7,9 that the secondary carboxyamide
group provides an excellent possibility for regiospeci®c
preparation of 2-aryl-3-hydroxyisoindolin-1-ones, which
are key starting materials here. Therefore 2-aryl-3-hydroxy-
isoindolin-1-ones 3 were obtained in a good yield by lithia-
tion of benzanilides 1 using butyllithium (BuLi) in
tetrahydrofuran (THF)9 followed by a reaction of the gener-
ated bis-(N- and C-ortho) lithiated anilides 2 with methyl
benzoates. In the next step the conversion of 2-aryl-3-
hydroxyisoindolin-1-ones 3 into N-acyliminium cations
and their subsequent alkylation by treatment with a nucleo-
philic reagent as a route to required 3-carboxymethylphtha-
limides 6 was applied. Thus, 2-aryl-3-hydroxyisoindolin-1-
ones 3a, f±h (R5±H) upon treatment in acetic anhydride in
the presence of methanesulfonic acid reacted with diethyl
malonate to give the desired isoindol-1-one-3-malonates 4
(49%±59%), which were unexpectedly accompanied by the
corresponding dihydroisoindolo[2,1-a]quinolin-5,11-diones
5 (21±28%) (Table 1, Scheme 2).
This methodology for introduction of formyl or benzoyl
groups at the ortho position of benzanilides and then the
reaction of the resulting 2-aryl-3-hydroxyisoindolin-1-ones
with 1-methoxy-1-trimethylsiloxyethene shows a consider-
able versatility for the regiospeci®c synthesis of 2-aryl-3-
carboxymethylphthalimides. This coupled with an effective
cyclization of 2-aryl-3-carboxymethylphthalimides to the
corresponding isoindolo[2,1-a]quinoline-5,11-diones allows
access to this type of aza-polyheterocyclic system.
Experimental
Melting points were determined using a Boetius hot-stage
apparatus and they are uncorrected. IR spectra were
recorded on a Zeiss±Jena Specord 71-IR. The H NMR
1
spectra were determined on
a
Varian-Gemini-200
(200 MHz) spectrometer using TMS as an internal standard.
The ascending thin layer chromatography was performed on
precoated silica gel 60 F 254 (Merck) and the spots were
visualised using UV lamp or iodine vapour. Macherey
Nagel & Co. (silica gel (100±200 mesh ATSM) was used
for column chromatography. All reagents, commercially
available materials, were used without puri®cation unless
otherwise stated. Tetrahydrofuran (THF) was dried by
distillation from sodium benzophenone ketyl before use.
Anilides 1 were prepared from benzoil chlorides and
aromatic amines according to a known procedure.15
Attempts to alter the ratio of products in favour of 5 via
prolongation of the reaction time resulted only in disappear-
ance of the isoindolo-1-one-3-malonates 4 without any
improvement in the yield of the desired isoindolo[2,1-
a]quinoline-5,11-diones. In the case of 3-aryl-3-hydroxy-
isoindolin-1-ones 3i, j, in which substituent R5 is 4-nitrophe-
nyl or 4-pyridyl, the process failed. This is probably due to
decreased stability of the N-acyliminium cations caused by
strong electron-withdrawing effects of the substituents.
In the case of 2-aryl-3-hydroxyisoindolin-1-ones 3c,e
(R5ˆH), a reaction with diethyl malonate in acetic
anhydride in the presence of methanesulphonic acid gave
only an intractable mixture. This obliged us to consider an
alternative route. It is known that the alkylation at the
carbon atom of N-hydroxymethylamides by their reaction
with nucleophiles such as silyl enol ethers in the presence of
Lewis acid generally proceeds in good yield.8a,b,c,10±12 Thus,
the reaction of 2-aryl-3-hydroxyisoindolin-1-ones 3 with
1-methoxy-1-trimethylsiloxyethene in the presence of
titanium(IV) chloride in methylene chloride was attempted
and, indeed, 3-carboxymethylphthalimides 7 were obtained
in good yield. The observed independence of the reactivity
with regard to the nature of substituent (R5ˆH or Aryl) at
Preparation of 3-hydroxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-ones 3
To the anilide 1 (0.025 mol) stirred in THF (150 cm3) at
2788C under argon was added BuLi (34.4 cm3 1.6 mol/
dm3 solution in hexane, 0.055 mol). The solution was held
at 2788C for 0.5 h then allowed to warm to 08C and kept at
08C for 6 min. The mixture was cooled to 2788C and the
electrophile was added [in the cases 3c, 3eÐDMF (2.56 g,
0.035 mol), 3a, 3f, 3hÐmethyl benzoate (4.08 g, 0.03 mol),
3b, 3d, 3gÐmethyl 4-chlorobenzoate (5.12 g, 0.03 mol),
3iÐmethyl 4-nitrobenzoate (4.53 g, 0.025 mol), 3jÐN,N-
dimethylisonicotinic amide (3.75 g, 0.025 mol) in THF
(20 cm3)]. The reaction mixture after 0.5 h at 2788C was

4840
J. Epsztajn et al. / Tetrahedron 56 (2000) 4837±4844
warmed to room temperature, and kept for 1 h. Then in the
case of compounds 3a±h water (25 cm3) was added. The
mixture was adjusted to pH<2 with hydrochloric acid
(2.0 mol/dm3 solution in water) and the organic layer was
separated. The water layer was extracted with CHCl3/THF
mixture 1:1 (3£30 cm3). The combined organic solutions
were dried with magnesium sulphate and evaporated to
give the crude products 3a±h. In the case of compounds
3i and 3j methanol (20 cm3) was added and the solvents
were removed under reduced pressure. To the residue
water (100 cm3) was added and the mixture was neutralised
by addition of hydrochloric acid (2.0 mol/dm3 solution in
water). The insoluble crude products were ®ltered off and
washed with water. The compounds 3 were puri®ed by
crystallisation.
3-Hydroxy-7-methoxy-3-(4-methoxyphenyl)-2-phenyl-
2,3-dihydro-1H-isoindol-1-one 3h. Yield 74%, mp 196±
1998C (crystallised from water/acetone 1:1); (Found: C,
73.1; H, 5.2; N, 3.9: Calcd for C22H19NO4: C, 73.12; H,
5.30; N, 3.88%); nmax(KBr)/cm21 1680 (CO); dH(DMSO-
d6) 7.58±7.45 (1H, m, 5-H), 7.42 (1H, s, OH), 7.40±7.05
(8H, m, 4-H, 2,6Ar-H and Ph), 6.88±6.75 (3H, m, 6-H and
3,5Ar), 3.90 (3H, s, OMe), 3,66 (3H, s, OMe).
3-Hydroxy-7-methoxy-3-(4-nitrophenyl)-2-phenyl-2,3-
dihydro-1H-isoindol-1-one 3i. Yield 53%, mp 2858C
(decomp., crystallised from acetic acid); (Found: C, 66.7;
H, 4.2; N, 7.5: Calcd for C21H16N2O5: C, 67.02; H, 4.28; N,
7.44%); nmax(KBr)/cm21 1690 (CO); dH(DMSO-d6) 8.18±
8.06 (2H, m, 3,5Ar), 7.89 (1H, s, OH), 7,70±7.52 (3H, m,
5-H and 2,6Ar), 7.50±7.40 (2H, m, 2,6Ph), 7,34±7,04 (4H,
m, 4-H and 3,4,5Ph), 6.81 (1H, d Jˆ7.6 Hz, 5-H), 3.94 (3H,
s, OMe).
3-Hydroxy-2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-
1H-isoindol-1-one 3a. Yield 82%, mp 199±2028C (crystal-
lised from acetic acid) (lit.13 mp 201±2038C).
3-Hydroxy-7-methoxy-2-phenyl-3-(4-pyridyl)-2,3-dihydro-
1H-isoindol-1-one 3j. Yield 80%, mp 282±2858C (decom-
pose, crystallised from methanol) (lit.9c mp 282±2848C
decomp.).
3-Hydroxy-3-(4-chlorophenyl)-2-(2-methoxyphenyl)-2,3-
dihydro-1H-isoindol-1-one 3b. Yield 55%, mp 134±1378C
(crystallised from hexane/ethyl acetate 3:1); (Found: C,
69.1; H, 4.7; Cl, 9.4; N, 3.6: Calcd (for C21H16ClNO3: C,
68.95; H, 4.41; Cl, 9.69; N, 3.83%); nmax(KBr)/cm21
1700 (CO); dH(CDCl3) 7.90±7.84 (1H, m, 7-H), 7.63±
7.53 (9H, 4-H, 5-H, 6-H, (4Cl)Ar, 6(2OMe)Ar and OH),
7.04±6.94 (1H, m, 5(2OMe)Ar), 6.90±6.80 (1H, m,
4(2OMe)Ar), 6.77±6.98 (1H, m, 3(2OMe)Ar), 3.79 (3H, s,
OMe).
Reaction of 3-hydroxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-ones 3a,f±h with diethyl malonate
To a mixture of acetic anhydride (5 cm3) methanesulfonic
acid (0.49 g, 0.005 mol) and diethyl malonate (2.40 g,
0.015 mol) 2-aryl-3-hydroxyisoindolone 3a, f±h (0.005 mol)
was added and the solution was heated at 1108C for 6 h.
After cooling to room temperature the reaction mixture
was poured into water (50 cm3) and made alkaline
(Na2CO3 saturated water solution). The mixture was
extracted with CHCl3 (3£15 cm3). The extract was dried
(MgSO4) and the solvents were evaporated under reduced
pressure. The brown residue was puri®ed by chromato-
graphy to give the products 4a,f±h and 5a,f±h. Compounds
4a,f±h and 5a,f±h were puri®ed by crystallisation.
3-Hydroxy-4-methoxy-2-phenyl-2,3-dihydro-1H-isoindol-
1-one 3c. Yield 72%, mp 168±1708C (crystallised from
methanol) (lit.9b mp 167±1698C).
3-Hydroxy-3-(4-chlorphenyl)-4-methoxy-2-phenyl-2,3-
dihydro-1H-isoindol-1-one 3d. Yield 78%, mp 244±2458C
(crystallised from methanol); (Found: C, 69.0; H, 4.4; Cl,
9.8; N, 3.8: Calcd for C21H16ClNO3: C, 68.95; H, 4.41; Cl,
9.69; N, 3.83%); nmax(KBr)/cm21 1680 (CO); dH(DMSO-
d6) 7.64±7.08 (13H, m, 5-H, 6-H, 7-H, Ar, Ph and OH), 3.65
(3H, s, OMe).
Diethyl 2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-
isoindol-1-on-3-malonate 4a. Yield 59%, Rfˆ0.42 (chloro-
form/ethyl acetate 5:1), mp 144±1478C (crystallised from
ethyl acetate); (Found: C, 70.9; H, 5.7; N, 2.9: Calcd for
C28H27NO6: C, 71.02; H, 5.75; N, 2.96%); nmax(KBr)/cm21
1750, 1730 and 1700 (CO); dH(CDCl3) 8.27±8.20 (1H, m,
7-H), 8.00±7.92 (1H, m, 4-H), 7.73±7.52 (2H, m, 5-H and
6-H), 7.35±7.11 (3H, m, 3,4,5Ph), 6.88±6.55 (6H, m, Ar
and 2,6Ph), 4.69 (1H, s, CH), 4.10 (2H, q Jˆ7.1 Hz,
CH2), 3.97±3.65 (5H, m, CH2 and OMe), 1.15 (3H, t
Jˆ7.1 Hz, Me), 0.91 (3H, t Jˆ7.1 Hz, Me).
3-Hydroxy-7-methoxy-2-phenyl-2,3-dihydro-1H-isoindol-
1-one 3e. Yield 70%, mp 148±1508C (crystallised from
methanol), (lit.6d mp 147±1488C).
3-Hydroxy-7-methoxy-2,3-diphenyl-2,3-dihydro-1H-iso-
indol-1-one 3f. Yield 71%, mp 221±2238C (crystallised
from toluene); (Found: C, 76.0; H, 5.2; N, 4.3: Calcd for
C21H17NO3: C, 76.12; H, 5.17; N, 4.23%); nmax(KBr)/cm21
1690 (CO); dH(DMSO-d6) 7.63±7.02 (13H, m, 4-H, 5-H,
Ph, and OH), 6.78 (1H, d, Jˆ7.5 Hz, 6-H), 3.92 (3H, s,
OMe).
Diethyl 7-methoxy-2,3-diphenyl-2,3-dihydro-1H-isoin-
dol-1-on-3-malonate 4f. Yield 52%, Rfˆ0.22 (chloro-
form/ethyl acetate 5:1), mp 167±1708C (crystallised from
hexane/ethyl acetate 1:1); (Found: C, 71.1; H, 5.8; N, 3.0:
Calcd for C28H27NO6: C, 71.02; H, 5.75; N, 2.96%);
3-Hydroxy-3-(4-chlorophenyl)-7-methoxy-2-phenyl-2,3-
dihydro-1H-isoindol-1-one 3g. Yield 52%, mp 259±2628C
(crystallised from methanol); (Found: C, 69.1; H, 4.3; Cl,
9.6; N, 3.9: Calcd for C21H16ClNO3: C, 68.95; H, 4.41; Cl,
9.69; N, 3.83%); nmax(KBr)/cm21 1690 (CO); dH(DMSO-
d6) 7.66 (1H, s, OH), 7.57 (1H, dd Jˆ8.2 and 7.5 Hz, 5-H),
7.49±7.05 (10H, m, 4-H, Ar and Ph), 6.80 (1H, d Jˆ7.5 Hz,
6-H), 3.92 (3H, s, OMe).
n
max(KBr)/cm21 1750, 1730 and 1700 (CO); dH(CDCl3)
7.82±7.72 (1H, m, 4-H), 7.64±7.52 (1H, m, 5-H), 7.37±
6.70 (11H, m, 6-H and Ph), 4.70 (1H, s, CH), 4.18±3.79
(7H, m, CH2 and OMe), 1.14 (3H, t Jˆ7.1 Hz, Me), 0.98
(3H, t Jˆ7.1 Hz, Me).

J. Epsztajn et al. / Tetrahedron 56 (2000) 4837±4844
4841
Diethyl 3-(4-chlorphenyl)-7-methoxy-2-phenyl-2,3-dihy-
dro-1H-isoindol-1-on-3-malonate 4g. Yield 49%, Rfˆ0.22
(chloroform/ethyl acetate 5:1), mp 708C (decomp., crystal-
lised from hexane); (Found: C, 66.2; H, 5.1; Cl, 6.8; N, 2.9:
Calcd for C28H26ClNO6: C, 66.21; H, 5.16 Cl, 6.98; N,
2.76%); nmax(KBr)/cm21 1750, 1730 and 1710 (CO);
dH(CDCl3) 7.78±7.68 (1H, m, 4-H), 7.66±7.53 (1H, m,
5-H), 7.40±6.64 (10H, m, 6-H, Ar and Ph), 4.67 (1H, s,
CH), 4.20±3.80 (7H, m, CH2 and OMe), 1.15 (3H, t
Jˆ7.1 Hz, Me), 0.98 (3H, t Jˆ7.1 Hz, Me).
7.47 (1H, dd Jˆ8.3 and 7.6 Hz, 8-H), 7.40±7.12 (7H, m,
2-H, 4-H and Ph), 6.92 (1H, d Jˆ8.3 Hz, 7-H), 6.83 (1H, d
Jˆ7.6 Hz, 9-H), 4.03 (3H, s, OMe), 3.93 (1H, d Jˆ16.4 Hz,
6-H), 3.77 (3H, s, OMe), 3.00 (1H, d Jˆ16.4 Hz, 6-H).
Transformation of diethyl isoindol-1-on-3-malonate
4a,f±h into acetic acid derivatives 6a,f±h
The mixture of diethyl isoindol-1-on-3-malonate 4a,f±h
(0.001 mol) propan-2-ol (10 cm3) water (7 cm3) and potas-
sium hydroxide (0.11 g, 0.003 mol) was re¯uxed for 30 h.
After cooling to room temperature the solution was adjusted
(HCl 1.0 mol/dm3 solution in water) to pH<2 and the result-
ing precipitate was washed with water (3£5 cm3).
Compounds 6a,f±h were puri®ed by crystallisation.
Diethyl 7-methoxy-2-(4-methoxyphenyl)-3-phenyl-2,3-
dihydro-1H-isoindol-1-on-3-malonate 4h. Yield 56%,
Rfˆ0.23 (chloroform/ethyl acetate 3:1), mp 148±1518C
(crystallised from ethyl acetate); (Found: C, 69.1; H, 5.7;
N, 2.9: Calcd for C29H29NO7: C, 69.17; H, 5.80; N, 2.78%);
n
max(KBr)/cm21 1730 and 1700 (CO); dH(CDCl3) 7.81±7.67
2-(4-Methoxyphenyl)-3-phenyl-2,3-dihydro-1H-isoindol-
1-on-3-acetic acid 6a. Yield 98%, mp 1928C (decomp.,
crystallised from methanol/water 1:1), (Found: C, 74.3 H,
5.1; N, 3.8: Calcd for C23H19NO4: C, 73.98; H, 5.13; N,
3.75%);nmax(KBr)/cm21 1710 and 1660 (CO); dH(DMSO-
d6) 12.14 (1H, br s, OH), 7.83±7.75 (1H, m, 7-H), 7.65±7.44
(2H, m, 5-H and 6-H), 7.43±7.10 (6H, m, 4-H and Ph), 6.85
(4H, s, Ar), 3.84±3.66 (4H, overlapping 1H, d Jˆ16.0 Hz,
CH2 and 3H, s, OMe), 3.18 (1H, d Jˆ16.0 Hz, CH2).
(1H, m, 4-H), 7.65±7.52 (1H, m, 5-H), 7.35±7.08 (3H, m,
3,4,5Ph), 7.07±6.99 (1H, m, 6-H), 6.83±6.61 (6H, m, Ar and
2,6Ph), 4.68 (1H, s, CH), 4.18±3.74 (10H, m CH2 and OMe),
1.14 (3H, t Jˆ7.1 Hz, Me), 0.97 (3H, t Jˆ7.1 Hz, Me).
3-Methoxy-6a-phenyl-6,6a-dihydroisoindolo[2,1-a]quin-
oline-5,11-dione 5a. Yield 21%, Rfˆ0.61 (chloroform/ethyl
acetate 5:1), mp 205±2068C (crystallised from ethyl
acetate); (Found: C, 77.8; H, 4.9; N, 4.0: Calcd for
C23H17NO3: C, 77.73; H, 4.82; N, 3.94%); nmax(KBr)/
cm21 1710 and 1690 (CO); dH(CDCl3) 8.39 (1H, d,
Jˆ8.8Hz, 1-H), 8.06±7.77 (1H, m, 10-H), 7.62±7.45 (2H,
m, 8-H and 9-H), 7.37 (1H, d Jˆ3.2 Hz, 4-H), 7.33±7.11
(7H, m, 2-H, 7-H and Ph), 3.99 (1H, d Jˆ16.4 Hz, 6-H),
3.78 (1H, s, OMe), 3.00 (1H, d Jˆ16.4 Hz, 6-H).
7-Methoxy-2,3-diphenyl-2,3-dihydro-1H-isoindol-1-on-
3-acetic acid 6f. Yield 97%, mp 2398C (decomp., crystal-
lised from methanol/water 1:2); (Found: C, 74.0; H, 4.9;
N,3.8: Calcd for C23H19NO4: C, 73.98; H,5.13; N, 3.75%);
n
max(KBr)/cm21 1730 and 1660 (CO); dH(DMSO-d6) 12.12
(1H, br s, OH), 7.55±7.43 (1H, m, 5-H), 7.40±6.85 (12H, m,
4-H, 6-H and Ph), 3.90 (3H, s, OMe), 3.81 (1H, d
Jˆ16.2 Hz, CH2), 3.15 (1H, d Jˆ16.2 Hz, CH2).
10-Methoxy-6a-phenyl-6,6a-dihydroisoindolo[2,1-a]quin-
oline-5,11-dione 5f. Yield 28%, Rfˆ0.49 (chloroform/ethyl
acetate 5:1), mp 275±2778C (crystallised from ethyl
acetate); (Found: C, 70.8; H, 4.6; N, 4.0: Calcd for
C23H17NO3: C, 77.73; H, 4.82; N, 3.94%); nmax(KBr)/
cm21 1710 and 1690 (CO); dH(CDCl3) 8.52±8.43 (1H, m,
1-H), 7.93±7.84 (1H, m, 4-H), 7.68±7.56 (1H, m, 2-H), 7.49
(1H, dd Jˆ8.2 and 7.6 Hz, 8-H), 7.35±7.70 (6H, m, 3-H and
Ph), 6.93 (1H, d Jˆ8.2 Hz, 7-H), 6.84 (1H, d Jˆ7.6 Hz,
9-H), 4.04(3H, s, OMe), 3.94 (1H, d Jˆ16.4 Hz, 6-H),
3.02 (1H, d Jˆ16.4 Hz, 6-H).
3-(4-Chlorphenyl)-7-methoxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-on-3-acetic acid 6g. Yield 94%, mp 2488C
(decomp., crystallised from methanol/water 2:1); (Found:
C, 67.7; H, 4.5; Cl, 8.6; N, 3.5: Calcd for C23H18ClNO4:
C,67.73; H, 4.45; Cl, 8.69; N, 3.43%); nmax(KBr)/cm21
1720 and 1650 (CO); dH(DMSO-d6) 12.16 (1H, br s, OH),
7.58±7.46 (1H, m, 5-H), 7.45±7.14 (7H, m, Ar and
3,4,5Ph), 7.09±6.85 (4H, m, 4-H, 6-H and 2,6Ph) 3.90
(3H, s, OMe), 3.80 (1H, d Jˆ16.2 Hz, CH2), 3.16 (1H, d
Jˆ16.2 Hz, CH2).
6a-(4-Chlorophenyl)-10-methoxy-6,6a-dihydroisoindolo-
[2,1-a]quinoline-5,11-dione 5g. Yield 26%, Rfˆ0.48
(chloroform/ethyl acetate 5:1), mp 288±2908C (crystallised
from ethyl acetate); (Found: C, 70.6; H, 4.1; Cl, 8.9; N, 3.6:
Calcd for C23H16ClNO3: C, 70.86; H, 4.14; Cl, 9.09; N,
3.59%); nmax(KBr)/cm21 1710 and 1690 (CO); dH(CDCl3)
8.52±8.41 (1H, m, 1-H), 7.96±7.86 (1H, m, 4-H), 7.70±7.58
(1H, m, 2-H), 7.50 (1H, dd Jˆ8.3 and 7.5 Hz, 8-H), 7.30±
7.06 (5H, m, 3-H and Ar), 6.95 (1H, d Jˆ8.3 Hz, 7-H), 6.82
(1H, d Jˆ7.5 Hz, 9-H), 4.04 (3H, s, OMe), 3.88 (1H, d
Jˆ16.4 Hz, 6-H), 3.03 (1H, d Jˆ16.4 Hz, 6-H).
7-Methoxy-2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-
1H-isoindol-1-on-3-acetic acid 6h. Yield 77%, mp 2108C
(decomp., crystallised from methanol/water 2:1); (Found:
C, 71.2; H, 5.1; N, 3.6: Calcd for C24H21NO5: C, 71.45;
H, 5.25; N, 3.47%); nmax(KBr)/cm21 1720 and 1650 (CO);
dH(DMSO-d6) 12.12 (1H, br s, OH), 7.55±7.43 (1H, m,
5-H), 7.40±6.85 (5H, m, Ph), 7.03 (1H, d Jˆ8.2 Hz, 4-H),
6.92±6.79 (5H, m, 6-H and Ar) 3.90 (3H, s, OMe), 3.76±
3.62 (4H, overlapping 1H, d Jˆ16.0 Hz, CH2 and 3H, s,
OMe), 3.11 (1H, d Jˆ16.0 Hz, CH2).
3,10-Dimethoxy-6a-phenyl-6,6a-dihydroisoindolo[2,1-
a]quinoline-5,11-dione 5h. Yield 26%, Rfˆ0.51 (chloro-
form/ethyl acetate 3:1), mp 264±2688C (crystallised from
ethyl acetate); (Found: C, 74.7; H, 5.0; N, 3.7: Calcd for
C24H19NO4: C,74.79; H, 4.97; N, 3.63%); nmax(KBr)/cm21
1710 and 1690 (CO); dH(CDCl3) 8.43±8.34 (1H, m, 1-H),
Reaction of 3-hydroxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-ones 3 with 1-methoxy-1-trimethylsiloxy-
ethene
A solution of hydroxyisoindolone 3 (0.0014 mol) and 1-
methoxy-1-trimethylsiloxyethene (0.0042 mol) in dry

4842
J. Epsztajn et al. / Tetrahedron 56 (2000) 4837±4844
dichloromethane (30 cm3) was added to a stirred solution of
titanium(IV) chloride (0.81 g, 0042 mol) in dry dichloro-
methane (5 cm3) under argon at 08C. The resulting solution
was allowed to warm slowly to room temperature and was
left for 24 h. Then 5% aqueous NaHSO4 solution (6 cm3)
was added. The organic layer was separated, dried (MgSO4),
®ltered, and concentrated. The obtained crude product 7 was
puri®ed by crystallisation. [1-Methoxy-1-trimethylsiloxy-
ethene was prepared according to a known procedure14
from methyl acetate anion and chlorotrimethylsilane and
was used as a mixture with methyl (trimethylsilyl)acetate.
The isomeric composition of the used mixture of C- and
O-silylated products was measured by integrating the
OCH3 proton signals in CDCl3.]
(1H, dd Jˆ16.1 and 4.1 Hz, CH2), 2.47 (1H, dd Jˆ16.1 and
8,5 Hz, CH2).
Methyl 7-methoxy-2,3-diphenyl-2,3-dihydro-1H-isoindol-
1-on-3-acetate 7f. Yield 85%, mp 221±2238C (crystallised
from ethyl acetate/hexane 2:1); (Found: C, 74.8; H, 5.5; N
3.6; Calcd for C24H21NO4: C, 74.40; H, 5.46; N, 3.62%);
n
max(KBr)/cm21 1750 and 1690 (CO); dH(CDCl3) 7.52±
7.41 (1H, m, 5-H), 7.36±6.97 (10H, m, Ph-H), 6.93 (1H, d
Jˆ8.3, 4-H), 6.77 (1H, d Jˆ7.5, 6-H), 4.02 (3H, s, OMe),
3.53 (1H, d Jˆ14.8, CH2), 3.42 (3H, s, OMe), 3.31 (1H, d
Jˆ14.8, CH2).
Methyl 3-(4-chlorophenyl)-7-methoxy-2-phenyl-2,3-di-
hydro-1H-isoindol-1-on-3-acetate 7g. Yield 60%, mp
225±2278C (crystallised from ethyl acetate/hexane 1:1);
(Found: C, 68.4; H, 4.8; Cl, 8.1; N, 3.4: Calcd for
C24H20ClNO4: C, 68.33; H, 4.78; Cl, 8.40; N, 3.32%);
Methyl 2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-1H-
isoindol-1-on-3-acetate 7a. Yield 85%, mp 164±1658C
(crystallised from ethyl acetate/hexane 1:2); (Found: C,
74.5; H, 5.5; N, 3.6: Calcd for C24H21NO4: C, 74.40; H,
5.46; N, 3.62%); nmax(KBr)/cm21 1750 and 1690 (CO);
dH(CDCl3) 8.04±7.93 (1H, m, 7-H), 7.61±7.45 (2H, m, 5-
H, 6-H), 7.37±7.03 (6H, m, 4-H, Ph), 6.90±6.71 (4H, m,
Ar), 3.76 (3H, s, OMe), 3.50 (1H, d Jˆ15.1, CH2), 3.39 (3H,
s, OMe), 3.30 (1H, d Jˆ15.1, CH2).
n
max(KBr)/cm21 1750 and 1700 (CO); dH(CDCl3) 7.54±
7.42 (1H, m, 6-H), 7.33±6.90 (10H, m, 4-H, Ar and Ph,),
6.76 (1H, d Jˆ7.7, 5-H), 4.02 (3H, s, OMe), 3.53±3.39 (4H,
m, OMe, CH2), 3.26 (1H, d Jˆ15.1, CH2).
Methyl 7-methoxy-2-(4-methoxyphenyl)-3-phenyl-2,3-
dihydro-1H-isoindol-1-on-3-acetate 7h. Yield 80%, mp
194±1988C (crystallised from ethyl acetate/hexane 1:1);
(Found: C, 72.1; H, 5.5; N,3.4: Calcd for C25H23NO5: C,
71.93; H, 5.55; N, 3.36%); nmax(KBr)/cm21 1730 and
1690 (CO); dH(CDCl3) 7.53±7.41 (1H, m, 5-H), 7.36±
7.08 (5H, m, Ph), 6.97±6.69 (6H, m, 4-H, 6-H and Ar,),
4.01 (3H, s, OMe), 3.75 (3H, s, OMe), 3.52±3.40 (4H, m,
OMe, CH2), 3.27 (1H, d Jˆ14.8, CH2).
Methyl 3-(4-chlorophenyl)-2-(2-methoxyphenyl)-2,3-di-
hydro-1H-isoindol-1-on-3-acetate 7b. Yield 66%, mp
158±1618C (crystallised from ethyl acetate/hexane 1:1);
(Found: C, 68.5; H, 4.7; Cl,8.6; N, 3.4: Calcd for
C24H20ClNO4: C, 68.33; H, 4.78; Cl, 8.40; N, 3.32%);
n
max(KBr)/cm21 1740 and 1700 (CO); dH(CDCl3) 8.04±
7.96 (1H, m, 7-H), 7.70±7.43 (3H, m, 4-H, 5-H and
6-H), 7.40±6.74 (8H, m, (4Cl)Ar and (2OMe)Ar), 3.50
(3H, s OMe), 3.46 (3H, s, OMe), 3.36 (2H, d Jˆ4.7 Hz,
CH2).
Hydrolysis of methyl esters 7 into acetic acid
derivatives 6
Methyl 4-methoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-
on-3-acetate 7c. Yield 60%, mp 108±1108C (crystallised
from ethyl acetate/hexane 1:3); (Found: C, 69.4; H, 5.4;
N, 4.5: Calcd for C18H17NO4: C, 69.44; H, 5.50; N,
4.50%); nmax(KBr)/cm21 1740 and 1690 (CO); dH(CDCl3)
7.63±7.36 (6H, m, 6-H, 7-H and 2,3,5,6Ph), 7.32±7.20 (1H,
m, 4Ph), 7.08 (1H, dd Jˆ7.3 and 1.7 Hz, m, 5-H), 5.61 (1H,
t Jˆ5.2 Hz, CH), 3.92 (3H, s, OMe) 3.45 (3H, s, OMe),
2.90±2.80 (2H, two overlapping d Jˆ5.2 Hz, CH2).
A mixture of K2CO3 (0.50 g, 0.0036 mol) methyl acetate
derivatives 7 (0.001 mol) water (2 cm3) and methanol
(10 cm3) was re¯uxed for 5 h. Then methanol was removed
under reduced pressure, water (20 cm3) was added to the
residue and solution lot was adjusted to pH<2 to precipi-
tated crude acids 6. The compounds 6 were puri®ed by
crystallisation.
2-(4-Methoxyphenyl)-3-phenyl-2,3-dihydro-1H-isoindol-
1-on-3-acetic acid 6a. Yield 98%, mp 1928C (decomp.,
crystallised from methanol/water 1:1), identical to that
made by other route.
Methyl
3-(4-chlorophenyl)-4-methoxy-2-phenyl-2,3-
dihydro-1H-isoindol-1-on-3-acetate 7d. Yield 60%, mp
164±1678C (crystallised from ethyl acetate/hexane 1:1);
(Found: C, 68.5; H, 4.6; Cl, 8.7; N, 3.4: Calcd for
C24H20ClNO4: C, 68.33; H, 4.78; Cl, 8.40; N, 3.32%);
4-Methoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-on-3-
acetic acid 6c. Yield 97%, mp 1858C (decomp., crystallised
from ethyl acetate/methanol 6:1); (Found: C, 69.0; H, 5.1;
N, 4.6: Calcd for C17H15NO4: C, 68.68; H, 5.09; N, 4.71%);
n
max(KBr)/cm21 1750 and 1710 (CO); dH(CDCl3) 7.65±
7.45 (2H, m, 6-H and 7-H), 7.35±6.89 (10H, m, 5-H, Ar
and Ph), 3.85 (1H, d Jˆ14.6 Hz, CH2), 3.71 (3H, s, OMe),
3.38 (3H, s, OMe), 3.23 (1H, d Jˆ14.6 Hz, CH2).
n
max(KBr)/cm21 1740 and 1650 (CO); dH(DMSO-d6)
12.30±11.90 (1H, br s, OH), 7.80±7.08 (8H, m, 5-H, 6-H,
7-H and Ph), 5.63±5.55 (1H, m, CH), 3.80 (3H, s, OMe),
2.80 (1H, dd Jˆ15.9 and 3.9 Hz, CH2), 2.59 (1H, dd Jˆ15.9
and 4,9 Hz, CH2).
Methyl 7-methoxy-2-phenyl-2,3-dihydro-1H-isoindol-1-
on-3-acetate 7e. Yield 80%, mp 129±1328C (crystallised
from benzene/hexane 1:2); (Found: C, 69.7 H, 5.5 N, 4.51
Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50%);
7-Methoxy-2,3-diphenyl-2,3-dihydro-1H-isoindol-1-on-
3-acetic acid 6f. Yield 97%, mp 2398C (decomp., crystal-
lised from methanol/water 1:2), identical to that made by
other route.
n
max(KBr)/cm21 1750 and 1690 (CO); dH(CDCl3) 7.64±
6.86 (8H, m, 4-H, 5-H, 6-H and Ph), 4.51 (1H, dd Jˆ8.5
and 4.1 Hz, CH), 3.98 (3H, s, OMe), 3.63 (3H, s, OMe), 2.89

J. Epsztajn et al. / Tetrahedron 56 (2000) 4837±4844
4843
3-(4-Chlorphenyl)-7-methoxy-2-phenyl-2,3-dihydro-1H-
isoindol-1-on-3-acetic acid 6g. Yield 94%, mp 2488C
(decomp., crystallised from methanol/water 2:1), identical
to that made by other route.
ethyl acetate 3:1), mp 264±2688C (crystallised from ethyl
acetate), identical to that made by other route.
Acknowledgements
7-Methoxy-2-(4-methoxyphenyl)-3-phenyl-2,3-dihydro-
1H-isoindol-1-on-3-acetic acid 6h. Yield 90%, mp 2108C
(decomp., crystallised from methanol/water 2:1), identical
to that made by other route.
This work was supported by Grant in Aid for Scienti®c
Research [No. 505/610 (1998) and 505/278 (1999)] from
 Â
the University of èodz and a Grant from the Polish State
Committee for Scienti®c Research (KBN) that is gratefully
acknowledged.
Cyclization of acetic acid derivatives 6 into isoindolo[2,1-
a]quinoline-5,11-dione system 5
References
To isoindolinone acetic acid 6 (0.001 mol) were added
oxalyl chloride (0.76 g, 0.006 mol) and 1,2-dichloroethane
(5 cm3). The mixture was stirred and gently re¯uxed for
0.3 h. The excess of oxalyl chloride was removed under
reduced pressure. Then 1,2-dichloroethane (5 cm3) and
aluminium chloride (0.40 g, 0.003 mol) were added and
the mixture was gently re¯uxed for 2 h. The mixture was
cooled to room temperature and water (5 cm3) was added.
The obtained mixture was adjusted (HCl) to pH<2. The
organic layer was separated and the solvents were removed
under reduced pressure. Then acetone (20 cm3) potassium
carbonate (0.28 g, 0.002 mol) and methyl iodide (0.29 g,
0.002 mol) were added to the residue and the mixture was
re¯uxed for 10 h. The solvent was removed under reduced
pressure and to resulting residue was added chloroform
(10 cm3). Then the precipitate was separated and washed
with chloroform (3£5 cm3). The ®ltrate was concentrated
and products 5 were separated by column chromatography
and puri®ed by crystallisation.
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heptane 1:1); (Found: C, 72.9 H, 4.7, N; 4.9; Calcd for
C17H13NO3: C, 73.11; H, 4.69; N, 5.02%); nmax(KBr)/
cm21 1710 and 1680 (CO); dH(CDCl3) 8.58±8.46 (1H, m,
1-H), 8.10±8.02 (1H, m, 4-H), 7.73±7.42 (3H, m, 2-H, 9-H
and 10-H), 7.30±7.06 (2H, m, 3-H and 8-H), 5.26 (1H, dd
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quinoline-5,11-dione 5h. Yield 57%, Rfˆ0.51 (chloroform/

4844
J. Epsztajn et al. / Tetrahedron 56 (2000) 4837±4844
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