Regioselective Reduction of 2-(Arylideneamino)isoindole-1,3-diones - Synthesis of Alkaloid Analogues by N-Acylhydrazonium Ion Aromatic π-Cyclization

Article abstract of DOI:10.1002/ejoc.200300072

Hydroxylactams 6a-c and 7a-c were synthesized by successive regioselective reductions of arylideneaminophthalimides 3a-c, which were easily available from aminophthalimide 1 and benzaldehyde (2a) or thiophenecarboxaldehydes 2b and 2c. N-Acylhydrazonium io

Full text of DOI:10.1002/ejoc.200300072

FULL PAPER
Regioselective Reduction of 2-(Arylideneamino)isoindole-1,3-diones ؊ Synthesis
of Alkaloid Analogues by N-Acylhydrazonium Ion Aromatic π-Cyclization
[a]
[a]
[a]
[a]
¨
¨
Alain Fogain-Ninkam, Adam Daıch, Bernard Decroix, and Pierre Netchitaılo*
Keywords: Alkaloids / Cyclization / Nitrogen heterocycles / Reduction
Hydroxylactams 6a−c and 7a−c were synthesized by succes-
isoindolo-phthalazines 10a and 11a and thienopyridazino-
sive regioselective reductions of arylideneaminophthalim- isoindolones 12b and 12c. On the other hand, hydroxylac-
ides 3a−c, which were easily available from aminophthalim-
ide 1 and benzaldehyde (2a) or thiophenecarboxaldehydes
2b and 2c. N-Acylhydrazonium ions III, generated in the
presence of Lewis acid from acetoxy derivatives 8a and 9a of
hydroxylactams 6a and 7a, or in organic acid medium dir-
ectly from hydroxylactams 6b and 6c, induced the expected
tams 7b and 7c under acidic conditions gave the unexpected
N-thienylmethyl-substituted thienopyridazino-isoindolones
13b and 13c.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
analogues of cocaine, and (nor-)azatropanes, by the Spe-
ckamp group,[5] or alkaloids with the phenanthro-quinolizi-
dine skeleton.[6] Tetracyclic compounds depicted in the pre-
sent paper have the ϪCOϪNϪNϪ structural feature com-
mon to several tetracyclic molecules such as diphthalazine-
diones, which present analgesic and antiinflammatory
activities.[7]
In the course of our investigations concerning the syn-
thesis of analogues of tetracyclic alkaloids containing an
isoindole moiety, such as nuevamine, we have recently de-
scribed the synthesis of fused oxazino-isoindolones I
(Scheme 1).[1]
Results and Discussion
As indicated in Scheme 2, our strategy involved the for-
mation of hydroxy lactams 6 and 7 from aryliminophthal-
imides 3, easily available through condensation of aminoph-
thalimide and aromatic aldehydes. As hydroxylactams 6 and
7 could generate the N-acylhydrazoniums ions III under
acidic conditions,[8] ring closure could occur through an in-
Scheme 1
The cyclization step was an intramolecular carbonϪ
carbon bond formation involving an N-acyliminium ion
and a π-aromatic system. Examples of this reaction have
been reviewed by Speckamp,[2] while we have previously re-
ported the synthesis of isoindolo-dibenzazepine[3] and vari-
ous diaza heterocycles[4] by this process. As a further devel-
opment of our research, we described there the synthesis of
tetracyclic systems containing a pyridazino-isoindole moi-
ety II, based on an amidoalkylation step with use of an N-
acylhydrazonium ion. Such intermediates have previously
been employed to synthesize cyclic hydrazides, cyclic hy-
drazino acid derivatives, bridged bicyclic hydrazines aza
[a]
´
Universite du Havre, URCOM, EA 3221, UFR des Sciences
et Techniques
25 Rue Philippe Lebon, BP540, 76058 Le Havre Cedex, France
Fax: (internat.) ϩ 33-2-32744391
Email: pierre.netchitailo@univ-lehavre.fr
Scheme 2
Eur. J. Org. Chem. 2003, 4273Ϫ4278
DOI: 10.1002/ejoc.200300072
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4273

A. Fogain-Ninkam, A. Da¨ıch, B. Decroix, P. Netchita¨ılo
FULL PAPER
tramolecular α-heteroamido-alkylation reaction to provide conditions starting from acetoxylactams.[13] Accordingly,
II.
hydroxylactams 6a and 7a were acetylated with acetic anhy-
The 2-arylideneaminophthalimides 3aϪc were produced dride in CH2Cl2 in the presence of DMAP to provide ace-
by condensations between N-aminophthalimide (1) and toxylactams 8a and 9a. Treatment of these with three equiv-
benzaldehyde (2a), thiophene-2-carboxaldehyde (2b), or alents of SnCl4 in CH2Cl2 at room temperature provided
thiophene-3-carboxaldehyde (2c) in good yields of up to the expected isoindolo-phthalazines 10a and 11a in moder-
80% (Scheme 3). Some attempts to reduce both hydrazone ate yields (65 and 58%, respectively, Scheme 4). Treatment
and imide functions in the same time failed. Use of various of hydroxylactams 6b and 6c under the organic acid con-
hydrides such as BH3 or DIBAH gave complex mixtures of ditions described above afforded N-methyl pyridazino-iso-
partially reduced compounds, while that of LiAlH4 resulted indolones 12b and 12c. Since it has been demonstrated that
in the opening of the phthalimide ring. In addition, NaBH4, α-chloroalkylamine can serve as an N-acyliminium ion
which reduces phthalimide derivatives to give hydroxyisoin- source, the cyclization reaction was examined in the pres-
dolones[1,4] and reduces α-nitrohydrazones,[9] did not affect ence of SOCl2. All these distinct conditions produced only
here the hydrazone function. Regioselective reduction of the variation in the reaction yield. The best results (81 and 85%
hydrazone function was accomplished by use of NaBH3CN, yields for 12b and 12c, respectively) were obtained by use
which had been already used in the reductive methylation of a catalytic amount of p-toluenesulfonic acid diluted in
of hydrazones.[10,11] The reduction takes place in a continu- CH2Cl2.
ously buffered (pH 3Ϫ5) solution of the hydride and form-
The structures of these compounds were confirmed by
1
aldehyde (method A), through the addition of a methanolic spectroscopic data and microanalysis. For instance, the H
solution of hydrochloric acid. Thus, N-methylhydrazines NMR spectra of 12b and 12c each revealed the presence of
4aϪc were isolated in satisfactory yields of 63 to 68%. In a singlet at δ ϭ 5.7Ϫ5.8, corresponding to the isoindolic
the absence of formaldehyde (method B) we obtained sim- proton 11b, and two doublets of an AB system for the
ple reduction compounds 5aϪc in good yields of 68 to 74%. methylene group, due to the diastereotopic effect with a
As described previously, treatment of 4aϪc and 5aϪc with coupling constant J ϭ 15Ϫ17 Hz characteristic of gem pro-
NaBH4 in methanolic solution at 5 °C produced hy- tons. In addition, the thiophene protons appeared as two
droxylactams 6aϪc and 7aϪc, respectively, in good yields doublets with a coupling constant characteristic of a 2,3-
of up to 70%.
disubstituted thiophene ring. Surprisingly, cyclization of hy-
droxylactams 7b and 7c afforded not unsubstituted pyridaz-
ino-isoindolones, but N-thienylmethyl-substituted com-
pounds 13b and 13c. The structures of 13b and 13c were
confirmed by an array of mono- and bidimensional NMR
experiments (homodecoupling, 1H-13C heterocorrelation,
DEPT). The key feature was the appearance of an ad-
ditional methylene, appearing as a doublet of doublets in
1
each H NMR spectrum and as one signal in the aliphatic
region and four additional peaks in the aromatic region of
each 13C NMR spectrum. Whatever the acidic conditions,
the cyclization reaction invariably occurred to give N-sub-
stituted 13b and 13c. The best results here were obtained
by use of pure trifluoroacetic acid (41 and 42% yields for
13b and 13c, respectively). As thioalkyl N-acyliminium ions
could rearrange via cyclic sulfenium intermediates,[14] the
reaction sequence shown in Scheme 5 may be proposed as
a mechanism for the formation of 13b and 13c starting from
the N-acylhydrazonium ion intermediate III.
Scheme 3
The reaction takes place through an unstable diaziridi-
nium ion IV (Scheme 5), which rearranges through a π cat-
Cyclization of compounds 6 and 7 in acidic medium ionic cyclization in the case of all benzo derivatives and N-
takes place through the generation of N-acylhydrazonium methylthieno derivatives to give the expected pyridazines
ions, which react with the aromatic systems. Actually, pre- 10, 11, and 12. In contrast, the formation of N-thienylme-
vious investigations into the production of N-acyliminium thyl-substituted thienopyridazino-isoindolones 13b and 13c
ions in our laboratory have shown that various organic ac- could be followed by transformation of IV into the diazirid-
ids such as p-toluenesulfonic acid, formic acid, or trifluoro- ine V and the formation of a thienylmethyl ion, which
acetic acid (pure or diluted in CH2Cl2) could give satisfac- would be trapped by the thienopyridazino-isoindolone VI.
tory results.[1,12] Treatment of hydroxylactams 6a and 7a un- It may be noted that we have previously reported the cleav-
der acidic conditions produced only complex mixtures of age of a benzyl CϪO bond of a 2-(benzyloxy)isoindolone
insoluble polymerized material. In contrast, cyclization oc- in acidic medium.[15] Unfortunately, those attempts to iso-
curred on treatment with SnCl4 under typical Lewis acid late V failed. Only insoluble, unidentified material was reco-
4274
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4273Ϫ4278

Regioselective Reduction of 2-(Arylideneamino)isoindole-1,3-diones
FULL PAPER
Scheme 4
Scheme 5
Eur. J. Org. Chem. 2003, 4273Ϫ4278
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4275

A. Fogain-Ninkam, A. Da¨ıch, B. Decroix, P. Netchita¨ılo
FULL PAPER
ppm. 13C NMR: δ ϭ 123.7, 125.3, 126.8, 130.3, 130.6, 134.5, 137.1,
153.6, 165.0 ppm. C13H8N2O2S (256.28): calcd. C 60.93, H 3.15, N
10.93; found C 61.07, H 3.29, N 10.82.
vered during the purification steps for 13b and 13c. The fact
that the yields of the syntheses of 13b and 13c were good
(41 and 42%; 50% theoretical) strongly suggests that the
polymerized material originates from V rather than directly
from 13b and 13c.
Typical Procedure for Reductive Methylation of 3aϪc (Method A):
Bromocresol green (2 drops) and NaBH3CN (10 mmol, portion-
wise) were added at 10 °C to a cooled, stirred solution of 3aϪc
(2 mmol) and formaldehyde (5 mmol of a 37% aqueous solution)
in methanol (35 mL). During the addition, the solution was main-
tained at an acidic pH by addition of a methanolic HCl solution
(2M). After stirring at room temperature for an additional 2 h, the
mixture was quenched with saturated aqueous NaHCO3 solution
(25 mL) and the methanol was evaporated. The mixture was ex-
tracted twice with CH2Cl2 (50 mL), and the combined organic lay-
ers were washed with saturated NaHCO3 solution (50 mL) and
water (50 mL) and then dried with Na2SO4 prior to concentration
and chromatography (CH2Cl2/EtOAc, 95:5).
Conclusion
We have described the synthesis of aryliminophthalim-
ides from easily available aromatic carboxaldehydes and N-
aminophthalimide. Consecutive regioselective reduction of
imine and carbonyl functions of aryliminophthalimides and
generation of N-acylhydrazonium ions in acidic medium
can easily provide isoindolobenzopyridazines and thienopy-
ridazino-isoindolones.
2-[Benzyl(methyl)amino]phthalimide (4a): Chromatographic purifi-
cation of the crude product obtained from 3a afforded a white solid
1
(0.34 g, 63%), m.p. 93Ϫ95 °C. IR: ν˜max ϭ 1776 cmϪ1. H NMR:
Experimental Section
δ ϭ 3.04 (s, 3 H), 4.38 (s, 2 H), 7.18 (m, 3 H), 7.35 (m, 2 H),
7.59Ϫ7.71 (m, 4 H) ppm. 13C NMR: δ ϭ 43.3, 60.6, 123.1, 127.7,
128.3, 129.1, 129.9, 134.1, 136.3, 167.1 ppm. C16H14N2O2 (266.30):
calcd. C 72.17, H 5.30, N 10.52; found C 72.01, H 5.45, N 10.71.
General Remarks: Analytical thin layer chromatography was per-
formed on precoated plates of silica gel 60 F 254 (Merck) and col-
umn chromatography on Merck silica gel 60F (70Ϫ300 mesh). The
melting points were determined on a Leitz hot plate apparatus and
were uncorrected. The infrared spectra of solids (KBr) were re-
corded on a PerkinϪElmer FTIR paragon 1000 spectrometer. The
1H and 13C NMR spectra were recorded on a Bruker AC 200 in-
strument in CDCl3 as solvent, except in the cases of compounds
13b and 13c ([D6]DMSO), and chemical shifts (δ) are expressed in
2-[Methyl(thien-2Ј-ylmethyl)amino]phthalimide (4b): Chromato-
graphic purification of the crude product obtained from 3b af-
forded a white solid (0.36 g, 67%), m.p. 138Ϫ140 °C. IR: ν˜max
ϭ
1722 cmϪ1 1H NMR: δ ϭ 3.07 (s, 3 H), 4.57 (s, 2 H), 6.77 (dd,
.
J ϭ 3.2, 5.0 Hz, 1 H), 6.91 (dd, J ϭ 1.3, 3.2 Hz, 1 H), 7.13 (dd,
J ϭ 1.3, 5.0 Hz, 1 H), 7.63Ϫ7.74 (m, 4 H) ppm. 13C NMR: δ ϭ
43.3, 54.5, 123.1, 126.0, 126.3, 127.3, 129.9, 138.7, 166.9 ppm.
C14H12N2O2S (272.33): calcd. C 61.75, H 4.44, N 10.29; found C
61.96, H 4.17, N 10.05.
1
ppm relative to residual CHCl3 at δ ϭ 7.27 for H and δ ϭ 77.16
for 13C. The elemental analyses of final compounds were carried
out by the microanalysis laboratory of INSA, Mont-Saint-Aig-
nan, France.
2-[Methyl(thien-3Ј-ylmethyl)amino]phthalimide (4c): Chromato-
graphic purification of the crude product obtained from 3c afforded
a white solid (0.37 g, 68%), m.p. 111Ϫ113 °C. IR: ν˜max ϭ 1714
2-Benzylideneaminophthalimide (3a): A stirred solution of 1 (3.2 g,
0.02 mol) and benzaldehyde (2a, 3.18 g, 0.03 mol) in EtOH (50 mL)
was heated at reflux for 6 h and was then allowed to come slowly
to 0 °C. The solid that precipitated was filtered and recrystallized
from ethanol to give a pale-yellow solid (4.25 g, 86%), m.p.
162Ϫ165 °C. IR: ν˜max ϭ 1775 cmϪ1. 1H NMR: δ ϭ 7.45 (m, 3 H),
7.76 (m, 2 H), 7.90 (m, 4 H), 9.38 (s, 1 H) ppm. 13C NMR: δ ϭ
123.7, 128.3, 128.7, 130.2, 131.6, 133.5, 134.6, 158.5, 165.0 ppm.
C15H10N2O2 (250.26): calcd. C 71.99, H 4.03, N 11.19; found C
71.76, H 4.17, N 11.28.
cmϪ1 1H NMR: δ ϭ 3.04 (s, 3 H), 4.39 (s, 2 H), 7.08 (m, 1 H),
.
7.15 (m, 2 H), 7.62 (m, 2 H), 7.70 (m, 2 H) ppm. 13C NMR: δ ϭ
43.3, 55.1, 123.0, 123.9, 125.7, 128.2, 129.8, 134.1, 137.1, 167.0
ppm. C14H12N2O2S (272.33): calcd. C 61.75, H 4.44, N 10.29;
found C 61.66, H 4.22, N 10.38.
Typical Procedure for Reduction of 7aϪc (Method B): This method
was identical to method A except that formaldehyde was omitted.
The crude product was recrystallized from ethanol.
2-(Thien-2Ј-ylideneamino)phthalimide (3b): A stirred solution of 1
(2 g, 0.012 mol) and thiophene-2-carboxaldehyde (2b, 1.2 g, 0.014
mol) and a catalytic amount of p-toluenesulfonic acid in toluene
(40 mL) was heated at reflux for 4 h. The solvent was evaporated
and the residue was recrystallized from EtOH to afford a yellow
2-(N-Benzylamino)phthalimide (5a): Recrystallization of the crude
product obtained from 3a afforded a colorless solid (0.35 g, 69%),
1
m.p. 103Ϫ105 °C. IR: νmax ϭ 1712 cmϪ1. H NMR: δ ϭ 4.18 (d,
˜
J ϭ 5.9 Hz, 2 H), 4.78 (t, J ϭ 5.9 Hz, 1 H, NH), 7.27 (m, 3 H),
7.42 (m, 2 H), 7.69 (m, 2 H), 7.80 (m, 2 H) ppm. 13C NMR: δ ϭ
55.2, 123.2, 128.0, 128.5, 129.2, 130.1, 134.2, 135.9, 166.3 ppm.
C15H12N2O2 (252.28): calcd. C 71.42, H 4.79, N 11.10; found C
71.59, H 4.68, N 11.23.
1
solid (2.55 g, 83%), m.p. 159Ϫ161 °C. IR: ν˜max ϭ 1729 cmϪ1. H
NMR: δ ϭ 7.11 (dd, J ϭ 3.7, 4.8 Hz, 1 H), 7.49 (m, 2 H), 7.77 (m,
2 H), 7.87 (m, 2 H), 9.50 (s, 1 H) ppm. 13C NMR: δ ϭ 123.7, 127.6,
130.3, 130.6, 132.9, 134.6, 138.5, 152.7, 164.9 ppm. C13H8N2O2S
(256.28): calcd. C 60.93, H 3.15, N 10.93; found C 60.69, H 3.33,
N 11.12.
2-(Thien-2Ј-ylmethylamino)phthalimide (5b): Recrystallization of
the crude product obtained from 3b afforded a colorless solid
(0.38 g, 74%), m.p. 159Ϫ161 °C. IR: ν˜max ϭ 1719 cmϪ1. 1H NMR:
δ ϭ 4.45 (s, 2 H), 6.83 (dd, J ϭ 3.5, 5.1 Hz, 1 H), 7.00 (dd, J ϭ
1.0, 3.5 Hz, 1 H), 7.18 (dd, J ϭ 1.0, 5.1 Hz, 1 H), 7.60Ϫ7.71 (m, 4
2-(Thien-3Ј-ylideneamino)phthalimide (3c): This compound was ob-
tained as described above, with 5 and thiophene-3-carboxaldehyde
(2c) as starting materials, to give a pale yellow solid (2.6 g, 84%),
m.p. 166Ϫ168 °C. IR: ν˜max ϭ 1721 cmϪ1. 1H NMR: δ ϭ 7.36 (dd, H) ppm. 13C NMR: δ ϭ 52.9, 123.1, 126.0, 126.3, 127.3, 129.7,
J ϭ 2.9, 5.1 Hz, 1 H), 7.69 (dd, J ϭ 0.8, 5.1 Hz, 1 H), 7.74 (m, 2
134.0, 138.8, 166.8 ppm. C13H10N2O2S (258.30): calcd. C 60.45, H
H), 7.78 (dd, J ϭ 0.8, 2.9 Hz, 1 H), 7.88 (m, 2 H) 9.34 (s, 1 H) 3.90, N 10.85; found C 60.21, H 4.09, N 10.71.
4276
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4273Ϫ4278

Regioselective Reduction of 2-(Arylideneamino)isoindole-1,3-diones
FULL PAPER
2-(Thien-3Ј-ylmethylamino)phthalimide (5c): Purification of the
crude product obtained from 3c afforded a white solid (0.35 g,
141.8, 166.8 ppm. C15H14N2O2 (254.29): calcd. C 70.85, H 5.55, N
11.02; found C 70.77, H 5.29, N 10.87.
68%), m.p. 132Ϫ134 °C. IR: ν˜max ϭ 1718 cmϪ1 1H NMR: δ ϭ
.
3-Hydroxy-2-(thien-2Ј-ylmethylamino)-2,3-dihydro-1H-isoindol-1-
one (7b): This compound was obtained from 5b and was purified
by flash chromatography to afford a white solid (0.74 g, 71%), m.p.
4.47 (s, 2 H), 7.17 (m, 2 H), 7.21 (m, 1 H), 7.60 (m, 2 H), 7.65 (m,
2 H) ppm. 13C NMR: δ ϭ 43.3, 55.1, 123.0, 123.9, 125.7, 128.2,
129.8, 134.1, 137.1, 167.0 ppm. C13H10N2O2S (258.30): calcd. C
60.45, H 3.90, N 10.85; found C 60.30, H 4.15, N 10.62.
1
158Ϫ160 °C. IR: ν˜max ϭ 3352, 1672 cmϪ1. H NMR: δ ϭ 2.63 (d,
J ϭ 5.9 Hz, 1 H, OH), 4.40Ϫ4.90 (m, 2 H), 5.04 (d, J ϭ 5.9 Hz, 1
H), 6.87 (d, J ϭ 4.0 Hz, 1 H), 6.95 (m, 1 H), 7.21 (d, J ϭ 4.0 Hz,
1 H), 7.31Ϫ7.53 (m, 3 H), 7.73Ϫ7.77 (m, 1 H) ppm. 13C NMR:
δ ϭ 82.5, 82.9, 123.2, 125.6, 126.0, 126.7, 127.4, 129.6, 130.6, 132.5,
140.7, 141.6, 166.9 ppm. C13H12N2O2S (260.32): calcd. C 59.98, H
4.65, N 10.76; found C 60.11, H 4.45, N 10.55.
Typical Procedure for the Synthesis of Hydroxylactams 6aϪc and
7aϪc: NaBH4 (4 mmol in the cases of 4a and 5a or 10 mmol in the
cases of 4b, 4c, 5b, and 5c) was added portionwise at 5 °C to a
stirred solution of 4 or 5 (4 mmol) in methanol (40 mL). The mix-
ture was stirred at 5 °C for 4 h and was then acidified to pH ϭ 4
with dilute HCl. The solvent was evaporated and the residue was
hydrolyzed with cold water (20 mL). The aqueous phase was ex-
tracted with CH2Cl2 (3 ϫ 20 mL) and discarded. The organic layer
was washed with brine, dried, and concentrated. The residue was
purified by flash chromatography with cyclohexane/EtOAc (1:1)
as eluent.
3-Hydroxy-2-(thien-3Ј-ylmethylamino)-2,3-dihydro-1H-isoindol-1-
one (7c): The crude product obtained from 5c was purified by flash
chromatography to afford a white solid (0.76 g, 73%), m.p.
1
130Ϫ132 °C. IR: ν˜max ϭ 3235, 1672 cmϪ1. H NMR: δ ϭ 2.09 (d,
J ϭ 7.5 Hz, 1 H, OH), 4.10Ϫ4.75 (m, 2 H), 4.81 (d, J ϭ 7.5 Hz, 1
H), 7.10Ϫ7.32 (m, 3 H), 7.42Ϫ7.49 (m, 3 H), 7.70Ϫ7.75 (m, 1 H)
ppm. 13C NMR: δ ϭ 82.5, 82.9, 123.2, 125.6, 126.0, 126.7, 127.4,
129.6, 130.6, 132.5, 140.7, 141.6, 166.9 ppm. C13H12N2O2S
(260.32): calcd. C 59.98, H 4.65, N 10.76; found C 59.88, H 4.51,
N 10.49.
2-[Benzyl(methyl)amino]-3-hydroxy-2,3-dihydro-1H-isoindol-1-one
(6a): The crude product obtained from 4a was purified by flash
chromatography to afford colorless needles (0.84 g, 78%), m.p.
1
100Ϫ102 °C. IR: ν˜max ϭ 3320, 1665 cmϪ1. H NMR: δ ϭ 2.77 (d,
J ϭ 6.4 Hz, 1 H, OH), 3.07 (s, 3 H), 4.29 (d, J ϭ 12.4 Hz, 1 H),
4.47 (d, J ϭ 12.4 Hz, 1 H), 5.24 (d, J ϭ 6.4 Hz, 1 H), 7.20Ϫ7.29
(m, 3 H), 7.32Ϫ7.40 (m, 3 H), 7.44Ϫ7.55 (m, 2 H), 7.68Ϫ7.74 (m,
1 H) ppm. 13C NMR: δ ϭ 43.6, 60.4, 82.0, 123.0, 123.2, 127.7,
128.4, 129.5, 129.7, 131.0, 132.3, 137.5, 141.6, 166.5 ppm.
C16H16N2O2 (268.32): calcd. C 71.62, H 6.01, N 10.44; found C
71.79, H 5.82, N 10.29.
3-Acetyloxy-2-[benzyl(methyl)amino]-2,3-dihydro-1H-isoindol-1-one
(8a): DMAP (3.5 mmol) and acetic anhydride (2.5 mmol) were ad-
ded under inert atmosphere to a solution of hydroxylactam 6a
(2.3 mmol) in CH2Cl2 (25 mL). The mixture was stirred at room
temperature for 20 h and was then washed successively with 20 mL
saturated aqueous NaHCO3, water, 5% HCl and water. After dry-
ing, the solvent was evaporated and purification of the residue by
column chromatography with a CH2Cl2/acetone mixture (98:2) as
eluent gave a white solid (0.55 g, 77%), m.p. 86Ϫ88 °C. IR: ν˜max ϭ
1726 cmϪ1. 1H NMR: δ ϭ 2.08 (s, 3 H), 2.97 (s, 3 H), 4.24 (d, J ϭ
12.5 Hz, 1 H), 4.50 (d, J ϭ 12.5 Hz, 1 H), 6.60 (s, 1 H), 7.22Ϫ7.36
(m, 5 H), 7.45Ϫ7.52 (m, 3 H), 7.71Ϫ7.77 (m, 1 H) ppm. 13C NMR:
δ ϭ 21.1, 42.7, 60.5, 81.7, 123.1, 123.7, 127.5, 128.3, 129.1, 130.1,
131.2, 132.5, 137.3, 139.6, 167.1, 170.8 ppm. C18H18N2O3 (310.36):
calcd. C 69.66, H 5.85, N 9.03; found C 69.79, H 5.69, N 9.17.
3-Hydroxy-2-[methyl(thien-2Ј-ylmethyl)amino]-2,3-dihydro-1H-
isoindol-1-one (6b): This compound was obtained from 4b and was
purified by flash chromatography to afford a white solid (0.82 g,
1
75%), m.p. 147Ϫ149 °C. IR: ν˜max ϭ 2991, 1713 cmϪ1. H NMR:
δ ϭ 3.05 (s, 3 H), 3.86 (d, J ϭ 5.4 Hz, 1 H, OH), 4.36 (d, J ϭ
13.4 Hz, 1 H), 4.74 (d, J ϭ 13.4 Hz, 1 H), 5.38 (d, J ϭ 5.4 Hz, 1
H), 6.82 (dd, J ϭ 3.2, 4.9 Hz, 1 H), 6.91 (dd, J ϭ 1.0, 3.2 Hz, 1
H), 7.16 (dd, J ϭ 1.0, 4.9 Hz, 1 H), 7.39Ϫ7.50 (m, 3 H), 7.61Ϫ7.73
(m, 1 H) ppm. 13C NMR: δ ϭ 43.4, 54.4, 82.2, 123.0, 123.5, 125.4,
126.5, 127.3, 129.6, 130.9, 132.3, 140.2, 141.1, 166.5 ppm.
C14H14N2O2S (274.34): calcd. C 61.29, H 5.14, N 10.21; found C
61.55, H 5.01, N 10.05.
3-Acetyloxy-2-(benzylamino)-2,3-dihydro-1H-isoindol-1-one
(9a):
This compound was obtained from 7a by the same procedure as
described above. Purification of the residue by column chromatog-
raphy with a CH2Cl2/acetone mixture (98:2) as eluent gave a white
solid (0.48 g, 71%), m.p. 90Ϫ92 °C. IR: ν˜max ϭ 1713 cmϪ1 1H
.
3-Hydroxy-2-[methyl(thien-3Ј-ylmethyl)amino]-2,3-dihydro-1H-
isoindol-1-one (6c): The crude product obtained from 4c was puri-
fied by flash chromatography to afford a white solid (0.82 g, 75%),
NMR: δ ϭ 2.05 (s, 3 H), 4.13 (dd, J ϭ 5.5, 11.7 Hz, 1 H), 4.26
(dd, J ϭ 5.5, 11.7 Hz, 1 H), 5.83 (t, J ϭ 5.5 Hz, 1 H), 6.82 (s, 1
H), 7.26Ϫ7.43 (m, 5 H), 7.45Ϫ7.57 (m, 3 H), 7.78Ϫ7.80 (m, 1 H)
ppm. 13C NMR: δ ϭ 21.0, 55.0, 81.5, 123.4, 123.9, 127.6, 128.5,
129.1, 130.5, 132.8, 137.1, 139.6, 167.1, 170.7 ppm. C17H16N2O3
(296.33): calcd. C 68.91, H 5.44, N 9.45; found C 69.17, H 5.59,
N 9.58.
m.p. 133Ϫ136 °C. IR: ν˜max ϭ 3322, 1681 cmϪ1 1H NMR: δ ϭ
.
3.04 (s, 3 H), 3.70 (d, J ϭ 7.2 Hz, 1 H, OH), 4.19 (d, J ϭ 12.6 Hz,
1 H), 4.53 (d, J ϭ 12.6 Hz, 1 H), 5.25 (d, J ϭ 7.2 Hz, 1 H),
7.10Ϫ7.20 (m, 3 H), 7.36Ϫ7.54 (m, 3 H), 7.66Ϫ7.69 (m, 1 H) ppm.
13C NMR: δ ϭ 43.6, 54.6, 82.1, 123.3, 124.2, 125.7, 126.1, 128.4,
129.6, 130.9, 132.3, 138.1, 141.8, 166.5 ppm. C14H14N2O2S
(274.34): calcd. C 61.29, H 5.14, N 10.21; found C 61.20, H 5.05,
N 10.14.
6-Methyl-5,12b-dihydroisoindolo[1,2-a]phthalazin-8-one
(10a):
SnCl4 (5.7 mmol) was added dropwise under inert conditions to a
solution of 8a (1.9 mmol) in CH2Cl2 (20 mL) and the mixture was
heated at reflux for 24 h. The reaction was quenched with saturated
aqueous NaHCO3 (20 mL) and the organic layer was washed twice
with water (20 mL). After drying, the solvent was evaporated, and
purification of the residue by flash column chromatography with a
2-(Benzylamino)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (7a): The
crude product obtained from 5a was purified by flash chromatogra-
phy to afford a white solid (0.75 g, 74%), m.p. 124Ϫ126 °C. IR:
1
ν˜max ϭ 3268, 1656 cmϪ1. H NMR: δ ϭ 3.38 (d, J ϭ 7.0 Hz, 1 H, CH2Cl2/acetone mixture (95:5) as eluent gave a white solid (0.31 g,
1
OH), 4.15 (d, J ϭ 12.4 Hz, 1 H), 4.24 (d, J ϭ 12.4 Hz, 1 H), 4.90
(s, 1 H, NH), 5.50 (d, J ϭ 7.0 Hz, 1 H), 7.28Ϫ7.40 (m, 5 H),
65%), m.p. 94Ϫ96 °C. IR: ν˜max ϭ 1698 cmϪ1. H NMR: δ ϭ 2.53
(s, 3 H), 3.46 (d, J ϭ 16.5 Hz, 1 H), 4.14 (d, J ϭ 16.5 Hz, 1 H),
7.45Ϫ7.57 (m, 3 H), 7.68Ϫ7.76 (m, 1 H) ppm. 13C NMR: δ ϭ 55.1, 5.40 (s, 1 H), 6.72Ϫ6.78 (m, 1 H), 6.86Ϫ7.19 (m, 3 H), 7.22Ϫ7.43
82.2, 123.3, 123.5, 127.8, 128.6, 129.1, 129.8, 130.3, 132.5, 137.4,
(m, 2 H), 7.53Ϫ7.57 (m, 2 H) ppm. 13C NMR: δ ϭ 41.5, 50.9, 55.2,
Eur. J. Org. Chem. 2003, 4273Ϫ4278
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4277

A. Fogain-Ninkam, A. Da¨ıch, B. Decroix, P. Netchita¨ılo
122.8, 123.3, 124.9, 126.6, 127.0, 127.1, 127.8, 128.9, 130.4, 130.9, 124.9, 126.0, 126.3, 126.4, 128.5, 130.0, 130.4, 131.4, 132.4, 140.2,
FULL PAPER
131.6, 142.5, 165.8 ppm. C16H14N2O (250.30): calcd. C 76.78, H
5.64, N 11.19; found C 76.59, H 5.69, N 11.31.
142.9, 165.4 ppm. C18H14N2OS2 (338.45): calcd. C 63.88, H 4.17,
N 8.28; found C 64.14, H 4.26, N 8.02.
5-(Thien-3-ylmethyl)-4,11b-dihydrothieno[2Ј,3Ј:4,5]pyridazino[3,2-
a]isoindol-7-one (13c): The same procedure as described above,
starting from 7c, gave a white solid (0.29 g, 85%), m.p. 184Ϫ186 °C.
IR: ν˜max ϭ 1693 cmϪ1. 1H NMR: δ ϭ 4.00 (dd, J ϭ 1.3, 16.7 Hz, 1
H), 4.17 (d, J ϭ 13.4 Hz, 1 H), 4.27 (d, J ϭ 13.4 Hz, 1 H), 4.40
(dd, J ϭ 2.4, 16.7 Hz, 1 H), 5.65 (s, 1 H), 6.82 (d, J ϭ 5.1 Hz, 1
H), 7.22Ϫ7.34 (m, 4 H), 7.38Ϫ7.48 (m, 1 H), 7.54Ϫ7.69 (m, 2 H),
7.80Ϫ7.89 (m, 1 H) ppm. 13C NMR: δ ϭ 52.0, 52.5, 54.0, 122.6,
122.9, 124.2, 124.8, 125.2, 125.7, 126.1, 127.6, 128.8, 130.7, 130.8,
132.3, 136.7, 142.6, 166.7 ppm. C18H14N2OS2 (338.45): calcd. C
63.88, H 4.17, N 8.28; found C 63.76, H 4.15, N 8.25.
5,12b-Dihydro-6H-isoindolo[1,2-a][2,3]phthalazin-8-one (11a): This
compound was obtained from 9a by the same procedure as de-
scribed above. After purification, a white solid (0.26 g, 58%) was
obtained, m.p. 200Ϫ202 °C. IR: ν˜max ϭ 1678 cmϪ1. 1H NMR: δ ϭ
3.96 (d, J ϭ 15.7 Hz, 1 H), 4.34 (d, J ϭ 15.7 Hz, 1 H), 5.73 (s, 1
H), 7.07 (m, 1 H), 7.16Ϫ7.22 (m, 1 H), 7.26Ϫ7.35 (m, 1 H),
7.41Ϫ7.50 (m, 1 H), 7.55Ϫ7.70 (m, 2 H), 7.81Ϫ7.87 (m, 2 H) ppm.
13C NMR: δ ϭ 49.8, 57.9, 123.2, 124.0, 126.0, 127.0, 127.3, 128.6,
131.2, 132.2, 132.7, 132.8, 143.5, 167.2 ppm. C15H12N2O (236.28):
calcd. C 76.25, H 5.12, N 11.86; found C 76.37, H 5.27, N 11.72.
5-Methyl-4,11b-dihydrothieno[3Ј,2Ј:4,5]pyridazino[3,2-a]isoindol-7-
one (12b): A solution of hydroxylactam 6b (2 mmol) and a catalytic
amount of PTSA in CH2Cl2 (15 mL) was heated at reflux for 8 h.
After cooling, the solution was washed with diluted NaHCO3
(15 mL) and water (15 mL) and then dried with Na2SO4. The sol-
vent was evaporated and the residue was recrystallized from etha-
nol to give a white solid (0.42 g, 82%), m.p. 181Ϫ183 °C. IR:
[1]
A. Bartovic, B. Decroix, P. Netchita¨ılo, J. Heterocyclic Chem.
2000, 37, 827Ϫ830.
[2]
W. N. Speckamp, M. J. Moolenaar, Tetrahedron 2000, 56,
3817Ϫ3856.
[3]
P. Pigeon, B. Decroix, Tetrahedron Lett. 1997, 38, 1041Ϫ1044.
M. Othman, P. Pigeon, P. Netchita¨ılo, A. Da¨ıch, B. Decroix,
[4]
ν˜max ϭ 1697 cmϪ1 1H NMR: δ ϭ 2.87 (s, 3 H), 3.93 (d, J ϭ
.
Heterocycles 2000, 52, 273Ϫ281.
[5] [5a]
F. P. J. T. Rutjes, H. Hiemstra, H. H. Mooiweer, W. N.
15.3 Hz, 1 H), 4.51 (d, J ϭ 15.3 Hz, 1 H), 5.71 (s, 1 H), 7.25 (m, 2
H), 7.42Ϫ7.49 (m, 1 H), 7.57Ϫ7.64 (m, 1 H), 7.69Ϫ7.76 (m, 1 H),
7.86Ϫ7.92 (m, 1 H) ppm. 13C NMR: δ ϭ 42.7, 52.5, 52.7, 123.1,
123.7, 124.4, 128.6, 130.4, 130.5, 130.7, 132.3, 142.5, 166.6 ppm.
C14H12N2OS (256.33): calcd. C 65.60, H 4.72, N 10.93; found C
66.33, H 4.55, N 11.09.
[5b]
Speckamp, Tetrahedron Lett. 1988, 29, 6975Ϫ 6978.
F. P.
J. T. Rutjes, N. M. Teerhuis, H. Hiemstra, W. N. Speckamp,
F. P. J. T. Rutjes, H.
Hiemstra, F. O. H. Pirrung, W. N. Speckamp, Tetrahedron
[5c]
Tetrahedron 1993, 49, 8605Ϫ8628.
[5d]
1993, 49, 10027Ϫ10048.
N. M. Teerhuis, H. Hiemstra, W.
[5e]
N. Speckamp, Tetrahedron Lett. 1997, 38, 159Ϫ162.
N. M.
Teerhuis, H. Hiemstra, W. N. Speckamp, Tetrahedron Lett.
1997, 38, 155Ϫ158.
5-Methyl-4,11b-dihydrothieno[2Ј,3Ј:4,5]pyridazino[3,2-a]isoindol-7-
one (12c): The same procedure as described above, starting from
[6]
[7]
[8]
H. Suzuki, S. Aoyagi, C. Kibayashi, J. Org. Chem. 1995, 60,
6c, gave a white solid (0.44 g, 85%), m.p. 178Ϫ180 °C. IR: ν˜max
ϭ
6114Ϫ6122.
1693 cmϪ1. H NMR: δ ϭ 2.97 (s, 3 H), 3.83 (d, J ϭ 16.7 Hz, 1
H), 4.37 (d, J ϭ 16.7 Hz, 1 H), 5.80 (s, 1 H), 6.80 (d, J ϭ 5.4 Hz,
1 H), 7.24 (d, J ϭ 5.4 Hz, 1 H), 7.41Ϫ7.51 (m, 1 H), 7.57Ϫ7.66
(m, 1 H), 7.68Ϫ7.74 (m, 1 H), 7.85Ϫ7.90 (m, 1 H) ppm. 13C NMR:
δ ϭ 43.1, 51.6, 53.9, 122.8, 123.3, 124.2, 124.6, 125.6, 128.8, 130.4,
130.8, 132.4, 142.6, 166.3 ppm. C14H12N2OS (256.33): calcd. C
65.60, H 4.72, N 10.92; found C 66.45, H 4.49, N 10.69.
1
V. Pestellini, M. Gellardoni, G. Volterra, P. Del Soldato, Eur.
J. Med. Chem. 1978, 13, 296.
H. Hiemstra, W. N. Speckamp, in Comprehensive Organic Syn-
thesis (Eds.: B. M. Trost, I. Fleming) Pergamon, Oxford, 1991,
2, 1047Ϫ1082.
S. E. Denmark, J. A. Stenberg, R. Luoend, J. Org. Chem. 1988,
53, 1251Ϫ1263.
R. F. Borch, M. D. Bernstein, H. D. Durst, J. Am. Chem. Soc.
1971, 93, 2897Ϫ2904.
S. F. Nelsen, G. R. Weisman, Tetrahedron Lett. 1973, 14,
2321Ϫ2324.
[9]
[10]
[11]
5-(Thien-2-ylmethyl)-4,11b-dihydrothieno[3Ј,2Ј:4,5]pyridazino[3,2-
a]isoindol-7-one (13b): A solution of hydroxy lactam 7b (2 mmol)
in TFA (12 mL) was stirred at room temperature for 7 h. After
evaporation of the acid, the residue was dissolved in CH2Cl2
(10 mL), washed with saturated aqueous NaHCO3 (12 mL) and
water (12 mL), and then dried with Na2SO4. The solvent was eva-
porated and the residue was recrystallized from ethanol to give a
[12] [12a]
A. Korenova, P. Netchita¨ılo, B. Decroix, J. Heterocyclic
[12b]
Chem. 1998, 35, 9Ϫ12.
P. Pigeon, M. Othman, P. Netchi-
ta¨ılo, B. Decroix, Tetrahedron 1998, 54, 1497Ϫ1506.
[13] [13a]
´
H. Dhimane, C. Vanucci-Bacque, L. Hamon, G. Lhommet,
[13b]
Eur. J. Org. Chem. 1998, 1955Ϫ1963.
E. Metais, L. E.
Overman, M. I. Rodriguez, B. A. Stears, J. Org. Chem. 1997,
white solid (0.28 g, 82%), m.p. 178Ϫ180 °C. IR: ν˜max ϭ 1694 cmϪ1
.
62, 9210Ϫ9216.
1H NMR: δ ϭ 4.01 (dd, J ϭ 1.0, 16.1 Hz, 1 H), 4.13 (d, J ϭ
13.7 Hz, 1 H), 4.27 (d, J ϭ 13.7 Hz, 1 H), 4.41 (dd, J ϭ 2.4,
16.1 Hz, 1 H), 5.66 (s, 1 H), 6.83 (d, J ϭ 5.2 Hz, 1 H), 7.23Ϫ7.34
(m, 3 H), 7.40Ϫ7.48 (m, 1 H), 7.54Ϫ7.70 (m, 3 H), 7.78Ϫ7.86 (m,
1 H) ppm. 13C NMR: δ ϭ 50.6, 52.3, 52.7, 123.2, 124.1, 124.8,
[14]
[15]
T. J. Dudley, I. P. Smolakovia, M. R. Hoffmann, J. Org. Chem.
1999, 64, 1247Ϫ1253.
A. Bartovic, B. Decroix, P. Netchita¨ılo, J. Heterocyclic Chem.
2000, 37, 827Ϫ830.
Received February 6, 2003
4278
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4273Ϫ4278