Synthesis of 3-alkyl-1-isoindolinones by alkylation of a benzotriazolyl substituted N-dimethylamino-phthalimidine

Article abstract of DOI:10.1016/S0040-4020(01)00073-4

A convenient and versatile synthesis of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones (isoindolinones) based upon sequential metalation, alkylation alpha to nitrogen and C,N-deprotection from 3-benzotriazolyl-2-dimethylamino-phthalimidine is described.

Full text of DOI:10.1016/S0040-4020(01)00073-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2581±2588
Synthesis of 3-alkyl-1-isoindolinones by alkylation of a
benzotriazolyl substituted N-dimethylamino-phthalimidine
²
Eric Deniau and Dieter Endersp
È È
Institut fur Organische Chemie, Rheinisch-Westfalische Technische Hochschule, Professor-Pirlet-Straûe 1, 52074 Aachen, Germany
Dedicated to Professor H. B. Kagan
Received 1 August 2000; accepted 2 October 2000
AbstractÐA convenient and versatile synthesis of 3-alkyl-2,3-dihydro-1H-isoindol-1-ones (isoindolinones) based upon sequential meta-
lation, alkylation alpha to nitrogen and C,N-deprotection from 3-benzotriazolyl-2-dimethylamino-phthalimidine is described. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
the presence of a carbonyl function and a benzylic position
adjacent to nitrogen in these sensitive models, which render
both connection and disconnection of the metalation
auxiliary problematic.
Functionalisation alpha to nitrogen in a number of acyclic
systems or saturated heterocycles has attracted considerable
attention over the years. Groups that have tackled this
challenge have adopted cation methodology1 or radical
chemistry,2 although methods based on carbanion chemistry
are still the most general routes for electrophilic substitution
alpha to nitrogen.3 This approach depicted in Scheme 1
provides a powerful general strategy for the elaboration of
amine derivatives by Umpolung (polarity inversion) of the
customary amine reactivity.4
In this general sequence a group G is connected to the amine
in order to facilitate the deprotonation step and avoid a
possible competitive metalation reaction at the nitrogen
atom. In general, this group must be stable towards strong
bases, must not interfere with the electrophilic substitution
and must be conveniently removed in the last step. Whereas
considerable efforts have been devoted to apply this strategy
to the synthesis of numerous mono- and bicyclic amines,
such as pyrrolidines, piperidines, indols or isoquinolines,
only a few papers report on the sequential alkylation of
compounds possessing an isoindol skeleton. To the best of
our knowledge, only tetrahydro derivatives 1 (XˆH) bear-
ing an oxazoline5 or a formamidine6 group have been
subjected to the complete deprotonation, alkylation, depro-
tection sequence. In the case of the corresponding lactams 2
(XˆO of carbonyl group) known as phthalimidines (2,3-
dihydro-1H-isoindol-1-ones or 1-isoindolinones) only the
®rst two steps have been exempli®ed,7 probably owing to
In recent years, 3-substituted-isoindolinones have elicited a
certain interest in the scienti®c community since they
represent the core unit of numerous naturally occurring
substances8 and several members belonging to this family
have shown interesting biological properties.9 For example,
piperazine derivatives 3 and indolocarbazoles 4 have been
recently reported to display a high af®nity for dopamine
receptors10 and proteine kinase activity, respectively.11
Paradoxically, in spite of extensive work in this ®eld, few
general methodologies have been developed to synthesize
these heterobicyclic compounds. Isoindolinones are acces-
sible by different chemical processes which include
(i) rearrangement of six membered rings.12 (ii) Elimination
reactions from 3,3-disubstituted compounds.13 (iii) The
Keywords: alkylation; benzotriazole; carbanions; hydrazines; lactams.
Corresponding author. Fax: 149-0-241-8888-127;
p
e-mail: enders@rwth-aachen.de
On leave from UST Lille 1 F-59655 Villeneuve d'Ascq Cedex.
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00073-4

2582
E. Deniau, D. Enders / Tetrahedron 57 (2001) 2581±2588
Scheme 1.
Scheme 2.
Parham protocol14 or more recently a carbocationic path-
way.15 but the most commonly employed synthetic
method16 involves, in the ®nal step, the construction of the
lactam unit from a elaborated benzenic precursor. However,
these methods are rather restricted in scope and do not
permit an ef®cient functionalisation at the three position
of the lactam ring.
carbanion formation alpha to nitrogen has been reported by
Grieco et al.,17 who have studied the functionalisation of the
pyrrol nucleus at C(2) position via a metalation pathway. On
the other hand, the choice of the dimethylamino group was
dictated by the properties of the N±N bond, present in these
N-acyl hydrazines (hydrazides), which is well known to be
cleaved under various conditions.18 This synthetic route
necessitated the preliminary elaboration of the lactam 7.
The synthesis of this N-amino lactam proved to be unex-
pectedly dif®cult. Indeed, in contrast to the known synthesis
of 2-alkyl or 2-aryl phthalimidines via different synthetic
pathways,19 elaboration of their 2-amino analogues seems
rather problematic. The condensation between differently
substituted hydrazines and a phthalide derivative20 or an
o-halogenomethylbenzoic acid ester21 has been reported,
but always in moderate yields. The lack of ef®ciency of
these synthetic approaches led us to investigate a new
reaction pathway depicted in Scheme 3. This new approach
is based on the chemoselective mono reduction of the
phthalimide 8 and involves, as the key step, the reduction
of the transient iminium ion 10.
2. Results and discussion
These different limitations led us to propose the following
retrosynthetic analysis (Scheme 2), in which the key step
consists in the sequential alkylation of the parent phthalimi-
dine 7 bearing an appropriate protecting group on the nitro-
gen atom of the lactam unit. This kind of strategy should
offer the potential advantage of facilitating incorporation of
substituents alpha to nitrogen within the heterocyclic ring
via 6 leading to the title compounds 5.
Critical to the success of our strategy was therefore to iden-
tify an auxiliary group, which would be suf®ciently robust to
survive the intended metalation step and would be also
labile enough to be removed in the ®nal step in order to
regenerate the lactam nucleus. This dual requirement
prompted us to incorporate the dimethylamino group in
the parent model 7. Indeed, the ability of this group to direct
We found that the imide 8, easily prepared by condensation
between phthalic anhydride and dimethylhydrazine,22 could
be readily reduced with NaBH4 to give the 3-hydroxy
derivative 9. Exposure of this N,O-hemiacetal to tri¯uoro-
acetic acid then induced the formation of the iminium salt
Scheme 3.

E. Deniau, D. Enders / Tetrahedron 57 (2001) 2581±2588
2583
Table 1. Sequential alkylation of 7
experiments by changing the solvent, the reaction time or
use of a metalation additive, were unrewarding. In addition,
a qualitative analysis of the methylation reaction (entry 2)
showed the presence of starting material 7 in the crude
reaction product, in addition to mono and dialkylated iso-
indolinones 6a and 13, respectively (Scheme 4), which
rendered puri®cation steps particularly problematic. These
results can be rationalized, in part, if we consider a possible
transmetalation reaction between the monomethylated
product 6a and the preliminary formed carbanion 11 to
give 12 faster than the alkylation step.
Entry
Compound
LHMDS (equiv.)
RX (equiv.)
Yield (%)
1
2
3
4
5
6
6a
6a
6a
6a
6b
6c
1.1
1.1
1.1
1.1
1.1
1.1
Me2SO4 (1.1)
MeBr (1.1)
MeI (1.1)
MeI (2.0)
EtI (1.1)
30
42
62
48
55
46
PrI (1.1)
10, which was reduced in situ with Et3SiH23 to afford the
desired 2-(dimethylamino)-isoindolinone 7 in a yield of
77% over two steps. In order to evaluate the in¯uence of
both stoichiometry and the nature of the electrophile on the
alkylation step, phthalimidine 7 was deprotonated under
optimized conditions with lithium hexamethyldisilazide
(LHMDS, 1.1 equiv./THF/2788C/15 min) and then
quenched by various alkyl halides (Scheme 3, Table 1).
Unfortunately, whatever conditions were used, the desired
alkylated products 6 were always obtained in low to
moderate yields.
In order to circumvent these dif®culties, we modi®ed the
pattern of our model without changing the strategy by
connecting a temporary protecting group X at the 3-position
of the phthalimidine nucleus via 15 and 14 as depicted in the
retrosynthetic Scheme 5.
To assure the viability of this new methodology, it was
necessary to ®nd a protecting group easily introduced,
compatible with the metalation conditions and most impor-
tantly, easy to remove in the ®nal step. Katritzky and co-
workers24 reported the regioselective lithiation of numerous
aminals at the methylene bridge linking an heterocyclic
While more reactive alkyl iodides permitted a slight
improvement in terms of yields (entries 1±3), further
Scheme 4.
Scheme 5.
Scheme 6.

2584
E. Deniau, D. Enders / Tetrahedron 57 (2001) 2581±2588
Table 2. Preparation of compounds 18, 6 and 5
were registered on a Varian MAT 212 (EI 70 eV) with
DIE ionisation. IR spectra were registered on a Perkin±
Elmer FT/IR 1750. Preparative column chromatography:
Merck silica gel 60, particle size 0.040±0.063 mm (230±
400 mesh, ¯ash). Analytical TLC: silica gel 60 F254 plates,
Merck, Darmstadt. All melting points (BuÈchi apparatus,
system Dr. Tottoli) are uncorrected. Microanalyses were
obtained with a Heraeus CHN-O-RAPID element analyser.
Tetrahydrofuran (THF) was freshly distilled over Na and
dichloromethane (CH2Cl2) over CaH2.
RX
18 (Yield %)
6 (Yield %)
5 (Yield %)
a
b
c
d
e
f
MeI
EtI
PrI
BuI
HexI
BnBr
90
93
94
92
91
95
94
91
89
90
87
94
76
69
71
78
73
80
amine and a benzotriazole moiety and demonstrated the
possibility to remove this metalation auxiliary under reduc-
tive conditions. These results led us to investigate the possi-
bility to use the benzotriazolyl group to protect the benzylic
position in our model in the synthetic sequence depicted in
Scheme 6.
4.1.1. Synthesis of 2-(dimethylamino)-3-hydroxy-2,3-
dihydro-1H-isoindol-1-one (9). Phthalimide
8 (15 g,
79 mmol) was dissolved in absolute MeOH (150 ml) and
carefully treated with NaBH4 (3.3 g, 87 mmol) under N2
in a ice-cooled ¯ask. The mixture was stirred for additional
30 min, saturated aqueous NH4Cl solution was added and
the MeOH was removed under vacuum. The crude product
was extracted with CH2Cl2 (3£100 ml) which was then
dried over Na2SO4. Evaporation of the solvent furnished
an oily product, which slowly solidi®ed on standing and
afforded the 3-hydroxy derivative 9 (12.4 g, 82%) which
was then used in the next step without further puri®cation.
The parent phthalimidine 16 was readily prepared from the
carbinolamine 9 after treatment with an excess of benzo-
triazole under catalytic acidic conditions (p-toluenesulfonic
acid, PTSA) and was then smoothly deprotonated with
LHMDS in THF at 2788C to give the corresponding
a-metalloamine 17. This carbanionic species was then
allowed to react with an array of alkyl halides to afford
excellent yields of the 3,3-disubstituted-1-isoindolinones
18a±f (Table 2).
1
9: mp 85±868C; H NMR d 3.08 (s, 6H, NMe2), 5.52 (d,
Jˆ8.0 Hz, 1H, NCHAr), 5.76 (d, Jˆ8.0 Hz, 1H, OH), 7.33±
7.50 (m, 3H, Harom), 7.54±7.59 (m, 1H, Harom); 13C NMR C
166.1 (CO), 142.0, 131.0, CH 132.4, 129.6, 123.3, 122.9,
81.0, CH3 44.7. m/z (%): 192 (M1, 36), 150 (56), 133 (67),
105 (37), 59 (100). IR (KBr) 1701 (CO), 3285, 3097. Anal.
calcd for C10H12N2O2: C, 62.49; H, 6.29; N, 14.57. Found:
C, 62.83; H, 6.11; N, 14.69.
In order to carry out the C(3)-deprotection of these aminals,
benzotriazole being a well known leaving group owing to its
electron withdrawing nature, we anticipated that it could be
possible to remove this auxiliary under acidic conditions in
the presence of a carbocation scavenger. Gratifyingly, treat-
ment of compounds 18a±f with an excess of tri¯uoroacetic
acid gave the transient iminium ions 19, which were
successfully reduced with triethylsilane to afford the desired
3-alkylated-1-isoindolinones 6a±f. Finally, removal of the
N-dimethylamino group in compounds 6a±f was achieved
cleanly by heating with excess of zinc in re¯uxing
acetic acid.25 This protocol delivered the targeted 3-alkyl
phthalimidines 5a±f in good yields.
4.1.2. Synthesis of 2-(dimethylamino)-2,3-dihydro-1H-
isoindol-1-one (7). A solution of compound 9 (11.6 g,
60.4 mmol) in a mixture of tri¯uoroacetic acid (10 ml)
and CH2Cl2 (30 ml) was stirred under argon and cooled
with an ice bath. The solution was then treated with triethyl-
silane (12 ml, 75 mmol). After removal of the ice-bath, the
stirring was continued for 1 h. The mixture was then poured
into ice-water, made alkaline by the addition of solid K2CO3
and extracted with CH2Cl2 (3£100 ml). The extracts were
combined, dried over Na2SO4 and evaporated under
vacuum. The oily residue was chromatographed on a SiO2
column using acetone/hexane as eluent (50:50) and ®nally
recrystallized from pentane±toluene to afford isoindolinone
7 (10.0 g, 94%) as pale yellow solid. 7: mp 133±1348C; 1H
NMR d 2.68 (s, 6H, NMe2), 4.32 (s, 2H, NCH2Ar), 7.13±
7.46 (m, 3H, Harom), 7.73 (d, Jˆ7.8 Hz, 1H, Harom); 13C
NMR C 166.3 (CO), 139.2, 132.0, CH 131.4, 127.9,
123.5, 122.6, CH2 43.8, CH3 44.2. m/z (%): 176 (M1, 46),
134 (100). IR (KBr) 1676 (CO). Anal. calcd for C10H12N2O:
C, 68.16; H, 6.86; N, 15.90. Found: C, 67.92; H, 6.91; N,
16.22.
3. Conclusions
By means of a new synthetic approach involving as the key
step the alkylation of an a-aminocarbanion derived from
a cyclic hydrazide, we have disclosed a concise and
ef®cient synthesis of 3-alkyl-1-isoindolinones. Owing to
the ef®ciency and simplicity of the new methodology, this
protocol shows potential for further development and work
aimed at performing these reactions with asymmetric
induction are currently under investigation.
4. Experimental
4.1. General
4.2. General procedure for the alkylation of
phthalimidine 7
A solution of LHMDS (1 M in hexane, 1.1 equiv.) was
added dropwise to a solution of 7 (528 mg, 3 mmol) in
THF (50 ml) at 2788C under N2. The yellow solution was
stirred for 15 min and then the alkylating agent was added.
The mixture was allowed to warm to room temperature and
treated with a saturated NH4Cl aqueous solution (20 ml).
1H (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Varian VXR 300 (solvent CDCl3, TMS as
internal standard). Chemical shifts are expressed in ppm.
Abbreviations used are s (singlet), d (doublet), t (triplet), q
(quadruplet), m (multiplet) and br. (broad). Mass spectra

E. Deniau, D. Enders / Tetrahedron 57 (2001) 2581±2588
2585
After extraction with Et2O (2£50 ml), the organic layer was
dried over Na2SO4. Evaporation of the solvent gave the
alkylated products, which were carefully chromatographed
on a SiO2 column using acetone/hexane (40:60) as eluent.
6.60 (d, Jˆ8.4 Hz, 1H, Harom), 7.22±7.38 (m, 3H, Harom),
7.39 (s, 1H, NCHN), 7.55±7.71 (m, 2H, Harom), 7.99±8.05
(m, 1H, Harom), 8.07±8.13 (m, 1H, Harom); 13C NMR C 166.1
(CO), 151.7, 146.9, 137.8, 131.4, CH 133.3, 130.9, 128.0,
124.5, 123.9, 123.6, 120.5, 110.0, 72.0, CH3 44.0. m/z (%):
293 (M1, 78), 251 (38), 221 (100), 207 (40), 179 (37), 131
(55). IR (KBr) 1719 (CO). Anal. calcd for C16H15N5O: C,
65.52; H, 5.15; N, 23.88. Found: C, 65.33; H, 5.19; N, 23.73.
4.2.1. 2-(Dimethylamino)-3-methyl-2,3-dihydro-1H-iso-
1
indol-1-one (6a). Oil; H NMR d 1.48 (d, Jˆ6.6 Hz, 3H,
Me), 2.97 (s, 6H, NMe2), 4.45 (q, Jˆ6.6 Hz, 1H, NCHAr),
7.32 (d, Jˆ7.8 Hz, 1H, Harom), 7.37±7.42 (m, 1H, Harom),
7.46±7.53 (m, 1H, Harom), 7.75 (d, Jˆ7.7 Hz, 1H, Harom);
13C NMR C 166.9 (CO), 145.5, 131.8, CH 131.6, 128.0,
123.1, 122.0, 57.0, CH3 44.4, 17.9. m/z (%): 190 (M1,
23), 148 (100), 132 (34). IR (KBr) 1694 (CO), 1767.
Anal. calcd for C11H14N2O: C, 69.45; H, 7.42; N, 14.72.
Found: C, 69.40; H, 7.56; N, 14.79.
4.3. General procedure for the alkylation of the
3-benzotriazolyl-isoindolinone 16
Isoindolinones 18a±f were obtained following the same
procedure as described for the alkylation of 7 but the ®nal
compounds were puri®ed by recrystallisation from hexane±
toluene.
4.2.2. 2-(Dimethylamino)-3,3-dimethyl-2,3-dihydro-1H-
isoindol-1-one (13). Mp 134±1358C; H NMR d 1.48 (s,
1
4.3.1. 3-(1H-1,2,3-benzotriazol-1-yl)-2-(dimethylamino)-
3-methyl-2,3-dihydro-1H-isoindol-1-one (18a). Mp 152±
1538C; 1H NMR d 2.42 (br. s, 9H, Me1NMe2), 6.12 (d, Jˆ
8.3 Hz, 1H, Harom), 6.96±7.06 (m, 1H, Harom), 7.08±7.18 (m,
2H, Harom), 7.41±7.56 (m, 2H, Harom), 7.83±7.96 (m, 2H,
Harom); 13C NMR C 165.5 (CO), 146.6, 134.4, 131.3, 130.4,
79.9, CH 133.4, 130.6, 127.6, 124.1, 123.8, 122.4, 120.2,
110.7, CH3 44.7, 23.3. m/z (%): 307 (M1, 15), 221 (24), 188
(26), 146 (79), 145 (100), 119 (37), 91 (45). IR (KBr) 1708
(CO). Anal. calcd for C17H17N5O: C, 66.43; H, 5.58; N,
22.79. Found: C, 66.58; H, 5.62; N, 22.56.
6H, 2Me), 3.01 (s, 6H, NMe2), 7.31±7.35 (m, 1H, Harom),
7.40 (dt, Jˆ7.7, 1.1 Hz, 1H, Harom), 7.52 (dt, Jˆ7.7, 1.4 Hz,
1H, Harom), 7.75±7.79 (m, 1H, Harom); 13C NMR C 166.1
(CO), 150.2, 130.6, 63.5, CH 131.7, 127.8, 123.2, 120.9,
CH3 45.1, 24.7. m/z (%): 204 (M1, 35), 189 (19), 175
(27), 162 (100), 146 (80). IR (KBr) 1683 (CO). Anal.
calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found:
C, 70.69; H, 7.74; N, 13.92.
4.2.3.
2-(Dimethylamino)-3-ethyl-2,3-dihydro-1H-iso-
1
indol-1-one (6b). Oil; H NMR d 0.72 (t, Jˆ7.4 Hz, 3H,
Me), 1.90±2.13 (m, 2H, CH2), 2.97 (s, 6H, NMe2), 4.43 (t,
Jˆ4.7 Hz, 1H, NCHAr), 7.31±7.44 (m, 2H, Harom), 7.49 (dt,
Jˆ7.4, 1.4 Hz, 1H, Harom), 7.75 (d, Jˆ7.4 Hz, 1H, Harom);
13C NMR C 167.7 (CO), 143.6, 132.5, CH 131.4, 127.9,
123.1, 122.2, 61.7, CH2 23.3, CH3 44.0, 7.6. m/z (%): 205
(M1, 70), 162 (81), 146 (26), 132 (67). IR (KBr) 1697 (CO).
Anal. calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71.
Found: C, 70.40; H, 7.85; N, 13.94.
4.3.2. 3-(1H-1,2,3-benzotriazol-1-yl)-2-(dimethylamino)-
3-ethyl-2,3-dihydro-1H-isoindol-1-one (18b). Mp 172±
1
1738C; H NMR d 1.00 (t, Jˆ7.4 Hz, 3H, CH3), 2.65 (br.
s, 6H, NMe2), 3.20±3.35 (m, 1H, CH2), 3.38±3.53 (m, 1H,
CH2), 6.21 (d, Jˆ8.5 Hz, 1H, Harom), 7.22±7.30 (m, 1H,
Harom), 7.36±7.46 (m, 2H, Harom), 7.72±7.86 (m, 2H,
Harom), 8.15±8.22 (m, 2H, Harom); 13C NMR C 166.0 (CO),
146.4, 141.2, 131.7, 131.5, 83.4, CH 133.2, 130.6, 127.6,
124.1, 123.8, 122.8, 120.2, 110.7, CH2 26.9, CH3 44.4, 8.0.
m/z (%): 321 (M1, 100), 249 (32), 234 (63), 221 (55), 220
(88), 206 (80), 178 (28), 160 (56). IR (KBr) 1709 (CO).
Anal. calcd for C18H19N5O: C, 67.27; H, 5.96; N, 21.79.
Found: C, 67.33; H, 5.78; N, 21.50.
4.2.4. 2 (Dimethylamino)-3-propyl-2,3-dihydro-1H-iso-
1
indol-1-one (6c). Mp 54±558C; H NMR d 0.81 (t, Jˆ
7.3 Hz, 3H), 0.88±1.08 (m, 1H), 1.09±1.31 (m, 1H),
1.72±1.86 (m, 1H), 1.911±2.04 (m, 1H), 2.98 (s, 6H,
NMe2), 4.57 (dd, Jˆ6.3, 3.8 Hz, 1H, NCHAr), 7.27±7.40
(m, 2H, Harom), 7.49 (dt, Jˆ7.7, 1.4 Hz, 1H, Harom), 7.71 (d,
Jˆ8.0 Hz, 1H, Harom); 13C NMR C 167.6 (CO), 143.8,
132.6, CH 131.6, 128.1, 123.2, 122.2, 61.2, CH2 31.9,
16.6, CH3 44.1, 14.1. m/z (%): 218 (M1, 30), 176 (100),
146 (80), 132 (57). IR (KBr) 1700 (CO). Anal. calcd for
C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C, 71.59;
H, 8.05; N, 12.98.
4.3.3. 3-(1H-1,2,3-benzotriazol-1-yl)-2-(dimethylamino)-
3-propyl-2,3-dihydro-1H-isoindol-1-one (18c). Mp 178±
1798C; 1H NMR d 0.81±1.08 (m, 4H), 1.10±1.28 (m, 1H),
2.48 (br. s, 6H, NMe2), 2.99±3.19 (m, 2H), 6.00 (d, Jˆ
8.2 Hz, 1H, Harom), 7.05 (t, Jˆ7.7 Hz, 1H, Harom), 7.16±
7.25 (m, 2H, Harom), 7.51±7.64 (m, 2H, Harom), 7.94 (d,
Jˆ7.4 Hz, 1H, Harom), 7.98 (d, Jˆ8.5 Hz, 1H, Harom); 13C
NMR C 165.9 (CO), 146.5, 141.6, 131.7, 131.4, 82.9, CH
133.2, 130.6, 127.6, 124.1, 123.8, 122.8, 120.3, 110.8, CH2
35.8, 16.9, CH3 44.4, 13.8. m/z (%): 335 (M1, 100), 264
(26), 248 (39), 234 (57), 221 (48), 220 (80), 193 (41), 174
(63), 173 (63), 172 (83). IR (KBr) 1707 (CO). Anal. calcd
for C19H21N5O: C, 68.04; H, 6.31; N, 20.88. Found: C,
68.32; H, 6.28; N, 20.53.
4.2.5. Synthesis of the 3-(1H-1,2,3-benzotriazol-1-yl)-2-
(dimethylamino)-3-methyl-2,3-dihydro-1H-isoindol-1-one
(16). To a suspension of benzotriazole (6.8 g, 57.2 mmol)
and hydroxyphthalimidine 9 (10 g, 52.1 mmol) in toluene
(200 ml) was added p-toluenesulfonic acid (100 mg). The
mixture was re¯uxed for 3 h while removing the reaction
water with a Dean±Stark trap. The solution was then cooled,
washed with a saturated aqueous solution of NaHCO3
(25 ml) and dried over Na2SO4. After removal of the
solvent, the crude compound was recrystallized from
hexane±toluene to afford 16 (13.9 g, 91%) as a colourless
4.3.4. 3-(1H-1,2,3-benzotriazol-1-yl)-3-butyl-2-(dimethyl-
amino)-2,3-dihydro-1H-isoindol-1-one (18d). Mp 176±
1778C; 1H NMR d 0.81±1.04 (m, 4H), 1.06±1.26 (m,
1H), 1.32±1.50 (m, 2H), 2.47 (br. s, 6H, NMe2), 2.99±
3.29 (m, 2H), 6.02 (d, Jˆ8.5 Hz, 1H, Harom), 7.03±7.12
1
solid. 16: mp 150±1518C; H NMR d 2.68 (s, 6H, NMe2),

2586
E. Deniau, D. Enders / Tetrahedron 57 (2001) 2581±2588
(m, 1H, Harom), 7.18±7.27 (m, 2H, Harom), 7.53±7.69 (m, 2H,
Harom), 7.90±8.06 (m, 2H, Harom); 13C NMR C 166.0 (CO),
146.4, 141.5, 131.6, 131.4, 82.9, CH 133.2, 130.8, 127.5,
124.0, 123.8, 122.9, 120.2, 110.7, CH2 33.5, 25.5, 22.5, CH3
44.4, 13.9. m/z (%): 349 (M1, 6), 230 (15), 187 (70), 186
(100), 172 (40), 158 (44). IR (KBr) 1711 (CO). Anal. calcd
for C20H23N5O: C, 68.75; H, 6.63; N, 20.04. Found: C,
68.69; H, 6.50; N, 20.28.
4.43 (dd, Jˆ6.0, 4.0 Hz, 1H, NCHAr), 7.31±7.44 (m, 2H,
H
arom), 7.49 (dt, Jˆ7.4, 1.4 Hz, 1H, Harom), 7.75 (d, Jˆ
7.4 Hz, 1H, Harom); 13C NMR C 167.5 (CO), 144.1, 132.4,
CH 131.4, 127.8, 123.1, 122.3, 61.0, CH2 31.6, 30.8, 29.4,
23.5, 22.5, CH3 44.1, 14.0. m/z (%): 260 (M1, 31), 218 (98),
146 (100), 132 (54). IR (KBr) 1699 (CO). Anal. calcd for
C16H24N2O: C, 73.81; H, 9.29; N, 10.76. Found: C, 73.69;
H, 9.43; N, 10.38.
4.3.5. 3-(1H-1,2,3-benzotriazol-1-yl)-2-(dimethylamino)-
3-hexyl-2,3-dihydro-1H-isoindol-1-one (18e). Mp 103±
1048C; 1H NMR d 0.78±0.85 (m, 3H), 0.88±1.03 (m,
1H), 1.13±1.29 (m, 5H), 1.33±1.43 (m, 2H), 2.49 (br. s,
6H, NMe2), 3.02±3.13 (m, 1H), 3.15±3.25 (m, 1H), 6.02
(d, Jˆ8.5 Hz, 1H, Harom), 7.04±7.10 (m, 1H, Harom), 7.20±
7.24 (m, 2H, Harom), 7.55±7.66 (m, 2H, Harom), 7.96±8.04
(m, 2H, Harom); 13C NMR C 165.9 (CO), 146.4, 141.6, 131.7,
131.4, 83.0, CH 133.2, 130.6, 127.6, 124.0, 123.8, 122.9,
120.3, 110.8, CH2 33.9, 31.7, 29.2, 23.5, 22.7, CH3 44.5,
14.1. m/z (%): 337 (M1, 100), 348 (17), 290 (22), 264 (22),
259 (30), 234 (50), 221 (47), 220 (54), 216 (40), 193 (32). IR
(KBr) 1713 (CO). Anal. calcd for C22H27N5O: C, 70.00; H,
7.21; N, 18.55. Found: C, 69.87; H, 7.34; N, 18.59.
4.4.3. 3-Benzyl-2-(dimethylamino)-2,3-dihydro-1H-iso-
indol-1-one (6f). Mp 132±1338C; H NMR d 2.49 (dd,
1
Jˆ13.1, 10.2 Hz, 1H, CH2Ph), 3.02 (s, 6H, NMe2), 3.75
(dd, Jˆ13.1, 4.1 Hz, 1H, CH2Ph), 4.59 (dd, Jˆ10.2,
4.1 Hz, 1H, NCHAr), 6.55 (d, Jˆ7.7 Hz, 1H, Harom),
7.15±7.20 (m, 2H, Harom), 7.22±7.37 (m, 5H, Ph), 7.73 (d,
Jˆ7.4 Hz, 1H, Harom); 13C NMR C 166.9 (CO), 143.5,
137.0, 131.9, CH 130.9, 129.6, 128.4, 127.9, 126.8, 123.1,
122.9, 62.3, CH2 38.4, CH3 44.5. m/z (%): 266 (M1, 35), 224
(46), 175 (100), 132 (90). IR (KBr) 1695 (CO). Anal. calcd
for C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C,
76.74; H, 6.69; N, 10.64.
4.5. General procedure for the N-deprotection of
phthalimidines 6a±f
4.3.6. 3-(1H-1,2,3-benzotriazol-1-yl)-3-benzyl-2-(dimethyl-
amino)-2,3-dihydro-1H-isoindol-1-one (18f). Mp 163±
1648C; 1H NMR d 2.68 (s, 6H, NMe2), 3.96 (d, Jˆ
14.3 Hz, 1H, CH2Ph), 5.28 (d, Jˆ14.3 Hz, 1H, CH2Ph),
5.89 (d, Jˆ8.5 Hz, 1H, Harom), 6.88 (d, Jˆ7.7 Hz, 1H,
Harom), 7.21 (t, Jˆ7.7 Hz, 1H, Harom), 7.26±7.37 (m, 5H,
Ph), 7.41 (t, Jˆ7.8 Hz, 1H, Harom), 7.62 (t, Jˆ7.6 Hz, 1H,
Harom), 7.82 (t, Jˆ7.4 Hz, 1H, Harom), 8.13 (d, Jˆ7.4 Hz, 1H,
Harom), 8.23 (d, Jˆ8.5 Hz, 1H, Harom); 13C NMR C 165.5
(CO), 146.6, 140.3, 133.9, 132.0, 82.7, 68.5, CH 132.2,
131.6, 130.9, 128.1, 127.7, 127.4, 125.3, 124.2, 123.7,
120.3, 111.0, CH2 41.2, CH3 44.9, 14.0. m/z (%): 383
(M1, 3), 264 (31), 221 (72), 220 (100), 193 (25), 165
(24). IR (KBr) 1717 (CO). Anal. calcd for C23H21N5O: C,
72.04; H, 5.52; N, 18.26. Found: C, 72.16; H, 5.39; N, 18.20.
Hydrazides 6a±f (2 mmol) and zinc dust (2.6 g, 40 mmol)
were stirred in glacial acetic acid (100 ml) under re¯ux until
no starting material could be detected (TLC control, usually
24±36 h). The cold reaction mixture was ®ltered, evapo-
rated, poured into aqueous Na2CO3 (5% solution, 50 ml)
then extracted with CH2Cl2 (3£100 ml). The combined
organic layers were washed with water, dried over
Na2SO4 and evaporated to afford the crude phthalimidines,
which were ®nally puri®ed by chromatography on SiO2
using acetone/hexane (70:30) as eluent.
4.5.1. 3-Methyl-2,3-dihydro-1H-isoindol-1-one (5a). Mp
1
115±1168C (lit.16a 1158C); H NMR d 1.49 (t, Jˆ6.9 Hz,
3H, Me), 4.68 (q, Jˆ6.9 Hz, 1H, NCHAr), 7.36±7.47 (m,
2H, Harom), 7.53 (dt, Jˆ7.4, 1.1 Hz, 1H, Harom), 7.82 (d, Jˆ
7.4 Hz, 1H, Harom), 8.54 (br. s, 1H, NH); 13C NMR C 171.4
(CO), 149.0, 131.9, CH 131.8, 128.0, 123.5, 122.2, 52.8,
CH3 13.9. m/z (%): 147 (M1, 85), 132 (100). IR (KBr)
1658 (CO), 3224 (NH).
4.4. General procedure for the C(3)-deprotection of
phthalimidines 18a±f
Compounds 18a±f were deprotected following the same
procedure previously described for the reduction of 9 but
were puri®ed by chromatography on SiO2 using acetone/
hexane (40:60) as eluent.
4.5.2. 3-Ethyl-2,3-dihydro-1H-isoindol-1-one (5b). Mp
1
104±1058C (lit.26 1058C); H NMR d 0.94 (t, Jˆ6.9 Hz,
3H, Me), 1.63±1.73 (m, 1H), 1.94±2.07 (m, 1H), 4.59
(dd, Jˆ6.9, 4.7 Hz, 1H, NCHAr), 7.39±7.45 (m, 2H,
Harom), 7.52 (dt, Jˆ7.4, 1.1 Hz, 1H, Harom), 7.83 (d, Jˆ
7.4 Hz, 1H, Harom), 8.48 (br. s, 1H, NH); 13C NMR C
171.5 (CO), 147.4, 132.2, CH 131.6, 127.9, 123.5, 122.3,
58.3, CH2 27.4, CH3 9.6. m/z (%): 161 (M1, 19), 132 (100).
IR (KBr) 1658 (CO), 1692, 3202 (NH).
4.4.1.
3-Butyl-2-(dimethylamino)-2,3-dihydro-1H-iso-
1
indol-1-one (6d). Oil; H NMR d 0.83 (t, Jˆ7.2 Hz, 3H),
0.96±1.07 (m, 1H), 1.15±1.32 (m, 3H), 1.81±1.94 (m, 1H),
1.96±2.07 (m, 1H), 2.96 (s, 6H, NMe2), 4.43 (dd, Jˆ5.8,
4.1 Hz, 1H, NCHAr), 7.31±7.43 (m, 2H, Harom), 7.49 (dt, Jˆ
7.7, 1.4 Hz, 1H, Harom), 7.75 (d, Jˆ7.4 Hz, 1H, Harom); 13C
NMR C 167.6 (CO), 144.1, 132.3, CH 131.4, 127.9, 123.1,
122.3, 61.0, CH2 30.5, 25.7, 22.8, CH3 44.1, 13.9. m/z (%):
232 (M1, 28), 190 (100), 146 (89), 132 (48). IR (KBr) 1697
(CO). Anal. calcd for C14H20N2O: C, 72.38; H, 8.68; N,
12.06. Found: C, 72.60; H, 8.39; N, 12.11.
4.5.3. 3-Propyl-2,3-dihydro-1H-isoindol-1-one (5c). Mp
1
137±1388C (lit.27 135±1368C); H NMR d 0.94 (t, Jˆ
7.3 Hz, 3H, Me), 1.33±1.68 (m, 3H), 1.86±1.97 (m, 1H),
4.62 (dd, Jˆ7.4, 4.4 Hz, 1H, NCHAr), 7.36±7.44 (m, 2H,
Harom), 7.50 (dt, Jˆ7.4, 1.1 Hz, 1H, Harom), 7.83 (d,
Jˆ7.4 Hz, 1H, Harom), 8.80 (br. s, 1H, NH); 13C NMR C
171.3 (CO), 147.8, 132.0, CH 131.5, 127.8, 123.6, 122.3,
4.4.2. 2-(Dimethylamino)-3-hexyl-2,3-dihydro-1H-iso-
1
indol-1-one (6e). Oil; H NMR d 0.83 (t, Jˆ6.9 Hz, 3H),
0.91±1.10 (m, 1H), 1.14±1.33 (m, 7H), 2.97 (s, 6H, NMe2),

E. Deniau, D. Enders / Tetrahedron 57 (2001) 2581±2588
2587
57.0, CH2 36.8, 19.0, CH3 14.1. m/z (%): 175 (M1, 17), 132
(100). IR (KBr) 1681 (CO), 3194 (NH).
5. Gawley, R. E.; Chemburkar, S. R.; Smith, A. L.; Anklekar,
T. V. J. Org. Chem. 1988, 53, 5381±5383.
6. (a) Beeley, L. J.; Rockell, C. J. M. Tetrahedron Lett. 1990, 31,
417±420. (b) Meyers, A. I.; Santiago, B. Tetrahedron Lett.
1995, 36, 5877±5880.
4.5.4. 3-Butyl-2,3-dihydro-1H-isoindol-1-one (5d). Mp
1
88±898C (lit.12b 85±868C); H NMR d 1.06 (t, Jˆ7.0 Hz,
3H, Me), 1.38±1.72 (m, 4H), 1.75±1.91 (m, 1H), 2.03±2.22
(m, 1H), 4.81 (dd, Jˆ7.1, 5.2 Hz, 1H, NCHAr), 7.56±7.67
(m, 2H, Harom), 7.69±7.77 (m, 1H, Harom), 8.03 (d, Jˆ
7.4 Hz, 1H, Harom), 8.33 (br. s, 1H, NH); 13C NMR C
171.4 (CO), 147.9, 132.0, CH 131.7, 128.0, 123.7, 122.4,
57.1, CH2 34.2, 27.6, 22.6, CH3 13.9. m/z (%): 189 (M1, 14),
132 (100). IR (KBr) 1687 (CO), 3194 (NH).
7. (a) Beak, P.; Kerrick, S. T.; Gallagher, D. J. J. Am. Chem. Soc.
1993, 115, 10628±10636. (b) Couture, A.; Deniau, E.;
Ionescu, D.; Grandclaudon, P. Tetrahedron Lett. 1998, 39,
2319±2320. (c) Luzzio, F. A.; Zacherl, D. P. Tetrahedron
Lett. 1998, 39, 2285±2238.
8. (a) Kundu, N. G.; Khan, M. W.; Mukhopadhyay, R.
Tetrahedron 1999, 55, 12361±12376 (and references cited).
(b) Luzzio, A. F.; Zacherl, D. P.; Figg, W. D. Tetrahedron
Lett. 1999, 40, 2087±2090 (and references cited). (c) Cai, Y.;
Fredenhagen, A.; Hug, P.; Meyer, T.; Petre, H. J. Antibiot.
Chem. 1996, 49, 519±526. (d) Campello, M. J.; Castedo, L.;
4.5.5. 3-Hexyl-2,3-dihydro-1H-isoindol-1-one (5e). Mp
1
84±858C; H NMR d 0.83 (t, Jˆ6.9 Hz, 3H, Me), 1.18±
1.51 (m, 7H), 1.57±1.68 (m, 1H), 1.87±1.99 (m, 1H), 4.60
(dd, Jˆ7.4, 4.7 Hz, 1H, NCHAr), 7.38±7.46 (m, 2H, Harom),
7.52 (dt, Jˆ7.4, 1.1 Hz, 1H, Harom), 7.82 (d, Jˆ7.4 Hz, 1H,
Harom), 8.22 (br. s, 1H, NH); 13C NMR C 171.3 (CO), 147.8,
132.0, CH 131.5, 127.8, 123.6, 122.3, 57.2, CH2 34.6, 31.6,
29.2, 25.5, 22.6, CH3 14.1. m/z (%): 217 (M1, 16), 132
(100). IR (KBr) 1686 (CO), 3192 (NH).). Anal. calcd for
C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.64; H,
8.85; N, 6.31.
Â
Â
Domõnguez, D.; Rodriguez de Lera, A.; Saa, J. M.; Suau, R.;
Tojo, E.; Vidal, M. C. Tetrahedron Lett. 1984, 25, 5933±5936.
(e) Valencia, E.; Fajardo, V.; Freyer, A. J.; Shamma, M.
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9. (a) Belliotti, T. R.; Brink, W. A.; Kesten, S. R.; Rubin, J. R.;
Wustrow, D. J.; Zoski, K. T.; Whetzel, S. Z.; Corbin, A. E.;
Pugsley, T. A.; Heffner, T. G.; Wise, L. D. Bioorg. Med.
Chem. Lett. 1998, 8, 1499±1502. (b) Takahashi, I.; Hirano,
E.; Kawakami, T.; Kitajima, H. Heterocycles 1996, 43, 2343±
2346. (c) Takahashi, I.; Kawakami, T.; Hirano, E.; Yokota, H.;
Kitajima, H. Synlett 1996, 353±355.
4.5.6. 3-Benzyl-2,3-dihydro-1H-isoindol-1-one (5f). Mp
140±1418C (lit.27 135±1368C); 1H NMR d 2.91 (dd,
Jˆ13.8, 8.4 Hz, 1H, CH2Ph), 3.16 (dd, Jˆ13.8, 5.7 Hz,
1H, CH2Ph), 4.81 (dd, Jˆ8.4, 5.7 Hz, 1H, NCHAr), 7.17±
7.37 (m, 7H, NH1Harom), 7.42±7.56 (m, 2H, Harom), 7.83 (d,
Jˆ7.1 Hz, 1H, Harom); 13C NMR C 170.2 (CO), 146.9,
138.8, 132.1, CH 131.6, 129.3, 128.7, 128.3, 127.1, 123.8,
122.8, 58.0, CH2 41.2. m/z (%): 223 (M1, 6), 132 (100). IR
(KBr) 1683 (CO), 3193 (NH).
10. Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med.
Chem. 1998, 41, 157±166.
11. Wood, J. L.; Petsch, D. T.; Stoltz, B. M.; Hawkins, E. M.;
Elbaum, D.; Stover, D. R. Synthesis 1999, 1529±1533.
Â
12. (a) Helberger, J. H.; Rebay, A. V.; Hever, D. B. Liebigs Ann.
Chem. 1938, 197±212. (b) Noguchi, T.; Kawanami, M.
J. Pharm. Soc. Jpn 1937, 57, 196±208. (c) Tikk, I.; Deak,
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17, 4±12.
Acknowledgements
This work was supported by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie. We
thank Degussa AG, BASF AG, the former Hoechst AG,
and Bayer AG for the donation of chemicals.
14. Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J.
Tetrahedron Lett. 1990, 31, 5015±5018.
15. (a) Allin, S. M.; North®eld, C. J.; Page, M. I.; Slawin, A. M. Z.
Tetrahedron Lett. 1999, 40, 141±142. (b) Allin, S. M.;
North®eld, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron
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