Complementary synthetic approaches to constitutionally diverse N-aminoalkylated isoindolinones: Application to the synthesis of falipamil and 5-HT1A receptor ligand analogues

Article abstract of DOI:10.1055/s-0028-1088048

Different synthetic approaches for the elaboration of poly and diversely substituted isoindolinones tailed with constitutionally diverse aminoalkylated chains have been developed. The key step is based upon the preliminary assembly of the isoindolinone te

Full text of DOI:10.1055/s-0028-1088048

PAPER
1897
Complementary Synthetic Approaches to Constitutionally Diverse N-Amino-
alkylated Isoindolinones: Application to the Synthesis of Falipamil and 5-HT1A
Receptor Ligand Analogues
S
ynthesisof Falipamilaand 5-H A
T
1 g
R
eceptor
L
i
gand
A
nalo
l
gues i Lorion,a,b Axel Couture,*a,b Eric Deniau,a,b Pierre Grandclaudona,b
a
LCOP, Université des Sciences et Technologies de Lille 1, Bâtiment C3(2), 59655 Villeneuve d’Ascq, France
Fax +33(3)20336309; E-mail: axel.couture@univ-lille1.fr
b
CNRS, UMR 8009 ‘Chimie Organique et Macromoléculaire’, 59655 Villeneuve d’Ascq, France
Received 21 January 2009
O
Abstract: Different synthetic approaches for the elaboration of
poly and diversely substituted isoindolinones tailed with constitu-
tionally diverse aminoalkylated chains have been developed. The
key step is based upon the preliminary assembly of the isoindoli-
none template equipped with hydroxyalkyl appendages. Subse-
quent manipulation of the terminal hydroxy functionality afforded
the targeted compounds and the synthetic utility of these approaches
has been emphasized by the synthesis of the bradycardic agent fali-
pamil and 5-HT1A receptor ligand analogues.
MeO
MeO
N
OMe
OMe
N
Me
falipamil (1)
R1
O
R2
R3
MeO
( )n
N
Key words: carbanions, metalation, lactams, ring closure, ring
opening
N
N
R4
2a
R
1 = R2 = R3 = R4 = H
n = 1
n = 1
n = 1
n = 2
2b R1 = R2 = R3 = H, R4 = Ph
2c R1 = R2 = R3 = OMe, R4 = H
2d R1 = R4 = H, R2 = R3 = OMe
The isoindolinone ring system lies at the heart of a great
number of poly and diversely functionalized compounds
that have gained considerable attention in the last decade
due to their profound physiological and chemotherapeutic
properties. Thus, many compounds containing the isoin-
dolinone skeleton are known to exhibit antiviral,1 antileu-
kemic,2 anticancer,3 antipsychotic,4 antiulcer,5 and
antifibrilogenic6 properties. Such compounds are also of
significant interest for the treatment of neuropsychiatric
disorders.7
O
MeO
I
N
N
N
N
p-MPPI (3)
Figure 1 Isoindolinone-centered bioactive compounds
noalkyl appendage3c,4b,c or of a NH-free model with ensu-
ing N-alkylation.4c However, these reactions are fraught
with difficulties associated with elaboration of the hetero-
bicyclic system with dense functionalities on the benzene
nucleus. The lack of generality, accessibility of the appro-
priate precursors, that is, the polyfunctionalized alkylated
amine or aminated alkylating agent required for the above
mentioned synthetic strategies, are also some of the main
hurdles that must be overcome. Furthermore, the reduc-
tion of unsymmetrically substituted phthalimidine is
regioselectively compromised. Consequently, the devel-
opment of synthetic methodologies, which may find gen-
erality for constructing a variety of poly and diversely
substituted isoindolinones equipped with diverse ami-
noalkyl appendages constitutes an area of current interest
and alternative methods are currently the object of syn-
thetic endeavor.
The rationale for developing this ring system, which rep-
resents a conformationally constrained variant of the ben-
zamide nucleus, is that the cyclized amide bond may
extend in vivo stability without extensive degradation.
The benzolactamic nucleus may generally serve as a link-
er for a variety of pharmacophores,3c,8 but in most cases,
bioactive isoindolinone-centered compounds constitu-
tionally comprise a benzolactam unit tailed with alkyl or
aryl chains equipped with appropriate functionalities,
namely aminoalkyl moieties, liable to act on the pharma-
cological profile. Falipamil (1)9 and the piperazine deriv-
atives 2a,b4b fall into this class of compounds (Figure 1).
Traditionally, synthesis of compounds structurally related
to 1, 2 relies on the treatment of a lactone4c,8 or of an
ortho-bromobenzoyl ester1a,b,4c,6 with a suitably substitut-
ed primary amine. Alternatively, synthetic approaches are
based upon the reduction of the carbonyl function either
of a phthalimide preequipped with the appropriate ami-
In this context we wish to delineate complementary and
tactically new synthetic approaches to these polyaminated
isoindolinone derivatives. The feasibility of these routes
has been further emphasized by the assembling of the spe-
cific embodiment of these aminoalkyl tethered models, 1
and 2a–d. Initially we planned to develop the synthetic
SYNTHESIS 2009, No. 11, pp 1897–1903
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0028-1088048; Art ID: Z01309SS
© Georg Thieme Verlag Stuttgart · New York

1898
M. Lorion et al.
PAPER
R1
O
R5
R2
R3
X
N
path a
R1
O
N
R2
R3
( )n
R6
R5
5
N
( )n
N
R1
R1
O
1, 2 or 4
R2
R3
R2
R3
X
O
O
( )n
path b
N
( )n
N
OH
9
10
Scheme 1 Retrosynthetic analysis for the synthesis of compounds 1, 2 or 4
1. NaH, DMF
approach portrayed in retrosynthetic analysis (Scheme 1,
path a).
2.
MeO
X
Br
We surmised that the intramolecular interception of the
aryllithiated species derived from 5 (X = Br or I) by the
imidazolone acting as the internal electrophile would pro-
vide the potential for a direct access to the isoindolinone
ring system with the concomitant connection of the ami-
noalkyl appendage, therefore providing the targeted N-
alkylaminated models 4. For this purpose, compound 5d
was initially selected as the model substrate. Assembly of
this precursor was readily achieved as depicted in
Scheme 2 by coupling the anion of the monoprotected im-
idazolone 6 with the appropriate benzyl bromide deriva-
tive 7d. The carbanionic Parham type cyclization
process10 was performed upon exposure of the parent
compound 5d to n-BuLi at –78 °C in THF in the presence
of TMEDA in order to ensure the mandatory bromine–
lithium exchange giving rise to 8. Unfortunately this pro-
cedure delivered a rather low yield of the N-alkylami-
noalkyl compound 4d along with trace amounts of several
unidentified products. Variation of the ethereal solvent,
temperature profile, inclusion of anion modifiers had no
impact on the efficiency of the process.
MeO
O
7d X = Br
7e X = I
O
X
Bn
N
MeO
MeO
Bn
HN
N
51–56%
N
6
5d X = Br
5e X = I
Bn
N
O
n-BuLi, TMEDA
MeO
MeO
Li
THF, –78 °C, 1 h
N
8
O
MeO
H3O+
N
X = Br 23%
NH
Bn
MeO
X = I
54%
4d
Scheme 2 Synthesis of 4d
compounds can be regarded as excellent candidates for
the elaboration of models bearing terminal carbonyl or
alkylating functions as well and we conjectured that ensu-
ing manipulation of these functional groups should lend to
the assembling of the targeted compounds 1, 2a–d. The
diversely substituted hydroxyethyl and hydroxypropyl
tethered isoindolinones 9a–d were readily obtained upon
exposure to a lithiated base of the parent compounds 10a–
d10b easily assembled by coupling the bromobenzyl bro-
mides 7a–d with oxazolidin-2-one (11) and oxazinan-2-
one (12) (Scheme 3).
To alleviate this problem and to avoid the likely competi-
tive nucleophilic attack by organolithium base on the sen-
sitive urea group we envisioned to take advantage of the
very fast rate of metal–iodine exchange and for this pur-
pose the synthesis of the iodinated analogue 5e was envis-
aged (Scheme 2). Exposure of 5e upon the experimental
conditions defined above significantly improved the yield
for the formation of the annulated compound 4d, but effi-
ciency of this annulation process remained rather modest
(54% vs. 23%). Furthermore, it was anticipated that this
synthetic route would not face with problems associated
with the assembly of models incorporating a nitrogen
atom embedded in a heteroring unit, for example, 2.
According to the synthetic routes depicted in Scheme 3,
we began evaluating synthetic pathway a. Nucleophilic
displacement of the halogen atom of 13a by the N-arylpip-
erazine 15 proceeded uneventfully to afford excellent
yield of the 5-HT1A receptor ligand 2a. It is worth noting
that this approach allowed access to the constitutionally
unsymmetrical model 2c from the suitably substituted
precursor 13c and to the C-3 arylated analogue 2b incor-
porating a diarylmethylene carboxamide unit, a valuable
pharmacophore endowed with a wide range of biological
activities.11 Compounds 2a,b have been shown to display
high in vitro binding affinity for 5-HT1A receptors, which
exceeds that of the lead compound in this series, that is, p-
MPPI (3).4b
We then decided to switch our plans and set out to achieve
an alternative synthetic strategy to secure the formation of
a variety of structurally and constitutionally diverse N-
aminoalkylated isoindolinones. The key step of the new
synthetic route, which is depicted in retrosynthetic
Scheme 1 (path b) hinges upon the preliminary construc-
tion of the N-hydroxyalkyl tethered isoindolinones 9 that
should allow for later structural divergence. Indeed such
Synthesis 2009, No. 11, 1897–1903 © Thieme Stuttgart · New York

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Synthesis of Falipamil and 5-HT1A Receptor Ligand Analogues
1899
1. NaH, DMF
R1
2.
R2
Br
R1
R1
Br
R3
O
O
n-BuLi, TMEDA
R2
R2
R3
Br
O
THF, –78 °C to r.t.
7a–d
R4
O
HN
( )n
O
N
( )n
71–84%
54–65%
N
R3
OH
( )n
R4
11 n = 1
12 n = 2
R4
9a–d
10a–d
a
R1 = R2 = R3 = R4 = H
1 = R2 = R3 = H, R4 = Ph
1 = R2 = R3 = OMe, R4 = H n = 1
1 = R4 = H, R2 = R3 = OMe n = 2
n = 1
n = 1
b
c
d
R
R
R
R1
O
R2
R3
SOCl2, toluene
0 °C then 60 °C , 3 h
Swern oxidation
pathway b
N
( )n
pathway a
83–96%
OH
R4
R1
R1
9a–d
O
O
R2
R3
R2
R3
N
( )n
N
( )n
O
Cl
14a–c (n = 1; <12%)
14d (n = 2; 71%)
R4
13a–d
from 14d
from 13a–c
from 13d
OMe
OMe
OMe
OMe
MeO
MeO
HN
N
HN
Me
18
HN
N
Me
15
NaBH(OAc)3
16
15
NaBH(OAc)3
EtOH
Me NH
EtOH
Et3N, MeCN, Δ, 24 h
2a–c (53–71%)
DMF, KI, Δ, 12 h
1 (53%)
O
OMe
OMe
MeO
2d 91%)
N
MeO
N
17 (79%)
Me
Me
Scheme 3 Synthesis of falipamil (1) and related compounds
The potential of this process, which offers, at least, com- 2d and 17 structurally related to the biologically active
plementary and, at best, significant advantages over the compounds, 2a and 1, respectively. For this purpose the
classical methodologies was further demonstrated by the propionaldehyde derivative 14d was allowed to react with
conceptually new synthesis of the bradycardic agent fali- the arylated piperazine 15 and with the N-methylmethyl-
pamil (1). Falipamil (1) is endowed with a rather unique benzylamine 18 under reductive amination conditions.
biological profile. It reduces heart rate specifically but is This operation delivered excellent yields of the homolo-
not a b-blocker,12 it does not interfere with the cardiac gated analogue of 2a, that is, 2d, and of the isomeric fali-
conducting system at therapeutic doses,13 and its benefit pamil 17. Curiously the synthesis of compound 17 seemed
in myocardial ischemia has been shown in a number of an- to be precedented,16 but closer analysis of the purported
imal models14 and in human studies.15 For this purpose structure of the synthetic material led to the conclusion
installation of the requisite N-methyl-N-dimethoxy- that the structure should be revised from 17 to 1. Thus, the
phenethylamino moiety was readily secured by coupling synthesis of the C-methyl isomeric model 17 can arguably
the N-chloropropylisoindolinone 13d with N-methylho- be deemed as the first total synthesis of this falipamil
moveratrylamine 16 under basic conditions to afford a sat- analogue. It is noteworthy that this synthetic route could
isfactory yield of the targeted compound 1.
not be applied to the synthesis of 2a–c due to the hardly
explainable low efficiency of the Swern oxidation process
applied to 9a–c that furnished only trace amounts of the
required aldehydes 14a–c (e.g., 14a–c: yield 12%).
Evaluation of a proposed alternative approach (pathway
b) was next envisaged. Since interest in designing effi-
cient synthetic procedures is to allow structure–activity
relationship studies and to find analogues with improved The analytical and spectral data of all the new synthesized
biological activities we set out to achieve the assembly of compounds are listed in Table 1 and Table 2.
Synthesis 2009, No. 11, 1897–1903 © Thieme Stuttgart · New York

1900
M. Lorion et al.
PAPER
Table 1 Spectroscopic and Physical Data of Imidazolinones 5d,e and Oxazolidinones 10a,b
Producta Mp (°C)
1H NMR (CDCl3/TMS); d, J (Hz)
13C NMR (CDCl3/TMS); d
42.1 (CH2), 42.2 (CH2), 47.6 (CH2), 48.3 (CH2), 56.0
5d
90–91
3.06–3.19 (m, 4 H, 2 ꢀ NCH2), 3.77 (s, 3 H, OCH3),
(pale yellow 3.79 (s, 3 H, OCH3), 4.33 (s, 2 H, NCH2Ph), 4.42 (s, 2 (CH3), 56.1 (CH3), 112.7 (C), 113.9 (CH), 115.1 (CH),
crystals)
H, ArCH2N), 6.87 (s, 1 Harom), 6.91 (s, 1 Harom), 7.19– 127.4 (2 ꢀ CH), 128.0 (CH), 128.4 (2 ꢀ CH), 128.5 (C),
7.27 (m, 5 Harom
)
137.1 (C), 148.8 (C), 148.9 (C), 160.9 (C=O)
5e
95–96
3.07–3.20 (m, 4 H, 2 ꢀ NCH2), 3.77 (s, 3 H, OCH3),
42.1 (CH2), 42.3 (CH2), 48.3 (CH2), 56.1 (CH2), 56.0
(white
crystals)
3.79 (s, 3 H, OCH3), 4.35 (s, 2 H, NCH2Ph), 4.40 (s, 2 (CH3), 56.1 (CH3), 87.4 (C), 112.1 (CH), 121.2 (CH), 127.4
H, ArCH2N), 6.86 (s, 1 Harom), 7.13 (s, 1 Harom), 7.19– (CH), 128.1 (2 ꢀ CH), 128.6 (2 ꢀ CH), 132.0 (C), 137.2 (C),
7.29 (m, 5 Harom
)
148.9 (C), 149.7 (C), 160.9 (C=O)
10a
10b
51–52
(white
crystals)
3.44 (t, J = 8.0, 2 H, CH2N), 4.27 (t, J = 8.0, 2 H,
OCH2), 4.52 (s, 2 H, ArCH2N), 7.12 (td, J = 2.0, 7.5, 1 129.6 (CH), 129.9 (CH), 133.0 (CH), 135.0 (C), 158.5
H), 7.23–7.33 (m, 2 Harom), 7.47 (d, J = 7.9, 1 H) (C=O)
44.1 (CH2), 48.1 (CH2), 62.0 (CH2), 123.7 (C), 128.0 (CH),
111–112
(white
crystals)
3.13–3.32 (m, 2 H, NCH2), 4.27 (t, J = 7.9, 2 H, CH2O), 43.3 (CH2), 60.6 (CH2), 62.3 (CH), 124.9 (C), 127.5 (CH),
6.42 (s, 1 H, ArCHPh), 6.99 (dd, J = 1.8, 7.8, 1 Harom), 127.8 (CH), 127.9 (2 ꢀ CH), 128.8 (2 ꢀ CH), 129.7 (CH),
7.06–7.13 (m, 3 Harom), 7.17–7.30 (m, 4 Harom), 7.53 (dd, 129.9 (CH), 133.6 (CH), 137.9 (C), 138.2 (C), 157.8 (C=O)
J = 1.4, 7.8, 1 Harom
)
a Satisfactory microanalyses obtained: C 0.24, H 0.27, N 0.22.
Table 2 Spectroscopic and Physical Data of N-Alkyl-Functionalized Isoindolinones
Product
Mp (°C)
1H NMR (CDCl3/TMS); d, J (Hz)
13C NMR (CDCl3/TMS); d
4d
125–126
(fawn
2.86 (t, J = 6.1, 2 H, CH2N), 3.66 (t, J = 6.1, 2 H,
NCH2), 3.76 (s, 2 H, NCH2Ph), 3.84 (s, 3 H, OCH3),
3.85 (s, 3 H, OCH3), 4.25 (s, 2 H, ArCH2N), 6.81 (s, 1 127.1 (CH), 128.2 (2 ꢀ CH), 128.4 (2 ꢀ CH), 134.9 (C),
42.4 (CH2), 47.5 (CH2), 50.4 (CH2), 53.4 (CH2), 56.2
(CH3), 56.3 (CH3), 104.9 (CH), 105.2 (C), 125.0 (CH),
crystals)a
Harom), 7.12–7.27 (m, 6 Harom
)
139.6 (C), 149.6 (C), 152.4 (C), 163.9 (C=O)
9b
111–112
(yellow
2.86–2.95 (m, 1 H, NCH2), 3.54–3.68 (m, 2 H,
CH2OH), 3.74–3.82 (m, 1 H, NCH2), 4.40 (br s, 1 H,
OH), 5.55 (s, 1 H, ArCHPh), 6.95–7.00 (m, 3 Harom),
43.4 (CH2), 60.9 (CH2), 65.8 (CH), 123.1 (CH), 123.3
(CH), 127.7 (2 ꢀ CH), 128.2 (CH), 128.7 (2 ꢀ CH), 129.1
(CH), 131.2 (C), 131.9 (CH), 136.8 (C), 146.7 (C), 169.6
(CO)
crystals)a
7.13–7.27 (m, 5 Harom), 7.63–7.66 (m, 1 Harom
)
13a
13b
79–80b
(white
crystals)
3.74 (t, J = 5.6, 2 H, CH2Cl), 3.90 (t, J = 5.8, 2 H,
NCH2), 4.52 (s, 2 H, ArCH2N), 7.38–7.41 (m, 2 Harom), (CH), 128.1 (CH), 131.6 (CH), 132.2 (C), 141.4 (C), 168.8
7.43–7.52 (m, 1 Harom), 7.80 (d, J = 7.4, 1 Harom). (C=O)
42.7 (CH2), 44.6 (CH2), 51.4 (CH2), 122.8 (CH), 123.6
90–91
3.06–3.15 (m, 1 H, CH2Cl), 3.41–3.48 (m, 1 H, CH2Cl), 42.3 (2 ꢀ CH2), 65.6 (CH), 123.1 (CH), 123.6 (CH), 127.7
(yellowish 3.59–3.68 (m, 2 H, NCH2), 5.59 (s, 1 H, ArCHPh),
(2 ꢀ CH), 128.4 (CH), 128.9 (CH), 129.3 (2 ꢀ CH), 131.0
crystals)
7.01–7.06 (m, 3 Harom), 7.18–7.25 (m, 3 Harom), 7.30– (C), 132.1 (CH), 136.7 (C), 146.5 (C), 168.6 (C=O)
7.37 (m, 2 Harom), 7.78–7.81 (m, 1 Harom
)
13c
13d
114–115
(white
crystals)
3.71 (t, J = 5.8, 2 H, CH2Cl), 3.78–3.80 (m, 2 H,
NCH2), 3.81 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 4.05 (CH3), 62.5 (CH3), 101.3 (CH), 116.7 (C), 130.9 (C), 141.4
(s, 3 H, OCH3), 4.39 (s, 2 H, ArCH2N), 6.63 (s, 1 Harom) (C), 151.2 (C), 157.1 (C), 167.0 (C=O)
42.5 (CH2), 44.4 (CH2), 50.7 (CH3), 56.2 (CH2), 61.3
110–111
(white
crystals)
2.14 (quint, J = 6.7, 2 H, CH2), 3.58 (t, J = 6.5, 2 H,
CH2Cl), 3.72 (t, J = 6.9, 2 H, NCH2), 3.91 (s, 3 H,
OCH3), 3.92 (s, 3 H, OCH3), 4.32 (s, 2 H, ArCH2N),
31.4 (CH2), 40.2 (CH2), 42.3 (CH2), 50.3 (CH2), 56.2 (2 ꢀ
CH3), 104.9 (CH), 105.2 (CH), 124.9 (C), 134.6 (C), 149.6
(C), 152.5 (C), 169.1 (C=O)
6.90 (s, 1 Harom), 7.27 (s, 1 Harom
)
14a
14d
118–119
(white
4.51–4.53 (m, 4 H, 2 ꢀ CH2), 7.46–7.51 (m, 2 Harom),
7.56–7.59 (m, 1 Harom), 7.87–7.90 (m, 1 Harom), 9.74 (s, (CH), 131.6 (C), 131.9 (CH), 141.5 (C), 169.2 (C=O),
1 H, CHO) 196.8 (CHO)
50.8 (CH2), 52.4 (CH2), 122.9 (CH), 124.0 (CH), 128.2
crystals)a
122–123
(white
2.85 (t, J = 6.2, 2 H, CH2CO), 3.82 (s, 1 H, NCH2), 3.84 36.0 (CH2), 42.9 (CH2), 50.3 (CH2), 56.0 (CH3), 56.1
(s, 1 H, NCH2), 3.86 (s, 3 H, OCH3), 3.87 (s, 3 H, (CH3), 104.8 (CH), 104.9 (CH), 124.4 (C), 134.9 (C), 149.4
OCH3), 4.30 (s, 2 H, ArCH2N), 6.84 (s, 1 Harom), 7.22 (s, (C), 152.3 (C), 168.8 (C=O), 197.7 (CHO)
crystals)a
1 Harom), 9.79 (s, 1 H, CHO)
Synthesis 2009, No. 11, 1897–1903 © Thieme Stuttgart · New York

PAPER
Synthesis of Falipamil and 5-HT1A Receptor Ligand Analogues
1901
Table 2 Spectroscopic and Physical Data of N-Alkyl-Functionalized Isoindolinones (continued)
Product
Mp (°C)
117–118
1H NMR (CDCl3/TMS); d, J (Hz)
13C NMR (CDCl3/TMS); d
39.4 (CH2), 50.6 (2 ꢀ CH2), 50.8 (CH2), 53.5 (2 ꢀ CH2),
2a
2.58–2.62 (m, 6 H, 3 ꢀ CH2), 2.93–2.99 (m, 4 H, 2 ꢀ
(yellowish CH2), 3.66 (t, J = 6.4, 2 H, CH2N), 3.72 (s, 3 H, OCH3), 55.3 (CH3), 56.7 (CH2), 111.2 (CH), 118.1 (CH), 120.9
crystals)a
4.39 (s, 2 H, ArCH2N), 6.71–6.74 (m, 1 Harom), 6.78– (CH), 122.7 (CH), 122.9 (CH), 123.5 (CH), 127.8 (CH),
6.81 (m, 2 Harom), 6.85–6.90 (m, 1 Harom), 7.28–7.33 (m, 131.1 (CH), 132.8 (C), 141.2 (C), 141.5 (C), 152.2 (C),
2 Harom), 7.39–7.42 (m, 1 Harom), 7.71–7.74 (m, 1 Harom
)
168.4 (C=O)
2b
2c
2d
17
168–169
2.36–2.64 (m, 6 H, 3 ꢀ CH2), 2.90–2.99 (m, 5 H, 2 ꢀ
37.1 (CH2), 50.7 (2 ꢀ CH2), 53.4 (2 ꢀ CH2), 55.4 (CH3),
(yellowish CH2 + 1 H NCH2), 3.72 (s, 3 H, OCH3), 3.96–4.04 (m, 57.0 (CH2), 65.4 (CH), 111.2 (CH), 118.1 (CH), 121.0
crystals)a
1 H, NCH2), 5.67 (s, 1 H, ArCHPh), 6.72–6.90 (m, 4
Harom), 7.04–7.06 (m, 3 Harom), 7.21–7.23 (m, 3 Harom), 128.2 (2 ꢀ CH), 128.6 (CH), 129.1 (2 ꢀ CH), 131.2 (CH),
(CH), 122.9 (CH), 123.0 (CH), 123.5 (CH), 127.5 (CH),
7.30–7.33 (m, 2 Harom), 7.78–7.81 (m, 1 Harom
)
131.5 (C), 137.3 (C), 141.3 (C), 146.7 (C), 152.2 (C), 168.6
(C=O)
118–119
(white
2.56–2.62 (m, 6 H, 3 ꢀ CH2), 2.93–3.02 (m, 4 H, 2 ꢀ
39.3 (CH2), 50.3 (CH2), 50.7 (2 ꢀ CH2), 53.4 (2 ꢀ CH2),
CH2), 3.61 (t, J = 6.3, 2 H, CH2N), 3.75 (s, 3 H, OCH3), 55.3 (CH3), 56.2 (CH3), 56.7 (CH2), 61.4 (CH3), 62.6
3.78 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.03 (s, 3 H, (CH3), 101.2 (C), 111.1 (CH), 117.5 (CH), 118.0 (CH),
OCH3), 4.31 (s, 2 H, ArCH2N), 6.62 (s, 1 Harom), 6.74– 120.9 (CH), 122.9 (CH), 139.1 (C), 141.2 (C), 141.5 (C),
6.76 (m, 1 Harom), 6.80–6.83 (m, 2 Harom), 6.88–6.91 (m, 151.3 (C), 152.2 (C), 156.8 (C), 166.8 (C=O)
crystals)a
1 Harom
)
56–57
1.86 (quint, J = 7.5, 2 H, CH2), 2.45 (t, J = 7.2, 2 H,
CH2), 2.63 (br s, 4 H, Hpiperazine), 3.01 (br s, 4 Hpiperazine), ꢀ CH2), 55.2 (CH3), 55.5 (CH3), 56.1 (CH2), 56.1 (CH3),
3.55 (t, J = 7.3, 2 H, CH2), 3.72 (s, 3 H, OCH3), 3.80 (s, 105.0 (2 ꢀ CH), 111.1 (CH), 118.1(CH), 120.9 (C), 123.0
3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.22 (s, 2 H,
ArCH2N), 6.72–6.74 (m, 1 Harom), 6.78–6.81 (m, 3
25.4 (CH2), 40.4 (CH2), 49.6 (CH2), 50.0 (2 ꢀ CH2), 53.2 (2
(fawn
crystals)a
(CH), 124.8 (CH), 134.7(C), 140.8 (C), 149.4 (C), 152.0
(C), 152.3 (C), 168.8 (C=O)
Harom), 6.85–6.90 (m, 1 Harom), 7.18 (s, 1 Harom
)
207–208
(white
1.20 (d, J = 6.6, 3 H, NCHCH3), 1.64-1.73 (m, 2 H,
CH2), 2.11 (s, 3 H, NCH3), 2.17–2.24 (m, 1 H, NCH2), (CH2), 55.6 (CH3), 56.0 (CH3), 56.1 (CH2), 56.1 (CH3),
2.29–2.35 (m, 1 H, NCH2), 3.32–3.37 (m, 1 H, NCH2), 56.3 (CH3), 65.7 (CH), 104.8 (CH), 105.1 (CH), 110.7
23.5 (CH3), 29.5 (CH2), 39.4 (CH2), 49.6 (CH3), 51.0
crystals)a
3.40–3.52 (m, 2 H, NCH2 + NCHMe), 3.71 (s, 3 H,
(CH), 111.6 (CH), 121.3 (CH), 123.9 (C), 126.2 (C), 135.0
OCH3), 3.77 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.82 (C), 149.3 (C), 149.4 (C), 149.8 (C), 152.5 (C), 169.2
(s, 3 H, OCH3), 4.03 (br s, 2 H, ArCH2N), 6.61–6.70 (m, (C=O)
2 Harom), 6.77 (s, 1 Harom), 6.80 (s, 1 Harom), 7.16 (s, 1
Harom
)
a Satisfactory microanalyses obtained: C 0.22, H 0.26, N 0.28.
b Lit.24 mp 81–82 °C.
ternal standard. The o-bromobenzyl bromides 7a,17 7b,18 7c,19 7d,20
and o-bromobenzyl iodide 7e21 were prepared according to reported
procedures. Amines 15 and 16 are commercially available and
amine 1822 was synthesized following literature methods.
In summary, complementary and tactically new synthetic
approaches to aminoalkyl-tethered isoindolinones with a
variety of bridging units have been developed. The main
synthetic route hinges upon the assembling of the poly
and diversely substituted benzolactam units tailed with
hydroxyalkyl chains, which allow for sufficient versatility
for further tailor-made structural modifications. We be-
lieve that the methodology established for the synthesis of
the exemplary representatives may find utility for abbre-
viated synthesis of structurally related congeners of phar-
maceutical interest.
N-Substituted Imidazolinones 5d,e, 6, Oxazolidinones 10a–c
and Oxazinanone 10d; General Procedure
A solution of the parent heterocycle (4 mmol) in THF (10 mL) was
added to a stirred suspension of pentane-prewashed NaH (108 mg,
4.5 mmol, from a 60% suspension in mineral oil) in THF (20 mL)
under argon. The mixture was stirred for 1 h at r.t. and a solution of
benzyl bromide or o-halobenzyl bromide derivative 7a–e (4.5
mmol) in THF (10 mL) was then added dropwise. The mixture was
refluxed overnight and after cooling, H2O (20 mL) was added, and
the mixture was extracted with Et2O (3 ꢀ 20 mL). The combined or-
ganic layers were dried (Na2SO4), and the solvent was evaporated
under vacuum affording a crude solid residue, which was purified
by flash column chromatography on silica gel using EtOAc–hex-
anes–CH2Cl2 (30:20:50) as eluent for 5d (824 mg, 51%); EtOAc–
hexanes (40:60) as eluent for 5e (1.01 g, 56%); EtOAc–hexanes–
CH2Cl2 (30:20:50) as eluent for 10a (601 mg, 59%), EtOAc–hex-
anes (50:50) as eluent for 10b (715 mg, 54%). Compounds 623 (649
mg, 92%), 10c10b (814 mg, 59%), 10d10b (855 mg, 65%) were puri-
fied according to literature (Table 1).
THF was predried with anhyd Na2SO4 and distilled over sodium
benzophenone ketyl under argon before use. CH2Cl2, Et3N, and tol-
uene were distilled from CaH2. Dry glassware was obtained by
oven-drying and assembled under dry argon. The glassware was
equipped with rubber septa and reagent transfer was performed by
syringe techniques. For flash chromatography, Merck silica gel 60
(40–63 mm; 230–400 mesh ASTM) was used. Melting points were
obtained on a Reichert-Thermopan apparatus and are not corrected.
Elemental analyses were obtained using a Carlo-Erba CHNS-11110
equipment. NMR spectra were recorded on a Bruker AM 300 (300
MHz and 75 MHz, for 1H, and 13C), CDCl3 as solvent, TMS as in-
Isoindolinones 4d and 9a–d; General Procedure
Synthesis 2009, No. 11, 1897–1903 © Thieme Stuttgart · New York

1902
M. Lorion et al.
PAPER
A solution of n-BuLi (2 M in hexane, 1.50 mL, 3.0 mmol) and
TMEDA (350 mg, 3.0 mmol) in anhyd THF (4 mL) was carefully
degassed by three freeze-thaw cycles and stirred at –78 °C under
dry deoxygenated argon. A solution of compound 5d, 10a–d (1.0
mmol) in degassed THF (15 mL) was then added dropwise through
a cannula. The mixture was stirred at –78 °C for 30 min. After
quenching with aq sat. NH4Cl (5 mL) and dilution with H2O (30
mL), THF was removed under vacuum in a rotary evaporator and
the aqueous phase was extracted with CH2Cl2 (2 ꢀ 30 mL). The
combined organic layers were dried (Na2SO4), and the solvent was
evaporated under vacuum to leave the isoindolinone as a solid resi-
due, which was purified by flash column chromatography on silica
gel using acetone–hexanes–Et3N (80:15:5) as eluent for 4d (75 mg,
23%); acetone–hexanes (80:20) as eluent for 9a (126 mg, 71%),4b,24
9c (214 mg, 80%),10b 9d (198 mg, 79%);10b and acetone–hexanes
(60:40) as eluent for 9b (213 mg, 84%) (Table 2).
using acetone–hexanes–Et3N (40:55:5) as eluent; yield: 2a (249 mg,
71%), 2b (260 mg, 61%), 2c (234 mg, 53%) (Table 2).
Aldehydes 14a,d by Oxidation of 9a,d
Anhyd DMSO (351 mg, 4.5 mmol) was added dropwise to a solu-
tion of oxalyl chloride (280 mg, 2.2 mmol) in anhyd CH2Cl2 (15
mL) at –78 °C under argon. The mixture was stirred at –78 °C for
30 min and a solution of 9a,d (1.1 mmol) in CH2Cl2 (25 mL) was
added slowly. After stirring for 1 h, Et3N (606 mg, 6 mmol) was
added and the reaction mixture was allowed to warm to r.t. over 2
h. H2O (20 mL) was added and the mixture concentrated under vac-
uum. The residue was redissolved in CH2Cl2 (30 mL) and the solu-
tion was washed with H2O (3 ꢀ 10 mL) and brine (10 mL). The
solution was dried (MgSO4) and evaporated under vacuum. Purifi-
cation of the solid residue by flash column chromatography using
acetone–hexanes (80:20) as eluent afforded 14a (22 mg, 12%) and
14d (195 mg, 71%), respectively (Table 2).
2-(2-Benzylaminoethyl)-5,6-dimethoxy-2,3-dihydro-1H-iso-
indol-1-one (4d) Starting from 5e; Improved Procedure
Reductive Amination Reaction Involving 14d; General Proce-
dure
A solution of o-iodobenzyl derivative 5e (452 mg, 1.0 mmol) and
TMEDA (203 mg, 2.2 mmol) in anhyd THF (20 mL) was carefully
degassed by three freeze-thaw cycles and stirred at –78 °C under
dry deoxygenated argon. A solution of n-BuLi (2 M in hexane, 1.1
mL, 2.2 mmol) was then added dropwise. The mixture was stirred
for 30 min at –78 °C, then treated as described above to afford 4d
(176 mg, 54%); fawn crystals.
NaBH(OAc)3 (297 mg, 1.4 mmol) was added portionwise to a solu-
tion of 14d (249 mg, 1.0 mmol) and amine 15 or 18 (1.0 mmol) in
1,2-dichloroethane (10 mL) followed by AcOH (60 mg, 1.0 mmol).
The mixture was stirred at r.t. under argon for 24 h, then quenched
by addition of aq 1 N NaOH (10 mL). CH2Cl2 (10 mL) was added
and the organic layer separated. The aqueous layer was extracted
with CH2Cl2 (2 ꢀ 10 mL). The combined organic layers were
washed with brine (5 mL) and dried (MgSO4). The solvent was
evaporated to give the crude free base; yield: 2d (387 mg, 91%), 17
(338 mg, 79%) (Table 2).
N-(Chloroalkyl)isoindolinones 13a–d; General Procedure
SOCl2 (400 mg, 3.4 mmol) was added dropwise to an ice-water
cooled solution of N-hydroxyalkylisoindolinone 9a–c (3.0 mmol) in
toluene (50 mL). The reaction mixture was allowed to stand at r.t.
for 4 h with occasional swirling, then the mixture was heated at
60 °C for 3 h. The toluene and the excess SOCl2 were removed by
distillation under vacuum and the hot residue was poured into hex-
anes (50 mL) to afford a brown solid. After filtration, the solid was
dissolved in refluxing toluene (20 mL). The solution was filtered
hot, and the hot filtrate was poured into hexanes (30 mL) with stir-
ring. The precipitate was filtered, washed with hexanes, and dried
in a vacuum oven to afford 13a–d as white solid, which was used
without further purification. Yield of crude products: 13a (557 mg,
95%), 13b (717 mg, 88%), 13c (823 mg, 96%), 13d (671 mg, 83%)
(Table 2).
Acknowledgment
This research was supported by the Centre National de la Recherche
Scientifique and MENESR (grant to M.L.).
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(MgSO4). Evaporation of the solvent in vacuo left an oily residue,
which was purified by flash column chromatography on silica gel
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