Preparation of poly and diversely substituted N-alkylated and free-NH isoindolin-1-ones

Article abstract of DOI:10.1055/s-2007-965955

A variety of diversely substituted N-alkylated and free-NH isoindolin-1-ones have been efficiently prepared by treatment of suitably substituted di- and monoacylated halobenzylamines, respectively, with a lithiated base. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965955

1434
PRACTICAL SYNTHETIC PROCEDURES
Preparation of Poly and Diversely Substituted N-Alkylated and Free-NH
Isoindolin-1-ones
Preparation of
Isoi
x
ndolin-1-one
e
s
l Couture,* Eric Deniau, Marc Lamblin, Magali Lorion, Pierre Grandclaudon
UMR 8009 ‘Chimie Organique et Macromoléculaire’, Laboratoire de Chimie Organique Physique,
Université des Sciences et Technologies de Lille, Bâtiment C3(2), 59655 Villeneuve d’Ascq Cedex, France
Fax +33(3)20336309; E-mail: axel.couture@univ-lille1.fr
PSP
Received 11 January 2007
No82
Abstract: A variety of diversely substituted N-alkylated and free-NH isoindolin-1-ones have been efficiently prepared by treatment of suit-
ably substituted di- and monoacylated halobenzylamines, respectively, with a lithiated base.
Key words: lactams, metalations, ring closure
Procedure 1
R1
R1
1. t-BuLi, THF, –90 °C , 0.5 h then r.t.
O
R2
R3
Br
R2
R3
2. H3O+
O
R5
OMe
N
N
55–85%
R5
R4
R4
3
1
Procedure 2
R1
R1
1. n-BuLi, THF, –90 °C , then reflux, 0.5 h
2. H3O+
O
R2
R3
R2
I
O
OMe
OMe
N
H
R3
N
55–65%
R4
R4
O
2
4
Scheme 1
Isoindolin-1-ones and their derivatives of generic struc- timate creation of the lactam unit. It is worth noting that
ture 1, 2 have gained considerable attention due to their none of these synthetic routes has been secured by ex-
diverse and demonstrated physiological and chemothera- ploiting the reactivity and functionalization of the parent
peutic activities.1 The interest in these heterobicyclic phthalimidines. All these synthetic approaches are of pro-
models stems also from their importance as key interme- cedural simplicity and generally proceed in satisfactory
diates in organic synthesis namely for the construction of yields. However these methods suffer from several draw-
various drugs and biologically active compounds.2 The backs and particularly from restrictions in the choice of
isoindolinone moiety is also an integral part of a great va- substituents in their nature, their number and their specific
riety of naturally occurring compounds, namely alka- position on the basic aromatic nucleus. Furthermore, the
loids.3
elaboration of free-NH models 2 requires an additional
and somewhat erratic deprotection step.4
Organic chemists have at their disposal a great number of
synthetic methods for the preparation of substituted isoin- A new synthetic approach to these bicyclic lactams 1, 2
dolinones. The most common synthetic routes are por- that is based on the Parham cyclization protocol,5 i.e., cre-
trayed in Scheme 2, Table 1. All these synthetic strategies ation of an aryllithiated species by halogen–metal ex-
are based upon the annulation of an aromatic precursor change and subsequent trapping by an internal
equipped with appropriate functionalities to ensure the ul- electrophile, has been developed. The procedures summa-
rized in Scheme 1 encompass a unique set of reactions
which allow equally well for the assembly of poly, di-
SYNTHESIS 2007, No. 9, pp 1434–1437
Advanced online publication: 28.02.2007
DOI: 10.1055/s-2007-965955; Art ID: Z01007SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7
versely, symmetrically and unsymmetrically substituted
N-alkylated and free-NH isoindol-1-one models
(Table 2).

PRACTICAL SYNTHETIC PROCEDURES
Preparation of Isoindolin-1-ones
1435
O
O
COOEt
N
R
R
N
O
O
Me
P
Br
Ph
Ph
O
a
j
b
O
NHR
i
c
O
N
R
X
O
d
h
1
I
NHR
e
g
Br
X = N
f
OH
COOH
O
NHR
NEt2
Br
CHO
N
Scheme 2 Synthetic routes to N-alkylated isoindolin-1-ones 1
Table 1 Reagents and Conditions for the Synthesis of 16–15
applied to the model compound where the carbamate
function is embedded in an oxazolinone ring system, e.g.,
3g, as exemplified by the product benzolactam 1g
equipped with an hydroxyalkyl chain which may serve as
a handle for further synthetic development (Table 2, entry
7). Unfortunately, probably due to unfavorable geometry
of the parent compound and/or steric congestion of this
precursor all attempts to cyclize the bromoaryl piperidine
5 (Figure 1) met with no success.
Entry
Reagents and conditions
Ref.
a
b
c
Zn, AcOH, reflux
6
7
8
KHMDS, –78 °C to r.t., then H2O, OH–, reflux
Pd(OAc)2/Cu(OAc)2, air, CO (1 atm), toluene,
reflux
d
e
f
Pd Cys, CO (1 atm), RNH2, K2CO3, DMF
PPh3, n-Bu3N, CO (1 atm)
LTMP, RCH2CN, aq NH4Cl
RNH2, AcOH, reflux
9
10
11
12
13
14
15
Br
O
i-Pr-O
Me
Br
O
N
OMe
O
N
MeO
g
h
i
3g
5
i-PrMgCl, DMI, ClP(O)(NMe2)2
RNH2, reflux
Figure 1 Compounds 3g and 5
j
NBS, AIBN, CCl4, then RNH2, MeOH
Procedures
Herein we describe two typical procedures for the two
substrate classes depicted in Scheme 1 and in Table 2.
Some of the products 1, 2 have not been previously de-
scribed. Therefore, detailed analytical data for these com-
pounds are provided.
In order to ensure the optimal formation of the target an-
nulated compounds 1, 2, variations of the metalating
agent, temperature profile, and time were screened. The
procedures are technically simple and readily provide an
array of aromatic bicyclic lactams that can be used for fur-
ther synthetic planning, e.g., functionalization, but not
limited at C-3.16
Procedure 1
A solution of t-BuLi (1.7 M in pentane, 1.3 mL, 2.2 mmol) was add-
ed dropwise at –90 °C under argon to a solution of the carbamate 3
(2 mmol) in THF (30 mL). The solution was stirred at –90 °C for 30
min, and then aq sat. NH4Cl solution (5 mL) was added. The cooled
mixture was extracted with Et2O (2 × 25 mL). The combined ex-
tracts were dried (Na2SO4) and evaporated under reduced pressure
to leave a solid, which was purified by column chromatography on
Scope and Limitations
The annulation technique tolerates the presence of fluori-
nated substituents that survive the halogen–metal inter-
conversion reaction required to secure the lactam unit
formation (Table 2, entries 5,6). This process can also be silica gel using EtOAc–hexanes (50:50) as eluent [acetone–hexanes
(80:20) for 1g] to give the isoindolinone 1 (Table 2).
Synthesis 2007, No. 9, 1434–1437 © Thieme Stuttgart · New York

1436
A. Couture et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Isoindol-1-ones 1, 2 Prepared17–21
6,6,7-Trimethoxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-
1H-isoindol-1-one (1c)
Mp 94–95 °C (hexane–toluene).
Entry Producta
Yield (%) Ref.
1H NMR (300 MHz, CDCl3): d = 3.75 (s, 3 H), 3.84 (s, 6 H), 4.09
(s, 2 H), 4.12 (s, 3 H), 4.62 (s, 2 H), 6.60 (s, 1 H), 6.81 (d, J = 8.7
Hz, 2 H), 7.19 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 45.5, 48.8, 55.3, 56.2, 61.4, 62.6,
101.3, 114.0, 117.4, 129.4, 129.5, 138.7, 141.6, 151.5, 157.0, 159.0,
166.8.
O
1
1a
1b
63
17
O
O
N
PMB
2
55
18
O
i-PrO
Me
Anal. Calcd for C19H21NO5 (343.4): C, 66.46; H, 6.16; N, 4.08.
Found: C, 66.31; H, 6.07; N, 3.92.
N
PMB
OMe
6-Benzyloxy-5,7-dimethoxy-2-[(4-methoxyphenyl)methyl]-2,3-
dihydro-1H-isoindol-1-one (1d)
Oil.
3
4
5
1c
1d
1e
85
82
70
–
–
–
OMe
O
MeO
MeO
BnO
MeO
1H NMR (300 MHz, CDCl3): d = 3.76 (s, 3 H), 3.81 (s, 3 H), 4.10
(s, 5 H), 4.64 (s, 2 H), 5.01 (s, 2 H), 6.60 (s, 1 H), 6.84(d, J = 8.0 Hz,
2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.25–7.37 (m, 3 H), 7.48–7.50 (m, 2
H).
13C NMR (75 MHz, CDCl3): d = 45.6, 48.9, 55.3, 56.2, 62.6, 75.7,
101.4, 114.1, 117.5, 128.0, 128.3, 128.5, 129.4, 129.5, 137.5, 138.9,
140.6, 151.8, 157.3, 159.1, 166.8.
N
PMB
PMB
OMe
O
N
O
N
Anal. Calcd for C25H25NO5 (419.5): C, 71.58; H, 6.01; N, 3.34.
Found: C, 71.71; H, 6.12; N, 3.53.
F
2-[2-(3-Fluorophenyl)ethyl]-2,3-dihydro-1H-isoindol-1-one (1e)
Mp 82–84 °C (hexane–toluene).
6
7
1f
69
69
19
20
O
1H NMR (300 MHz, CDCl3): d = 2.96 (t, J = 7.3 Hz, 2 H), 3.83 (t,
J = 7.3 Hz, 2 H), 4.20 (s, 2 H), 6.85–7.00 (m, 3 H), 7.18–7.25 (m, 1
H), 7.35–7.51 (m, 3 H), 7.81 (d, J = 7.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 34.6, 43.8, 50.5, 113.5 (d, JC,F = 21
Hz), 115.5 (d, JC,F = 21 Hz), 122.7, 123.6, 124.4 (d, JC,F = 3 Hz),
128.0, 130.1 (d, JC,F = 8 Hz), 131.3, 132.7, 141.1, 141.3 (d, JC,F = 7
Hz), 162.9 (d, JC,F = 244 Hz), 168.5.
F
O
O
N
O
1g
i-PrO
Me
N
OH
Anal. Calcd for C16H14FNO (255.3): C, 75.28; H, 5.53; N, 5.49.
Found: C, 75.03; H, 5.65; N, 5.40.
OMe
O
8
2a
55
21
OMe
Procedure 2
A solution of n-BuLi (1.4 mL, 1.6 M in hexanes, 2.2 mmol) was add-
ed dropwise at –90 °C under argon to a solution of the dicarbamate
4 (2 mmol) in anhyd THF (30 mL). The mixture was stirred at
–90 °C for an additional 15 min, slowly allowed to warm to r.t. over
1 h, and then refluxed for 30 min. The mixture was cooled to r.t.,
quenched with aq sat. NH4Cl solution (10 mL), and extracted with
Et2O (3 × 10 mL). The combined organic extracts were washed with
brine (5 mL) and dried (Na2SO4). After evaporation of the solvent,
the crude oily residue was purified by column chromatography us-
ing EtOAc as eluent to afford the annulated compounds 2 (recrys-
tallization from MeCN–Et2O) (Table 2).
NH
9
10
11
2b
2c
2d
51
64
65
21
21
21
O
NH
MeO
OMe
O
BnO
NH
O
Acknowledgment
NH
This research was supported by the Centre National de la Recherche
Scientifique and MENESR (grant to M.L. and M.L.).
a PMB: p-methoxybenzyl.
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PRACTICAL SYNTHETIC PROCEDURES
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1437
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Synthesis 2007, No. 9, 1434–1437 © Thieme Stuttgart · New York