A convenient synthesis of 4-alkoxylated isoindolin-1-ones

Article abstract of DOI:10.1055/s-2004-829114

A short synthesis of 4-alkoxylated isoindolin-1-ones based upon the S _NAr reaction applied to phosphorylated 2-methoxybenzamides followed by alkaline cleavage of the phosphoryl auxiliary is reported.

Full text of DOI:10.1055/s-2004-829114

1664
PAPER
A Convenient Synthesis of 4-Alkoxylated Isoindolin-1-ones
S
ynthesis of 4-Alk
n
oxylate
d
Iso
n
indolin-1-one
e
s
Moreau, Axel Couture,* Eric Deniau, Pierre Grandclaudon
Laboratoire de Chimie Organique Physique, UMR 8009 ‘Laboratoire de Chimie Organique et Macromoléculaire’, Université des Sciences
et Technologies de Lille, Bâtiment C3(2), 59655 Villeneuve d'Ascq Cédex, France
Fax +33(3)20336119; E-mail: axel.couture@univ-lille1.fr
Received 22 January 2004; revised 2 April 2004
O
Abstract: A short synthesis of 4-alkoxylated isoindolin-1-ones
based upon the SNAr reaction applied to phosphorylated 2-meth-
oxybenzamides followed by alkaline cleavage of the phosphoryl
auxiliary is reported.
N
1
OMe
Key words: metalations, carbanions, nucleophilic aromatic substi-
tutions, ring closure, cleavage
N
O
O
Ph
Ph
The isoindolinone ring system has featured in recent years
as a desirable synthetic target since it represents the core
unit of a wide range of natural compounds as exemplified
by fumaridine,1 nuevamine,2,3 lennoxamine3 and chile-
nine,4 and of synthetic pharmaceuticals with biological
activity such as indoprofen5 and DN 2327 (pazinaclone).6
N
N
2
F
OH
OMe
OMe
O
Ph
N
N
Within this family of 6,5-fused heterobicyclic com-
pounds, model compounds bearing alkoxy or hydroxy
groups at the 4-position of the aromatic nucleus occupy a
place of choice as witnessed by a great number of recent
patents emphasizing the biological potential of the pipe-
ridinyl derivatives 1 (sigma receptor ligand),7 2 (microso-
mal triglyceride transfer protein inhibitor),8 3 (psychoses
treatment)9 and of the anilinoethyl derivative 4 (inflam-
mation and allergy inhibitor).10 The 4-alkoxyisoindoli-
none moiety is also present in a wide array of natural
products such as zinnimidine (5),11 porritoxin (6),12 and
constitutes the framework of architecturally sophisticated
cularines as exemplified by aristoyagonine (7)13
(Figure 1).
3
O
NHMe
N
4
MeO
O
O
O
N
Me
O
MeO
N
R
O
Me
Organic chemists have at their disposal a great number of
synthetic methods for the preparation of substituted isoin-
dolinones but their applicability is quite insufficient be-
cause of restrictions in the choice of substituents namely
in their nature, their number and above all their position
on the aromatic nucleus.14–21 The most convenient routes
to these bicyclic lactams involve (i) the treatment of bro-
minated alkyl ortho-toluate with a primary amine,14 (ii)
the reductive amination process applied to ortho-acyl-
benzoic acids,15 (iii) the partial reduction of phthalimides
via their aminals or thioaminals,16 and (iv) the reaction of
ortho-phthalaldehyde17 or isobenzofuranones18 with a pri-
mary amine. Isoindolinones can also be synthesized by
reaction of ortho-bromobenzylamines with carbon
monoxide in the presence of n-Bu3N, Pd(OAc)2 and
OMe
MeO
MeO
7
5 R = H
6 R = (CH2)2-OH
Figure 1 Some compounds of biological interest containing the
isoindolino ring system
Ph3P19 and by base-induced cyclization of ortho-halo-
methylbenzamide derivatives.20 Finally, they have been
recently prepared by a palladium-catalyzed 3-component
carbonylation-amination cascade process.21 However,
these strategies have been mainly confined to the elabora-
tion of 2- and/or 3- substituted isoindolinones and in most
cases are inadequate for the synthesis of models with di-
verse and dense functionality, particularly with hydroxy
or alkoxy functions in specific positions on the basic ben-
zene nucleus. They are notably plagued by difficulties as-
sociated with the presence of such functions at the 4-
position of the aromatic unit. As a representative example,
partial reduction of 4-alkoxyphthalide derivatives affords
SYNTHESIS 2004, No. 10, pp 1664–1670
x
x.
x
x
.
2
0
0
4
Advanced online publication: 23.06.2004
DOI: 10.1055/s-2004-829114; Art ID: T00704SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 4-Alkoxylated Isoindolin-1-ones
1665
O
O
O
R1
N
O
P
R4
R3
R4
R3
R4
R1
N
R1
N
R3
OMe
Ph
P
R2
R2
R2
O
Ph
Ph
Ph
8, 9
10, 11
12, 13
Scheme 1
exclusively the corresponding 7-substituted phthalim- cedure inevitably gave rise to models which were
idines.22 We therefore considered that the development of unsubstituted at the 4-position of the aromatic nucleus;25
a more concise and efficient synthesis giving access to (ii) The sensitivity of alkoxy groups activated by ester,26
differentially substituted 4-alkoxyisoindolinones 8, 9 was amide,27 and above all oxazoline groups (the Meyers reac-
required.
tion)28 to nucleophilic aromatic substitution by various
nucleophiles, inter or intramolecularly, and (iii) The sen-
sitivity of the phosphoryl group with respect to SNP(V)
nucleophilic attack and consequently the possibility to
trigger the formation of the target compound by its release
from the phosphoryl appendage by alkaline cleavage.29
Our new synthetic approach which is depicted in the ret-
rosynthetic Scheme 1 hinges upon the exploitation of a
number of chemical properties linked to the anions de-
rived from the opened or cyclized phosphorylated benz-
amide derivatives 10, 11 and 12, 13, respectively.
The first facet of the synthesis, the elaboration of poly-
alkoxylated and phosphorylated benzamide derivatives
12a–d, 13a–c was readily accomplished by coupling the
suitably substituted benzoic acid derivatives 14a–d, via
their acyl chlorides, to the appropriate phosphorylated
amines 15, 16 (Scheme 2).
The key features of the method are based on: (i) The re-
markable nucleophilicity of phosphorylated aminocar-
banions, a property mainly used thus far in related systems
for the synthesis of aromatic enamines23 and enamides24
(Horner protocol). These carbanionic entities have also
been involved in the aryne-mediated cyclization of phos-
phorylated ortho-halobenzamide derivatives but this pro-
Scheme 2
Synthesis 2004, No. 10, 1664–1670 © Thieme Stuttgart · New York

1666
A. Moreau et al.
PAPER
Exposure of the phosphorylated ortho-methoxybenz- this protocol affords excellent yields of the target poly and
amide derivatives 12a–d and 13a–c to potassium bis(tri- diversely alkoxylated isoindolinones 8a–d and 9a–c (87–
methylsilyl)amide (KHMDS, 1.1 equiv) at –78 °C in the 95%, Table 1). Interestingly, isolation of the phosphory-
presence of 18-crown-6 induced the formation of the lated isoindolinones is not a prerequisite for the conver-
phosphoryl-stabilized a-aminocarbanion. Subsequent sion of the phosphorylated opened models into the desired
ortho-methoxy displacement by the transient carbanion, lactam compounds. Thus the phosphorylated benzamides
according to the nucleophilic aromatic substitution pro- 12, 13 could be treated with KHMDS at low temperature
cess (SNAr) portrayed in Scheme 2, brought about the in- and then with aqueous NaOH in sequence (Scheme 2,
tramolecular arylation reaction and usual acidic workup Method B). Gratifyingly this protocol delivered straight-
delivered the phosphorylated isoindolinones 10a–d and forwardly the fused lactam compounds albeit in more
11a–c.
modest yields (65–75%, Table 1). The analytical and
spectral data of compounds 8–14 are assembled in
Table 2.
It is noteworthy that, while SNAr reactions are usually car-
ried out with two equivalents of base, the methoxylate re-
leased in the annulation step was of sufficient kinetic
basicity to ensure deprotonation of the phosphorylated
benzylic position (Scheme 2). Consequently this new cy-
clization process can be performed with one equivalent of
base only. It is also worth noting that the methoxy dis-
placement required in the annulation process is not condi-
tioned by the presence of a vicinal alkoxy function as
shown by the formation of the isoindolinone 10d starting
from 12d.
Table 1 Compounds 8–14 Prepared
R1
R2
R3
H
R4
H
8, 10, 12, 14
a
b
c
Me
OMe
OBn
OCH2O
H
Me
H
H
Me
H
d
a
b
c
Me
OMe
H
OMe
H
The final removal of the temporary activating auxiliary
was not problematic and basic treatment of the primary
annulated compounds 10a–d and 11a–c with aqueous
NaOH solution (2.5 M) afforded the desired polyalkoxy-
lated isoindolinones released from the phosphoryl ap-
pendage (Scheme 2; Method A). A collection of
annulated compounds which have been prepared by this
method are presented in Table 1 where it may be seen that
9, 11, 13
PMB
PMB
PMB
OMe
OBn
OCH2O
H
H
H
Table 2 Spectroscopic and Physical Data of the Phosphorylated Amides 12, 13 and Isoindolin-1-ones 8–11 Prepared
Prod- Yield Mp
ucta,b (%) (°C)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d, J (Hz)
31P NMR
(CDCl3/H3PO4) d
12a 91 118–119 3.05 (s, 3 H, NCH3), 3.58 (s, 3 H, OCH3), 3.82 (s, 38.1, 46.9 (d, JC,P = 77), 55.7, 61.2, 113.1,
3 H, OCH3), 4.33 (br s, 1 H, NCH2P), 4.85 (br s, 1 118.6, 124.5, 128.7 (d, JC,P = 12), 130.6, 130.9
H, NCH2P), 6.19 (dd, J = 7.6, 1.7, 1 Harom), 6.84 (d, JC,P = 97), 131.2 (d, JC,P = 10), 132.2 (d,
(dd, J = 8.1, 1.6, 1 Harom), 6.93 (t, J = 7.9, 1Harom), JC,P = 2), 144.9, 152.6, 169.0 (d, JC,P = 3)
31.0
7.42–7.54 (m, 6 Harom), 7.84–7.99 (m, 4 Harom
)
12b 88 119–120 3.06 (s, 3 H, NCH3), 3.62 (s, 3 H, OCH3), 4.37 (br 38.2, 46.9 (d, JC,P = 76), 61.2, 70.8, 115.2,
s, 1 H, NCH2P), 4.84 (br s, 1 H, NCH2P), 5.06 (s, 119.1, 124.4, 127.3, 128.0, 128.6, 128.7 (d,
2 H, OCH2Ph), 6.23 (t, J = 4.6, 1 Harom), 6.90 (d, JC,P = 13), 130.8, 131.1 (d, JC,P = 98), 131.2 (d,
31.2
31.6
J = 4.6, 1 Harom), 7.28–7.42 (m, 6 Harom), 7.46–
7.59 (m, 6 Harom), 7.82–8.06 (m, 4 Harom
JC,P = 10), 132.2 (d, JC,P = 2), 136.6, 145.4,
151.7, 169.1 (d, JC,P = 2)
)
12c 86 oil
3.06 (s, 3 H, NCH3), 3.72 (s, 3 H, OCH3), 4.56 (br 38.0, 47.0 (d, JC,P = 76), 59.5, 101.1, 102.8,
s, 2 H, NCH2P), 5.87 (s, 2 H, OCH2O), 6.17 (d, 120.8, 122.0, 128.6 (d, JC,P = 12), 128.6 (d,
J = 8.0, 1 Harom), 6.40 (d, J = 8.0, 1 Harom), 7.47– JC,P = 12), 130.9 (d, JC,P = 98), 131.1 (d,
7.55 (m, 6 Harom), 7.87–7.93 (m, 4 Harom
)
JC,P = 10), 132.1 (d, JC,P = 2), 135.9, 139.7,
150.1, 168.7 (d, JC,P = 2)
12d 84 84–85
3.00 (s, 3 H, NCH3), 3.50 (s, 3 H, OCH3), 3.64 (s, 37.9, 47.3 (d, JC,P = 76), 56.0, 56.1, 56.4, 97.1, 31.9
3 H, OCH3), 3.77 (s, 3 H, OCH3), 4.54 (br s, 2 H, 111.1, 115.8, 128.6 (d, JC,P = 12), 130.9 (d,
NCH2P), 6.17 (s, 1 Harom), 6.34 (s, 1 Harom), 7.41– JC,P = 98), 131.3 (d, JC,P = 10, 132.1 (d,
7.45 (m, 6 Harom), 7.83–7.90 (m, 4 Harom
)
JC,P = 3), 143.1, 149.8, 150.6, 169.1 (d,
JC,P = 2)
Synthesis 2004, No. 10, 1664–1670 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Alkoxylated Isoindolin-1-ones
1667
Table 2 Spectroscopic and Physical Data of the Phosphorylated Amides 12, 13 and Isoindolin-1-ones 8–11 Prepared (continued)
13a 84 oil
3.64 (s, 3 H, OCH3), 3.76 (s, 3 H, OCH3), 3.82 (s, 41.9 (d, JC,P = 76), 52.6, 55.2, 55.8, 61.5,
3 H, OCH3), 4.20 (dd, J = 16.0, JH,P = 6.2, 1 H, 113.1, 114.0, 118.9, 124.5, 127.3, 128.7 (d,
NCH2P), 4.54–4.68 (m, 3 H, NCH2P + NCH2Ar), JC,P = 12), 313.2 (d, JC,P = 10), 131.3, 131.4 (d,
6.25 (dd, J = 7.6, 1.3, 1 Harom), 6.82 (d, J = 8.5, 2 JC,P = 97), 132.2 (d, JC,P = 3), 136.2, 145.0,
31.1
31.0
Harom), 6.86 (dd, J = 8.3, 1.2, 1 Harom), 6.95 (t,
J = 8.0, 1 Harom), 7.24 (d, J = 8.3, 2 Harom), 7.42–
152.9, 159.2, 161.6
7.58 (m, 6 Harom), 7.86–7.98 (m, 4 Harom
)
13b 81 113–114 3.66 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3), 4.28
41.8 (d, JC,P = 76), 52.7, 55.2, 61.4, 114.0,
(dd, J = 15.1, JH,P = 5.6, 1 H, NCH2P), 4.58–4.74 115.2, 119.4, 124.4, 127.3, 127.5, 128.0, 128.4,
(m, 3 H, NCH2P + NCH2Ar), 5.03 (s, 2 H,
OCH2Ph), 6.30 (t, J = 4.6, 1 Harom), 6.82 (d,
128.6 (d, JC,P = 12), 129.9, 130.1, 130.9, 131.3
(d, JC,P = 10), 131.9 (d, JC,P = 97), 145.7,
J = 8.3, 2 Harom), 6.89 (d, J = 3.9, 2 Harom), 7.26– 151.9, 159.2, 168.9 (d, JC,P = 2)
7.47 (m, 13 Harom), 7.87–7.96 (m, 4 Harom
)
13c 85 148–149 3.74 (s, 6 H, 2 OCH3), 4.36–4.77 (m, 4 H, NCH2P 42.1 (d, JC,P = 76), 52.6, 55.2, 59.7, 101.2,
31.4
30.0
+ NCH2Ar), 5.86 (s, 2 H, OCH2O), 6.22 (d,
J = 8.0, 1 Harom), 6.41 (d, J = 8.1, 1 Harom), 6.81
(d, J = 8.5, 2 Harom), 7.19 (d, J = 8.5, 2 Harom),
102.9, 114.0, 121.2, 121.9, 128.6 (d, JC,P = 12),
127.7, 129.7, 131.2 (d, JC,P = 10), 132.1 (d,
JC,P = 2), 132.1 (d, JC,P = 97), 136.2, 140.1,
150.2, 159.2, 168.7 (d, JC,P = 2)
7.45–7.51 (m, 6 Harom), 7.83–7.97 (m, 4 Harom
)
10a 75 250–252 3.06 (s, 3 H, NCH3), 3.15 (s, 3 H, OCH3), 5.37 (d, 30.7, 54.6, 63.8 (d, JC,P = 70), 112.6 (d,
JH,P = 8.1, 1 H, NCHP), 6.72 (d, J = 7.3, 1 Harom), JC,P = 2), 115.8 (d, JC,P = 1), 126.6 (d, JC,P = 3),
7.23–7.50 (m, 10 Harom), 7.71–7.77 (m, 2 Harom
)
127.4 (d, JC,P = 98), 128.2 (d, JC,P = 12), 128.3
(d, JC,P = 12), 131.4 (d, JC,P = 10), 131.6 (d,
JC,P = 9), 131.7 (d, JC,P = 2), 132.0 (d,
JC,P = 93), 132.1 (d, JC,P = 2), 132.4 (d,
JC,P = 2), 134.8 (d, JC,P = 3), 154.1 (d, JC,P = 2),
168.4
10b 72 171–172 3.13 (s, 3 H, NCH3), 4.24 (d, J = 12.5, 1 H,
30.8, 63.9 (d, JC,P = 69), 69.7, 114.3, 116.1,
29.8
29.3
30.6
30.5
OCH2Ar), 4.68 (d, J = 12.5, 1 H, OCH2Ar), 5.45 127.0, 127.4, (d, JC,P = 3), 128.0, 128.15 (d,
(d, JH,P = 7.1, 1 H, NCHP), 6.76 (d, J = 7.3, JC,P = 12), 128.2 (d, JC,P = 12), 128.4 (d,
1 Harom), 7.03–7.46 (m, 15 Harom), 7.63–7.77 (m, JC,P = 102), 128.5, 130.7 (d, JC,P = 2), 131.4 (d,
2 Harom
)
JC,P = 95), 131.5 (d, JC,P = 9), 132.1 (d,
JC,P = 3), 132.3 (d, JC,P = 3), 134.8 (d, JC,P = 3),
135.9, 153.4 (d, JC,P = 3), 168.5
10c 69 oil
3.03 (s, 3 H, NCH3), 5.35 (d, JH,P = 9.0, 1 H,
NCHP), 5.41 (d, J = 1.1, 1 H, OCH2O), 5.72 (d,
30.5, 62.6 (d, JC,P = 72), 102.0, 109.3, 118.5
(two peaks overlapping), 127.6 (d, JC,P = 98),
J = 1.1, 1 H, OCH2O), 6.84 (d, J = 8.0, 1 Harom), 127.7 (d, JC,P = 2), 128.5 (d, JC,P = 12), 128.6
7.27 (d, J = 8.0, 1 Harom), 7.35–7.54 (m, 8 Harom), (d, JC,P = 12), 129.6 (d, JC,P = 96), 131.7 (d,
7.71–7.80 (m, 2 Harom
)
JC,P = 9), 131.75 (d, JC,P = 9), 132.6 (d,
JC,P = 3), 132.9 (d, JC,P = 3), 142.0 (d, JC,P = 3),
150.7 (d, JC,P = 2), 167.8 (d, JC,P = 1)
10d 71 206–207 3.04 (s, 3 H, NCH3), 3.53 (s, 3 H, OCH3), 3.84 (s, 30.7, 55.9, 56.2, 63.6 (d, JC,P = 73), 105.0,
3 H, OCH3), 5.22 (d, JH,P = 11.0, 1 H, NCHP), 105.8 (d, JC,P = 2), 127.3 (d, JC,P = 98), 128.8
6.19 (s, 1 Harom), 7.12 (s, 1 Harom), 7.34–7.39 (m, (d, JC,P = 12), 128.85 (d, JC,P = 12), 129.3 (d,
4 Harom), 7.45–7.58 (m, 4 Harom), 7.64–7.69 (m, JC,P = 98), 130.0, 131.7 (d, JC,P = 9), 131.75 (d,
2 Harom
)
JC,P = 19), 131.9, 132.8 (d, JC,P = 2), 133.0 (d,
JC,P = 2), 150.1, 151.9 (d, JC,P = 2), 169.0 (d,
JC,P = 2)
11a 69 144–145 3.02 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 4.52 (d, 45.0, 54.5, 55.2, 59.8 (d, JC,P = 70), 112.7 (d,
J = 14.7, 1 H, NCH2Ar), 5.26–5.30 (m, 2 H, JC,P = 2), 114.0, 116.1, 127.0 (d, JC,P = 3),
NCH2Ar + NCHP), 6.68–6.70 (m, 1 Harom), 6.75 127.8 (d, JC,P = 98), 128.1 (d, JC,P = 1), 128.3
(d, J = 8.4, 2 Harom), 7.13 (d, J = 8.4, 2 Harom),
7.23–7.54 (m, 10 Harom), 7.69–7.75 (m, 2 Harom
(d, JC,P = 12), 129.0, 130.1, 130.7 (d, JC,P = 2),
131.4 (d, JC,P = 11), 131.7 (d, JC,P = 8), 132.0
(d, JC,P = 95), 132.2 (d, JC,P = 3), 132.3 (d,
JC,P = 3), 134.7 (d, JC,P = 3), 154.1 (d, JC,P = 2),
159.0, 168.3
)
Synthesis 2004, No. 10, 1664–1670 © Thieme Stuttgart · New York

1668
A. Moreau et al.
PAPER
Table 2 Spectroscopic and Physical Data of the Phosphorylated Amides 12, 13 and Isoindolin-1-ones 8–11 Prepared (continued)
11b 66 oil
3.75 (s, 3 H, OCH3), 4.21 (d, J = 12.5, 1 H,
NCH2Ar), 4.45 (d, J = 14.9, 1 H, OCH2Ar), 4.64 114.3, 116.5, 127.2, 127.7 (d, JC,P = 3), 128.0
(d, J = 12.2, 1 H, NCH2Ar), 5.29-5.34 (m, 2H, (d, JC,P = 12), 128.1 (d, JC,P = 13), 128.4,
45.1, 55.2, 60.0 (d, JC,P = 70), 69.9, 114.0,
30.4
OCH2Ar + NCHP), 6.73–6.78 (m, 3 Harom), 7.06– 128.5, 128.9, 128.95 (d, JC,P = 98), 130.1,
7.12 (m, 4 Harom), 7.24–7.46 (m, 13 Harom), 7.66– 130.6 (d, JC,P = 2), 131.4 (d, JC,P = 95), 131.5
7.73 (m, 2 Harom
)
(d, JC,P = 9), 131.6 (d, JC,P = 8), 132.2 (d,
JC,P = 3), 132.25, 134.6 (d, JC,P = 3), 135.8,
153.5, 159.0, 168.3
11c 74 159–160 3.73 (s, 3 H, OCH3), 4.23 (d, J = 14.9, 1 H,
55.2, 58.8 (d, JC,P = 73), 102.0, 109.4, 118.9 (d, 29.6
NCH2Ar), 5.23 (d, J = 14.9, 1 H, NCH2Ar), 5.26 JC,P = 2), 127.7 (d, JC,P = 2), 127.8 (d,
(d, JH,P = 8.3, 1 H, NCHP), 5.35 (d, J = 0.7, 1 H, JC,P = 98), 128.7, 129.9, 129.9 (d, JC,P = 96),
OCH2O), 5.63 (d, J = 0.7, 1 H, OCH2O), 6.77 (d, 131.7 (d, JC,P = 9), 131.9 (d, JC,P = 9), 132.6 (d,
J = 8.6, 2 Harom), 6.82 (d, J = 7.8, 1 Harom), 7.09
(d, J = 8.6, 2 Harom), 7.30 (d, J = 7.8, 1 Harom),
JC,P = 3), 132.8 (d, JC,P = 3), 142.2 (d, JC,P = 3),
150.7 (d, JC,P = 2), 159.1, 167.8 (d, JC,P = 2)
7.33–7.54 (m, 8 Harom), 7.69–7.75 (m, 2 Harom
)
8a 72c 60–61
3.18 (s, 3 H, NCH3), 3.87 (s, 3 H, OCH3), 4.23 (s, 29.6, 50.0, 55.4, 112.6, 115.8, 129.0, 129.7,
–
–
–
92d
2 H, NCH2Ar), 6.97 (d, J = 7.3, 1 Harom), 7.36– 134.5, 154.3, 168.8
7.43 (m, 2 Harom
)
8b 65c 130–131 3.17 (s, 3 H, NCH3), 4.34 (s, 2 H, NCH2Ar), 5.15 29.5, 50.0, 70.1, 113.9, 116.0, 122.9, 127.3,
87d
(s, 2 H, ArCH2O), 7.04 (d, J = 7.6, 1 Harom), 7.25– 128.2, 128.7, 129.6, 134.7, 153.5, 159.7, 170.9
7.41 (m, 7 Harom
)
8c 70c 184–185 3.09 (s, 3 H, NCH3), 4.23 (s, 2 H, NCH2Ar), 6.00 29.5, 48.6, 102.0, 108.5, 117.8, 120.5, 128.0,
89d
(s, 2 H, OCH2O), 6.84 (d, J = 7.7, 1 Harom), 7.30 141.5, 150.3, 167.8
(d, J = 7.7, 1 Harom
)
e
e
8d 68c 133–134
–
–
–
–
89d
9a 65c 91–92
3.77 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3), 4.17 (s, 45.8, 47.2, 55.3, 112.6, 114.1, 115.9, 129.2,
88d
2 H, NCH2Ar), 4.71 (s, 2 H, NCH2Ar), 6.84 (d,
J = 8.8, 2 Harom), 6.96 (d, J = 7.6, 1 Harom), 7.23
(d, J = 8.8, 2 Harom), 7.40 (t, J = 7.6, 1 Harom), 7.47
129.3, 129.6, 129.7, 134.4, 154.4, 168.5
(d, J = 7.6, 1 Harom
)
9b 70c 104–105 3.78 (s, 3 H, OCH3), 4.22 (s, 2 H, NCH2Ar), 4.73 45.8, 47.3, 55.3, 70.1, 113.9, 114.1, 116.2,
–
–
89d
(s, 2 H, NCH2Ar), 5.10 (s, 2 H, OCH2Ar), 6.85 (d, 127.4, 128.2, 128.7, 129.2, 129.5, 129.6, 129.7,
J = 8.5, 2 Harom), 7.03 (d, J = 8.1, 1 Harom), 7.14– 134.6, 136.3, 153.7, 159.1, 168.4
7.42 (m, 8 Harom), 7.50 (d, J = 7.6, 1 Harom
)
9c 75c 146–147 3.73 (s, 3 H, OCH3), 4.13 (s, 2 H, NCH2Ar), 4.65 45.8, 45.9, 55.2, 102.0, 108.6, 114.1, 118.1,
95d
(s, 2 H, NCH2Ar), 5.96 (s, 2 H, OCH2O), 6.81 (d, 120.8, 127.8, 129.0, 129.5, 141.7, 150.4, 159.1,
J = 8.5, 2 Harom), 6.85 (d, J = 8.0, 1 Harom), 7.18 167.6
(d, J = 8.5, 2 Harom), 7.37 (d, J = 7.8, 1 Harom
)
a Satisfactory microanalyses obtained: C 0.29, H 0.30, N 0.27.
b IR: 1629–1665 (C=O), 1241–1275 (PO) cm–1 for 12, 13; 1663–1688 (C=O), 1215–1285 (PO) cm–1 for 10, 11; 1660–1680 (C=O) cm–1 for 8, 9.
c Method A.
d Method B.
e See Ref.36
at the CNRS microanalysis centre. For flash chromatography, silica
gel 60 M (230–400 mesh ASTM) was used. All solvents were dried
and distilled according to standard procedures. Dry glassware for
moisture-sensitive reactions were oven dried and assembled under
argon. An inert atmosphere was obtained with a stream of argon and
glassware equipped with rubber septa; reagent transfer was per-
formed by syringe.
In conclusion, we have developed a new and concise one-
step method for the preparation of various mono and poly-
alkoxylated 4-alkoxyisoindolinones from phosphorylated
2-methoxybenzamides through metalation, SNAr mediat-
ed cyclization and ultimate alkaline cleavage of the phos-
phorylated auxiliary.
Compounds 14a and 14d are commercially available. The 2-meth-
oxybenzoic acid derivatives 14b30 and 14c31 were obtained by oxi-
dation (CrO3/H2SO4/H2O/acetone) of the corresponding
benzaldehydes. Beforehand, the aromatic carboxaldehyde
precursor32 of 14b was obtained by sequential O-methylation
(K2CO3, MeI, DMF) and O-benzylation (K2CO3, BnBr, EtOH) of
Melting points were determined on a Reichert-Thermopan appara-
1
tus and are uncorrected. H, 13C and 31P NMR spectra were mea-
sured at 300, 75 and 121 MHz, respectively, on a Bruker AM 300
spectrometer as solutions in CDCl3 with TMS as internal standard
or H3PO4 as external standard. Elemental analyses were performed
Synthesis 2004, No. 10, 1664–1670 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Alkoxylated Isoindolin-1-ones
1669
commercially available dihydroxy-2,3-benzaldehyde. The methyl-
enedioxybenzaldehyde precursor33 of 14c was synthesized by O-
methylation (K2CO3, MeI, DMF) of the phenolic parent compound
prepared according to a reported procedure.34
The phosphorylated amines 15,35 16,25a were synthesized according
to the literature. The 2-methoxybenzoic acid derivatives were con-
verted by the conventional method (SOCl2, DMF cat., CH2Cl2) into
their corresponding acid chlorides which were used directly with
the phosphorylated amines 15, 16 by following an already reported
procedure.35
(6) (a) Kondo, T.; Yoshida, K.; Yamamoto, M.; Tanayama, S.
Arzneim. Forsch. 1996, 46, 11. (b) Linden, M.; Hadler, D.;
Hofmann, S. Human Psychopharm. 1997, 12, 445.
(7) Yamabe, H.; Okuyama, M.; Nakao, A.; Ooizumi, M.; Saito,
K. PCT Int. Appl. WO 2001064670, 2001; Chem. Abstr.
2001, 135, 226879.
(8) Biller, S. A.; Dickson, J. K.; Lawrence, R. M.; Magnin, D.
R.; Poss, M. A.; Sulsky, R. B.; Tino, J. A. US Patent US
5739135, 1998; Chem. Abstr. 1998, 128, 282780.
(9) Bengtsson, K. S.; Thorberg, S. O.; Oegren, S. O. Eur. Pat.
App. EP 26749, 1981; Chem. Abstr. 1981, 95, 62013.
(10) Inaba, T.; Kaya, T.; Iwamura, H. PCT Int. Appl. WO
9729079, 1997; Chem. Abstr. 1997, 127, 190528.
(11) Suemitsu, R.; Ohnishi, K.; Morikawa, Y.; Nagamoto, S.
Phytochemistry 1995, 38, 495.
Phosphorylated Isoindolin-1-ones 10a–d and 11a–c; General
Procedure
A solution of KHMDS (8.8 mL, 0.5 M in toluene, 4.4 mmol) was
added dropwise to a carefully degassed and stirred solution of the
phosphorylated 2-methoxybenzamide derivative 12 or 13 (4.0
mmol) in THF (50 mL) in the presence of 18-crown-6 (1.16 g, 4.4
mmol) at –78 °C under argon. The solution was stirred for 15 min
at this temperature and then allowed to warm to r.t. over a period of
2 h. Aq NH4Cl solution (10%, 10 mL) was added and after dilution
with H2O, the mixture was extracted with Et2O (2 × 25 mL) and
CH2Cl2 (2 × 25 mL). The combined organic extracts were washed
with H2O and brine, dried (Na2SO4) and evaporated in vacuo. Flash
column chromatography on silica gel with EtOAc–hexanes (90:10)
as eluent allowed isolation of the phosphorylated isoindolinones
10a–d and 11a–c which were finally purified by recrystallization
from hexane–toluene (Table 2).
(12) Horiuchi, M.; Maoka, T.; Iwase, N.; Ohnishi, K. J. Nat.
Prod. 2002, 65, 1204.
(13) Tojo, E.; Dominguez, D.; Castedo, L. Phytochemistry 1991,
30, 1005.
(14) (a) Pendergast, W.; Dickerson, S. H.; Dev, I. K.; Ferone, R.;
Duch, D. S.; Smith, G. K. J. Med. Chem. 1994, 37, 838.
(b) Taylor, E. C.; Jennings, L. D.; Mao, Z.; Hu, B.; Jun,
J.-G.; Zhou, P. J. Org. Chem. 1997, 62, 5392. (c) Wang,
H.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9097.
(15) Anderson, P. S.; Christy, M. E.; Colton, C. D.; Shepard, K.
L. J. Org. Chem. 1978, 43, 3719.
(16) Kigazawa, K.; Hiiragi, M.; Ishimaru, H.; Haga, S.;
Shirayama, K. Japanese Patent JP 54092954, 1979; Chem.
Abstr. 1980, 92, 76287.
Isoindolin-1-ones 8, 9; General Procedures
(17) Takahashi, I.; Hirano, E.; Kawkani, T.; Kitajima, H.
Heterocycles 1996, 43, 2343.
Method A: An aq NaOH solution (2.5 M, 0.8 mL, 2 mmol) was add-
ed to a solution of the phosphorylated isoindolin-1-ones 10, 11 (1
mmol) in THF (30 mL) and the mixture was then refluxed for 3 h.
H2O (10 mL) was added and the mixture was extracted with Et2O (3
× 10 mL). The organic layer was washed with water and brine,
dried (MgSO4), concentrated in vacuo to a residue which was puri-
fied by recrystallization from hexane–toluene (Table 2).
(18) (a) Becke, F.; Jagla, E. British Patent GB 1049007, 1966;
Chem. Abstr. 1967, 66, 37763. (b) Norman, M. H.; Kelley,
J. L.; Hollingsworth, E. B. J. Med. Chem. 1993, 36, 3417.
(19) (a) Mori, M.; Chiba, K.; Ban, Y. J. Org. Chem. 1978, 43,
1684. (b) Anderson, J. C.; Flaherty, A.; Schwarbrick, M. E.
J. Org. Chem. 2000, 65, 9152.
Method B: The annulation reaction was carried out as described
above for the synthesis of 10, 11 but the crude reaction mixture ob-
tained after warming to r.t., was treated with aq NaOH (2.5 M, 8
mmol) by dropwise addition before refluxing the solution for an ad-
ditional 3 h. The crude reaction mixture was then treated as de-
scribed above in Method A (Table 2).
(20) Anzini, M.; Capelli, A.; Vomero, S. Heterocycles 1994, 38,
103.
(21) Grigg, R.; Zhang, L.; Collard, S.; Keep, A. Tetrahedron Lett.
2003, 44, 6979.
(22) Shah, J. H.; Swartz, G. M.; Papathanassiu, A. E.; Treston, A.
M.; Fogler, W. E.; Madsen, J. W.; Green, S. J. J. Med. Chem.
1999, 42, 3014.
(23) Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S.
Tetrahedron: Asymmetry 2003, 14, 1309.
Acknowledgment
(24) Hoarau, C.; Couture, A.; Deniau, E.; Grandclaudon, P. J.
Org. Chem. 2002, 67, 5846.
(25) (a) Couture, A.; Deniau, E.; Grandclaudon, P.; Hoaurau, C.
J. Org. Chem. 1998, 63, 3128. (b) Hoarau, C.; Couture, A.;
Cornet, H.; Deniau, E.; Grandclaudon, P. J. Org. Chem.
2001, 66, 8064.
This research was supported by the Centre National de la Recherche
Scientifique and MENESR (grant to A. M.). Also we acknowledge
helpful discussions and advice from Dr. T. G. C. Bird (Astra-Zene-
ca Pharma).
(26) For a recent paper, see: Hattori, T.; Takeda, A.; Suzuki, K.;
Koike, N.; Koshiishi, E.; Miyano, S. J. Chem. Soc., Perkin
Trans. 1 1998, 3661.
(27) Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003, 44, 3059.
(28) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(29) (a) Allen, D. W.; Hutley, B. G.; Mellor, M. T. J. J. Chem.
Soc., Perkin Trans. 2 1977, 1705. (b) Hoarau, C.; Couture,
A.; Deniau, E.; Grandclaudon, P. Synthesis 2000, 655.
(c) Eymery, F.; Iorga, B.; Savignac, P. Tetrahedron 1999,
55, 13109.
References
(1) Shamma, M.; Moniot, J.-L. J. Chem. Soc., Chem. Commun.
1975, 89.
(2) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V.
Tetrahedron Lett. 1984, 25, 599.
(3) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923.
(4) (a) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M.
Tetrahedron Lett. 1982, 23, 39. (b) Fang, F. G.;
Danishefsky, S. J. Tetrahedron Lett. 1989, 30, 2747.
(5) Lawrence, N. J.; Liddle, J.; Bushell, S. M.; Jackson, D. A. J.
Org. Chem. 2002, 67, 457.
(30) Datta, S. C.; Murti, V. V. S.; Seshadri, T. R. Indian J. Chem.
1969, 7, 110.
Synthesis 2004, No. 10, 1664–1670 © Thieme Stuttgart · New York

1670
A. Moreau et al.
PAPER
(31) Loyd, H. A.; Warren, K. S.; Fales, H. M. J. Am. Chem. Soc.
1966, 88, 5544.
(34) Garcia, A.; Castedo, L.; Dominguez, D. Tetrahedron 1995,
51, 8585.
(32) Giles, R. G. F.; Green, I. R.; Gruchlik, Y.; Oosthuizen, F. J.
Austr. J. Chem. 2000, 53, 341.
(35) Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S.
Tetrahedron Lett. 1996, 37, 7749.
(33) Loriot, M.; Robin, J.-P.; Brown, E. Tetrahedron 1984, 40,
2529.
(36) Barr, N.; Bartley, J. P.; Clark, P. W.; Dunstan, P.; Dyke, S.
F. J. Organomet. Chem. 1986, 302, 117.
Synthesis 2004, No. 10, 1664–1670 © Thieme Stuttgart · New York