A concise synthesis of mono- and polysubstituted and diversely N-function-alized isoindolinones and isoquinolones

Article abstract of DOI:10.1055/s-2008-1067125

A variety of differently substituted and diversely N-(sul-fanyl) hydroxyalkyl functionalized isoindolinones and isoquinolones have been obtained by anionic cyclization of cyclic bromobenzyl or bromophenethylcarbamates and thiocarbamates. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067125

PAPER
2141
A Concise Synthesis of Mono- and Polysubstituted and Diversely N-Function-
alized Isoindolinones and Isoquinolones
Synthesis of
N
-Functio
a
nalized
I
so
g
indolinones
a
a
nd Isoquin
l
olone
s
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 4 April 2008
O
Abstract: A variety of differently substituted and diversely N-(sul-
fanyl)hydroxyalkyl functionalized isoindolinones and isoquinol-
ones have been obtained by anionic cyclization of cyclic
bromobenzyl or bromophenethylcarbamates and thiocarbamates.
O
OMe
N
N
OMe
CONH2
OH
Key words: lactams, carbanions, ring closure, ring opening, bicy-
clic compounds
2
O
1
O
O
MeO
Over the past few years, the isoindolinone ring system has
emerged as a valuable pharmacophore due to the profound
physiological and chemotherapeutic properties of many
of its derivatives.1 Many isoindolinone-centered com-
pounds have indeed been shown to display very promising
antiviral,2 antileukemic,3 anti-inflammatory,4 antipsy-
chotic,5 and antiulcer6 properties. For example compound
1, a bioisostere of the corresponding lactone exhibits a
significant antiviral activity against Hepatitis B virus,7
and isoindolinone 2 is a selective cytokine inhibitory drug
for managements of cancers8 (Figure 1). The thioalkyl
isoindolinone 3 has been studied as a reverse transcriptase
inhibitor,9 whereas the amino derivative 4 has been shown
to display high selective binding affinities to 5HT1a recep-
tors.10 Isoindolinones are also the key structural feature of
structurally sophisticated naturally occurring molecules
like phytotoxin porritoxin 5.
O
N
N
N
N
4
S
Me
O
Me
O
Me
N
3
Me
OH
Me
OMe
5
Figure 1 Some biologically active isoindolinone derivatives
R1
R1
O
R2
R3
R2
R3
Br
O
( )n
N
X
XH
N
( )n
R4
R4
Consequently, interest in the development of new synthet-
ic methodologies for the preparation of functionalized
isoindolinone derivatives continues unabated. An impor-
tant aspect of the rationale leading to the discovery of this
class of lactamic compounds endowed with biological ac-
tivities hinges upon the preliminary construction of the
isoindolinone template equipped with suitable substitu-
ents liable to secure the ultimate installation of appropri-
ate functionalities. This strategy allows access to an array
of diversely functionalized models,1–7 but is also inevita-
bly plagued with the exquisite arrangement of diverse and
dense functionalities within the compact molecular
framework.
9–11
6–8
Scheme 1
an aryl lithiated species and reaction with an internal elec-
trophile.11 The feasibility and versatility of this process
has been further demonstrated by its extension to the iso-
quinolinones series. We initially anticipated that capture
of the aryllithiated species derived from the parent com-
pounds 6–8 (retrosynthetic Scheme 1) by an oxazolidin-
one (X = O, n = 1), a thiazolidinone (X = S, n = 1), or an
oxazinanone (X = O, n = 2) acting as the internal electro-
phile would provide the potential for a direct access to di-
versely substituted isoindolinone ring systems with the
concomitant connection of hydroxy and sulfanyl append-
ages, therefore providing the N-functionalized models 9–
11.
Herein we delineate a tactically new synthetic approach to
a range of differently substituted and diversely N-func-
tionalized isoindolinones that is based upon the exploita-
tion of the Parham cyclization process, that is, creation of
The first facet of the synthesis was then the assembling of
the parent compounds 6–8 – candidates for the planned
Parham cyclization process. In the first instance, the
SYNTHESIS 2008, No. 13, pp 2141–2147
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1067125; Art ID: Z08008SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

2142
M. Lorion et al.
PAPER
1. NaH , THF
This simple operation allowed installation of the oxazoli-
dinone unit and delivered the cyclic carbamate precursors
6a–c (Table 1). To ensure the optimal formation of the
mandatory lithiated species 16, variation of the ethereal
solvent (THF or Et2O), base (n-BuLi or t-BuLi), tempera-
ture profile (–78 °, 0 °C, r.t.), course of the addition pro-
cess (normal or reverse), and inclusion of anion modifiers
(TMEDA, crown ether) were all screened in order to facil-
itate halogen/metal interconversion while sparing the
oxazolidinone moiety. After considerable experimenta-
tion, we found that adding the parent compounds 6a–c (1
equiv) in THF to n-BuLi (3 equiv) and TMEDA (3 equiv)
in degassed THF at –78 °C for 30 minutes (reverse addi-
tion) led to complete consumption of the starting material
and isolation solely of the targeted hydroxyethyl chain
tethered isoindolinones 9a–c in fairly good yields
(Scheme 2, Table 1).
2.
R1
R2
R3
Br
O
R1
Br
12a–e
R2
R3
Br
R4
O
N
X
HN
X
n( )
( )n
R4
13 X = O , n = 1
14 X = S , n = 1
15 X = O , n = 2
6a–c
7c,d
8b–e
n-BuLi (3 equiv)
TMEDA (3 equiv)
THF, –78 °C
R1
R2
Li
O
X
R3
N
( )n
R4
16
At this stage we set out to investigate the scope and limi-
tations of this synthetic approach. We were then pleased
to observe that the annulation/functionalization sequence
could be successfully extended to the thiazolidinone se-
ries. Thus exposure of the sulfur analogue derivatives
7c,d, similarly assembled by connecting 12c,d to thiazoli-
dinone 14, to the same basic conditions led to the corre-
sponding sulfanylethyl derivatives 10c,d in quite
satisfactory yields (Table 1). It was also demonstrated that
ring enlargement of the heterocyclic unit embedded in the
parent compound was not detrimental to the anionic cy-
clization process. Indeed, treatment of the oxazinanone
derivatives 8b–e under the same conditions triggered off
the creation of the hydroxypropyl appendage, hence giv-
ing rise to the homologated isoindolinones 11b–e in good
yields (Table 1). The analytical and spectroscopic data of
compounds 6, 9–11 prepared are given in Table 2.
1. –78 °C
30 min
R1
O
2. H3O+
R2
R3
( )n
N
XH
R4
9a–c X = O , n = 1
10c,d X = S , n = 1
11b–e X = O , n = 2
Scheme 2
oxazolidinone derivatives 6a–c were readily obtained by
coupling the corresponding o-bromobenzyl bromides
12a–c with the sodium salt of oxazolidinone 13
(Scheme 2).
Table 1 Starting Materials and Isoindolinones 9–11
Starting Materials
Carbamates 6–8
Isoindolinones 9–11
o-Bromobenzyl bromides
Cyclic carbamates
R1
R2
R3
R4
X
O
O
O
S
n
1
1
1
1
1
2
2
2
2
Yield (%)a
59
Yield (%)a
80
12a
12b
12c
12c
12d
12b
12c
12d
12e
OMe
OMe
H
OMe
OMe
H
OMe
H
H
13
13
13
14
14
15
15
15
15
6a
6b
6c
7c
7d
8b
8c
8d
8e
9a
H
52
59
61
63
58
68
65
49
9b
74
74
71
76
74
77
79
70
OMe
OMe
OMe
H
OMe
OMe
H
9c
H
H
10c
10d
11b
11c
11d
11e
H
OMe
OMe
H
S
OMe
H
H
O
O
O
O
OMe
OMe
OMe
OMe
H
H
OMe
H
H
H
a Purified products.
Synthesis 2008, No. 13, 2141–2147 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Functionalized Isoindolinones and Isoquinolones
2143
Table 2 Spectroscopic and Physical Data of Carbamates 6–8 and Isoindolinones 9–11 Prepared
Producta,b Mp (°C)
(appearance)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
6a
6b
6c
7c
7d
8b
79–80 (white
crystals)
3.53 (t, J = 7.9, 2 H, CH2N), 3.84 (s, 3 H, OCH3), 3.88 (s, 3 H, 44.5, 48.1, 56.3, 61.0, 61.1, 62.0, 109.1,
OCH3), 3.89 (s, 3 H, OCH3), 4.31 (t, J = 8.1, 2 H, OCH2), 4.56 110.5, 130.7, 143.0, 150.9, 153.2, 158.6
(s, 2 H, ArCH2), 6.80 (s, 1 Harom
)
(C=O)
100–101 (white
crystals)
3.48 (t, J = 8.1, 2 H, CH2N), 3.85 (s, 3 H, OCH3), 3.87 (s, 3 H, 44.3, 47.9, 56.1, 60.5, 61.9, 111.5, 119.7,
OCH3), 4.30 (t, J = 7.9, 2 H, OCH2), 4.54 (s, 2 H, ArCH2), 6.86 125.3, 127.9, 146.3, 153.3, 158.4 (C=O)
(d, J = 8.5, 1 Harom), 7.11 (d, J = 8.3, 1 Harom
)
56–57 (light yellow 3.30 (t, J = 8.0, 2 H, CH2N), 3.79 (s, 3 H, OCH3), 3.80 (s, 3 H, 44.1, 47.6, 56.0, 56.1, 62.0, 112.9, 114.1,
crystals)
OCH3), 4.17 (t, J = 8.0, 2 H, OCH2), 4.58 (s, 2 H, ArCH2), 6.74 115.2, 127.1, 148.9, 149.4, 158.5 (C=O)
(d, J = 8.9, 1 Harom), 7.21 (d, J = 8.8, 1 Harom
)
72–73 (white
crystals)
3.04 (t, J = 7.2, 2 H, SCH2), 3.31 (t, J = 7.2, 2 H, CH2N), 3.73 25.6, 43.2, 47.4, 56.0, 61.1, 113.6, 115.5,
(s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 4.55 (s, 2 H, ArCH2), 6.73 128.0, 128.7, 149.2, 152.3, 171.4 (C=O)
(d, J = 8.9, 1 Harom), 7.17 (d, J = 8.9, 1 Harom
)
118–119 (white
crystals)
3.25 (t, J = 7.3, 2 H, SCH2), 3.56 (t, J = 7.3, 2 H, CH2N), 3.82 25.7, 47.9, 48.1, 56.1, 56.2, 112.8, 114.0,
(s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 4.53 (s, 2 H, ArCH2), 6.85 115.1, 127.2, 148.8, 149.2, 172.4 (C=O)
(s, 1 Harom), 6.96 (s, 1 Harom
)
153–154 (white
crystals)
2.03 (quint, J = 5.8, 2 H, CH2), 3.25 (t, J = 6.2, 2 H, NCH2), 3.84 22.3, 44.9, 52.1, 56.1, 60.5, 66.6, 111.5,
(s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 4.28 (t, J = 5.3, 2 H, 119.5, 124.3, 128.4, 146.5, 153.0, 153.9
CH2O), 4.64 (s, 2 H, ArCH2), 6.86 (d, J = 8.6, 1 Harom), 7.06 (d, (C=O)
J = 8.6, 1 Harom
)
8c
(colorless oil)
1.95 (quint, J = 5.9, 2 H, CH2), 3.02 (t, J = 6.1, 2 H, NCH2), 3.84 22.0, 43.0, 46.4, 55.9, 61.0, 66.2, 113.3,
(s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.19 (t, J = 5.3, 2 H, 115.6, 128.0, 128.8, 149.4, 152.3, 153.5
CH2O), 4.84 (s, 2 H, ArCH2), 6.80 (d, J = 8.9, 1 Harom), 7.29 (d, (C=O)
J = 8.6, 1 Harom
)
8d
8e
90–91 (white
crystals)
1.95 (quint, J = 5.8, 2 H, CH2), 3.21 (t, J = 6.2, 2 H, NCH2),
3.79, (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 4.21 (t, J = 5.3, 2 H, 114.0, 115.1, 128.0, 148.9, 149.1, 154.0
CH2O), 4.60 (s, 2 H, ArCH2), 6.92 (s, 1 Harom), 6.94 (s, 1 Harom
22.2, 44.5, 51.5, 56.0, 56.1, 66.5, 112.5,
)
(C=O)
65–66 (white
crystals)
1.93 (quint, J = 5.8, 2 H, CH2), 3.15 (t, J = 6.2, 2 H, NCH2),
3.64, (s, 3 H, OCH3), 4.17 (t, J = 5.3, 2 H, CH2O), 4.49 (s, 2 H, 114.5, 133.4, 136.5, 153.8, 159.3 (C=O)
ArCH2), 6.59 (dd, J = 3.0, 8.7, 1 Harom), 6.73 (d, J = 3.0, 1 Harom),
22.2, 45.0, 52.3, 55.4, 66.7, 113.6, 114.4,
7.30 (d, J = 8.7, 1 Harom
)
9a
147–148 (light grey 3.31 (br s, 1 H, OH), 3.61 (t, J = 4.6, 2 H, NCH2), 3.79 (s, 3 H, 46.1, 51.3, 56.3, 61.5, 61.7, 62.6, 101.1,
crystals)
OCH3), 3.80–3.81 (m, 2 H, CH2O), 3.83 (s, 3 H, OCH3), 4.01 (s, 117.2, 139.1, 141.5, 151.2, 157.1, 168.2
3 H, OCH3), 4.31 (s, ArCH2), 6.58 (s, 1 Harom (C=O)
)
9b
9c
75–76 (orange
crystals)
3.60 (t, J = 4.7, 2 H, NCH2), 3.75 (s, 3 H, OCH3), 3.80 (s, 3 H, 46.1, 50.7, 56.7, 61.4, 62.4, 116.4, 117.8,
OCH3), 3.92 (t, J = 5.3, 2 H, CH2O), 4.30 (s, 2 H, ArCH2), 6.91– 124.8, 134.8, 146.9, 152.1, 167.9 (C=O)
6.95 (m, 2 Harom
)
150–151 (light
yellow crystals)
1.67 (br s, 1 H, OH), 3.68 (t, J = 4.9, 2 H, NCH2), 3.83–3.84 (m, 46.0, 49.4, 60.3, 61.3, 63.8, 112.7, 119.6,
2 H, CH2O), 3.87 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 4.36 (s, 125.9, 133.4, 143.6, 154.9, 169.5 (C=O)
2 H, ArCH2), 6.96 (d, J = 8.4, 1 Harom), 7.47 (d, J = 7.9, 1 Harom
)
10c
98–99 (light yellow 1.39 (t, J = 8.3, 1 H, SH), 2.72–2.81 (m, 2 H, CH2S), 3.70 (t, J 23.2, 45.7, 48.4, 56.2, 60.3, 112.7, 119.4,
crystals)
= 6.9, 2 H, NCH2), 3.87 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
125.9, 133.1, 143.4, 154.7, 168.3 (C=O)
4.42 (s, 2 H, ArCH2), 6.95 (d, J = 8.3, 1 Harom), 7.48 (d, J = 8.2,
1 Harom
)
10d
11b
118–119 (light
yellow crystals)
1.45 (t, J = 8.3, 1 H, SH), 2.83 (q, J = 7.4, 2 H, CH2S), 3.78 (t, 23.5, 45.8, 50.4, 56.2 (2 × CH3), 105.0,
J = 6.9, 2 H, NCH2), 3.94 (s, 3 H, OCH3), 3.95 (s, 3 H, OCH3), 105.3, 124.8, 133.7, 149.7, 152.6, 169.0
4.41 (s, 2 H, ArCH2), 6.92 (s, 1 Harom), 7.31 (s, 1 Harom
)
(C=O)
light brown oil
1.75 (quint, J = 6.1, 2 H, CH2), 3.51 (t, J = 5.7, 2 H, NCH2), 3.64 30.7, 38.8, 49.4, 56.7, 58.3, 62.4, 116.5,
(t, J = 6.3, 2 H, CH2O), 3.82 (s, 3 H, OCH3), 3.98 (s, 3 H,
OCH3), 4.25 (s, 2 H, ArCH2), 7.03–7.04 (m, 2 Harom
117.9, 124.5, 134.4, 146.9, 152.3, 167.9
(C=O)
)
Synthesis 2008, No. 13, 2141–2147 © Thieme Stuttgart · New York

2144
M. Lorion et al.
PAPER
Table 2 Spectroscopic and Physical Data of Carbamates 6–8 and Isoindolinones 9–11 Prepared (continued)
Producta,b Mp (°C)
(appearance)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
11c
11d
11e
87–88 (fawn
crystals)
1.79 (quint, J = 6.0, 2 H, CH2), 3.53 (t, J = 5.8, 2 H, NCH2), 3.68 30.7, 38.9, 48.2, 56.2, 58.4, 60.3, 112.7,
(t, J = 6.3, 2 H, CH2O), 3.89 (s, 3 H, OCH3), 3.90 (s, 3 H, 119.4, 125.6, 133.0, 143.4, 154.7, 169.4
OCH3), 4.37 (s, 2 H, ArCH2), 6.98 (d, J = 8.2, 1 Harom), 7.46 (d, (C=O)
J = 8.3, 1 Harom
)
121–122 (fawn
crystals)
1.66 (br s, 1 H, OH), 1.74 (quint, J = 5.8, 2 H, CH2), 3.48–3.50 31.0, 38.9, 49.9, 56.0, 56.1, 58.5, 104.9,
(m, 2 H, NCH2), 3.69 (t, J = 6.1, 2 H, CH2O), 3.87 (s, 3 H,
OCH3), 3.88 (s, 3 H, OCH3), 4.26 (s, 2 H, ArCH2), 6.86 (s, 1
105.0, 124.3, 134.8, 149.4, 152.4, 169.5
(C=O)
Harom), 7.24 (s, 1 Harom
)
70–71 (fawn
crystals)
1.74 (quint, J = 6.0, 2 H, CH2), 3.49 (t, J = 5.7, 2 H, NCH2), 3.64 30.8, 38.8, 50.2, 55.7, 58.4, 107.7, 114.7,
(t, J = 6.2, 2 H, CH2O), 3.78 (s, 3 H, OCH3), 3.99 (br s, 1 H,
OH), 4.27 (s, 2 H, ArCH2), 6.86–6.91 (m, 2 Harom), 7.63 (d, J =
124.8, 124.9, 143.5, 162.7, 169.6 (C=O)
8.3, 1 Harom
)
a Satisfactory microanalyses obtained: C 0.31, H 0.25, N 0.26.
b IR (KBr or neat): 6a–c, 1747–1760 cm–1 (C=O); 7c,d, 1661–1668 cm–1 (C=O); 8b–e, 1679–1687 cm–1 (C=O); 9–11, 1648–1673 cm–1 (C=O);
10c,d, 2506–2510 cm–1 (SH).
Encouraged by these results, we then set out to achieve a one 13 by treatment with paraformaldehyde and Me3SiCl
synthetic strategy prone to give access to the upper term delivered the transient highly reactive chloromethylated
of the series, that is, isoquinolones 17d–f. On reliance compound 22, which was subsequently intercepted with
with the conceptually related synthetic strategy portrayed ethyl diphenylphosphinite to afford the desired phosphi-
in retrosynthetic Scheme 3, the development of a synthet- noylmethylcarbamate 21 in an excellent yield. Horner re-
ic route to the parent compounds 18d–f was required.
action between metalated 21 and o-bromobenzaldehydes
20d–f proceeded uneventfully to afford almost quantita-
tively the arylmethyleneoxazolidinones 19d–f (Table 3).
Stereochemical considerations about the central double
bond were not crucial for the subsequent reduction reac-
tion. This operation was readily and efficiently achieved
by treatment of 19d–f with Et3SiH/TFA to provide excel-
lent yields of the bromophenethyloxazolidinones 18d–f.
To our delight exposure of compounds 18d–f to lithiated
bases led to the isolation of the targeted hydroxyethyliso-
quinolones 17d–f (Table 3). However, it is worth noting
that the yield for this anionic cyclization/N-functionaliza-
tion sequence was significantly improved by making use
of t-BuLi (1.1 equiv) at –100 °C upon normal addition,
that is, addition of the metalating agent onto the solution
of the parent compound and TMEDA in THF (e.g., for
17f: yield 53% versus 32% under conditions defined in
Scheme 2). The analytical and spectroscopical data of
compounds 17–19 prepared are listed in Table 4.
We conjectured that these compounds could be conceiv-
ably obtained by hydrogenation of the bromoarylenecar-
bamates 19d–f and we envisaged building up these
arylmethyleneoxazolidinones under the agency of the
Horner process between the suitably substituted bro-
mobenzaldehydes 20d–f and the N-diphenylphosphinoyl-
methyloxazolidin-2-one (21). This phosphorylated cyclic
carbamate was initially obtained by the two-step sequence
depicted in Scheme 4. Chloromethylation of oxazolidin-
O
R2
R3
R2
R3
Br
OH
O
N
O
N
18d–f
17d–f
R2
R3
Br
Table 3 Starting Materials and Isoquinolones 17
CH=O
R2
R3
R2
R3
19
E/Z
Yield 18
(%)
Yield 17
Yield
(%)a
Br
O
20d–f
(%)a
O
N
+
O
N
OMe OMe 19d 65:35
74
69
73
18d 86
18e 81
18f 89
17d 53
O
O
19d–f
P
H
H
OMe 19e 60:40
17e
17f
51
49
Ph
Ph
H
19f 65:35
21
a Purified products.
Scheme 3
Synthesis 2008, No. 13, 2141–2147 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Functionalized Isoindolinones and Isoquinolones
2145
1. n-BuLi, THF
2.
R2
R3
Br
(CH2O)n
Me3SiCl
O
O
O
CH=O
CHCl3, ∆, 5 h
Ph2POEt
20d–f
O
O
O
N
NH
N
O
P
Cl
Ph
Ph
13
21
22
1. t-BuLi (1 equiv)
THF, TMEDA
–100 °C
O
2. H3O+
Et3SiH, TFA
CH2Cl2, ∆
R2
R2
R2
R3
OH
Br
Br
O
O
N
R3
O
O
N
N
R3
17d–f
19d–f
18d–f
Scheme 4
Table 4 Spectroscopic and Physical Data of Carbamates 19 and 18 and Isoquinolones 17 Prepared
Producta,b Mp (°C)
(Appearance)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
(E)-19d
(Z)-19d
(E)-19e
(Z)-19e
(E)-19f
(Z)-19f
18d
167–168 (yel-
low crystals)
3.88 (s, 3 H, OCH3), 3.89–3.95 (m, 5 H, NCH2 + OCH3), 4.55 (t, J = 42.6, 56.2 (2 × CH3), 62.4, 107.8, 110.1,
8.1, 2 H, OCH2), 6.03 (d, J = 14.6, 1 H, ArCH=), 6.96 (s, 1 Harom),
7.01 (s, 1 Harom), 7.25 (d, J = 14.6, 1 H, =CHN)
113.4, 115.4, 124.4, 127.7, 148.6, 148.8,
155.5 (C=O)
(yellow oil)
3.35 (t, J = 8.0, 2 H, NCH2), 3.86 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 44.4, 56.1 (2 × CH3), 62.7, 110.7, 113.7,
4.27 (t, J = 8.0, 2 H, OCH2), 5.79 (d, J = 9.7, 1 H, ArCH=), 6.71–6.74 114.6, 114.7, 124.8, 127.9, 147.6, 148.4,
(m, 2 Harom), 7.03 (d, J = 9.6, 1 H, =CHN)
158.6 (C=O)
130–131 (yel-
low crystals)
3.70 (s, 3 H, OCH3), 3.78 (t, J = 8.1, 2 H, NCH2), 4.41 (t, J = 8.0, 2 42.5, 55.6, 62.5, 110.0, 110.4, 113.8,
H, OCH2), 5.93 (d, J = 14.6, 1 H, ArCH=), 6.55 (dd, J = 2.9, 8.9, 1 114.7, 125.9, 133.5, 136.3, 155.4, 159.1
Harom), 6.90 (d, J = 2.8, 1 Harom), 7.24–7.32 (m, 2 H, 1 Harom + =CHN) (C=O)
89–90 (white
crystals)
3.26 (t, J = 8.0, 2 H, NCH2), 3.72 (s, 3 H, OCH3), 4.19 (t, J = 8.0, 2 44.5, 55.6, 62.7, 110.5, 114.6, 115.0,
H, OCH2), 5.72 (d, J = 9.8, 1 H, ArCH=), 6.62–6.69 (m, 3 Harom), 7.36 117.1, 125.1, 132.8, 137.1, 156.8, 158.2
(d, J = 8.7, 1 H, =CHN)
(C=O)
(fawn oil)
3.91 (t, J = 8.1, 2 H, NCH2), 4.53 (t, J = 8.1, 2 H, CH2O), 6.09 (d, J = 42.5, 62.5, 109.9, 125.9, 127.6, 128.0,
14.6, 1 H, ArCH=), 7.06–7.13 (m, 1 Harom), 7.22–7.36 (m, 2 H, 1 Harom 128.7, 133.0, 135.7, 140.0, 156.9 (C=O)
+ =CHN), 7.49–7.59 (m, 2 Harom
)
96–97 (white
crystals)
3.29 (t, J = 8.0, 2 H, NCH2), 4.26 (t, J = 8.0, 2 H, OCH2), 5.85 (d, J = 44.6, 62.6, 110.7, 124.5, 125.1, 126.7,
9.8, 1 H, ArCH=), 6.78 (d, J = 9.8, 1 H, =CHN), 7.13–7.18 (m, 1 128.9, 131.5, 132.3, 136.3, 155.9 (C=O)
Harom), 7.22–7.33 (m, 2 Harom), 7.58 (dd, J = 1.1, 8.0, 1 Harom
)
80–81 (fawn
crystals)
2.88 (t, J = 7.7, 2 H, ArCH2), 3.41–3.46 (m, 4 H, 2 × NCH2), 3.78 (s, 33.6, 43.9, 45.0, 56.1 (2 × CH3), 61.8,
3 H, OCH3), 3.79 (s, 3 H, OCH3), 4.21 (t, J = 8.0, 2 H, OCH2), 6.73 113.1, 114.0, 115.4, 129.4, 148.3, 148.5,
(s, 1 Harom), 6.93 (s, 1 Harom
)
158.4 (CO)
18e
(fawn oil)
(fawn oil)
2.79 (t, J = 7.4, 2 H, ArCH2), 3.31–3.37 (m, 4 H, 2 × NCH2), 3.59 (s, 34.1, 43.8, 44.8, 55.3, 61.8, 114.1, 114.5,
3 H, OCH3), 4.08 (t, J = 8.0, 2 H, OCH2), 6.50 (dd, J = 3.0, 8.8, 1 116.1, 133.2, 138.6, 158.2, 159.0 (C=O)
Harom), 6.68 (d, J = 3.0, 1 Harom), 7.23 (d, J = 8.8, 1 Harom
)
18f
2.80 (t, J = 7.4, 2 H, ArCH2), 3.25–3.32 (m, 4 H, 2 × NCH2), 4.02 (t, 33.9, 43.8, 44.8, 61.8, 124.3 (CH), 124.3
J = 7.6, 2 H, OCH2), 6.86–6.92 (m, 1 Harom), 7.04–7.07 (m, 2 Harom), (CBr), 128.4, 130.8, 132.7, 137.7, 158.2
7.31–7.34 (m, 1 Harom
)
(C=O)
17d
90–91 (white
crystals)
2.98 (t, J = 6.8, 2 H, ArCH2), 3.67 (t, J = 6.8, 2 H, NCH2), 3.76 (t, J 27.7, 48.0, 51.3, 56.1 (2 × CH3), 61.7,
= 4.6, 2 H, NCH2), 3.91 (t, J = 4.0, 2 H, OCH2), 3.95 (s, 3 H, OCH3), 109.2, 110.3, 121.6, 131.9, 147.9, 151.9,
3.96 (s, 3 H, OCH3), 6.67 (s, 1 Harom), 7.59 (s, 1 Harom
)
166.1 (C=O)
Synthesis 2008, No. 13, 2141–2147 © Thieme Stuttgart · New York

2146
M. Lorion et al.
PAPER
Table 4 Spectroscopic and Physical Data of Carbamates 19 and 18 and Isoquinolones 17 Prepared (continued)
Producta,b Mp (°C)
(Appearance)
1H NMR (CDCl3/TMS)
d, J (Hz)
13C NMR (CDCl3/TMS)
d
17e
108–109 (white 2.93 (t, J = 6.6, 2 H, ArCH2), 3.61 (t, J = 6.6, 2 H, NCH2), 3.67 (t,
28.4, 47.8, 51.1, 55.4, 61.5, 111.9, 112.5,
crystals)
J = 5.3, 2 H, NCH2), 3.81–3.84 (m, 5 H, OCH3 + OCH2), 3.96 (br s, 121.9, 130.2, 140.4, 162.3, 166.0 (C=O)
1 H, OH), 6.63 (s, 1 Harom), 6.79 (dd, J = 2.4, 8.6, 1 Harom), 7.94 (d,
J = 8.6, 1 Harom
)
17f
43–44 (Lit.19
44.5–45)
2.93 (t, J = 6.7, 2 H, ArCH2), 3.60 (t, J = 6.6, 2 H, NCH2), 3.65 (t,
J = 5.4, 2 H, NCH2), 3.80 (t, J = 5.4, 2 H, OCH2), 4.11 (br s, 1 H, OH), 128.6, 129.1, 131.8, 138.3, 165.6 (C=O)
28.0, 47.7, 50.9, 61.1, 126.9, 128.0,
(white crystals) 7.11 (d, J = 7.4, 1 Harom), 7.26 (td, J = 1.0, 7.5, 1 Harom), 7.36 (td, J =
1.5, 7.4, 1 Harom), 7.96 (dd, J = 1.5, 7.5, 1 Harom
)
a Satisfactory microanalyses obtained: C 0.29, H 0.30, N 0.25.
b IR (KBr or neat): 18d–f, 1719–1736 cm–1 (C=O); 17d–f, 1624–1638 cm–1 (C=O).
13C NMR (75 MHz, CDCl3): d = 44.6 (d, JC,P = 80.2 Hz, CH2P),
In summary, a concise and flexible approach to N-func-
tionalized isoindolinones and isoquinolinones was devel-
oped via the anionic cyclization of bromobenzyl and
bromophenethylcarbamates derivatives. The method is
versatile in scope because various hydroxy and sulfanyl-
alkyl chains can be introduced easily on the compact het-
erocyclic framework. The tethered functionalities may
serve as a handle for further synthetic planning and we be-
lieve that this methodology opens a way to a wide range
of biologically important derivatives of these classes of
compounds.
45.8 (d, JC,P = 2.7 Hz, CH2N), 62.2 (d, JC,P = 2.7 Hz, OCH2), 128.7
(d, JC,P = 11.5 Hz, 2 × CH), 128.8 (d, JC,P = 12.0 Hz, 2 × CH), 130.8
(d, JC,P = 9.8 Hz, 2 × CH), 130.9 (d, JC,P = 9.8 Hz, 2 × CH), 131.1
(d, JC,P = 98.0 Hz, 2 × C), 132.4 (d, JC,P = 2.7 Hz, CH), 132.5 (d,
JC,P = 2.9 Hz, CH), 158.3 (d, JC,P = 4.4 Hz, C=O).
31P NMR (121 MHz, CDCl3): d = 29.5.
Anal. Calcd for C16H16NO3P: C, 63.79; H, 5.35; N, 4.65. Found: C,
63.53; H, 5.46; N, 4.82.
N-Substituted Oxazolidin-2-ones 6a–c, Thiazolidin-2-ones 7c,d,
and [1,3]Oxazinan-2-ones 8b–e; General Procedure
A solution of the heterocyclic compound 13–15 (4.0 mmol) in THF
(10 mL) was added dropwise to a stirred suspension of NaH (pre-
pared by washing 1.1 equiv of a 60% suspension in mineral oil with
pentane, 0.176 g, 4.4 mmol) in THF (20 mL) under argon, and the
mixture was further stirred at r.t. for 1 h. A solution of the o-bro-
mobenzyl bromide 12a–e (4.0 mmol) in THF (10 mL) was added
dropwise and the mixture was refluxed overnight. After cooling,
H2O (20 mL) was added, and the mixture was extracted with Et2O
(3 × 25 mL). The combined organic layers were dried (Na2SO4) and
the solvent was evaporated under vacuum. The residue was purified
by flash column chromatography on silica gel [6a–c: EtOAc–hex-
anes–CH2Cl2 (30:30:40); 7d: EtOAc–hexanes–CH2Cl2 (40:30:30);
7c: acetone–hexanes–CH2Cl2 (10:10:80); 8b: acetone–hexanes
(50:50); 8d: acetone–hexanes (60:40); 8e: acetone–hexanes
(70:30); 8c: acetone–CH2Cl2 (40:60)] (Tables 1 and 2).
Melting point determinations were carried out on a Reichert-Ther-
1
mopan apparatus and are uncorrected. H and 13C NMR spectra
were measured at 300 MHz and 75 MHz, respectively, on a Bruker
AM 300 spectrometer as solutions in CDCl3 with TMS as internal
standard; 31P NMR spectra at 121 MHz with H3PO4 as external stan-
dard. Elemental analyses were obtained using a Carlo-Erba CHNS-
11110 equipment. 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 was obtained by oven drying and assembly 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.
The o-bromobenzyl bromides 12a,12 12b,13 12c,14 12d,15 12e,16
were prepared according to reported procedures. The thiazolidin-2-
one (14)17 and the [1,3]oxazinan-2-one (15)18 were synthesized ac-
cording to the literature procedures.
Isoindolinones 9a–c, 10c,d, and 11b–e; General Procedure
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 3 freeze-thaw cycles and stirred at –78 °C under dry
deoxygenated argon. A solution of compound 6, 7, or 8 (1.0 mmol)
in degassed THF (16 mL) was then added dropwise through a can-
nula. 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 organ-
ic layers were dried (Na2SO4) and the solvent was evaporated under
vacuum to leave the isoindolinone as a solid residue, which was pu-
rified by flash column chromatography on silica gel [9a–c, 11d:
acetone–hexanes (80:20); 10c,d, 11b: acetone–hexanes (60:40);
11c,e: acetone–hexanes (70:30)] (Tables 1 and 2).
3-[(Diphenylphosphinoyl)methyl]oxazolidin-2-one (21)
A solution of oxazolidin-2-one 13 (3.24 g, 37.2 mmol), paraformal-
dehyde (1.12 g, 37.2 mmol) and chlorotrimethylsilane (14.2 mL,
112 mmol) in CHCl3 (180 mL) was refluxed for 5 h. After cooling,
the solvent and excess reagent were evaporated under vacuum (0.02
Torr) and the crude oily 3-(chloromethyl)oxazolidin-2-one (22) was
used in the next step without further purification. Neat compound
22 (3.53 g, 26.0 mmol) was treated with ethyl diphenylphosphinite
(6.09 g, 26.0 mmol). A vigorous agitation was maintained until for-
mation of a solid residue, which was triturated with Et2O, filtered,
and recrystallized from hexane–toluene to afford 21 as white crys-
tals (5.37 g, 68%); mp 173–174 °C.
IR (KBr): 1740 (C=O), 1185 cm–1 (P=O).
1H NMR (300 MHz, CDCl3): d = 3.74 (s, 2 H, NCH2P), 4.08–4.14
(m, 4 H, 2 × CH2), 7.36–7.41 (m, 6 Harom), 7.72–7.75 (4 Harom).
o-Bromoarylmethyleneoxazolidinones 19d–f; General Proce-
dure
A solution of n-BuLi (1.6 M in hexane, 3.45 mL, 5.5 mmol) was
added dropwise to a solution of the phosphorylated derivative 21
(1.51 g, 5.0 mmol) in anhyd THF (100 mL). The mixture was stirred
Synthesis 2008, No. 13, 2141–2147 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Functionalized Isoindolinones and Isoquinolones
2147
at –78 °C under argon for 1 h, then a solution of o-halogenobenzal-
dehyde 20d–f (5.5 mmol) in anhyd THF (20 mL) was added drop-
wise. The mixture was allowed to warm to r.t. over 2 h and then
refluxed overnight. After cooling, quenching with aq sat. NH4Cl (5
mL) and dilution with H2O (30 mL), THF was removed under vac-
uum in a rotary evaporator. The aqueous residue was extracted with
CH2Cl2 (2 × 30 mL). The combined organic layers were dried
(Na2SO4), and the solvent was evaporated under vacuum to afford
compound 19d–f as a mixture of E- and Z-isomers. Flash column
chromatography on silica gel allowed the separation of the isomers
[19d: Et2O–hexanes–CH2Cl2 (30:20:50); 19e: Et2O–hexanes–
CH2Cl2 (20:40:40); 19f: EtOAc–hexanes (50:50)], but the subse-
quent reduction reaction was performed on the mixture of stereoiso-
mers (Tables 3 and 4).
1995, 38, 2491. (d) Bellioti, T. R.; Wustrow, D. J. US Patent
6087364, 2000; Chem. Abstr. 2000, 133, 89548.
(e) Hudkins, R. L.; Reddy, D.; Singh, J.; Stripathy, R.;
Underiner, T. L. PCT Int. Appl. WO 0047583, 2000; Chem.
Abstr. 2000, 133, 177158. (f) Duggan, M. E.; Hartman, G.
D.; Hoffman, W. F. PCT Int. Appl. WO 9737655, 1997;
Chem. Abstr. 1997, 127, 331749.
(2) Govindachari, T. R.; Ravindranath, K. R.; Viswanathan, N.
J. Chem. Soc., Perkin Trans. 1 1974, 1215.
(3) (a) Taylor, E. C.; Zhou, P.; Jenning, L. D.; Mao, Z.; Hu, B.;
Jun, J.-G. Tetrahedron Lett. 1997, 38, 521. (b) Fuska, J.;
Fuskova, A.; Proksa, B. Zb. Pr. Chemickotechnol. Fak.,
SVST, 1979-1981 (pub. 1986), 285–291; Chem. Abstr. 1987,
106, 95582.
(4) Li, S.; Wang, X.; Guo, H.; Chen, L. Yiyano Gongye 1985,
16, 543; Chem. Abstr. 1986, 105, 6378.
(5) (a) Linden, M.; Hadler, D.; Hofmann, S. Hum.
Psychopharmacol. 1997, 12, 445. (b) Norman, M. H.;
Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39, 149.
(6) Lippmann, W. US Patent 4267189, 1981; Chem. Abstr.
1981, 95, 61988.
(7) Yeo, H.; Li, Y.; Fu, L.; Zhu, J.-L.; Gullen, E. A.; Dutschman,
G. E.; Lee, Y.; Chung, R.; Huang, E.-S.; Austin, D. J.;
Cheng, Y.-C. J. Med. Chem. 2005, 48, 534.
o-Bromophenethyloxazolidinones 18d–f; General Procedure
Triethylsilane (0.7 g, 0.96 mL, 6.0 mmol) and trifluoroacetic acid
(0.15 mL, 2.0 mmol) were sequentially added dropwise to a stirred
solution of 19d–f (2.0 mmol, mixture of E- and Z-isomers) in
CH2Cl2 (5 mL) and the mixture was refluxed overnight. After cool-
ing, aq sat. NaHCO3 solution (10 mL) was added and the mixture
was extracted with CH2Cl2 (2 × 25 mL). The combined organic lay-
ers were dried (Na2SO4) and the solvent was evaporated under vac-
uum to leave a brown oily residue, which was purified by flash
column chromatography on silica gel [18d: EtOAc–hexanes
(70:30); 18e,f: EtOAc–hexanes–MeOH (60:35:5)] (Tables 3
and 4).
(8) Zeldis, J. B. PCT Int. Appl. WO 043378, 2004; Chem. Abstr.
2004, 140, 417925.
(9) Ren, J.; Esnouf, R. M.; Hopkins, A. L.; Stuart, D. I.;
Stammers, D. K. J. Med. Chem. 1999, 42, 3845.
(10) Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med.
Chem. 1998, 41, 157.
Hydroxyethylisoquinolones 17d–f; General Procedure
A solution of o-bromophenethyloxazolidinone 18d–f (1.0 mmol)
and TMEDA (128 mg, 1.1 mmol) in anhyd THF (20 mL) was care-
fully degassed by three freeze-thaw cycles and stirred at –78 °C un-
der dry deoxygenated argon. The mixture was cooled to –100 °C
and t-BuLi (2 M in pentane, 0.55 mL, 1.1 mmol) was added drop-
wise. The mixture was stirred for 30 min at this temperature, and
then quenched with aq sat. NH4Cl (5 mL). Dilution with H2O (30
mL) and evaporation of THF under vacuum in a rotary evaporator
left an aqueous residue, which was extracted with CH2Cl2 (2 × 30
mL). The combined organic layers were dried (Na2SO4), and the
solvent was evaporated under vacuum to afford the isoquinolone
17d–f as a solid residue which was purified by flash column chro-
matography on silica gel (acetone–CH2Cl2–MeOH, 25:70:5)
(Tables 3 and 4).
(11) (a) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982,
15, 300. (b) Wakefield, B. J. The Chemistry of
Organolithium Compounds; Pergamon: New York, 1990,
2nd ed. (c) Gray, M.; Tinkl, M.; Snieckus, V. In
Comprehensive Organometallic Chemistry II, Vol. 11; Abel,
E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Pergamon:
Oxford, 1995, 66–92. (d) Ardeo, A.; Collado, M. I.; Osante,
I.; Ruiz, J.; Sotomayor, N.; Lete, E. In Targets in
Heterocyclic Systems, Vol. 5; Atanassi, O.; Spinelli, D.,
Eds.; Italian Society of Chemistry: Rome, 2001, 393–418.
(e) Clayden, J. Organolithiums: Selectivity for Synthesis;
Elsevier: Oxford, 2002. (f) Sotomayor, N.; Lete, E. Curr.
Org. Chem. 2003, 7, 275.
(12) Lipshutz, B. H.; Liu, Z.-P.; Kayser, F. Tetrahedron Lett.
1994, 35, 5567.
Acknowledgment
(13) Paleo, M. R.; Castedo, L.; Dominguez, D. J. Org. Chem.
1993, 58, 2763.
(14) Markus, A. Synthesis 1996, 230.
(15) Dai-Ho, G.; Mariano, P. S. J. Org. Chem. 1987, 52, 704.
(16) Al-Maharik, N.; Engman, L.; Malmstroem, J.; Schiesser, C.
H. J. Org. Chem. 2001, 66, 6286.
(17) Wilmore, B. H.; Cassidy, P. B.; Warters, R. L.; Roberts, J. C.
J. Med. Chem. 2001, 44, 2661.
This research was supported by the Centre National de la Recherche
Scientifique and MENESR (grant to M.L.).
References
(1) (a) Fajardo, V.; Elango, V.; Cassels, B. K.; Shamma, M.
Tetrahedron Lett. 1982, 23, 39. (b) Pendrak, I.; Barney, S.;
Wittrock, R.; Lambert, D. M.; Kingsbury, W. D. J. Org.
Chem. 1994, 59, 2623. (c) De Clercq, E. J. Med. Chem.
(18) Kim, Y. J.; Varma, R. S. Tetrahedron Lett. 2004, 45, 7205.
(19) Schneider, M. Chem. Ber. 1960, 93, 1579.
Synthesis 2008, No. 13, 2141–2147 © Thieme Stuttgart · New York