A concise and flexible diastereoselective approach to heteroring-fused isoindolinones

Article abstract of DOI:10.1055/s-0030-1258313

A variety of poly and diversely substituted isoindoli-nones fused with six-membered heterocyclic moieties has been readily assembled through a sequence involving metalation of N-chloroalkylated models, subsequent interception with appropriate electrophiles and ultimate intramolecular annulation reaction. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258313

PAPER
147
A Concise and Flexible Diastereoselective Approach to Heteroring-Fused
Isoindolinones
H
eteroring-Fused I
a
soindolino
n
nes g Ahn,a,b Magali Lorion,a,b Vangelis Agouridas,a,b Axel Couture,*a,c Eric Deniau,a,b Pierre Grandclaudona,b
a
Univ Lille Nord de France, 59000 Lille, France
Fax +33(0)320436309; E-mail: axel.couture@univ-lille1.fr
b
c
USTL, Laboratoire de Chimie Organique Physique, EA CMF 4478, Bâtiment C3(2), 59655 Villeneuve d’Ascq, France
CNRS, UMR 8181 ‘UCCS’, 59655 Villeneuve d’Ascq, France
Received 7 September 2010; revised 23 September 2010
gard, we have aimed to develop new and convergent ap-
proaches to rapidly achieve molecular complexity in a
highly efficient manner. We have assumed that the pres-
ence of heteroatoms in the cyclic moieties embedded in
the compact molecular framework could retain the bioac-
tivity of the models and lead to a new generation of SAR
studies.
Abstract: A variety of poly and diversely substituted isoindoli-
nones fused with six-membered heterocyclic moieties has been
readily assembled through a sequence involving metalation of N-
chloroalkylated models, subsequent interception with appropriate
electrophiles and ultimate intramolecular annulation reaction.
Key words: carbanions, fused-ring systems, lactams, metalation,
cyclization
O
O
MeO
The isoindolinone ring system, which represents a confor-
mationally constrained variant of the benzamide nucleus,
is a ubiquitous structural feature of numerous naturally
occurring alkaloids, and can be frequently recognized in
the framework of structurally sophisticated drug candi-
dates.1 The benzolactam nucleus may serve as a linker for
a variety of pharmacophores2 and structural variations
that act on the pharmacological profile of the models can
be classified into two main categories. In most cases, bio-
active isoindolinone-centered compounds naturally com-
prise a benzolactam unit with appropriate functionalities
attached to the lactam nitrogen.3 Alternatively, the isoin-
dolinone ring can be fused with constitutionally diverse
heterocyclic moieties, and this class of compounds has re-
cently attracted considerable attention due to their pro-
found physiological and chemotherapeutic properties.4
The representative compounds 1–4 fall into this class of
compounds (Figure 1). Thus, the tricyclic g-lactams 1,
with heteroatomic substituents at the 3-position, have
been studied as selective non-nucleosidic HIV reverse
transcriptase inhibitors,5 and 2 has also been shown to
have a promising antibacterial activity.6 The amino-deriv-
ative 3 was recently reported to be a potent and selective
5-HT2C agonist as antiobesity agent,7 and compound 4
was recently tested as a cognition modulator.8 Conse-
quently, interest in designing efficient synthetic proce-
dures for the assembly of structurally and constitutionally
diverse isoindolinone-centered models is an area of cur-
rent investigation.9 Organic chemists have at their dispos-
al a great number of synthetic methods for the preparation
of substituted isoindolinones,10 but few flexible and gen-
eral methods are available for the construction of highly
heterofused models with structural variability.4 In this re-
N
N
( )n
O
Ar
X
OH
O
1
X = N, O, S, SO, SO2
2
CF3
O
N
N
Et
NH
N
3
4
SO2C6H4(4-F)
Figure 1 Bioactive isoindolinone-centered compounds
The present work originated from the following premises:
(i) isoindolinones with hydroxyalkyl chains that may
serve as a handle for further synthetic planning tethered
on the lactam nitrogen, can be readily accessed through
anionic cyclization of N-bromobenzylated carbamates;11
(ii) isoindolinones have been successfully metalated at the
benzylic position of the heteroring system thus allowing
the connection of a range of electrophiles at the 3-position
of the lactam ring.12 Consequently, one could envisage
triggering an intramolecular cyclization process by chem-
ical manipulation of appropriate appendages connected to
the lactam unit, which would give rise to tailor-made,
architecturally diverse fused models.
The first facet of the synthesis was the elaboration of the
N-hydroxylated isoindolinones 5a–d. These parent com-
pounds were readily obtained by capture of the lithiated
species 6, which were derived from the parent carbamates
7a–d with an oxazolidinone (n = 1) acting as an internal
electrophile. This technique provided the potential for
direct construction of the isoindolinone template with
concomitant connection of the required hydroxyalkyl ap-
pendage, thereby providing the N-functionalized models
5a–d (Scheme 1).11a
SYNTHESIS 2011, No. 1, pp 0147–0153
x
x
.
x
x
.2
0
1
0
Advanced online publication: 25.10.2010
DOI: 10.1055/s-0030-1258313; Art ID: Z22710SS
© Georg Thieme Verlag Stuttgart · New York

148
G. Ahn et al.
PAPER
R1
R1
R1
O
n-BuLi, TMEDA
THF, –78 °C to r.t.
R2
R3
Br
R2
R3
R2
R3
Li
O
O
O
O
N
( )n
N
N
OH
( )n
( )n
R4
R4
R4
7a–d n = 1
7e n = 2
6
5a–d n = 1
5e n = 2
1. KHMDS, THF, –78 °C to –50 °C
2.
R5
Y
SOCl2, toluene
0 °C then 60 °C, 3 h
or
R1
R1
O
R6
O
PBr3, toluene
reflux, 3 h
10f–i Y = O
R7
R2
R3
R2
R3
17f Y = NTs
( )n
N
N
( )n
X = Cl 95–97%
X = Br 83%
X
Cl
R4
Y
R4
8a–d n = 1, X = Cl
8e n = 2, X = Cl
11a n = 1, X = Br
R5
R6
R7
15
R1
O
R2
R3
N
( )n
Y
H
R4
H
R5
R6
R7
9j–p Y = O, n = 1, 53–93%
16 Y = NTs, n = 1, 36%
13 Y = O, n = 2
Scheme 1 Synthesis of fused isoindolinones
The next step was the conversion of the hydroxyalkyl get fused compounds 9j–p since we envisioned that the
tethered compounds 5a–d into the corresponding chlori- subsequent third and fourth phases of the synthesis could
nated derivatives 8a–d. This operation was readily and ef- be performed as a one-pot reaction. Compounds 8a–d
ficiently secured by treatment of 5a–d with thionyl were smoothly deprotonated with potassium hexameth-
chloride (Scheme 1, Table 1, Table 2). With compounds yldisylazide (KHMDS) at –78 °C and subsequently
8a–d in hand we were actually one step away from the tar- quenched with an array of unsaturated compounds 10f–h
Table 1 Compounds 8a–e, 9j–p, 16 and 14 Prepared
Starting material
Fusedisoindolinones
9, 16, 14
N-Chloroalkylisoindolinone 8
Benzaldehyde 10 or benzaldimine 17
R1
R2
R3
R4
OMe
H
n
1
1
1
1
1
1
1
1
2
Yield (%)
R5
R6
R7
Y
Yield (%)
8a
8b
8c
8c
8d
8d
H
H
OMe
H
95
93
97
10f
10f
10f
10g
10h
10g
H
H
H
O
9j
62
64
93
59
56
53
58a
36
68b
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
O
9k
9l
OMe
OMe
OBn
OBn
OH
H
H
H
H
O
H
H
MeSO2
OMe
MeSO2
MeSO2
H
H
O
9m
9n
9o
9p
H
97
OMe
H
OMe
H
O
H
H
O
H
H
H
H
O
8a
8e
H
OMe
OMe
OMe
H
17f
10i
H
H
NTs
O
16
14
H
OMe
83
H
OMe
H
a Compound 9p was prepared by deprotection of the benzylated analogue 9o.
b Primary adduct of condensation of anisaldehyde with lithiated isoindolinone; 50:50 mixture of diastereomers.
Synthesis 2011, No. 1, 147–153 © Thieme Stuttgart · New York

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Heteroring-Fused Isoindolinones
149
at –50 °C. Warming to 0 °C was followed by acidic aque- Unfortunately all attempts to synthesize the seven-mem-
ous work-up and, gratifyingly, conducting the reaction ac- bered analogues 13 by the same synthetic approach failed.
cording to this procedure led to the complete consumption Initially, exposure of 7e (n = 2) to n-BuLi led efficiently
of the starting material and smoothly afforded the tricyclic to the hydroxyalkylated isoindolinones 5e, and chlorina-
lactams 9j–p (Scheme 1, Table 1, Table 2).
tion proceeded uneventfully to provide the halogenated
compound 8e. However, deprotonation of 8e with KH-
MDS and interception of the transient lithiated species
with p-anisaldehyde 10i followed by standard work-up
delivered exclusively the adduct 14 (Figure 2, Table 1,
Table 2) as an equimolecular mixture of easily separable
erythro and threo isomers. In order to force the annulation
reaction of the primary adduct 14 and thus gain access to
compounds that are structurally related to 12 through the
intermediacy of 15, variation of the solvent (THF, DMF),
base (NaH, KH), temperature profile, and inclusion of an-
ion modifiers (TMEDA, crown ether) were all assessed.
Disappointingly, none of these operations met with suc-
cess. However, the method did allow the assembly of
oxygen- and nitrogen-containing, highly fused models, as
exemplified by the synthesis of the piperazine-containing
model 16 upon exposure of metalated isoindolinone 8b to
tosylimine 17f (Scheme 1, Table 1, Table 2).
It is worth mentioning that the decision to use chlorinated
compounds was rewarded here. Indeed, we observed that
treatment of the brominated analogue 11a under the con-
ditions described above did not lead to the target annulat-
ed compounds but led instead to the E2 elimination
product 12 (Figure 2).
O
O
Cl
MeO
MeO
N
N
MeO
H
OH
OMe
12
H
MeO
14
Figure 2 Unexpected products from the synthetic process
In summary, we have developed a rapid and convergent
method with which to construct a variety of fused ring
isoindolinones without the need for isolation and purifica-
tion of the key intermediates. The notable advantages of
this method are operational simplicity, mild reaction con-
ditions, and ease of isolation of products, which display
large molecular diversity and contain functional group
characteristics of all the precursors. The flexible protocol
developed in the present study paves the way for the con-
struction of related isoindolinone derivatives for further
biological studies.
A representative series of compounds that have been pre-
pared by this technique are presented in Table 1. It can be
seen that this simple procedure affords very satisfactory
yields of the previously unattainable benzo-fused lactams
9j–p. The reaction conditions were found to be compati-
ble with a broad range of substitution patterns within the
environmentally diverse aromatic units.
Interestingly, the six-membered models 9j–p were exclu-
sively obtained as the trans-stereoisomers. To establish
the stereochemistry at the 2-C and 19-C positions of the
fused compounds 9j–p, X-ray crystallographic analysis of
9j was performed. The ORTEP view (Figure 3) provides
direct evidence of the trans-configuration of these benzyl-
ic positions.
Tetrahydrofuran (THF) was pre-dried with anhydrous Na2SO4 and
distilled over sodium benzophenone ketyl under Ar before use. Tol-
uene was distilled from CaH2. Dry glassware was obtained by oven-
drying and assembly under anhydrous Ar. The glassware was
equipped with rubber septa and reagent transfer was performed us-
ing syringe techniques. For flash chromatography, Merck silica gel
60 (40–63 mm; 230–400 mesh ASTM) was used. Melting points
were obtained with a Reichert–Thermopan apparatus and are not
corrected. Elemental analyses were obtained with a Carlo–Erba
CHNS-11110 instrument. NMR spectra were recorded with a
Bruker AM 300 (300 MHz and 75 MHz, for 1H and 13C) instrument,
with CDCl3 as solvent and TMS as internal standard.
3-(5-Benzyloxy-2-bromo-4-methoxybenzyl)oxazolidin-2-one
(7d)
Oxazolidinones 7a–c and oxazinanone 7e were prepared according
to a previously reported procedure.11a
Following the same procedure, 7d was readily assembled by con-
densation of oxazolidin-2-one and 1-benzyloxy-4-bromo-5-bro-
momethyl-2-methoxybenzene prepared by bromination of the
corresponding benzyl alcohol13 with PBr3 in Et2O.
Yield: 1.36 g (87%); colorless crystals; mp 82–83 °C.
1H NMR (300 MHz, CDCl3): d = 3.28 (t, J = 8.0 Hz, 2 H, NCH2),
3.89 (s, 3 H, OCH3), 4.19 (t, J = 8.0 Hz, 2 H, CH2O), 4.46 (s, 2 H,
NCH2), 5.15 (s, 2 H, CH2Ph), 6.87 (s, 1 H, ArH), 7.03 (s, 1 H, ArH),
7.32–7.44 (m, 5 H, ArH).
Figure 3 ORTEP view of the X-ray crystal structure of 9j13
Synthesis 2011, No. 1, 147–153 © Thieme Stuttgart · New York

150
G. Ahn et al.
PAPER
N-(Chloroalkyl)isoindolinones 8a–e; General Procedure14
13C NMR (75 MHz, CDCl3): d = 44.0 (CH2), 56.3 (CH2), 56.3
(CH3), 61.9 (CH2), 70.0 (CH2), 114.3 (C), 115.1 (CH), 115.7 (CH),
127.4 (2 × CH), 128.0 (C), 128.6 (2 × CH), 128.8 (CH), 136.5 (C),
147.6 (C), 149.9 (C), 158.5 (CO).
Thionyl chloride (400 mg, 3.4 mmol) was added dropwise to an ice–
water cooled solution of N-hydroxyalkylisoindolinone 5a–e (3.0
mmol) in toluene (50 mL). The reaction mixture was allowed to
stand at r.t. for 4 h with occasional swirling and then heated at 60 °C
for 3 h. The toluene and the excess thionyl chloride were removed
by evaporation under vacuum and the hot residue was poured into
hexanes (50 mL) to afford a brown solid. After filtration, the solid
was dissolved in refluxing toluene. The solution was filtered hot and
the hot filtrate was poured into hexanes (30 mL) with stirring. The
precipitate was filtered, washed with hexanes and dried in a vacuum
oven to afford 8a–e as a light-fawn solid, which was used without
further purification.
Anal. Calcd for C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57. Found: C,
55.36; H, 4.48; N, 3.84.
5-Benzyloxy-2-(2-hydroxyethyl)-6-methoxy-2,3-dihydro-1H-
isoindol-1-one (5d)
N-Hydroxyalkylisoindolinones 5a–c and 5e were easily obtained by
treatment of oxazolidinones 7a–c and oxazinone 7e with n-BuLi as
previously described.11a The same procedure was applied to 7d to
furnish 5d as light-fawn crystals after purification by flash column
chromatography on silica gel (acetone–hexanes, 80:20).
2-(2-Bromoethyl)-4,5-dimethoxy-2,3-dihydro-1H-isoindol-1-
one (11a)
Yield: 160 mg (51%); mp 176–177 °C.
1H NMR (300 MHz, CDCl3): d = 3.70 (t, J = 5.0 Hz, 2 H, NCH2),
3.87 (t, J = 5.0 Hz, 2 H, CH2OH), 3.93 (s, 3 H, OCH3), 4.35 (s, 2 H,
NCH2), 5.20 (s, 2 H, CH2Ph), 6.88 (s, 1 H, ArH), 7.29 (s, 1 H, ArH),
7.32–7.46 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 46.2 (CH2), 51.3 (CH2), 56.3
(CH3), 61.7 (CH2), 71.1 (CH2), 105.5 (CH), 107.2 (CH), 125.1 (C),
127.1 (2 × CH), 128.1 (CH), 128.7 (2 × CH), 134.8 (C), 136.3 (C),
150.2 (C), 151.6 (C), 170.0 (CO).
A mixture of a 2-(2-hydroxyethyl)-4,5-dimethoxy-2,3-dihydro-1H-
isoindol-1-one (5a; 0.897 g, 3.00 mmol) and PBr3 (570 mg, 0.20
mL, 2.10 mmol) in toluene (20 mL) was heated at reflux for 3 h.
H2O (20 mL) was added to the reaction mixture with stirring and the
organic layer was separated, washed with aq 5% NaOH (2 × 5 mL),
H2O (5 mL) and then dried (K2CO3). The solvent was evaporated to
afford the crude product, which was purified by flash column chro-
matography on silica gel (CH2Cl2–EtOAc, 50:50) to afford 11a as
colorless crystals (718 mg, 80%).
Anal. Calcd for C18H19NO4: C, 69.00; H, 6.11; N, 4.47. Found: C,
68.13; H, 5.89; N, 4.49.
Table 2 Physical and Spectroscopic Data
Product Mp (°C) 1H NMR (CDCl3/TMS): d (ppm)
13C NMR (CDCl3/TMS): d (ppm)
8a
89–90
(fawn
3.80 (t, J = 6.0 Hz, 2 H, CH2Cl), 3.92–3.95 (m, 2 H, NCH2), 42.8 (CH2), 44.8 (CH2), 49.2 (CH2), 56.2 (CH3), 60.4
4.95 (s, 3 H, OCH3), 4.96 (s, 3 H, OCH3), 4.59 (s, 2 H,
(CH3), 112.7 (CH), 119.6 (CH), 125.8 (C), 133.4 (C),
143.7 (C), 155.5 (C), 168.7 (CO)
crystals) ArCH2), 7.04 (d, J = 8.3 Hz, 1 H, ArH), 7.57 (d, J = 8.3 Hz,
1 H, ArH)
8b
87–88
3.74 (t, J = 5.8 Hz, 2 H, CH2Cl), 3.84–3.88 (m, 5 H, OCH3 and 46.2 (CH2), 44.7 (CH2), 50.5 (CH3), 56.7 (CH2), 62.5
(light-fawn NCH2), 4.03 (s, 3 H, OCH3), 4.43 (s, 2 H, ArCH2), 7.04–7.07 (CH3), 116.6 (CH), 117.8 (CH), 124.5 (C), 136.4 (C),
crystals) (m, 2 H, ArH)
114–11514
147.1 (C), 152.2 (C), 167.0 (CO)
8c
8d
160–161 3.78 (t, J = 5.8 Hz, 2 H, CH2Cl), 3.94 (t, J = 5.9 Hz, 2 H,
(light-fawn NCH2), 3.96 (s, 3 H, OCH3), 4.45 (s, 2 H, ArCH2), 5.24 (s,
crystals) 2 H, CH2Ph), 6.93 (s, 1 H, ArH), 7.34–7.47 (m, 6 H, ArH)
42.9 (CH2), 44.7 (CH2), 51.1 (CH2), 56.3 (CH3), 71.1
(CH2), 105.7 (CH), 107.2 (CH), 124.9 (C), 127.1 (2 ×
CH), 128.1 (CH), 128.7 (2 × CH), 134.7 (C), 136.3 (C),
150.2 (C), 151.7 (C), 169.1 (CO)
8e
110–11114
11aa
98–99
3.63 (t, J = 6.3 Hz, 2 H, CH2), 3.94 (s, 3 H, OCH3), 3.95 (s,
30.1 (CH2), 44.7 (CH2), 48.8 (CH2), 56.2 (CH3), 60.4
(CH3), 112.7 (CH), 119.6 (CH), 125.7 (C), 133.3 (C),
143.4 (C), 154.9 (C), 168.4 (CO)
(colorless 3 H, OCH3), 4.00 (t, J = 6.3 Hz, 2 H, CH2), 4.57 (s, 2 H,
crystals) NCH2), 7.03 (d, J = 8.2 Hz, 1 H, ArH), 7.56 (d, J = 8.2 Hz,
1 H, ArH)
9ja
109–110 2.99 (s, 3 H, OCH3), 3.38 (td, J = 4.1, 12.6 Hz, 1 H, NCH2), 40.1 (CH2), 56.1 (CH3), 59.6 (CH), 61.5 (CH3), 66.9
(colorless 3.54 (td, J = 3.1, 11.6 Hz, 1 H, NCH2), 3.80 (s, 3 H, OCH3), (CH2), 85.8 (CH), 113.4 (CH), 119.4 (CH), 126.4 (C),
crystals) 3.86 (d, J = 9.2 Hz, 1 H, CHO), 4.09 (dd, J = 3.8, 11.1 Hz,
128.0 (2 × CH), 128.5 (2 × CH), 128.8 (CH), 133.3 (C),
1 H, CH2O), 4.43 (dd, J = 2.7, 12.9 Hz, 1 H CH2O), 4.80 (d, 138.7 (C), 144.7 (C), 155.5 (C), 166.3 (CO)
J = 9.1 Hz, 1 H, CHN),.6.98 (d, J = 8.3 Hz, 1 H, ArH), 7.37–
7.42 (m, 5 H, ArH), 7.58 (d, J = 8.3 Hz, 1 H, ArH).
9ka
124–125 3.41 (td, J = 4.0, 12.6 Hz, 1 H, NCH2), 3.58 (td, J = 3.2,
(colorless 11.7 Hz, 1 H, NCH2), 3.82 (s, 3 H, OCH3), 3.84 (d,
crystals) J = 9.3 Hz, 1 H, CHPh), 4.07 (s, 3 H, OCH3), 4.15 (dd,
39.7 (CH2), 56.5 (CH3), 61.5 (CH3), 62.5 (CH), 67.1
(CH2), 85.0 (CH), 115.5 (CH), 119.0 (CH), 125.0 (C),
128.2 (2 × CH), 128.8 (2 × CH), 129.3 (CH), 133.8 (C),
J = 4.0, 11.3 Hz, 1 H, CH2O), 4.40 (dd, J = 3.1, 13.2 Hz, 1 H, 137.4 (C), 147.2 (C), 152.9 (C), 164.6 (CO)
of CH2O), 4.44 (d, J = 9.4 Hz, 1 H, CHN), 6.00 (d, J = 8.2 Hz,
1 H, ArH), 6.83 (d, J = 8.3 Hz, 1 H, ArH), 7.38–7.46 (m, 5 H,
ArH)
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Heteroring-Fused Isoindolinones
151
Table 2 Physical and Spectroscopic Data (continued)
Product Mp (°C) 1H NMR (CDCl3/TMS): d (ppm)
13C NMR (CDCl3/TMS): d (ppm)
9la
161–162 3.43 (td, J = 4.5, 12.7 Hz, 1 H, NCH2), 3.52 (s, 3 H, OCH3), 39.5 (CH2), 55.7 (CH3), 61.4 (CH3), 62.0 (CH3), 62.6
(yellow 3.61 (td, J = 2.8, 11.7 Hz, 1 H, NCH2), 3.89 (d, J = 9.2 Hz, (CH), 67.1 (CH2), 85.0 (CH), 102.4 (CH), 117.5 (C),
crystals) 1 H, CHN), 3.89 (s, 3 H, OCH3), 4.14 (s, 3 H, OCH3), 4.19
128.3 (2 × CH), 128.6 (2 × CH), 129.4 (CH), 137.4 (C),
(dd, J = 4.0, 11.2, 1 H, CH2O), 4.39–4.44 (m, 2 H: 1 H, CH2O 138.0 (C), 142.1 (C), 151.5 (C), 156.2 (C), 164.7 (CO)
and 1 H CHPh), 5.53 (s, 1 H, ArH), 7.44–7.50 (m, 5 H, ArH)
9ma
213–215 3.26 (s, 3 H, SO2CH3), 3.31–3.40 (m, 1 H, NCH2), 3.43–3.53 39.1 (CH2), 43.9 (CH3), 55.9 (CH3), 61.3 (CH3), 61.4
(yellow
crystals) 3.97 (s, 3 H, OCH3), 4.10 (dd, J = 4.1, 10.3 Hz, 1 H, CH2O), 117.5 (C), 127.6 (2 × CH), 130.0 (2 × CH), 138.3 (C),
4.12 (d, J = 9.3 Hz, 1 H, CHN), 4.17 (dd, J = 2.3, 13.1 Hz, 141.8 (C), 142.0 (C), 143.5 (C), 151.4 (C), 156.2 (C),
(m, 1 H, NCH2), 3.45 (s, 3 H, OCH3), 3.70 (s, 3 H, OCH3),
(CH3), 62.8 (CH), 66.8 (CH2), 83.5 (CH), 102.8 (CH),
1 H, CH2O), 4.56 (d, J = 9.2 Hz, 1 H, CH), 5.42 (s, 1 H, ArH), 163.9 (CO)
7.75 (d, J = 8.3 Hz, 2 H, ArH), 8.06 (d, J = 8.3 Hz, 2 H, ArH)
9na
9oa
9pa
211–212 3.43 (td, J = 4.1, 12.6, 1 H, NCH2), 3.58 (td, J = 2.9, 11.6 Hz, 39.8 (CH2), 56.2 (3 × CH3), 60.1 (CH3), 62.0 (CH), 67.2
(light-
yellow
1 H, NCH2), 3.75 (d, J = 9.3 Hz, 1 H, CHO), 3.89 (s, 6 H, 2 × (CH2), 71.0 (CH2), 85.3 (CH), 105.5 (2 × CH), 108.2
OCH3), 3.92 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 4.17 (dd,
(CH), 125.4 (C), 127.0 (2 × CH), 127.1 (CH), 128.1 (CH),
crystals) J = 4.0, 11.3 Hz, 1 H, CH2O), 4.36–4.41 (m, 2 H: 1 H, CHN 128.7 (2 × CH), 132.9 (C), 133.9 (C), 135.9 (C), 138.6
and 1 H, CH2O), 4.71 (d, J = 12.0 Hz, 1 H, CH2Ph), 5.00 (d, (C), 150.6 (C), 150.9 (C), 153.5 (2 × C), 166.6 (CO)
J = 12.9 Hz, 1 H, CH2Ph), 5.95 (s, 1 H, ArH), 6.62 (s, 2 H,
ArH), 7.19–7.21 (m, 2 H, ArH), 7.26–7.32 (m, 3 H, ArH),
7.36 (s, 1 H, ArH)
113–114 3.09 (s, 3 H, SO2CH3), 3.43 (td, J = 3.7, 12.5 Hz, 1 H, NCH2), 39.8 (CH2), 44.5 (CH3), 56.3 (CH3), 62.0 (CH), 67.0
(light-
yellow
3.57 (td, J = 3.5, 11.4 Hz, 1 H, NCH2), 3.92 (d, J = 9.1 Hz,
1 H, CHN), 3.96 (s, 3 H, OCH3), 4.17 (dd, J = 3.4, 10.9 Hz,
(CH2), 70.6 (CH2), 83.9 (CH), 105.8 (CH), 125.5 (C),
126.4 (2 × CH), 126.9 (CH), 127.8 (2 × CH), 128.0 (2 ×
CH), 128.8 (2 × CH), 129.2 (CH), 133.2 (C), 135.8 (C),
crystals) 1 H, CH2O), 4.32 (d, J = 9.2 Hz, 1 H, CHO), 4.41 (d,
J = 13.0 Hz, 1 H, CH2O), 4.85 (d, J = 13.4 Hz, 1 H, CH2Ph), 141.3 (C), 143.5 (C), 150.8 (C), 150.9 (C), 066.4 (CO)
5.03 (d, J = 13.3 Hz, 1 H, CH2Ph), 5.80 (s, 1 H, ArH), 7.14–
7.24 (m, 2 H, ArH), 7.28–7.39 (m, 4 H, ArH), 7.56 (d,
J = 8.2 Hz, 2 H, ArH), 7.99 (d, J = 8.2 Hz, 2 H, ArH)
174–175 3.29 (s, 3 H, SO2CH3), 3.39–3.47 (m, 2 H, NCH2), 3.82 (s,
43.5 (CH3), 55.7 (CH3), 56.0 (CH2), 60.4 (CH), 66.4
(colorless 3 H, OCH3), 4.04–4.07 (m, 2 H: 1 H, CH2O and 1 H, CHN), (CH2), 83.1 (CH), 105.7 (CH), 109.7 (CH), 123.4 (C),
crystals) 4.16–4.20 (m, 1 H, CH2O), 4.64 (d, J = 9.1 Hz, 1 H, CHO),
5.78 (s, 1 H, ArH), 7.21 (s, 1 H, ArH), 7.74 (d, J = 8.2 Hz,
2 H, ArH), 8.04 (d, J = 8.2 Hz, 2 H, ArH), 9.73 (s, 1 H, OH)
127.2 (2 × CH), 129.3 (2 × CH), 134.3 (C),141.1 (C),
143.3 (C), 148.7 (C), 149.8 (C), 165.5 (CO)
16a
200–201 2.33 (s, 3 H, CH3), 3.21 (td, J = 4.0, 12.6 Hz, 1 H, NCH2),
21.4 (CH3), 38.3 (CH2), 39.7 (CH2), 56.3 (CH3), 58.5
(yellow
3.37 (td, J = 4.3, 12.6 Hz, 1 H, NCH2), 3.77 (s, 3 H, OCH3), (CH3), 59. 7 (CH), 61.4 (CH3), 62.5 (CH), 101.6 (CH),
crystals) 3.78–3.83 (m, 4 H: 3 H, OCH3 and 1 H, CH2NSO2), 4.02 (s, 117.4 (C), 126.4 (CH), 127.2 (2 × CH), 128.3 (2 × CH),
3 H, OCH3), 4.48 (dd, J = 3.4, 12.9 Hz, 1 H, CH2NSO2), 4.84 128.7 (2 × CH), 129.4 (2 × CH),.34.0 (C), 136.0 (C), 138.8
(d, J = 5.3 Hz, 1 H, CHN), 5.65 (d, J = 5.5 Hz, 1 H, CHPh),
6.49 (s, 1 H, ArH), 6.96–7.03 (m, 4 H, ArH), 7.07–7.10 (m,
3 H, ArH), 7.41–7.44 (m, 2 H, ArH)
(C), 141.8 (C), 143.5 (C), 151.4 (C), 157.1 (C), 165.4
(CO)
erythro- 85–86
2.08–2.51 (m, 2 H, CH2), 3.49–3.62 (m, 4 H: 1 H, NCH2 and 31.1 (CH2), 38.4 (CH2), 42.6 (CH2), 55.4 (CH3), 55.8
14a,b
(white
2 H, CH2 and 1 H, OH), 3.65 (s, 3 H, OCH3), 3.83 (s, 3 H,
(CH3), 55.9 (CH3), 65.7 (CH), 71.0 (CH), 105.0 (CH),
106.2 (CH), 113.8 (2 × CH), 125.3 (C), 127.3 (2 × CH),
131.6 (C), 134.9 (C), 149.8 (C), 151.5 (C), 159.3 (C),
crystals) OCH3), 3.86 (s, 3 H, OCH3), 4.10 (m, 1 H, NCH2), 4.74 (d,
J = 2.9 Hz, 1 H, CHN), 5.37 (s, 1 H, CHO), 6.01 (s, 1 H,
ArH), 6.94 (d, J = 8.5 Hz, 2 H, ArH), 7.10 (s, 1 H, ArH), 7.32 169.8 (CO)
(d, J = 8.5 Hz, 2 H, ArH)
threo- 95–96
2.04–2.31 (m, 2 H, CH2), 2.82 (br s, 1 H, OH), 3.51–4.00 (m, 31.3 (CH2), 40.0 (CH2), 42.6 (CH2), 55.3 (CH3), 55.8
3 H: 1 H, NCH2 and 2 H, CH2), 3.68 (s, 3 H, OCH3), 3.76 (s, (CH3), 56.0 (CH3), 64.5 (CH), 76.4 (CH), 104.6 (CH),
14a,b
(white
crystals) 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.06 (m, 1 H, CH2N), 4.72 106.7 (CH), 113.6 (2 × CH), 125.0 (C), 128.3 (2 × CH),
(d, J = 6.4 Hz, 1 H, CHN), 4.82 (d, J = 6.4 Hz, 1 H, CHO), 132.1 (C), 135.4 (C), 149.7 (C), 151.4 (C), 159.7 (C),
6.21 (s, 1 H, ArH), 6.80 (d, J = 8.5 Hz, 2 H, ArH), 7.08 (d, J = 169.3 (CO)
8.5 Hz, 2 H, ArH), 7.14 (s, 1 H, ArH)
a Satisfactory microanalyses were obtained: C 0.25, H 0.27, N 0.29.
b MS (ESI+): m/z (%) = 408 (39), 407 (22), 406 (100) [M + Na]+.
Synthesis 2011, No. 1, 147–153 © Thieme Stuttgart · New York

152
G. Ahn et al.
PAPER
von der Saal, W.; Zilch, H.; Nuber, B.; Ziegler, M. L.
J. Med. Chem. 1993, 36, 726. (g) Kato, Y.; Takemoto, M.;
Achiwa, K. Chem. Pharm. Bull. 1993, 41, 2003.
(h) Aboudi, A. F.; Al-Eisawi, D. M.; Sabri, S. S.; Abu Zarga,
M. H. J. Nat. Prod. 1986, 49, 370. (i) Blaskó, G.; Gula, D.
J.; Shamma, M. J. Nat. Prod. 1982, 45, 105. (j) Hussain, S.
F.; Minard, R. D.; Freyer, A. J.; Shamma, M. J. Nat. Prod.
1981, 44, 169.
1-Aryl-1,3,4,10b-tetrahydro[1,4]oxazino[3,4-a]isoindol-6-ones
(9j–p) and 7,8,9-Trimethoxy-1-phenyl-2-toluene-4-sulfonyl-
1,3,4,10b-tetrahydro-2H-pyrazino[2,1-a]isoindol-6-one (16);
General Procedure
A colorless solution of halogenated isoindolinone 8a–e or 11a (1.00
mmol) in anhydrous THF (25 mL) was cooled to –78 °C and a so-
lution of KHMDS (0.5 M in toluene, 2.20 mL, 1.10 mmol) was add-
ed dropwise. The colored (orange/red for 8a–d or greenish for 8e)
mixture was stirred and allowed to warm from –78 °C to –50 °C
over a 30 min period under stirring and a solution of aldehyde 10f–i
or tosylimine 17f15 (1.10 mmol) in THF (15 mL) was subsequently
added. The mixture was allowed to warm to r.t. over 30 min, then
poured into aq sat. NH4Cl (5 mL) diluted with H2O (10 mL). The
aqueous layer was extracted with CH2Cl2 (2 × 30 mL) and the or-
ganic layers were combined, washed with H2O (2 × 10 mL), dried
(Na2SO4) and concentrated under reduced pressure. Purification by
flash column chromatography on silica gel (hexanes–EtOAc,
50:50→25:75) afforded the target products 9j–o or 16.
(2) (a) Shinji, C.; Maeda, S.; Imai, K.; Yoshida, M.; Hashimoto,
Y.; Miyachi, H. Bioorg. Med. Chem. Lett. 2006, 14, 7625.
(b) Shinozuka, T.; Yamamoto, Y.; Hasegawa, T.; Saito, K.;
Naito, S. Tetrahedron Lett. 2008, 49, 1619.
(3) (a) Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med.
Chem. 1998, 41, 157. (b) Reiffen, M.; Eberlein, W.;
Mueller, P.; Psiorz, M.; Noll, K.; Heider, J.; Lillie, C.;
Kobinger, W.; Luger, P. J. Med. Chem. 1990, 33, 1496.
(4) Csende, F.; Stajer, G. Curr. Org. Chem. 2005, 9, 1261.
(5) Mertens, A.; Zilch, H.; König, B.; Schäfer, W.; Poll, T.;
Kampe, W.; Seidel, H.; Leser, U.; Leinert, H. J. Med. Chem.
1993, 36, 2526.
The diastereomers erythro-14 and threo-14 were separated by flash
column chromatography on silica gel (CH2Cl2–acetone, 90:10).
(6) Lübbers, T.; Angehrn, P.; Gmünder, H.; Herzig, S. Bioorg.
Compound 9p was prepared by deprotection of benzylated precur-
sor 9o under standard conditions. A mixture of oxazinoindolinone
9o (0.240 g, 0.5 mmol) and 10% Pd/C (15 mg) in MeOH (20 mL)
was stirred under a H2 atmosphere for 12 h. The reaction mixture
was filtered through a Celite pad and the filtrate was evaporated to
yield the debenzylated product 9p as colorless crystals (0.113 g,
58%).
Med. Chem. Lett. 2007, 24, 4708.
(7) Wacker, D. A.; Varnes, J. G.; Malmstrom, S. E.; Cao, X.;
Hung, C.-P.; Ung, T.; Wu, G.; Zhang, G.; Zuvich, E.;
Thomas, M. A.; Keim, W. J.; Cullen, M. J.; Rohrbach, K.
W.; Qu, Q.; Narayanan, R.; Rossi, K.; Janovitz, E.; Lehman-
McKeeman, L.; Malley, M. F.; Devenny, J.; Pelleymounter,
M. A.; Miller, K. J.; Robl, J. A. J. Med. Chem. 2007, 50,
1365.
(8) Martini, E.; Norcini, M.; Ghelardini, C.; Manetti, D.; Dei, S.;
Guandalini, L.; Melchiorre, M.; Pagella, S.; Scapecchi, S.;
Teodori, E.; Romanelli, M. N. Bioorg. Med. Chem. 2008, 16,
10034.
4,5-Dimethoxy-2-vinyl-2,3-dihydro-1H-isoindol-1-one (12)
Compound 12 was obtained by exposure of brominated isoindoli-
none 11a (300 mg) to n-BuLi as described in General Procedure.
Yield: 169 mg (77%); colorless crystals; mp 86–89 °C.
(9) (a) Ghosh, U.; Bhattacharyya, R.; Keche, A. Tetrahedron
2010, 66, 2148; and references cited therein. (b) Kim, S. H.;
Kim, S. H.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2010,
51, 860; and references cited therein.
1H NMR (300 MHz, CDCl3): d = 3.90 (s, 3 H, OCH3), 3.92 (s, 3 H,
OCH3), 4.43–4.46 (m, 3 H: 2 H, CH2N and 1 H, =CH2), 4.56 (dd,
J = 0.8, 16.0 Hz, 1 H, =CH2), 6.97 (d, J = 8.3 Hz, 1 H, ArH), 7.25
(dd, J = 9.2, 16.1 Hz, 1 H, NCH=), 7.51 (d, J = 8.3 Hz, 1 H, ArH).
(10) (a) Chiurato, M.; Boulahjar, R.; Routier, S.; Troin, Y.;
Guillaumet, G. Tetrahedron 2010, 66, 4647. (b)Medimagh,
R.; Marque, S.; Prim, D.; Marrot, J.; Chatti, S. Org. Lett.
2009, 11, 1817. (c) Murai, M.; Miki, K.; Ohe, K. J. Org.
Chem. 2008, 73, 9174. (d) Salcedo, A.; Neuville, L.; Zhu, J.
J. Org. Chem. 2008, 73, 3600. (e) Bertus, P.; Menant, C.;
Tanguy, C.; Szymoniak, J. Org. Lett. 2008, 10, 777.
(f) Sun, C.; Xu, B. J. Org. Chem. 2008, 73, 7361. (g) He,
Z.; Yudin, A. K. Org. Lett. 2006, 8, 5829. (h) Kobayashi,
K.; Hase, M.; Hashimoto, K.; Fujita, S.; Tanmatsu, M.;
Morikawa, O.; Konishi, H. Synthesis 2006, 2493.
(i) Majumdar, K. C.; Das, T. K.; Jana, M. Synth. Commun.
2005, 35, 1961. (j) Stajer, G.; Csende, F. Curr. Org. Chem.
2005, 9, 1277. (k) Osante, I.; Lete, E.; Sotomayor, N.
Tetrahedron Lett. 2004, 45, 1253. (l) Bahajaj, A. A.;
Vernon, J. M.; Wilson, G. D. Tetrahedron 2004, 60, 1247.
(m) Bertus, P.; Szymoniak, J. J. Org. Chem. 2003, 68, 7133.
(n) Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403.
(o) Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79,
1528. (p) Campbell, J. B.; Dedinas, R. F.; Trumbower-
Walsh, S. A. J. Org. Chem. 1996, 61, 6205. (q) Araki, S.;
Shimizu, T.; Johar, P. S.; Jin, S. J.; Butsugan, Y. J. Org.
Chem. 1991, 56, 2538.
13C NMR (75 MHz, CDCl3): d = 45.3 (CH2), 56.2 (CH3), 60.4
(CH3), 93.0 (CH2), 112.9 (CH), 120.1 (CH), 125.3 (C), 129.2 (CH),
132.8 (C), 143.5 (C), 155.6 (C), 166.6 (CO).
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C,
65.52; H, 6.10; N, 6.41.
Acknowledgment
This research was supported by the Centre National de la Recherche
Scientifique and MENESR (grant to M.L.). The authors wish to
thank Prof. G. Nowogrocki from UCCS-USTLille1 for single cry-
stal X-ray structure analysis.
References
(1) (a) Hamprecht, D.; Micheli, F.; Tedesco, G.; Checchia, A.;
Donati, D.; Petrone, M.; Terreni, S.; Wood, M. Bioorg. Med.
Chem. Lett. 2007, 17, 428. (b) Jagtap, P. G.; Southan, G. J.;
Baloglu, E.; Ram, S.; Mabley, J. G.; Marton, A.; Salzman,
A.; Szabó, C. Bioorg. Med. Chem. Lett. 2004, 14, 81.
(c) Kundu, N. G.; Khan, M. W.; Mukhopadhyay, R. J. Indian
Chem. Soc. 2001, 78, 671. (d) Muller, G. W.; Chen, R.;
Huang, S.-Y.; Corral, L. G.; Wong, L. M.; Patterson, R. T.;
Chen, Y.; Kaplan, G.; Stirling, D. I. Bioorg. Med. Chem.
Lett. 1999, 9, 1625. (e) Norman, M. H.; Minick, D. J.;
Rigdon, G. C. J. Med. Chem. 1996, 39, 149. (f) Schäfer,
W.; Friebe, W.-G.; Leinert, H.; Mertens, A.; Poll, T.;
(11) (a) Lorion, M.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2008, 2141. (b) Lorion, M.; Couture, A.; Deniau,
E.; Grandclaudon, P. J. Org. Chem. 2006, 71, 3303.
(12) (a) Couture, A.; Deniau, E.; Ionescu, D.; Grandclaudon, P.
Tetrahedron Lett. 1998, 39, 2319. (b) Guo, Z.; Schultz, A.
G. J. Org. Chem. 2001, 66, 2154.
Synthesis 2011, No. 1, 147–153 © Thieme Stuttgart · New York

PAPER
Heteroring-Fused Isoindolinones
153
(13) Selected X-ray crystallographic data for 9j: Empirical
formula: C19H19NO4; Mr = 325.35 g·mol–1; F(000) = 688;
white crystal; D = 1.353 g·cm–3; m(Mo Ka) = 0.095;
X-ray structure data are available on request from the
Cambridge Crystallographic Data Centre (CCDC 791641)
(14) Lorion, M.; Couture, A.; Deniau, E.; Grandclaudon, P.
Synthesis 2009, 1897.
(15) Tongshou, J.; Guoliang, F.; Mina, Y.; Tongshuang, L. Synth.
Commun. 2004, 34, 1277.
monoclinic; P21/n; a = 5.56820 (10) Å, b = 8.60050 (10) Å,
c = 33.3710 (6) Å; a = 90.00, b = 91.8710 (10), g = 90.00;
V = 1597.26 (4) Å3; Z = 4; T = 100 K. Further details of the
Synthesis 2011, No. 1, 147–153 © Thieme Stuttgart · New York