5-amino-2-furylmethylamines - Appealing precursors of amino-isoindolinones?

Article abstract of DOI:10.1055/S-0029-1218614

Isoindolinones were constructed according to an original [4+2]-cycloaddition strategy. Unprecedented 5-amino-2-furyl-methylamines were prepared and revealed as efficient precursors of new aminoisoindolinones, obtained via a Diels-Alder and lactamization sequence. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/S-0029-1218614

770
PAPER
5-Amino-2-furylmethylamines – Appealing Precursors of Amino-
isoindolinones?
5
-Amino-2-furylm
a
ethylamin
o
e
s
uf Medimagh,a Sylvain Marque,*a Damien Prim,a Saber Chattib
a
Université de Versailles Saint-Quentin-en-Yvelines, Institut Lavoisier de Versailles (ILV) UMR 8180, 45 Avenue des Etats-Unis,
78035 Versailles Cedex, France
Fax +33(1)39254452; E-mail: sylvain.marque@chimie.uvsq.fr
Institut National de Recherche et d’Analyse Physicochimique (INRAP), Pôle Technologique de Sidi Thabet, 2020 Sidi Thabet, Tunisia
b
Received 4 November 2009; revised 12 November 2009
O
Abstract: Isoindolinones were constructed according to an original
[4+2]-cycloaddition strategy. Unprecedented 5-amino-2-furyl-
methylamines were prepared and revealed as efficient precursors of
new aminoisoindolinones, obtained via a Diels–Alder and lactam-
ization sequence.
O
NR3R4
NR1
(a)
O
+
R2
(d)
O
Key words: Diels–Alder reactions, furans, isoindolinones, multi-
component reactions
O
H2N
R3
O
R2
+
+
NHR1
R2
(b)
(c)
N
R1
OH
The construction of the isoindolinone (2,3-dihydroisoin-
dol-1-one) core has been the subject of numerous investi-
gations. Interest in such condensed heterocycles arose
because of the biological activities of members of this
family, such as pazinaclone,1 pagoclone,2 lennoxamine,3
or nuevamine4. The isoindolinone backbone has been ob-
tained mainly using common approaches based on the
ring closure of ortho-functionalized aromatic precursors
R2
+
I2
O
I
(e)
O
NR1
OR3
R2
+ Bu3SnH
Br
R1NH2
+
(Scheme 1). Among the more-relevant strategies, the con- Scheme 1 Main strategies towards the formation of the isoindoli-
none core reported in the literature
struction of isoindolinone core has been elaborated
through (i) the addition of a benzamide anion to an imine
heterocycle. We also describe herein an extension of this
followed by intramolecular transamidation (route a),5 (ii)
methodology starting from the parent 5-aminofuran-2-
carbaldehydes 1 which includes the sequential formation
of four bonds and allows the five-step, one-pot prepara-
tion of the title compounds in moderate to high yields.
the electrophilic activation of an ortho-substituted phenyl-
acetylene followed by intramolecular cyclization (route
b),6 (iii) the addition of a primary amine to an ortho-sub-
stituted aromatic acid derivative (route c),7 (iv) the con-
This latter procedure involves the formation of (aminofu-
densation of phthalic anhydride and an amino alcohol
ryl)methanimines 3 and subsequent [4+2] cycloaddition
followed by the addition of a nucleophile (route d),8 and
prior to hydride addition and lactamization. Both strate-
gies might complement one another and they allow the
construction of the isoindolinone backbone using either
preformed aminofurylmethylamines 4 or in situ generated
(v) the radical-promoted cyclization of N-allenyliodo-
amides (route e).9
It is worth noting that further substitution of a preformed
isoindolinone has only been described at the condensed
(aminofuryl)methanimines 3.
heterocycle.10
We first studied the synthesis of 5-amino-2-furylmethyl-
We propose herein a fast and simple alternative route to
the isoindolinone skeleton. As outlined in Scheme 2, we
amines 4 starting from the parent 5-aminofuran-2-
carbaldehydes11 1. Classical reductive amination process-
based our strategy on two key steps: a [4+2] cycloaddition
starting from 5-amino-2-furylmethylamines [5-(amino-
methyl)furan-2-amines] and an intramolecular lactamiza-
tion. Thus, we first focused on the preparation of
aminofurylmethylamines 4 and investigated their behav-
ior as dienes in the [4+2] cycloaddition, as well as the fea-
sibility of the lactamization step to generate the fused
es using either sodium cyanoborohydride or triacetoxy-
borohydride in the presence of acetic acid in 1,2-
dichloroethane or tetrahydrofuran were unsatisfactory. In-
deed, if the expected aminofurylmethylamines 4 were ob-
served, they could only be obtained in mixtures with the
methyl alcohol derivatives resulting from the reduction of
the parent carbaldehydes.
Gratifyingly, the reduction of intermediate imines 3 using
sodium borohydride in methanol12 at 0 °C proved success-
ful and allowed the preparation of targets 4 (Scheme 3 and
SYNTHESIS 2010, No. 5, pp 0770–0774
Advanced online publication: 16.12.2009
DOI: 10.1055/s-0029-1218614; Art ID: Z23609SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0
1
Table 1). Careful H NMR spectroscopic analysis of the

PAPER
5-Amino-2-furylmethylamines
771
to high overall yields (Table 2). As highlighted by the re-
sults in Table 2, targets 6 were formed regardless of the
amine residue (benzylic derivatives or allylic). The results
obtained for this series are in full agreement with an en-
hanced reactivity of furans bearing electron-donating
groups (amino and methylamino) towards [4+2] cycload-
ditions with moderate dienophiles.13 In addition, it is
worth noting that aminofurylmethylamines 4 were re-
vealed to be considerably more stable under the aforemen-
tioned reaction conditions than the corresponding
aminofurylmethyl alcohols, which degraded even at room
temperature.
R3
C–N bond
amidation
C–C bonds
CO2Et
5
NH
Diels–Alder cycloaddition
CO2Et
R3
O
N
O
O
NR1R2
NR3
4
O
R3NH2
CO2Et
CO2Et
NR1R2
5
NR1R2
1
CO2Et
O
6
H–
NR1R2
3
Scheme 2 Alternative strategies towards the formation of isoindoli-
nones
R
N
EtO2C
CO2Et
O
5
crude material indicated the complete disappearance of
the starting carbaldehydes and confirmed the presence of
furans 4 as unique products of this procedure. Neverthe-
less, attempts to purify aminofurylmethylamines 4 by
chromatography on silica gel led to partial degradation;
hence, the aminofurylmethylamines were used without
further purification.
N
O
toluene, 70 °C
16–18 h
O
CO2Et
HN
R
N
O
4
6
Scheme 4 Access to isoindolinones 6
Table 2 Preparation of Isoindolinones 6 from 5-Amino-2-furyl-
methylamines 4a
NHR3
O
NR3
R3NH2
2
NaBH4
Entry
Substrate 4 Amino group R Compound 6 Yieldb
(%) of 6
O
O
O
MeOH, r.t.,
18 h
0 °C
2 h
NR1R2
NR1R2
NR1R2
1
2
3
4
4a
4b
4c
4d
Bn
6a
6b
43
79
60
55
1
3
4
(S)-CHMePh
Scheme 3 Preparation of 5-amino-2-furylmethylamines 4
Table 1 Preparation of 5-Amino-2-furylmethylamines 4a
2-pyridylmethyl 6c
CH2CH=CH2 6d
Entry Substrate
NR1R2
Primary amine 2
Product 4
a Reaction conditions: crude 5-amino-2-furylmethylamine 4, diethyl
maleate (5) (3 equiv), toluene, 70 °C, overnight.
1
b Isolated overall yield of product 6 from 5-morpholinofuran-2-carb-
aldehyde (1a), after chromatography.
1
2
3
4
5
morpholino 1a BnNH2 2a
4a
4b
morpholino 1a (S)-PhMeCHNH2 2b
The latter observation and the facile obtention of targets 6
from aminofurylmethylamines prompted us to examine
an extended three-component, one-pot procedure towards
the formation of isoindolinones 6, starting from the pre-
cursor 5-aminofuran-2-carbaldehydes 1, primary amines
2, and diethyl maleate (5). If first attempts in refluxing
ethanol or methanol14 led to low conversions of 1 and/or
side products, targets could be identified in the crude ma-
terial. As previously reported,15,16 the presence of water
resulting from the rearomatization process may be detri-
mental to high conversions and one-pot procedures in-
volving cycloadditions. In this context, we envisaged a
selective sequence that involved the in-situ trapping of
water generated during the early stages of the procedure
from the formation of imines 3 and the cycloaddition–
rearomatization steps. Consequently, the one-pot se-
quence was performed in toluene using a Dean–Stark ap-
paratus (Scheme 5) and the ratio of the reactants (1/2/5)
was set to 1:1:2. If the formation of the aminofuryl-con-
morpholino 1a 2-pyridylmethylamine 2c 4c
morpholino 1a H2C=CHCH2NH2 2d
4d
b
allyl(meth- 1b 2-thienylmethylamine
yl)amino
a See Scheme 3.
b Substrates used in the one-pot procedure for the formation of 6g (see
below).
5-Amino-2-furylmethylamines 4 were then evaluated as
dienes in the Diels–Alder cycloaddition. Reactions with
diethyl maleate (5) were performed in toluene at 70 °C un-
til complete conversion of the reactant had occurred
(Scheme 4). Under the aforementioned conditions, nei-
ther the classical oxabicyclic adducts nor the expected 4-
aminobenzylamines could be observed. In contrast, isoin-
dolinones 6a–d, resulting from a cycloaddition–rearoma-
tization–lactamization process, were isolated in moderate
Synthesis 2010, No. 5, 770–774 © Thieme Stuttgart · New York

772
R. Medimagh et al.
PAPER
out on Silica Gel 60 F254 (0.5-mm thickness). All chemical reagents
were obtained from commercial suppliers and used without purifi-
cation. The solvents toluene and MeOH were used without purifica-
tion; petroleum ether (PE) was distilled under argon. All reactions
were carried out under an inert atmosphere of argon unless other-
wise stated.
taining imine intermediates 3 had completed overnight, 55
additional hours were required to ensure both cycloaddi-
tion and rearomatization. The solvent was then removed
and the addition of sodium borohydride in ethanol afford-
ed the corresponding amine, which promoted the lactam-
ization to give isoindolinones 6a and 6e–g in 20–40%
yield (Figure 1).
N-Benzyl(5-morpholino-2-furyl)methylamine (4a); Typical
Procedure
In a 25-mL round-bottomed flask, 5-morpholinofuran-2-carbalde-
hyde (1a) (50.0 mg, 0.275 mmol) and benzylamine (2a) (30 mL,
0.275 mmol, 1 equiv) were stirred in MeOH (3 mL) at r.t. After 18
h, the mixture was cooled to 0 °C and then NaBH4 (10.6 mg, 0.275
mmol, 1 equiv) was added. After 3 h, the reaction was quenched
with sat. NaHCO3 (3 mL) and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated under reduced pressure to af-
ford the crude desired product 4a as a yellow oil.
CHO
1) Dean–Stark
CO2Et
apparatus
+
+
R3NH2
6
O
2) NaBH4, EtOH
CO2Et
NR1R2
1
2
5
Scheme 5 Three-component, one-pot procedure for the formation
of isoindolinones
1H NMR (CDCl3, 300 MHz): d = 1.82 (br s, 1 H, NH), 3.09–3.11
(m, 4 H, NCH2), 3.69 (s, 2 H, NCH2furyl), 3.79–3.84 (m, 6 H, OCH2
3
+ NCH2Ph), 5.12 (d, J = 3.3 Hz, 1 H, NC=CH), 6.06 (d, 3J = 3.1
OMe
Hz, 1 H, CH=CCH2NH), 7.21–7.34 (m, 5 H, Ph).
S
S
Ph
N
(S)-N-[(5-Morpholino-2-furyl)methyl]-1-phenylethylamine (4b)
Yellow oil.
N
N
N
1H NMR (300 MHz, CDCl3): d = 1.30 (d, 3J = 9.0 Hz, 3 H, Me), 1.81
(br s, 1 H, NH), 2.98–3.00 (m, 4 H, NCH2), 3.45 (q, 3J = 14.4 Hz, 2
H, NCH2furyl), 3.72–3.75 (m, 5 H, OCH2 + NCHMePh), 5.02 (d,
3J = 3.1 Hz, 1 H, NC=CH), 5.89 (d, 3J = 3.1 Hz, 1 H,
CH=CCH2NH), 7.16–7.26 (m, 5 H, Ph).
O
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
N
O
N
N
O
N
Me
O
N-[(5-Morpholino-2-furyl)methyl]-2-pyridylmethylamine (4c)
Yellow oil.
6a 40%
6e 21%
6f 20%
6g 23%
Figure 1 Target structures obtained using the one-pot procedure
1H NMR (200 MHz, CDCl3): d = 2.30 (br s, 1 H, NH), 3.04–3.10
(m, 4 H, NCH2), 3.72 (s, 2 H, NCH2furyl), 3.77–3.81 (m, 4 H,
OCH2), 3.90 (s, 2 H, NCH2py), 5.09 (d, 3J = 3.1 Hz, 1 H, NC=CH),
The use of molecular sieves (4 Å) instead of Dean–Stark
apparatus did not improve either the yields or the reaction
time required.
3
6.05 (d, J = 3.1 Hz, 1 H, CH=CCH2NH), 7.11–7.15 (m, 1 H,
NCH=CHCH=CHC), 7.17–7.31 (m, 1 H, NCH=CHCH=CHC),
7.59–7.67 (m, 1 H, NCH=CHCH=CHC), 8.54 (d, 3J = 4.5 Hz, 1 H,
NCH=CHCH=CHC).
In conclusion, we have succeeded in preparing new 5-
amino-2-furylmethylamines. These compounds have
been revealed as appealing substrates in the synthesis of
isoindolinones through cycloaddition–lactamization reac-
tions. A complementary procedure starting from the pre-
cursors of the furylmethylamines, the parent 5-
aminofuran-2-carbaldehydes, that involves the successive
formation of an imine and cycloaddition–rearomatization,
followed by hydride addition and lactamization has also
been described. This latter approach is the first reported
multicomponent one-pot synthesis of isoindolinones.
N-Allyl(5-morpholino-2-furyl)methylamine (4d)
Yellow oil.
1H NMR (200 MHz, CDCl3): d = 1.79 (br s, 1 H, NH), 3.04–3.09
(m, 4 H, NCH2), 3.22–3.25 (m, 2 H, NCH2CH=CH2), 3.67 (s, 2 H,
NCH2furyl), 3.77–3.82 (m, 4 H, OCH2), 5.07–5.22 (m, 3 H,
NCH2CH=CH2 + NC=CH), 5.79–5.98 (m, 1 H, NCH2CH=CH2),
6.03 (d, 3J = 3.7 Hz, 1 H, CH=CCH2NH).
Cycloaddition of Compound 4a To Give Ethyl 2-Benzyl-5-mor-
pholino-3-oxo-2,3-dihydro-1H-isoindole-4-carboxylate (6a);
Typical Procedure
In a 10-mL round-bottomed flask, crude N-benzyl(5-morpholino-2-
furyl)methylamine (4a) (as prepared above, 0.275 mmol) and dieth-
yl maleate (5) (137 mL, 0.847 mmol, 3 equiv) were stirred overnight
in toluene (3 mL) at 70 °C. The mixture was allowed to cool to r.t.
and then was concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography (PE–EtOAc, 50:50 to
35:65) to afford isoindolinone 6a as a yellow oil. Yield: 76 mg
(43%); Rf = 0.45 (PE–EtOAc, 1:1).
The NMR spectra were recorded on a 300- or 200-MHz Bruker
spectrometer. Chemical shifts were reported in ppm relative to the
residual solvent peak (7.26 ppm for CHCl3 and 77.00 ppm for
1
CDCl3 for the H and 13C NMR spectra, respectively). Melting
points were measured on a Büchi Melting Point B-545 apparatus
and are uncorrected. Electron impact and chemical ionization MS
were recorded on a Hewlett-Packard HP5989 B device; for ESI MS
an add-on 59 987 A was used (Branford source-type, 4 mL·min–1).
The HRMS data were recorded at the Centre Régional de Mesures
Physiques de Clermont-Ferrand on a Q-TOF micro Waters device
in positive ESI. Infrared spectra were recorded on a Nicolet Impact
400 D FTIR spectrometer from Nicolet Instruments in KBr for liq-
uid and solid compounds. Thin-layer chromatography was carried
3
1H NMR (200 MHz, CDCl3): d = 1.44 (t, J = 7.2 Hz, 3 H,
CO2CH2CH3), 3.01–3.05 (m, 4 H, NCH2), 3.77–3.81 (m, 4 H,
OCH2), 4.19 (s, 2 H, NCH2Ar), 4.52 (q, 3J = 7.2 Hz, 2 H,
CO2CH2CH3), 4.74 (s, 2 H, NCH2Ph), 7.26–7.35 (m, 7 H, NC=CH
+ CH=CCH2N + Ph).
Synthesis 2010, No. 5, 770–774 © Thieme Stuttgart · New York

PAPER
5-Amino-2-furylmethylamines
773
13C NMR (75 MHz, CDCl3): d = 14.3 (CO2CH2CH3), 46.4
(NCH2Ar), 48.9 (NCH2Ph), 53.4 (2 C, NCH2), 61.7 (CO2CH2CH3),
67.3 (2 C, OCH2), 124.0 (CH), 124.3 (CH, Ph), 126.9 (C), 127.7
(CH), 128.3 (2 CH, Ph), 128.4 (2 CH, Ph), 130.2 (C), 136.7 (C),
140.3 (C), 149.9 (C), 166.5 (CO2CH2CH3), 167.3 (CON).
H, NCH2CH=CH2), 5.75–5.86 (m, 1 H, NCH2CH=CH2), 7.31 (d,
3J = 8.1 Hz, 1 H, NCCH=CH), 7.42 (d, 3J = 8.2 Hz, 1 H,
NCCH=CH).
13C NMR (75 MHz, CDCl3): d = 14.3 (CO2CH2CH3), 45.1
(NCH2CH=CH2), 49.1 (NCH2Ar), 53.4 (2 C, NCH2), 61.7
(CO2CH2CH3), 67.3 (2 C, OCH2), 118.3 (NCH2CH=CH2), 124.0
(NCCH=CH), 124.4 (NCCH=CH), 128.3 (C), 130.4 (C), 132.9
(NCH2CH=CH2), 136.8 (C), 149.9 (C), 166.4 (CO2CH2CH3), 167.3
(CON).
MS (ESI+, MeCN): m/z (%) = 381.1 (100) [M + H]+.
(S)-Ethyl 5-Morpholino-3-oxo-2-(1-phenylethyl)-2,3-dihydro-
1H-isoindole-4-carboxylate (6b)
Yellow oil purified by silica gel flash chromatography (PE–EtOAc,
6:4). Yield: 65 mg (79%); Rf = 0.50 (PE–EtOAc, 1:1).
MS (CI, NH3): m/z (%) = 331.1 (100) [M + H]+.
IR (KBr): 2985, 2964, 2858, 1733, 1690, 1613, 1481, 1451, 1289,
1263, 1230, 1132, 1112, 1020, 905, 792, 700, 570 cm–1.
One-Pot Procedure with Compound 1a To Give Ethyl 5-Mor-
pholino-3-oxo-2-(2-thienylmethyl)-2,3-dihydro-1H-isoindole-4-
carboxylate (6e); Typical Procedure
3
1H NMR (300 MHz, CDCl3): d = 1.36 (t, J = 7.3 Hz, 3 H,
In a 25-mL round-bottomed flask, 5-morpholinofuran-2-carbalde-
hyde (1a) (75.0 mg, 0.414 mmol), 2-thienylmethylamine (43 mL,
0.419 mmol, 1 equiv), and diethyl maleate (5) (132 mL, 0.816 mmol,
2 equiv) were stirred in toluene (8 mL) under Dean–Stark condi-
tions. After 72 h, the mixture was allowed to cool to r.t. and the sol-
vent was evaporated under reduced pressure. Then, EtOH (3 mL)
was added to the residue, the mixture was cooled to 0 °C, and
NaBH4 (17.0 mg, 0.438 mmol, 1 equiv) was added. After 3 h, the
reaction was quenched with sat. NaHCO3 (3 mL) and the mixture
was extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were dried (MgSO4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash chromatogra-
phy (PE–EtOAc, 7:3) to afford isoindolinone 6e as a yellow solid.
Yield: 23 mg (21%); mp 146.8–148.1 °C.
3
CO2CH2CH3), 1.57 (d, J = 7.1 Hz, 3 H, NCHCH3Ph), 2.92–2.95
(m, 4 H, NCH2), 3.69–3.72 (m, 4 H, OCH2), 3.84 (d, 2J = 17.1 Hz,
1 H, NCH2Ar), 4.19 (d, 2J = 17.1 Hz, 1 H, NCH2Ar), 4.45 (q, 3J =
7.2 Hz, 2 H, CO2CH2CH3), 5.66 (q, 3J = 7.1 Hz, 1 H, NCHCH3Ph),
7.19–7.26 (m, 7 H, NC=CH + CH=CCH2N + Ph).
13C NMR (75 MHz, CDCl3): d = 14.3 (CO2CH2CH3), 17.2
(NCHCH3Ph), 45.0 (NCH2Ar), 49.1 (NCHCH3Ph), 53.3 (2 C,
NCH2), 61.7 (CO2CH2CH3), 67.3 (2 C, OCH2), 123.9 (CH), 124.3
(CH, Ph), 127.1 (2 CH, Ph), 127.6 (CH), 128.2 (C), 128.6 (2 CH,
Ph), 130.4 (C), 136.8 (C), 140.3 (C), 149.8 (C), 166.0
(CO2CH2CH3), 167.3 (CON).
MS (CI, NH3): m/z (%) = 395.1 (100) [M + H]+.
MS (ESI+, MeOH): m/z (%) = 417.1 (100) [M + Na]+, 811.5 (50)
[2M + Na]+.
IR (KBr): 2979, 2911, 2845, 1729, 1692, 1484, 1440, 1407, 1281,
1266, 1137, 1118, 1031, 946, 727 cm–1.
3
1H NMR (200 MHz, CDCl3): d = 1.44 (t, J = 7.1 Hz, 3 H,
Ethyl 5-Morpholino-3-oxo-2-(2-pyridylmethyl)-2,3-dihydro-
1H-isoindole-4-carboxylate (6c)
Brown solid purified by silica gel flash chromatography (PE–
EtOAc, 1:1 to EtOAc–MeOH, 95:5). Yield: 92 mg (60%); mp
116.2–118.3 °C; Rf = 0.50 (EtOAc–MeOH, 95:5).
CO2CH2CH3), 3.02–3.05 (m, 4 H, NCH2), 3.77–3.80 (m, 4 H,
OCH2), 4.28 (s, 2 H, NCH2Ar), 4.48 (q, 3J = 7.1 Hz, 2 H,
CO2CH2CH3), 4.92 (s, 2 H, NCH2thienyl), 6.90–6.96 (m, 1 H,
C=CHCH=CHS), 7.02–7.12 (m, 1 H, C=CHCH=CHS), 7.23 (d,
3
3J = 5.0 Hz, 1 H, C=CHCH=CHS), 7.31 (d, J = 8.1 Hz, 1 H,
IR (KBr): 2976, 2912, 2855, 1729, 1688, 1592, 1467, 1435, 1290,
1236, 1179, 1116, 1023, 766 cm–1.
NC=CH), 7.39 (d, 3J = 8.2 Hz, 1 H, CH=CCH2N).
13C NMR (75 MHz, CDCl3): d = 14.3 (CO2CH2CH3), 40.8
(NCH2Ar), 48.8 (NCH2thienyl), 53.4 (2 C, NCH2), 61.7
(CO2CH2CH3), 67.3 (2 C, OCH2), 124.1 (NC=CH), 124.4
(CH=CCH2N), 125.7 (C=CHCH=CHS), 127.0 (2 CH,
C=CHCH=CHS + C=CHCH=CHS), 128.4 (C), 130.2 (C), 136.7
(C), 138.9 (C), 150.0 (C), 166.2 (CO2CH2CH3), 167.2 (CON).
3
1H NMR (200 MHz, CDCl3): d = 1.35 (t, J = 7.2 Hz, 3 H,
CO2CH2CH3), 2.94–3.00 (m, 4 H, NCH2), 3.70–3.73 (m, 4 H,
OCH2), 4.34 (s, 2 H, NCH2Ar), 4.43 (q, 3J = 7.2 Hz, 2 H,
CO2CH2CH3), 4.79 (s, 2 H, NCH2py), 7.10–7.14 (m, 1 H,
NCH=CHCH=CHC), 7.21–7.24 (m,
2
H, NC=CH
+
3
NCH=CHCH=CHC), 7.34 (d, J = 8.3 Hz, 1 H, CH=CCH2NCO),
7.53–7.59 (m, 1 H, NCH=CHCH=CHC), 8.45 (d, 3J = 4.1 Hz, 1 H,
NCH=CHCH=CHC).
MS (ESI+, MeCN): m/z (%) = 409.2 (100) [M + Na]+, 795.3 (77)
[2M + Na]+.
13C NMR (75 MHz, CDCl3): d = 14.2 (CO2CH2CH3), 46.4
(NCH2Ar), 49.7 (NCH2py), 53.3 (2 C, NCH2), 61.7 (CO2CH2CH3),
67.2 (2 C, OCH2), 122.6 (2 CH, py), 124.0 (NCCH=CH), 124.1
(NCCH=CH), 128.1 (C), 129.9 (CH), 136.9 (C), 137.0 (CH, py),
149.1 (CH, py), 149.8 (C), 156.5 (C), 166.5 (CO2CH2CH3), 167.2
(CON).
Ethyl 2-(4-Methoxyphenyl)-5-morpholino-3-oxo-2,3-dihydro-
1H-isoindole-4-carboxylate (6f)
Brown powder purified by silica gel flash chromatography (PE–
EtOAc, 75:25 to 70:30). Yield: 33 mg (20%); mp 169.1–171.2 °C;
Rf = 0.36 (PE–EtOAc, 7:3).
MS (ESI+, MeOH): m/z (%) = 420.1 (20) [M + K]+, 404.1 (40) [M
IR (KBr): 2915, 2856, 1727, 1687, 1612, 1514, 1454, 1388, 1293,
1242, 1113, 1026, 825 cm–1.
+ Na]+, 382.1 (65) [M + H]+, 370.1 (100).
3
1H NMR (200 MHz, CDCl3): d = 1.38 (t, J = 7.1 Hz, 3 H,
HRMS: m/z [M + H]+ calcd for C21H24N3O4: 382.1767; found:
CO2CH2CH3), 2.95–2.98 (m, 4 H, NCH2), 3.73–3.81 (m, 7 H, OCH2
+ OMe), 4.24–4.38 (m, 4 H, NCH2Ar + CO2CH2CH3), 6.56 (d, 3J =
9.1 Hz, 2 H, C=CH), 6.75 (d, 3J = 9.1 Hz, 2 H, CH=COMe), 7.19
(d, 3J = 8.5 Hz, 1 H, NC=CH), 7.48 (d, 3J = 8.5 Hz, 1 H,
CH=CCH2N).
13C NMR (75 MHz, CDCl3): d = 14.2 (CO2CH2CH3), 47.1
(NCH2Ar), 53.1 (2 C, NCH2), 55.7 (OCH3), 61.8 (CO2CH2CH3),
67.2 (2 C, OCH2), 114.3 (2 C, CH=CHCOMe), 114.8 (2 C,
CH=COMe), 121.5 (C), 123.2 (CH), 130.9 (C), 131.3 (CH), 134.3
382.1757.
Ethyl 2-Allyl-5-morpholino-3-oxo-2,3-dihydro-1H-isoindole-4-
carboxylate (6d)
Colorless oil purified by silica gel flash chromatography (PE–
EtOAc, 6:4). Yield: 55 mg (55%); Rf = 0.37 (PE–EtOAc, 1:1).
1H NMR (200 MHz, CDCl3): d = 1.41 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 3.01–3.04 (m, 4 H, NCH2), 3.78–3.80 (m, 4 H,
3
3
OCH2), 4.18 (d, J = 6.2 Hz, 2 H, NCH2CH=CH2), 4.29 (s, 2 H,
NCH2Ar), 4.49 (q, 3J = 7.1 Hz, 2 H, CO2CH2CH3), 5.19–5.26 (m, 2
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PAPER
(C), 141.9 (C), 149.8 (C), 152.3 (C), 167.4 (CO2CH2CH3), 168.1
(CON).
References
(1) Wada, T.; Fukuda, N. Psychopharmacology 1991, 103, 314.
(2) Stuck, T. L.; Assink, B. K.; Bates, R. C. Jr.; Erdman, D. T.;
Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.; Smith,
T. L. Org. Process Res. Dev. 2003, 7, 851.
MS (ESI+, MeOH): m/z (%) = 443.2 (50), 419.1 (10) [M + Na]+,
397.1 (10) [M + H]+, 320.1 (100).
HRMS: m/z [M + H]+ calcd for C22H25N2O5: 397.1763; found:
(3) Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V.
Tetrahedron Lett. 1984, 25, 599.
397.1779.
(4) Alonso, R.; Castedo, L.; Dominguez, D. Tetrahedron Lett.
1985, 26, 2925.
Ethyl 5-(N-Allylmethylamino)-3-oxo-2-(2-thienylmethyl)-2,3-
dihydro-1H-isoindole-4-carboxylate (6g)
(5) (a) Enders, D.; Braig, V.; Raabe, G. Can. J. Chem. 2001, 79,
1528. (b) Campbell, J. B.; Dedinas, R. F.; Trumbower-
Walsh, S. A. J. Org. Chem. 1996, 61, 6205.
Orange solid purified by silica gel flash chromatography (PE–
EtOAc, 8:2). Yield: 78 mg (23%); mp 47.3–49.1 °C; Rf = 0.41 (PE–
EtOAc, 7:3).
(6) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432.
(7) (a) Ben-Othman, R.; Othman, M.; Coste, S.; Decroix, B.
Tetrahedron 2008, 64, 559. (b) Othman, M.; Pigeon, P.;
Decroix, B. Tetrahedron 1998, 54, 8737.
IR (KBr): 3091, 2979, 2932, 2900, 2812, 1728, 1690, 1610, 1486,
1459, 1408, 1361, 1286, 1233, 1190, 1140, 1021, 947, 919, 824,
723 cm–1.
3
1H NMR (200 MHz, CDCl3): d = 1.41 (t, J = 7.1 Hz, 3 H,
(8) Chen, M.-D.; He, M.-Z.; Zhou, X.; Huang, L.-Q.; Ruan,
Y.-P.; Huang, P.-Q. Tetrahedron 2005, 61, 1335.
(9) Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775.
(10) (a) Perard-Viret, J.; Prangé, T.; Tomas, A.; Royer, J.
Tetrahedron 2002, 58, 5103. (b) Deniau, E.; Enders, D.
Tetrahedron 2001, 57, 2581. (c) Commins, D. L.; Schilling,
S.; Zhang, Y. Org. Lett. 2005, 7, 95. (d) Allin, S. M.;
Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron
Lett. 1997, 38, 3627. (e) Allin, S. M.; Northfield, C. J.; Page,
M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1998, 39, 4905.
(f) Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M.
Z. Tetrahedron Lett. 1999, 40, 141.
(11) (a) Prim, D.; Kirsch, G.; Nicoud, J.-F. Synlett 1998, 383.
(b) Prim, D.; Kirsch, G. Tetrahedron 1999, 55, 6511.
(c) Migianu, E.; Prim, D.; Kirsch, G. Synlett 2000, 459.
(12) For a one-pot selective procedure using similar conditions,
see: Terrasson, V.; Marque, S.; Scarpacci, A.; Prim, D.
Synthesis 2006, 1858.
3
CO2CH2CH3), 2.76 (s, 3 H, NMe), 3.67 (d, J = 5.8 Hz, 2 H,
NCH2CH=CH2), 4.28 (s, 2 H, NCH2Ar), 4.49 (q, 3J = 7.1 Hz, 2 H,
CO2CH2CH3), 4.88 (s, 2 H, NCH2thienyl), 5.11–5.22 (m, 2 H,
NCH2CH=CH2), 5.74–5.87 (m, 1 H, NCH2CH=CH2), 6.93 (dd, 3J =
5.2, 3.5 Hz,
1 H, C=CHCH=CHS), 7.00–7.01 (m, 1 H,
3
C=CHCH=CHS), 7.18 (d, J = 8.5 Hz, 1 H, NC=CH), 7.21 (dd,
3J = 5.2 Hz, 4J = 1.1 Hz, 1 H, C=CHCH=CHS), 7.29 (d, 3J = 8.3 Hz,
1 H, CH=CCH2N).
13C NMR (75 MHz, CDCl3): d = 14.1 (CO2CH2CH3), 40.6
(NCH2Ar),
40.8
(NCH3),
48.8
(NCH2thienyl),
59.8
(NCH2CH=CH2), 61.7 (CO2CH2CH3), 117.1 (NCH2CH=CH2),
123.4 (NC=CH), 124.9 (CH=CCH2N), 125.1 (C=CHCH=CHS),
126.9 (2 CH, C=CHCH=CHS + C=CHCH=CHS), 130.0 (C), 134.3
(C), 134.5 (NCH2CH=CH2), 136.7 (C), 138.9 (C), 149.7 (C), 166.2
(CO2CH2CH3), 167.2 (CON).
MS (ESI+, MeOH): m/z (%) = 763.2 (10) [2M + Na]+, 409.1 (25)
[M + K]+, 393.1 (50) [M + Na]+, 371.1 (100) [M + H]+, 332.9 (20).
(13) Medimagh, R.; Marque, S.; Prim, D.; Chatti, S. Heterocycles
2009, 78, 679.
HRMS: m/z [M + H]+ calcd for C20H23N2O3S: 371.1429; found:
371.1434.
(14) A sequence involving the reaction between 1 and 2 prior to
the successive addition of NaBH4 and then 5 was first
envisaged, but did not succeed; the sequence between 1 and
2, then 5, prior to the addition of NaBH4 gave a mixture of
products.
(15) Medimagh, R.; Marque, S.; Prim, D.; Chatti, S.; Zarrouk, H.
J. Org. Chem. 2008, 73, 2191.
Acknowledgment
The authors are grateful to the Université de Versailles Saint-
Quentin-en-Yvelines, the CNRS for a grant (RM), and the ANR
program (07-CP2D-14-01) for financial support. The authors grate-
fully thank Vanessa Razafimahaleo for the implementation of the
mass spectrometry.
(16) Medimagh, R.; Marque, S.; Prim, D.; Marrot, J.; Chatti, S.
Org. Lett. 2009, 11, 1817.
Synthesis 2010, No. 5, 770–774 © Thieme Stuttgart · New York