Synthesis of 3-substituted N-allylisoindolinone derivatives by the acetate method

Article abstract of DOI:10.1007/s00706-013-1127-z

A series of N-allylisoindolinone derivatives were prepared by a novel sequential reaction of 2-allyl-3-oxoisoindolin-1-yl acetate with C-nucleophiles in the presence of trimethylsilyl trifluoromethanesulfonate. The nucleophiles included arenes, alkenes, and active methylene to give 3-substituted N-allylisoindolinone products. This method was applied to synthesize cyclohexane-fused indolizidine alkaloid mimics using Grubbs' catalyst. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-013-1127-z

Monatsh Chem
DOI 10.1007/s00706-013-1127-z
ORIGINAL PAPER
Synthesis of 3-substituted N-allylisoindolinone derivatives
by the acetate method
Ibrahim A. I. Ali
Received: 1 August 2013 / Accepted: 2 December 2013
Ó Springer-Verlag Wien 2014
Abstract A series of N-allylisoindolinone derivatives
were prepared by a novel sequential reaction of 2-allyl-3-
oxoisoindolin-1-yl acetate with C-nucleophiles in the pre-
sence of trimethylsilyl trifluoromethanesulfonate. The
nucleophiles included arenes, alkenes, and active methy-
lene to give 3-substituted N-allylisoindolinone products.
This method was applied to synthesize cyclohexane-fused
indolizidine alkaloid mimics using Grubbs’ catalyst.
products [13] and compound libraries [14]. Additionally,
3-methyleneisoindolin-1-one is a key intermediate in the
total synthesis of lennoxamine [15].
Trichloroacetimidates and an acetate method have been
widely used to activate anomeric oxygen exchange reac-
tions. The consequent glycosidic bond formation is useful
in glycoside synthesis [16]. Ali et al. [16–19] reported the
reaction of O-phthalimidomethyl trichloroacetimidate with
C-nucleophiles to afford N-substituted phthalimides. In the
work described in the present report, we extended the scope
of this process, enabling efficient and selective carbon–
carbon bond formation. This research offers the develop-
ment of a series of 3-substituted 2-allylisoindolinone via
C–C bond formation using the acetate method.
Keywords Isoindolinones Á Acetate Á Grubbs’ catalyst Á
C–C bond formation Á C-nucleophiles Á
Trimethylsilyl trifluoromethanesulfonate (TMSOTf)
Introduction
Isoindolinones are the core structures of numerous natural
alkaloids [1–3] and biologically active compounds (Fig. 1).
For example, the alkaloid fumaridine is a secophthalidei-
soquinoline ene lactam [4]; DN-2574 is an
isoindoloquinoline derivative used as a cognition-enhanc-
ing agent [5]; and many drug candidates, such as pagoclone
[6], are isoindolinones. They demonstrate a remarkably
wide array of biological activities [7], including anti-
inflammatory [7], anti-hypertensive [8], antipsychotic [9],
vasodilatory [10], and antileukemic [11] effects, meaning
that the development of new synthetic routes to these
heterocycles is particularly attractive. While several
methods have been reported for the preparation of isoind-
olinones [12], some lead to the synthesis of natural
Results and discussion
The trichloroacetimidate method was applied by our group
to synthesize a series of N-protected nonproteinogenic a-
amino acid esters via C–C bond formation. The base-cat-
alyzed addition reaction of trichloroacetonitrile to the
hydroxyl group of 2-allyl-3-hydroxyisoindolin-1-one (1)
[19, 20] failed to afford the trichloroacetimidate 2 but gave
N-(2-allyl-3-oxoisoindolin-1-yl)-trichloroacetamide
(3)
instead (Scheme 1).
The alternative simple method that was applied to per-
form the structural modification of 2-allylisoindolinone was
the acetate coupling method. The acetylation of hydroxy-
isoindolin-1-one 1 by acetic anhydride in pyridine afforded
2-allyl-3-oxoisoindolin-1-yl acetate (4). The reaction of 4
with C-nucleophiles in the presence of a catalytic amount of
trimethylsilyl trifluoromethanesulfonate (TMSOTf) at room
temperature readily afforded the isoindolinone products in
65–89 % yield.
I. A. I. Ali (&)
Department of Chemistry, Faculty of Science,
Suez Canal University, Ismailia, Egypt
e-mail: ibrahim3369@yahoo.com
123

I. A. I. Ali
OMe
O
O
MeO
MeO
O
MeO
NH
N
O
O
N
O
O
N
O
N
N
O
Me2N
Fumardine
O
NEt2
Cl
DN-2574
Lennoxamine
Pagoclone
Fig. 1 Structures of some natural products and biologically active 3-isoindolin-1-one compounds
Scheme 1
CCl3
The structure assignment of cyclohexanone 10 is based
on 1H and 13C NMR spectral analysis. The 1H NMR
spectrum gave multiplet signals at d 2.80-1.20 ppm,
attributed to cyclohexane moiety, while the 13C NMR
spectrum of 10 displays signals at d 44.1, 41.5, 25.8, 24.3,
24.2 and 53.6 ppm associated with four CH2 and CH
groups, respectively. The structure of ketone 14 was
HN
O
X
OH
N
N
CCl3CN
DBU
O
CCl3
NH
2
O
1
O
1
established by analyzing the H and 13C NMR spectra; the
73%
Acetic acid
Pyridine
N
O
1H NMR spectrum showed signals at 1.28, 2.29, 5.10 and
5.42 ppm, revealing the presence of 2 CH3 and 2 CH
groups, while the 13C NMR spectrum presented signals at
22.7, 24.0, 57.8 and 104.9 ppm, which arise from the
generated C-C linkage.
3
AAcccceeptor
TMSOTf
OCOCH3
X
Acceptor
N
O
Acceptor
TMSOTf
4
N
O
Methyl 2-(2-allyl-3-oxo-2,3-dihydro-1H-1-isoindolyl)-
2-methylpropanoate (16) was identified by 1H and 13C
NMR spectroscopy. The 1H NMR spectrum showed newly
introduced methyl propanoate group signals at 0.90, 1.20
and 3.73 ppm. The 13C NMR spectrum displays signals at
d 19.4, 22.8, and 52.1 corresponding to two CH3 and OCH3
groups, respectively.
Thus, acetate 4 was reacted with a series of substituted
benzene derivatives 5a–5c and styrene in the presence of
TMSOTf to give the 3-substituted 2-allylisoindolin-1-ones
6a–6c and 8 in 65–89 % yield (Scheme 2).
Similarly, functionalized hydrocarbon moieties can be
introduced onto 2-allylisoindolinones at position 3 by the
reaction of 4 with silylated reagents such as benzyltrimeth-
Structure assignment of 2-allyl-3-(2,4-dimethoxy-
phenyl)-1-isoindolinone (6b) was based on 1H and 13C
NMR spectral and physicochemical analysis. The 1H NMR
spectrum clearly confirms the selective aromatic electro-
ylsilane
(17),
allyltrimethylsilane
(19),
and
propargyltrimethylsilane (21) in the presence of TMSOTf to
give 18, 20 [20], and 22 in 76-88 % yield (Scheme 4).
Alkaloids incorporating indolizidine skeletons comprise
a large group of natural compounds with an interesting
range of biological activities [21]. In this context, we
perceive that the present synthetic route to benzoindolizi-
dine alkaloid mimics is highly applicable. We constructed
the desired indolizidine 23 in 64 % yield from 2,3-diallyl-
1-isoindolinone (20) by ring-closing metathesis followed
by olefin hydrogenation with Grubbs’ catalyst.
1
philic substitution site. Thus, the H NMR spectrum of 6b
gave two singlet signals at d = 3.73 and 3.72 ppm, asso-
ciated with two OCH3 groups. The 1H NMR spectrum also
presented an important signal at 5.10 ppm that is typically
associated with CH, confirming C–C linkage generation.
The 13C NMR spectrum of 6b displayed signals at
d = 55.4, 55.2, and 63.9 ppm, associated with two OCH3
and CH groups, respectively.
Similarly, functionalized ester and ketone moieties can be
introduced onto 2-allylisoindolinones at position 3 by the
reaction of 4 with silylated reagents such as 1-(trimethylsil-
oxy)cyclohexene (9), 1-phenyl-1-(trimethylsiloxy)ethylene
(11), 2-(trimethylsiloxy)pent-2-en-4-one (13), or 1-methoxy-
2-methyl-1-(trimethylsiloxy)propene (15) in the presence of
TMSOTf to give 10, 12, 14, and 16 in 79–83 % yield
(Scheme 3).
Tricyclic isoindol-6-one 24 was obtained by selective
reduction using catalytic hydrogenation of the indolizidine
23 [20, 22–24] in the presence of H2/Pd/C. Treatment of 24
with lithium aluminum hydride in THF led to the reduction
of the amide group to the corresponding amine, affording
25 [25] (Scheme 5).
The overall sequential reaction achieved by the acetate
coupling method and 2,3-diallyl-1-isoindolinone cyclo-
123

Synthesis of 3-substituted N-allylisoindolinone derivatives
condensation by Grubbs’ catalyst proved to be a versatile
method for the synthesis of tricyclic systems of promising
biological activity. This was further applied to perform the
synthesis of decahydropyrido[2,1-a]isoindol-6-one 30.
Reduction of 2-allylhexahydro-2H-isoindole-1,3-dione
(26) with sodium borohydride in methanol afforded monose-
lective reduction and gave 2-allyl-3-hydroxyoctahy-
droisoindol-1-one (27). Treatment with acetic anhydride in
pyridine furnished acetate 28 in 63 % yield. This acetate was
reacted with allyltrimethylsilane 21 as a C-nucleophile in the
presence of TMSOTf as catalyst to afford 2,3-diallyloctahy-
droisoindol-1-one (29). The ring closuremetathesisof29 under
the influence of Grubbs’ catalyst was successful and gave the
tricyclic ring system 30 in 72 % yield (Scheme 6).
Structure assignment of decahydropyrido[2,1-a]isoin-
dol-6-one (30) was based on spectral analysis (Fig. 2). The
Scheme 2
R2
R2
OCOCH3
R1
R3
R1
R3
7
N
N
TMSOTf
5
N
O
TMSOTf
CH2Cl2
CH2Cl2
65%
O
O
4
6a-6c
8
R1
H
R2
R3
H
5, 6
OCH3
a
68%
77%
89%
OCH3
OCH3
OCH3
OCH3
b
c
H
OCH3
Scheme 3
O
O
H3C
CH3
N
O
14
Me3SiO
O
TMSOTf
CH2Cl2
CH3
13
83%
OSiMe3
OCOCH3
O
O
OSiMe3
9
11
N
O
N
N
TMSOTf
CH2Cl2
TMSOTf
CH2Cl2
O
O
4
79%
12
10
80%
TMSOTf
CH2Cl2
83%
OCH3
OSiMe3
15
O
H3C
H3C
OCH3
N
O
16
123

I. A. I. Ali
Scheme 4
N
O
20
TMSOTf
CH2Cl2
SiMe
19
88%
SiMe3
OCOCH3
HC
C
C
CH2
Me3Si
21
17
N
O
N
N
TMSOTf
CH2Cl2
TMSOTf
CH2Cl2
76%
O
O
18
4
22
81%
Scheme 5
LiAlH4
THF
Grubbs catalyst
CH2Cl2
H2/Pd/C
N
N
N
N
r.t., 14 h
77%
Reflux,
O
Reflux, 12 h
64%
O
O
4 h
66%
20
23
24
25
Scheme 6
OAc
O
OH
N
NaBH4
MeOH
-5 oC
30 min
65%
Acetic
anhydride
N
N
Pyridine
63%
O
O
O
26
27
28
SiMe3
21
TMSOTf
CH2Cl2
71%
Grubbs catalyst
CH2Cl2
N
N
Reflux, 12 h
72%
O
O
30
29
1H NMR spectrum of 30 exhibited signals at 5.77–5.50,
4.20, and 2.41–2.01 ppm, corresponding to CHd?c, CHe,
and CHb, respectively. The 13C NMR spectrum of 30
showed signals at 175.3, 123.9, 123.6 ppm, attributable to
CO, Cd, and Cc, respectively.
of acetate 4 with C-nucleophiles. These derivatives are
then used for the synthesis of benzo- and cyclohexane-
fused indolizidine alkaloid mimics. The prepared com-
pounds may represent novel potential chemotherapeutic
agents.
Conclusions
Experimental
A general method has been developed for the formation
of isoindolinone derivatives by a novel sequential reaction
Solvents were purified and dried in the usual way. The
boiling range of the petroleum ether used was 40–60 °C.
123

Synthesis of 3-substituted N-allylisoindolinone derivatives
(CH3), 42.7 (CH2), 80.6 (CH), 117.5 (CH2), 123.3, 123.6,
129.9, 131.5 (C–Ar), 132.3 (CH), 140.7 (C–Ar), 167.2,
170.6 (2 CO) ppm.
m, 2.41-2.01 (Hb)
m, 5.77-5.50 (Hc)
38.1
123.6
c
b
m, 3.21-3.05 (Ha)
55.7
m, 5.77-5.50 (Hd)
123.9
a
d
General procedure for reaction of acetate 4 with
C-nucleophiles
N
e
dm, 4.20 (He)
dm, 3.45 (He)
40.1
175.3
A solution of 0.33 g acetate 4 (1.4 mmol) and C-nucleo-
phile as acceptor (1.4 mmol) in 40 cm3 dry
dichloromethane was stirred at room temperature, and then
13 mm3 TMSOTf (0.06 mmol) were added. After
20–90 min, the reaction mixture was neutralized with solid
sodium bicarbonate, filtered, and concentrated in vacuum.
The residue was purified by flash chromatography.
O
1
Fig. 2 Selected H NMR and 13C NMR spectral data for 30
Thin-layer chromatography (TLC) utilized silica gel 60
F254 plastic plates (E. Merck, layer thickness 0.2 mm).
Detection was by UV absorption. Melting points were
determined on a Bu¨chi 510 melting point apparatus. NMR
spectra were measured with a Bruker AC 250 (250 MHz)
using TMS (0.00 ppm) as the internal standard. Mass
spectra were measured on a GC-MSQP (1000EX, Shima-
dzu). Elemental analyses were performed on a Flash EA-
1112 instrument at the Microanalytical Laboratory, Faculty
of Science, Suez Canal University, Ismailia, Egypt.
2-Allyl-3-(4-methoxyphenyl)-1-isoindolinone (6a)
Colorless oil; yield 0.29 g (68 %); Rf = 0.54 (petroleum
ether/ethylacetate, 3/1); NMR data agree with those given
in [20].
2-Allyl-3-(2,4-dimethoxyphenyl)-1-isoindolinone
(6b, C19H19NO3)
Colorless oil; yield 0.34 g (77 %); Rf = 0.38 (petroleum
ether/ethylacetate, 3/1); 1H NMR (250 MHz, CDCl3):
d = 3.34–3.50 (m, 1H, NCH), 3.72 (s, 3H, OCH3), 3.73
(s, 3H, OCH3), 4.36–4.52 (m, 1H, NCH), 4.92–5.10 (m,
3H, CH2, CH), 5.52–5.73 (m, 1H, CH), 6.27–6.48 (m, 3H,
Ar–H), 7.35–7.83 (m, 4H, Ar–H) ppm; 13C NMR
(62.5 MHz, CDCl3): d = 42.6 (CH2), 55.2, 55.4 (2 CH3),
63.9 (CH), 98.7, 104.8 (C–Ar), 105.9, 116.6 (C–Ar), 117.2
(CH2), 122.8, 123.2, 127.7, 128.1, 129.3 (C–Ar), 131.4
(CH), 146.0, 158.7, 160.7 (C–Ar), 168.5 (CO) ppm.
N-(2-Allyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2,2,2-tri-
chloroacetamide (3, C13H11Cl3N2O2)
A stirred solution of 0.94 g 1 (5.0 mmol) in 20 cm3 dry
dichloromethane and
2.5 cm3 trichloroacetonitrile
(25 mmol) was treated with 35 mm3 DBU at room
temperature and then left for 2 h. The solvent was
evaporated and the product was purified by column
chromatography using 2 % triethylamine in toluene as
eluent to give a yellow oil. Yield 1.22 g (73 %); Rf = 0.53
(3 % triethylamine in toluene); 1H NMR (250 MHz,
CDCl3): d = 4.15 (d, J = 6.2 Hz, 2H, NCH2), 5.00–5.20
(m, 3H, CH2, CH), 5.98–6.05 (m, 1H, CH), 7.30–7.55 (m,
4H, Ar–H), 7.88 (d, J = 8.0 Hz, 1H, NH) ppm; 13C NMR
(62.5 MHz): d = 43.0 (CH2), 80.2 (CH), 91.1 (CCl3),
118.1 (CH2), 123.0, 124.1, 129.1, 132.1 (C–Ar), 129.3
(CH), 142.0 (C–Ar), 160.3, 169.4 (2 CO) ppm.
2-Allyl-3-(2,4,6-trimethoxyphenyl)-1-isoindolinone (6c)
White powder; yield 0.43 g (89 %); Rf = 0.31 (petroleum
ether/ethylacetate, 3/1); m.p.: 129–130 °C (128–130 °C
[20]).
(Z)-2-Allyl-3-(2-phenyl-1-ethenyl)-1-isoindolinone
(8, C19H17NO)
Colorless oil; yield 0.26 g (65 %); Rf = 0.22 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 3.59–3.70 (m, 1H, NCH), 4.51–4.60 (m, 1H, NCH),
5.00–5.32 (m, 3H, CH2, CH), 5.65–5.80 (m, 2H, CH, CH),
6.82 (d, J = 15.6 Hz, 1H, CHPh), 7.15–7.90 (m, 9H, Ar–
H) ppm; 13C NMR (62.5 MHz, CDCl3): d = 42.7 (CH2),
62.9 (CH), 117.6 (CH2), 123.1 (CH), 125.5, 126.5 (CH),
128.3, 128.4, 128.6 (C–Ar), 131.6, 133.1 (C–Ar), 135.6
(CH), 167.7 (CO) ppm.
2-Allyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl acetate
(4, C13H13NO3)
Compound 1 (5.3 mmol) was dissolved in 5 cm3 pyridine,
treated with 2.5 cm3 acetic anhydride, and then the mixture
was stirred at room temperature for 24 h. The solvent was
removed in vacuo and then coevaporated with toluene. The
residue was purified by flash chromatography using
petroleum ether/ethyl acetate as eluent. White powder;
yield 0.91 g (74 %); Rf = 0.32 (petroleum ether/ethylace-
tate, 3/1); m.p.: 55 °C; 1H NMR (250 MHz, CDCl3):
d = 2.09 (s, 3H, CH3), 3.86–3.96 (m, 1H, NCH),
4.27–4.35 (m, 1H, NCH), 5.14–5.20 (m, 2H, CH2),
5.73–5.85 (m, 1H, CH), 6.96 (s, 1H, CH), 7.50–7.85 (m,
4H, Ar–H) ppm; 13C NMR (62.5 MHz, CDCl3): d = 20.7
2-Allyl-3-(2-oxocyclohexyl)-1-isoindolinone
(10, C17H19NO2)
Colorless oil; yield 0.30 g (79 %); Rf = 0.32 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 1.20–2.13 (m, 6H, 3 CH2), 2.21–2.30 (m, 1H, CH),
123

I. A. I. Ali
2.48–2.55 (m, 1H, CH), 2.70–2.80 (m, 1H, CH), 3.42–3.62
(m, 1H, NCH), 4.29–4.40 (m, 1H, NCH), 5.00–5.11 (m,
2H, CH2), 5.41 (s, 1H, CH), 5.72–5.90 (m, 1H, CH),
7.28–7.47 (m, 2H, Ar–H), 7.70 (d, J = 7.4 Hz, 1H, Ar–H),
7.77 (d, J = 7.4 Hz, 1H, Ar–H) ppm; 13C NMR
(62.5 MHz, CDCl3): d = 24.2, 24.3, 25.8, 41.5, 44.1
(CH2), 53.6 (CH), 56.9, (CH), 117.8 (CH2), 121.1, 123.4,
128.0, 131.5 (C–Ar), 132.8 (CH), 144.9 (C–Ar), 169.0,
209.2 (2 CO) ppm.
7.15–7.88 (m, 4H, Ar–H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 26.8 (CH2), 42.5 (CH2), 63.6 (CH), 117.6
(CH2), 123.1, 123.3, 127.5, 128.0, 128.4, 131.6 (C–Ar),
132.9 (CH), 141.1, 146.5 (C–Ar), 168.0 (CO) ppm.
2,3-Diallyl-1-isoindolinone (20, C14H15NO)
Colorless oil; yield 0.27 g (88 %); Rf = 0.33 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 2.38–2.55 (m, 2H, CH2), 3.50–3.60 (m, 1H, CH),
4.41–4.50 (m, 2H, NCH, CH), 4.81–4.90 (m, 2H, CH2),
5.09–5.15 (m, 3H, CH2, CH), 5.66–5.70 (m, 1H, CH),
7.24–7.70 (m, 4H, Ar–H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 34.8, 42.3 (2 CH2), 57.9 (CH), 118.7, 117.4 (2
CH2), 127.7 (CH), 122.0, 123.0 (C–Ar), 132.8 (CH), 130.9,
131.0, 131.2 (C–Ar), 144.4 (C–Ar), 167.6 (CO) ppm.
2-Allyl-3-(2-oxo-2-phenylethyl)-1-isoindolinone
(12, C19H17NO2)
Yellow oil; yield 0.33 g (80 %); Rf = 0.27 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 2.96–3.13 (m, 1H, NCH), 3.28–3.44 (m, 1H, NCH),
3.70–3.80 (m, 1H, CHPh), 4.24–4.32 (m, 1H, CHPh),
4.92–5.10 (m, 3H, CH2, CH), 5.60–5.70 (m, 1H, CH),
7.21–7.83 (m, 9H, Ar–H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 41.7, 43.0 (CH2), 55.5 (CH), 117.4 (CH2),
122.6, 123.2, 127.2, 128.0, 128.5, 128.8, 129.8, 131.4,
132.8 (C–Ar), 133.4 (CH), 167.7, 196.8 (2 CO) ppm.
2-Allyl-3-(propa-1,2-dienyl)isoindolin-1-one
(22, C14H13NO)
Colorless oil; yield 0.21 g (81 %); Rf = 0.36 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 3.71–3.80 (m, 1H, NCH), 4.56–4.65 (m, 1H, NCH),
4.79–4.88 (m, 2H, CH2), 4.97 (d, J = 6.1 Hz, 1H, CH),
5.12–5.29 (m, 3H, CH2), 5.72–5.87 (m, 1H, CH), 7.41–7.79
(m, 3H, Ar–H), 7.80–7.85 (m, 1H, Ar–H) ppm; 13C NMR
(62.5 MHz, CDCl3): d = 42.7 (CH2), 57.6 (CH), 77.4 (CH2),
88.5 (CH), 117.4 (CH2), 123.4, 131.3, 131.5, 131.7 (C–Ar),
132.8 (CH), 133.1, 144.7 (C–Ar), 167.4 (CO), 210.0 (=C=)
ppm.
3-(2-Allyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2,4-pen-
tanedione (14, C16H17NO3)
Colorless oil; yield 0.34 g (83 %); Rf = 0.16 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 1.28 (s, 3H, CH3), 2.29 (s, 3H, CH3), 3.28–3.46 (m,
1H, NCH), 4.50–4.65 (m, 1H, NCH), 5.00–5.10 (m, 3H,
CH2, CH), 5.42 (s, 1H, CH), 5.69–5.80 (m, 1H, CH), 7.24
(d, J = 8.8 Hz, 1H, Ar–H), 7.39–7.46 (m, 2H, Ar–H), 7.79
(d, J = 6.8 Hz, 1H, Ar–H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 22.7, 24.0 (2 CH3), 42.2 (CH2), 57.8 (CH),
104.9 (CH), 117.8 (CH2), 122.0, 123.7, 128.5, 131.9, 132.1
(C–Ar), 133.2 (CH), 144.9 (C–Ar), 167.6, 189.6, 197.4 (3
CO) ppm.
2-Allyl-3-hydroxyhexahydro-1-isoindolone
(27, C11H15NO2)
Sodium borohydride (0.88 g, 23 mmol) was added in one
portion to a stirred solution of 2-allylhexahydro-1,3-isoin-
doledione (26, 4.5 mmol) [26] in 120 cm3 methanol, cooled
to -5 °C in an ice-salt bath, and the resulting solution was
stirred for 30 min. The reaction mixture was partitioned
between 200 cm3 of CH2Cl2 and 100 cm3 of saturated
aqueous sodium bicarbonate. The layers were separated and
the aqueous phase was extracted with three 150-cm3 portions
of CH2Cl2. The combined organic phase was dried with
MgSO4 and concentrated in vacuo to give 27 as a white solid.
Yield 0.59 g (65 %); Rf = 0.34 (petroleum ether/ethylace-
tate, 3/1); m.p.: 79 °C; 1H NMR (250 MHz, CDCl3):
d = 1.20–1.41 (m, 4H, 2 CH2), 1.55–1.70 (m, 4H, 2 CH2),
2.43–2.57 (m, 2H, 2 CH), 3.73 (d, J = 7.0 Hz, 1H, NCH),
3.77 (d, J = 7.0 Hz, 1H, CHOH), 4.13–4.22 (m, 1H, NCH),
5.06–5.32 (m, 3H, CH2, OH), 5.64–5.85 (m, 1H, CH) ppm;
13C NMR (62.5 MHz, CDCl3): d = 22.2, 23.1, 23.2, 24.3 (4
CH2), 37.0, 41.0 (2CH), 41.9 (CH2), 83.9 (CH), 117.4 (CH2),
132.9 (CH), 176.1 (CO) ppm.
Methyl 2-(2-allyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-2-
methylpropanoate (16, C16H19NO3)
Colorless oil; yield 0.32 g (83 %); Rf = 0.28 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 0.90 (s, 3H, CH3), 1.20 (s, 3H, CH3), 3.50 (d,
J = 7.0 Hz, 1H, NCH), 3.73 (s, 3H, OCH3), 4.58–4.70
(m, 1H, NCH), 5.03–5.21 (m, 3H, CH2, CH), 5.60–5.70 (m,
1H, CH), 7.28–7.81 (m, 4H, Ar–H) ppm; 13C NMR
(62.5 MHz, CDCl3): d = 19.4, 22.8 (2 CH3), 44.0 (C-
CH3), 45.9 (CH2), 52.1 (OCH3), 64.1 (NCH), 117.1 (CH2),
123.6, 128.3, 130.9 (C–Ar), 132.7 (CH), 142.8 (C–Ar),
169.2, 176.6 (2 CO) ppm.
2-Allyl-3-benzyl-1-isoindolinone (18, C18H17NO)
Yellow oil; yield 0.29 g (76 %); Rf = 0.45 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 2.03 (s, 2H, CH2Ph), 3.20–3.35 (m, 1H, NCH),
4.52–4.65 (m, 1H, NCH), 4.95–5.14 (m, 2H, CH2), 5.40
(s, 1H, CH), 5.60–5.71 (m, 1H, CH), 6.92 (s, 5H, Ar–H),
2-Allyl-3-oxohexahydroisoindol-1-yl acetate
(28, C13H19NO3)
Preparation was performed as described for 4, furnishing a
colorless oil which was chromatographed on silica gel
123

Synthesis of 3-substituted N-allylisoindolinone derivatives
(petroleum ether/ethyl acetate) as eluent to give 28.
Colorless oil; yield 0.79 g (63 %); Rf = 0.42 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 1.02–1.85 (m, 8H, 4 CH2), 1.94 (s, 3H, CH3),
2.00–2.15 (m, 1H, CH), 2.67–2.58 (m, 1H, CH), 3.53
(dd, J = 7.1 Hz, 15.2 Hz, 1H, NCH), 4.13 (dd,
J = 5.3 Hz, 15.2 Hz, 1H, NCH), 5.02–5.20 (m, 2H,
CH2), 5.57 (s, 1H, CH), 5.63 (m, 1H, CH) ppm; 13C
NMR (62.5 MHz, CDCl3): d = 20.3, 21.8, 22.0 (3 CH2),
22.6 (CH3), 24.9 (CH2), 33.9, 39.6 (2 CH), 42.5 (CH2),
84.8 (CHOAc), 116.7 (CH2), 131.8 (CH), 169.7, 176.8 (2
CO) ppm.
1,4,6,6a,7,8,9,10,10a,10b-Decahydropyrido[2,1-a]isoin-
dol-6-one (30, C12H17NO)
Colorless oil; yield 0.14 g (72 %); Rf = 0.51 (petroleum
ether/ethylacetate, 3/1); 1H NMR (250 MHz, CDCl3):
d = 1.13–1.45 (m, 4H, 2 cyclo-CH2), 1.50–1.70 (m, 4H,
2 cyclo-CH2), 1.75–1.90 (m, 2H, cyclo-CH), 2.01–2.14 (m,
1H, CHb), 2.20–2.41 (m, 1H, Hb), 3.05–3.21 (m, 1H, Ha),
3.45 (dm, J = 18.6 Hz, He), 4.20 (dm, 1H, J = 18.6 Hz,
He), 5.50–5.77 (m, 2H, Hd, Hc) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 22.7, 22.9, 23.7, 26.3, 28.6 (C-cyclo), 38.1
(Cb), 40.1 (Ce), 40.2 (C-cyclo), 55.7 (Ca), 123.6 (Cc), 123.9
(Cd), 175.3 (CO) ppm; EI-MS: m/z = 192.0.
1,2,3,4,6,10b-Hexahydropyrido[2,1-a]isoindol-6-one
(24, C12H13NO)
2,3-Diallylhexahydro-1-isoindolone (29, C14H21NO)
Preparation was performed as described for 6–22, furnish-
ing a colorless oil which was chromatographed on silica gel
(petroleum ether/ethyl acetate) as eluent to give 29.
Colorless oil; yield 0.22 g (71 %); Rf = 0.45 (petroleum
ether/ethylacetate, 4/1); 1H NMR (250 MHz, CDCl3):
d = 0.91–1.60 (m, 8H, 4 CH2), 1.85–2.05 (m, 2H, CH),
2.10–2.29 (m, 1H, CH), 2.38–2.50 (m, 1H, CH), 2.87–3.00
(m, 1H, CH), 3.33 (d, J = 7.8 Hz, 1H, NCH), 4.24 (d,
J = 4.4 Hz, 1H, NCH), 4.88–5.17 (m, 4H, 2 CH2),
5.47–5.70 (m, 2H, 2 CH) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 22.8, 23.1, 23.6, 28.5, 34.6, 36.2 (6 CH2),
39.3 (CH), 43.4 (CH), 61.2 (CH), 117.8, 118.0 (2 CH2),
132.8, 133.8 (2CH), 174.9 (CO) ppm.
Formic acid (four drops) was added to a solution of 23
(1.3 mmol) in 10 cm3 methanol and the mixture was
hydrogenated under hydrogen (0.14 g of 10 % Pd on
carbon). TLC monitoring indicated the reaction was
complete after 14 h. Filtration through Celite and column
chromatography (CH2Cl2/MeOH, 20:1) gave 24 as color-
less oil. Yield 0.18 g (77 %); Rf = 0.49 (petroleum ether/
1
ethylacetate, 3/1); H NMR (250 MHz, CDCl3): d = 0.98
(dd, 1H, J = 3.5 Hz, 12.8 Hz, CHd), 1.13–1.69 (m, 3H,
CHd, 2 CHc), 1.71–1.87 (m, 1H, CHb), 2.22 (dm, 1H,
J = 2.8 Hz, 12.9 Hz, CHb), 2.83 (dd, 1H, J = 3.6 Hz,
12.9 Hz, He), 4.14 (dd, 1H, J = 3.8 Hz, 11.8 Hz, Ha), 4.35
(dm, 1H, J = 4.9 Hz, 13.2 Hz, He), 7.31–7.55 (m, 3H, Ar–
H), 7.68–7.78 (d, J = 7.3 Hz, 1H, Ar–H) ppm; 13C NMR
(62.5 MHz, CDCl3): d = 23.3 (Cd), 25.0 (Cc), 31.5 (Cb),
39.3 (Ce), 58.6 (Ca), 121.4, 123.2, 127.7, 130.8, 132.1,
145.5 (C–Ar), 165.8 (CO) ppm; MS (MALDI, positive
mode, matrix: DHB): m/z = 188.2 ([M ? H]?), 210.2
([M ? Na]?), 226.2 ([M ? K]?).
General procedure for olefin metathesis
A solution of 0.003 g [bis(tricyclohexylphosphane)-ben-
zylidene)]-ruthenium(IV) dichloride (Grubbs’ catalyst,
0.004 mmol) in 5 cm3 CH2Cl2 was added to a solution of
diallyl derivatives 20 or 29 (1 mmol) in 10 cm3 CH2Cl2
under an argon atmosphere. The mixture was refluxed for
12 h. The solvent was removed under reduced pressure and
the oily residue was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate, 5:1) to give 23 or
30, respectively.
1,2,3,4,6,10b-Hexahydropyrido[2,1-a]isoindole
(25, C12H15N)
A solution of 24 (1.13 mmol) dissolved in 10 cm3 THF
was added to a suspension of 0.12 g LiAlH4 (2.3 mmol) in
5 cm3 THF and refluxed for 4 h. Excess hydride was
destroyed at 0 °C with 0.5 cm3 10 % aq. NH4Cl; the solid
was filtered and washed with 30 cm3 ethyl acetate. The
organic phase was dried (MgSO4) and evaporated, and the
crude material was purified by column chromatography on
silica gel to give 25 as a colorless oil. Yield 0.13 g (66 %);
Rf = 0.52 (petroleum ether/ethylacetate, 3/1); 1H NMR
(250 MHz, CDCl3): d = 0.96–1.75 (m, 4H, 4 CH2c, CH2c),
1.85–2.00 (m, 1H, CHb), 2.30 (dm, 1H, J = 2.9 Hz,
10.1 Hz, CHb), 2.90 (dd, 1H, J = 3.6 Hz, 12.9 Hz, He),
3.38–3.50 (m, 1H, He), 3.61–3.70 (m, 1H, CHa), 4.20 (dd,
1H, J = 3.6 Hz, 11.9 Hz, Hg), 4.44 (dd, 1H, J = 5.0 Hz,
13.9 Hz, Hg), 7.12–7.48 (m, 3H, Ar–H), 7.77–7.79 (d,
J = 7.2 Hz, 1H, Ar–H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 23.5 (Cd), 23.95 (Ce), 25.2 (Cc), 31.6 (Cb),
1,4,6,10b-Tetrahydropyrido[2,1-a]isoindol-6-one
(23, C12H11NO)
Colorless soild; yield 0.12 g (64 %); Rf = 0.43 (petroleum
ether/ethylacetate, 3/1); m.p.: 85–88 °C; 1H NMR
(250 MHz, CDCl3): d = 1.82–2.00 (m, 1H, CHb),
2.68–2.73 (m, 1H, CHb), 3.78–3.85 (m, 1H, CHf), 4.37
(dd, J = 5.0 Hz, 10.9 Hz, 1H, CHf), 4.58 (m, 1H, CHd),
5.76–5.90 (m, 2H, CHc, CHg), 7.35–7.57 (m, 3H, Ar–H),
7.74–7.85 (m, 1H, Ar–H) ppm; 13C NMR (62.5 MHz,
CDCl3): d = 29.8 (CHb), 39.4 (CHF), 54.3 (CHd), 121.6,
122.6 (C–Ar), 123.3 (CHc), 123.5 (CHg), 127.9, 131.0,
132.1, 145.7 (C–Ar), 166.6 (CO) ppm; MS (MALDI,
positive mode, matrix: DHB): m/z = 186.1 ([M ? H]?).
123

I. A. I. Ali
11. Taylor EC, Zhou P, Jennings LD, Mao Z, Hu B, Jun JG (1997)
Tetrahedron Lett 38:521
39.3 (Ca), 58.8 (Cg), 121.5, 123.5, 128.0, 131.0, 132.3,
145.6 (C–Ar) ppm; MS (MALDI, positive mode, matrix:
DHB): m/z = 174.4 ([M ? H]?).
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16. Ali IAI, El-Ashry ESH, Schmidt RR (2003) Eur J Org Chem
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